Washington University Medical School Research Articles

Acute Transverse Myelitis and Acute Disseminated Encephalomyelitis.

1. Ilana Kahn, MD* 1. *Children’s National Health System, George Washington University Medical School, Washington, DC * Abbreviations: ADEM: : acute disseminated encephalomyelitis ADS: : acquired demyelinating syndrome AQP4: : aquaporin-4 ATM: : acute transverse myelitis CNS: : central nervous system CSF: : cerebrospinal fluid IgG: : immunoglobulin G IVIg: : intravenous immunoglobulin MOG: : myelin oligodendrocyte glycoprotein MRI: : magnetic resonance imaging MS: : multiple sclerosis NMO: : neuromyelitis optica NMOSD: : neuromyelitis optica spectrum disorder OCB: : oligoclonal band Most pediatricians report lack of knowledge related to the understanding of the diagnosis and treatment of both acute disseminating encephalomyelitis and acute transvers myelitis. Pediatric providers should understand presenting symptoms, initial diagnostic testing, and acute treatment. Clinicians should know when to refer to a neurologist for evaluation of long-term treatment. After completing this article, readers should be able to: 1. Define and characterize acquired demyelinating syndromes. 2. Identify the prevalence, etiology, and clinical presentations of acute disseminating encephalomyelitis (ADEM) and acute transverse myelitis (ATM). 3. Initiate a diagnostic evaluation, including an evaluation for medical emergencies. 4. Make treatment decisions for acute management. 5. Counsel patients on long-term outcomes after ADEM and ATM. 6. Counsel patients on recurrence risks for multiphasic or chronic demyelinating diseases. Acquired demyelinating syndromes (ADSs) encompass a group of immune-mediated disorders in which there is breakdown of the myelin sheath, the lipid-rich covering around the axon that increases conduction speed and metabolic efficiency of the neuron. ADSs are characterized by a sudden onset of new neurologic symptoms in concurrence with neuroimaging evidence of demyelination. Outcomes vary from full neurologic recovery to long-term severe disability. ADSs are characterized based on location and frequency of the demyelinating events. Location is either focal, limited to 1 specific location, or polyfocal, involving several areas of the central nervous system (CNS). Frequency is classified as monophasic or multiphasic, meaning either a single 1-time event or a recurrent, potentially chronic, disease. It is important to keep at the forefront of your mind, however, that over time what seems to be a monophasic event may, in fact, turn out to be the initial or first attack of a multiphasic disorder. (1) …

Validity and Reliability of the Traffic Sign Naming Test (TSNT) and Written Exam for Driving Decisions (WEDD) as Measures of Fitness to Drive Among Older Adults.

Occupational therapists need valid and reliable tools to help determine fitness to drive of older drivers with medical conditions such as dementia. To establish the validity and reliability of the Traffic Sign Naming Test (TSNT) and Written Exam for Driving Decisions (WEDD) as measures of fitness to drive of adults with and without dementia. Cross-sectional. Washington University Medical School in St. Louis in collaboration with the Rehabilitation Institute of St. Louis. Older drivers diagnosed with dementia (n = 130) and without dementia (n = 34). Drivers with dementia required a physician referral indicating a medical need for a driving evaluation, a diagnosis of dementia, and an Alzheimer Detection 8 score of 2. Drivers without dementia were required to be age 55 yr or older and not meet criteria for dementia. Participants completed a comprehensive driving evaluation (CDE) that included clinical measures of vision, motor, and cognition; TSNT; and WEDD. The outcome measure was performance on a standardized on-road assessment. The TSNT's interrater reliability was determined to be strong (κ = .80). The TSNT and WEDD demonstrated convergent validity with cognitive measures (p < .001) and discriminant validity with visual and motor measures in the CDE. The TSNT (area under the curve [AUC] = .74) and WEDD (AUC = .71) had fair ability to predict failure on a standardized on-road assessment. TSNT and WEDD are recommended for use by occupational therapists in combination with other performance measures when determining fitness to drive or need for a CDE. The TSNT and WEDD can be included as screening tools (in addition to other performance measures) to assist clinicians in determining which clients need to be referred for a CDE. The TSNT and WEDD can also be included as part of a CDE to assist driving rehabilitation specialists in making final recommendations regarding fitness to drive. The scores generated from the TSNT and WEDD address driving knowledge in a way that may be more understandable to clients and more relatable to skills needed to actually drive.

NON-CONVENTIONAL PET NUCLIDES: PRODUCTION AND IMAGING

Los ciclotrones médicos son usados actualmente para la producción de Nucleidos de PET. Esos dispositivos son capaces de producir haces de protones de 10-15 MeV con suficiente intensidad para la producción de radionúcleos con decaimiento β+. Los nucleidos no convencionales de PET han surgido recientemente y ofrecen nuevas oportunidades para diagnóstico y farmacoterapia. En este artículo se hará mención de la capacidad de producción de tales nucleidos en la Washington University Medical School. Serán discutidos los retos en imagenología impuestos por las características del decaimiento.

Clinical Faceoff: Controversies in the Management of Distal Radius Fractures.

D istal radius fractures are among the most common fractures of the upper extremity, and account for approximately 20% of all fractures seen within the emergency room. The distal radius comprises of three articular surfaces, namely the scaphoid facet, lunate facet, and sigmoid notch. Treatment goals are centered on restoration of articular congruity, and where appropriate, early ROM with minimal complications to permit early functional recovery. Numerous fracture classifications exist which aim to define the fracture and guide treatment [1] (Fig. 1). Despite the frequency of these injuries, controversy exists about how best to manage them. The American Academy of Orthopaedic Surgeons practice guidelines on treatment of distal radius fractures recommend operative fixation for radial shortening greater than 3 mm, dorsal tilt greater than 10 from neutral, or intraarticular displacement greater than 2 mm [4]. To explore the controversies that are abound in terms of how to manage these injuries, it is my distinct pleasure to introduce two experts in the field of hand surgery. Ghazi Rayan MD is a Professor of Orthopaedic Surgery at University Oklahoma College of Medicine. Martin Boyer MD is the Jerome T. Loeb Professor of Orthopaedic Surgery at Washington University Medical School, St. Louis.

Editorial introductions

Editorial introductions

David W. Talmage, 1919–2014

David W. Talmage, born the sixth of seven children, was the child of Presbytarian missionaries in Kwangju, Korea and educated through high school in that country. He began his undergraduate studies at Maryville College and moved to Davidson College in North Carolina, from which he graduated in 1941. Talmage was awarded a scholarship to attend Washington University Medical School in St. Louis, hitchhiked from Davidson to St. Louis, and earned his doctorate in medicine in 1944. Apparently, when the United States entered World War II, Talmage’s entire class was inducted into the army, so eventually he found himself at the service of the army, back in Korea dealing with a cholera epidemic, and eventually becoming Advisor to the Korean Head of Public Health for the province of Chonju.

Emotional and Developmental Repair through Psychodrama: Floortime for Grown-Ups

Emotional and Developmental Repair through Psychodrama: Floortime for Grown-Ups

Editorial introductions

Editorial introductions

RAS testing for colorectal cancer

Dr Heinz-Josef Lenz is a professor of medicine in the USC Departments of Medicine and Preventive Medicine, Kathryn M Balakrishnan Chair for Cancer Research, Scientific Director of the Cancer Genetics Unit, Director of the Gastrointestinal Oncology Program and Co-Director of the Colorectal Center at the USC Norris Comprehensive Cancer Center (CA, USA). Dr Lenz earned his MD at the Johannes-Gutenberg Universität in Mainz, Germany. In 1991, he completed his internship, residency and fellowship training at the Eberhardt Karls Universität in Tübingen, Germany. He obtained a special fellowship training at Universität Wien (Austria), George Washington University (DC, USA) and Harvard Medical School (MA, USA). In 1991, he received the prestigious Research Fellowship Award from the Deutsche Krebshilfe (Bonn, Germany). He completed his research fellowship in biochemistry and molecular biology at the USC Norris Comprehensive Cancer Center before joining USC in 1994. He was awarded a Career Development Award from STOP CANCER (1994–1997). Based on his research, he also received a Young Investigator Award from the American Society of Clinical Oncology (ASCO) in 1994. In 1995, Dr Lenz was selected for the prestigious ASCO Career Development Award. The National Cancer Institute-funded laboratory of Dr Lenz has been interested in the identification and determination of molecular markers in precancerous and cancerous tissues that might predict cancer risk and clinical outcome in gastrointestinal and breast cancer. Dr Lenz is also the Institutional Principal Investigator on the UO1/NIH contract (California Cancer Consortium, USA) in collaboration with City of Hope and UC Davis (CA, USA), which allows him to design innovative clinical trials with novel promising anticancer drugs.

Comprehensive Genomic Studies

As part of the molecular revolution sweeping medicine, comprehensive genomic studies are adding powerful dimensions to medical research. However, their power exposes new regulatory, strategic, and quality assurance challenges for biorepositories. A key issue is that unlike other research techniques commonly applied to banked specimens, nucleic acid sequencing, if sufficiently extensive, yields data that could identify a patient. This evolving paradigm renders the concepts of anonymized and anonymous specimens increasingly outdated. The challenges for biorepositories in this new era include refined consent processes and wording, selection and use of legacy specimens, quality assurance procedures, institutional documentation, data sharing, and interaction with institutional review boards. Given current trends, biorepositories should consider these issues now, even if they are not currently experiencing sample requests for genomic analysis. We summarize our current experiences and best practices at Washington University Medical School, St Louis, MO, our perceptions of emerging trends, and recommendations.

ICAM-1 and Nanomedicine

Ligand-targeted nanomedicines, particularly those directed to vascular-accessible biomarkers,1,2 have evolved from fanciful concepts 25 years ago to product concepts now near or in clinical trials. While numerous chemical and biological barriers have been discovered and broached over this time frame, perhaps the single greatest challenge to success of nanomedicine technologies has been their inefficient access to extravascular constituents. In this issue of Arteriosclerosis, Thrombosis, and Vascular Biology , Serrano et al delineates the unique and complex cell biology surrounding ICAM-1 mediated intracellular (and presumably) transcellular delivery of nanoparticles up to 4.5 µm, and illustrates a close mechanistic similarity to leukocyte endothelial transmigration. See accompanying article on page 1178 Many have touted the concept of enhanced permeability and retention as a mechanism for nanoparticle delivery into tumors and inflammatory sites through a purportedly leaky vasculature.3,4 Considerable research, particularly studies conducted in subcutaneous mouse tumor models, has demonstrated this effect over the last decade, but the magnitude of the extravascular delivery has depended on high intravascular overdosing of agents, prolonging particle systemic half-life (eg, pegylation), and decreasing particle size.5 Unfortunately, clinical hope for the enhanced permeability and …

Acceptance of the 2010 George M. Kober Medal

Acceptance of the 2010 George M. Kober Medal

Contaminants in Heparins: Are All Facts Known?

D espite several publications on the issues related to the chemical nature of the heparin contaminants and their mechanism of action in mediating the adverse reactions, many questions related to this problem have remained unresolved. Several groups of investigators have continued to work to provide additional information. However, certain stipulations and restricted availability of the contaminated heparins and blood plasma samples from patients who suffered from adverse effects have delayed this work. Although the heparin contaminant was identified to be oversulfated chondroitin sulfate (OSCS) with similar molecular weight profile to heparin, its biologic actions were not fully explored. Moreover, the main mechanism of action was stated to be the activation of the contact system leading to the formation of the mediators causing hemodynamic aberrations. It should be noted that the OSCS may have different origins and can be obtained from bovine, porcine, ovine, and other sources. In addition to differences in their molecular profile, the biologic actions may also be different. Because heparin is a polypharmacologic agent, it is no surprise that oversulfated glycosaminoglycans such as OSCS may also exert multiple effects on blood and plasmatic processes. In this issue of CATH, The Washington University Medical School group led by Dr L. Zhang reports on some additional observations gleaned from a careful analysis of the contaminants in heparin. They have found evidence of a new pathway of thrombin formation that begins with the activation of the contact system component kallikrein and leads directly to the cleavage of prothrombin. These authors showed that kallikrein can directly activate prothrombin into thrombin, which may lead to some of the processes such as the upregulation of nitric oxide and activation of platelets among other complicated processes. Additionally, these investigators have also provided evidence that besides OSCS, contaminated heparins also contain chemically modified heparin byproducts as an additional group of contaminants in recalled heparins. The suggestion that OSCS and oversulfated heparin byproducts can directly generate thrombin that may result in the activation of platelets resulting in thrombocytopenia responses also makes sense. That is why, an initial occurrence of HIT response was observed during the time of the contaminant crisis. The same group has recently reported on the identification of chemically sulfated/desulfated glycosaminoglycans in recalled heparin and development of a simple assay for the measurement of contaminants in heparins. Contaminated heparin was linked to over 100 reported deaths and several hundreds of adverse reactions. While the published reports indicated that carryover dermatan sulfate and OSCS originating from animal cartilage were the main contaminants, the 3 communications in this issue, along with other publications, clearly indicate that the OSCS is not the sole contaminant in heparin and other contaminants such as chemically modified heparin byproducts, and carryover heparin From the Loyola University Medical Center, Maywood, IL, USA (JW, DAH); University of Michigan Medical School, Ann Arbor, MI (ER); and University of Calgary, Alberta, Canada (RDH).

A Teenage Girl with Rash

&lt;P&gt;A teenage girl presented with a 2-week history of a mildly pruritic, erythematous, maculopapular rash on her back. The patient reported that a few weeks prior to onset of this rash, she remembered seeing a large “spot” on her lower abdomen. She presented to the dermatologist because she was concerned that her rash was contagious. She denied any sick contacts. On physical examination, she had numerous pink macules and papules, with scaly borders located on her trunk along axial lines (see Figure 1 and Figure 2). However, we were not able to visualize the “spot” she described on her abdomen.&lt;/P&gt;&lt;H4&gt;ABOUT THE AUTHORS&lt;/H4&gt;&lt;P&gt;Amor Khachemoune, MD, CWS, is with the Department of Dermatology, New York University School of Medicine, New York, NY. Zoey Glick, BA, is a Medical Student, George Washington University Medical School, Washington, DC.&lt;/P&gt;&lt;P&gt;Address correspondence to: Amor Khachemoune, MD, CWS, 530 First Avenue, Suite 7R, New York, NY 10016; fax (212) 263-7680; or e-mail: &lt;a href="mailto:amorkh@pol.net"&gt;amorkh@pol.net&lt;/a&gt;.&lt;/P&gt;&lt;P&gt;The authors have disclosed no relevant financial relationships.&lt;/P&gt;

Celebrating Individual Heroes: The Continuing Relevance of Estelle Brodman

Celebrating Individual Heroes: The Continuing Relevance of Estelle Brodman

Evidence That Heparin Saccharides Promote FGF2 Mitogenesis through Two Distinct Mechanisms

Heparin-like saccharides play an essential role in binding to both fibroblast growth factors (FGF) and their receptors at the cell surface. In this study we prepared a series of heparin oligosaccharides according to their size and sulfation level. We then investigated their affinity for FGF2 and their ability to support FGF2 mitogenesis of heparan sulfate-deficient cells expressing FGFR1c. Tetra- and hexasaccharides bound FGF2, but failed to dimerize the growth factor. Nevertheless, these saccharides promoted FGF2-mediated cell growth. Furthermore, whereas enzymatic removal of the non-reducing end 2-O-sulfate group had little effect on the 1:1 interaction with FGF2, it eliminated the mitogenic activity of these saccharides. This evidence supports the symmetric two-end model of ternary complex formation. In contrast, even at very low concentrations, octasaccharide and larger heparin fragments conferred a potent mitogenic activity that was independent of terminal 2-O-sulfation. This correlated with the ability to dimerize FGF2 in an apparently cooperative manner. This data suggests that potent mitogenic signaling results from heparin-mediated trans-dimerization of FGF2, consistent with the asymmetric model of ternary complex formation. We propose that, depending on saccharide structure, there are different architectures and modes of ternary complex assembly that differ in stability and/or efficiency of transmembrane signaling.

Apolipoprotein E in Hypercholesteremia and Beyond

HomeStrokeVol. 38, No. 7Apolipoprotein E in Hypercholesteremia and Beyond Free AccessEditorialPDF/EPUBAboutView PDFView EPUBSections ToolsAdd to favoritesDownload citationsTrack citationsPermissions ShareShare onFacebookTwitterLinked InMendeleyReddit Jump toFree AccessEditorialPDF/EPUBApolipoprotein E in Hypercholesteremia and Beyond Hans H. Dietrich, PhD Hans H. DietrichHans H. Dietrich From the Department of Neurological Surgery, Washington University Medical School, St. Louis, Mo. Search for more papers by this author Originally published24 May 2007https://doi.org/10.1161/STROKEAHA.107.489856Stroke. 2007;38:2036Other version(s) of this articleYou are viewing the most recent version of this article. Previous versions: May 24, 2007: Previous Version 1 See related article, pages 2136–2141.Apolipoprotein E (ApoE) is a protein related to the receptor-mediated removal of lipids from the blood stream. When ApoE-deficient mice were introduced,1,2 these animals displayed hypercholesteremia and increased atherosclerosis, providing a new tool to study hypercholesteremia-related pathological mechanisms and have been used extensively ever since. With respect to the cerebral circulation, it is interesting to note that not until 1998 did the first study on ApoE deficiency and cerebral ischemia appear3 and only 5 more studies, mostly related to stroke and inflammation, followed to this date in this field.Kitayama et al are interested to study the effect of hypercholesteremia on pial arteriolar vasomotor responses. They used hemizygous (ApoE+/−) animals as their control (rather than homozygotes) and ApoE-deficient mice (ApoE−/−) that were fed normal or high-fat diets. The first observation is that the hemizygous control animals have similar cholesterol levels as homozygous mice, indicating that one functioning allel of ApoE may be sufficient to keep blood cholesterol at normal levels. After demonstrating that especially severe hypercholesteremia adversely affects pial arteriolar dilation, the group continues to show that scavenging oxygen radicals with Tempol or inhibiting NADPH oxidase with Apocynin can restore vessel dilation to Acetylcholine at the lower concentration tested. But at the higher concentration used, Acetylcholine did not achieve dilation comparable to control animals. This seems to indicate that another factor besides oxygen radicals affects the vascular dilation to Acetylcholine in severely hypercholesteremic arterioles. If there is another factor and what this factor could be need to be studied further. Lack of response to external nitric oxide, though, does not seem to be deficient.Another aspect of the study of ApoE effects in mice is that we now have mouse models with the mouse ApoE gene replaced with human ApoE alleles. The study of such alleles has come to the forefront in many research areas including stroke and Alzheimer disease.4,5 Thus understanding and knowing the physiological effects of mouse ApoE will help us to determine the effects and consequences of introducing human ApoE alleles into this organism including vascular regulation. It is therefore possible that the observations and results provided by Kitayama et al will have implications beyond the study of hypercholesteremia.The opinions in this editorial are not necessarily those of the editors or of the American Heart Association.Sources of FundingH.H.D. is supported by NIH grants NS 32636, NS30555, and HL041250.DisclosuresNone.FootnotesCorrespondence to Hans H. Dietrich, Department of Neurological Surgery, Washington University Medical School, 660 South Euclid Avenue, St. Louis, MO 63110. E-mail [email protected] References 1 Zhang SH, Reddick RL, Piedrahita JA, Maeda N. Spontaneous hypercholesterolemia and arterial lesions in mice lacking apolipoprotein E. Science. 1992; 258: 468–471.CrossrefMedlineGoogle Scholar2 Plump AS, Smith JD, Hayek T, alto-Setala K, Walsh A, Verstuyft JG, Rubin EM, Breslow JL. Severe hypercholesterolemia and atherosclerosis in apolipoprotein E-deficient mice created by homologous recombination in ES cells. Cell. 1992; 71: 343–353.CrossrefMedlineGoogle Scholar3 Bart RD, Sheng H, Laskowitz DT, Pearlstein RD, Warner DS. Regional CBF in apolipoprotein E-deficient and wild type mice during focal cerebral ischemia. Neuroreport. 1998; 9: 2615–2620.CrossrefMedlineGoogle Scholar4 Sudlow C, Martinez Gonzalez NA, Kim J, Clark C. Does apolipoprotein E genotype influence the risk of ischemic stroke, intracerebral hemorrhage, or subarachnoid hemorrhage? Systematic review and meta-analyses of 31 studies among 5961 cases and 17,965 controls. Stroke. 2006; 37: 364–370.LinkGoogle Scholar5 Martins IJ, Hone E, Foster JK, Sunram-Lea SI, Gnjec A, Fuller SJ, Nolan D, Gandy SE, Martins RN. Apolipoprotein E, cholesterol metabolism, diabetes, and the convergence of risk factors for Alzheimer’s disease and cardiovascular disease. Mol Psychiatry. 2006; 11: 721–736.CrossrefMedlineGoogle Scholar Previous Back to top Next FiguresReferencesRelatedDetails July 2007Vol 38, Issue 7 Advertisement Article InformationMetrics https://doi.org/10.1161/STROKEAHA.107.489856PMID: 17525383 Originally publishedMay 24, 2007 PDF download Advertisement

From the Editor

A new world of complex relationships and feelings opens up when the peer group takes its place alongside the family as the emotional focus of the child's life. Early peer relationships contribute significantly to the child's ability to participate in a group (and in that sense, society), deal with competition and disappointment, enjoy the intimacy of friendships, and intuitively understand social relationships as they play out at school, in the neighborhood, and later in the workplace and adult family. Stanley I. Greenspan, MD, Clinical Professor of Psychiatry, Behavioral Sciences, and Pediatrics at the George Washington University Medical School, in the Afterword to his book Playground Politics (Greenspan, 1993). You can't say you can't play. Vivian Gussin Paley, retired kindergarten teacher from the Laboratory Schools at the University of Chicago and recipient of the MacArthur award for genius, chose this as the title and theme for one of her books on the cognitive and social worlds of children (Paley, 1992). Social skills indicate more about children as individuals than perhaps any other aspect of their behavior. Social communication also opens the door to learning from peers as well as from adult mentors. It was Mavis Donahue from whom one of us (NWN) adopted the term “underground curriculum” in describing peer influences on the social curriculum that children learn from each other in school (Nelson, 1998). Active learning of social expectations from peers presumes, however, that children are open to the influences of their peers and can process the cues of social acceptance and social appropriateness adequately to learn from them. It also presumes that peers are available and have some motivation to make social overtures to children with special needs of various kinds. What happens when either side of this social equation fails to develop naturally? Social communication, verbal and nonverbal, bears evidence of the effects of both nature and nurture as much as any other area of cognitive- linguistic and communication development. In this issue of Topics in Language Disorders (TLD), Issue Editor Geralyn Timler has assembled a group of productive author/researchers who shed light from multiple angles on the dimensions of social interactions—from teachers' supports for children who rarely initiate (Girolametto and Weitzman) to assessment for children who bully or intimidate, and their victims (Ostrov and Godleski). The authors tackle aspects of social difficulties of many kinds and offer innovative assessment protocols and technologies (Hyter; Olswang, Coggins, and Svensson). In these pages, readers will find plenty of food for thought, as well as practical information about what clinicians and teachers might do to facilitate social communication when it goes astray or has little depth (Timler, Vogler-Elias, and McGill). Hyter also helps readers to conceptualize the social context of the preschool classroom in the broader context of societal power structures. This issue is particularly strong in capturing not only the products but also the process of scientific approaches to problem solving. In this respect, it exemplifies the journal's recently refined dual purposes: To serve as a scholarly resource for researchers and clinicians who share an interest in spoken and written language development and disorders across the lifespan, with a focus on interdisciplinary and international concerns, and To provide relevant information to support theoretically sound, culturally sensitive, research-based clinical practices. Goldstein, Schneider, and Thiemann, in particular, describe a body of research that has incorporated and expanded on practical questions about how to address the social interaction difficulties of children with special needs by working directly with their peers. They point out the importance and the effectiveness of encouraging peers to make overtures to children who might not otherwise be engaged in social interactions. This is a unique opportunity to gain an inside look into the evolution of a body of research with important implications for clinical practice. This issue addresses the purposes of TLD in another way—that is, in its focus on interdisciplinary approaches to addressing the special needs of students facing a variety of issues. The authors of this issue represent different disciplines themselves. They also recognize the importance of teachers and service providers from across disciplines, as well as peers, for their Nickola Wolf Nelson, PhD, Editor Katharine G. Butler, PhD, Editor Emerita

The Legacy of the CE and BMET: Safer Healthcare Technologies

The Legacy of the CE and BMET: Safer Healthcare Technologies

Impact of Anesthesia Management Characteristics on Severe Morbidity and Mortality: Are We Convinced?

We read with great interest the article by Arbous et al. 1Although we commend the authors for designing an ambitious and creative study to address this important topic, we do have several reservations about the study design, interpretation of the results, and hence the conclusion.Because anesthetic mortality and serious morbidity are rare events, the use of a case–control design is very appropriate. Case–control studies usually include several controls for every case to increase the power of the study and to increase the likelihood that the conclusions will be valid.2In this study, the investigators used only one control per case (807 cases vs. 883 controls). A higher number of controls would have increased the probability that the controls were a representative sample of the entire cohort.The main outcome in the study was death or coma within 24 h of surgery, an important and indisputable outcome measure. The limitation of this outcome is that many patients who experience perioperative complications die within days to weeks rather than within 24 h of surgery.3Intraoperative management factors may impact their postoperative course and their eventual demise.We understand that the investigators chose to limit the matching of controls only to age and sex to prevent bias and also to allow them to examine all factors affecting mortality in a multivariate model. The possible flaw with this approach in the context of their study is that American Society of Anesthesiologists (ASA) physical status classification is such a powerful confounding factor that it could have undermined their multivariate model. Most of the patients who died (&gt; 90%) had an ASA physical status of III–V. Fewer than 30% of the control patients had an ASA physical status of III–V (table 1).This brings into question whether there were enough ASA physical status III–V patients in the control category to validate a multivariate calculation for other factors relating to mortality. This could have been addressed in two ways: The study could prospectively have enrolled only ASA physical status III–V patients, or many more control patients could have been included.4In addition to presenting odds ratios for rare events, it is important to present the number needed to harm. For example, the investigators presented an odds ratio of 10:1 for preventing death by adopting a universal practice of reversing muscle relaxants. We made some assumptions and calculated that the number needed to harm for the entire cohort might be 1 in 25,000. This means that 25,000 people on average would have to have muscle relaxation not reversed to result in one additional death. The odds ratio for preventing death by having two anesthesia providers present for all inductions and emergences was 10:6. This may translate to an even larger number needed to harm than for not reversing muscle relaxants. The cost of providing two anesthesia providers for every anesthetic—no matter how minor the surgery and no matter how healthy the patient—would be staggering and may not result in many lives saved. A similar study focusing only on patients with an ASA physical status of III–V might be more useful in identifying which anesthetic management factors are most important in decreasing the likelihood of death among the sickest patients presenting for high-risk surgery.Despite our reservations, we appreciate the study of Arbous et al. and believe that it raises important issues. In particular, we believe that separating anesthetic from surgical death is a false distinction. This study highlights the contention that multiple aspects of perioperative care and management may impact on postoperative outcome. This is a seminal study that is likely to be extensively quoted. It is important to highlight some of its limitations and to avoid overinterpretation of the findings.*Washington University Medical School, St. Louis, Missouri. bilenrog@msnotes.wustl.edu