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Introduction Aging-related neurodegenerative diseases are posing an increasing public health burden as populations are getting older. Prominent among these conditions are the central Lewy body diseases (LBDs), Parkinson disease (PD), [...], BACKGROUND. In Lewy body diseases (LBDs) Parkinson disease (PD), and dementia with Lewy bodies (DLB), by the time parkinsonism or cognitive dysfunction manifests clinically, substantial neurodegeneration has already occurred. Biomarkers are needed to identify central LBDs in a preclinical phase, when neurorescue strategies might forestall symptomatic disease. This phase may involve catecholamine deficiency in the autonomic nervous system. We analyzed data from the prospective, observational, long-term PDRisk study to assess the predictive value of low versus normal cardiac [sup.18]F-dopamine positron emission tomography (PET), an index of myocardial content of the sympathetic neurotransmitter norepinephrine, in at-risk individuals. METHODS. Participants self-reported risk factor information (genetics, olfactory dysfunction, dream enactment behavior, and orthostatic intolerance or hypotension) at a protocol-specific website. Thirty-four with 3 or more confirmed risk factors underwent serial cardiac [sup.18]F-dopamine PET at 1.5-year intervals for up to 7.5 years or until PD was diagnosed. RESULTS. Nine participants had low initial myocardial [sup.18]F-dopamine-derived radioactivity ( CONCLUSION. Cardiac [sup.18]F-dopamine PET highly efficiently distinguishes at- risk individuals who are diagnosed subsequently with a central LBD from those who are not. TRIAL REGISTRATION. ClinicalTrials.gov NCT00775853. FUNDING. Division of Intramural Research, NIH, NINDS.

Introduction Gonadal steroids have powerful effects on bone. During puberty, increases in gonadal steroids stimulate osteoblast activity, causing bone mineral density (BMD) to increase markedly (1). At midlife in women, [...], BACKGROUND. Severe gonadal steroid deficiency induces bone loss in adult men; however, the specific roles of androgen and estrogen deficiency in hypogonadal bone loss are unclear. Additionally, the threshold levels of testosterone and estradiol that initiate bone loss are uncertain. METHODS. One hundred ninety-eight healthy men, ages 20-50, received goserelin acetate, which suppresses endogenous gonadal steroid production, and were randomized to treatment with 0, 1.25, 2.5, 5, or 10 grams of testosterone gel daily for 16 weeks. An additional cohort of 202 men was randomized to receive these treatments plus anastrozole, which suppresses conversion of androgens to estrogens. Thirty-seven men served as controls and received placebos for goserelin and testosterone. Changes in bone turnover markers, bone mineral density (BMD) by dual-energy x-ray absorptiometry (DXA), and BMD by quantitative computed tomography (QCT) were assessed in all men. Bone microarchitecture was assessed in 100 men. RESULTS. As testosterone dosage decreased, the percent change in C-telopeptide increased. These increases were considerably greater when aromatization of testosterone to estradiol was also suppressed, suggesting effects of both testosterone and estradiol deficiency. Decreases in DXA BMD were observed when aromatization was suppressed but were modest in most groups. QCT spine BMD fell substantially in all testosterone-dose groups in which aromatization was also suppressed, and this decline was independent of testosterone dose. Estradiol deficiency disrupted cortical microarchitecture at peripheral sites. Estradiol levels above 10 pg/ml and testosterone levels above 200 ng/dl were generally sufficient to prevent increases in bone resorption and decreases in BMD in men. CONCLUSIONS. Estrogens primarily regulate bone homeostasis in adult men, and testosterone and estradiol levels must decline substantially to impact the skeleton. TRIAL REGISTRATION. ClinicalTrials.gov, NCT00114114. FUNDING. AbbVie Inc., AstraZeneca Pharmaceuticals LP, NIH.

Introduction There is growing recognition that Parkinson disease (PD) is a generalized disorder that, in addition to its well-characterized motor symptoms, involves prominent non-motor manifestations such as dementia, depression, anosmia, [...], Several neurodegenerative disorders, including Parkinson disease (PD), are characterized by the presence of Lewy bodies--cytoplasmic inclusions containing α-synuclein protein aggregates--in the affected neurons. A poorly understood feature of Lewy body diseases is loss of sympathetic nerves in the heart and other organs, manifesting as orthostatic hypotension (OH; also known as postural hypotension). We asked whether sympathetic denervation is associated with decreased uptake of catecholamines, such as dopamine and norepinephrine, into storage vesicles within sympathetic neurons. We used 6-[[.sup.18]F]-dopamine ([.sup.18]F-DA) to track myocardial uptake and retention of catecholamines. Concurrently, the fate of intra-neuronal [.sup.18]-DA was followed by assessment of arterial plasma levels of the [.sup.18]-DA metabolite [.sup.18]-dihydroxyphenylacetic acid ([.sup.18]-DOPAC). The ratio of myocardial [.sup.18]-DA to arterial [.sup.18]-DOPAC provided an index of vesicular uptake. Tracer concentrations were measured in patients with PD with or without orthostatic hypotension (PD+OH, PD-No-OH); in patients with pure autonomic failure (PAF, a Lewy body disease without parkinsonism); in patients with multiple sys-tem atrophy (MSA, a non-Lewy body synucleinopathy); and in normal controls. Patients with PD+OH or PAF had decreased vesicular [.sup.18]-DA uptake and accelerated [.sup.18]-DA loss, compared with MSA and control subjects. PD-No-OH patients could be subtyped into one of these categories based on their initial [.sup.18]-DA uptake. We conclude that sympathetic denervation in Lewy body diseases is associated with decreased vesicular uptake of neuronal catecholamines, suggesting that vesicular monoamine transport is impaired. Vesicular uptake may constitute a novel target for diagnosis, treatment, and prevention.

The HLA-Clocus is distinct relative to the other classical HLA class I loci in that it has relatively limited polymorphism (1), lower expression on the cell surface (2,3), and more [...]

Several remote observations have indicated that water ice may be presented in permanently shadowed craters of the Moon. The Lunar Crater Observation and Sensing Satellite (LCROSS) mission was designed to provide direct evidence (1). On 9 October 2009, a spent Centaur rocket struck the persistently shadowed region within the lunar south pore crater Cabeus, ejecting debris, dust, and vapor. This material was observed by a second 'shepherding' spacecraft, which carried nine instruments, including cameras, spectrometers, and a radiometer. Near-infrared absorbance attributed to water vapor and ice and ultraviolet emissions attributable to hydroxyl radicals support the presence of water in the debris. The maximum total water vapor and water ice within the instrument field of view was 155 [+ or -] 12 kilograms. Given the estimated total excavated mass of regolith that reached sunlight, and hence was observable, the concentration of water ice in the regolith at the LCROSS impact site is estimated to be 5.6 [+ or -] 2.9% by mass. In addition to water, spectral bands of a number of other volatile compounds were observed, including light hydrocarbons, sulfur-bearing species, and carbon dioxide. 10.1126/science.1186986

A study was conducted to evaluate and compare the safety and efficacy of adjuvant chemotherapy treatment with fluorouracil plus folinic acid as against gemcitabine following pancreatic cancer resection. Results indicated that treatment with fluorouracil plus folinic acid was found to be more effective than gemcitabine in improving outcomes in the case of such patients.

A study is conducted to find a possible way to leverage the extensive genome-wide association studies (GWAS) data in the search for causal variants. The association signals detected in GWAS is attributed to the presence of multiple causal variants and hence researchers need to take caution in interpreting the true effect sizes and heritability explained by the causal variants.

Genome-wide screens were used to identify copy number variation in 3812 patients with a diverse spectrum of epilepsy syndromes and in 1299 neurologically-normal controls to evaluate the role of 16p13.11 deletions and other structural variation in epilepsy disorders. The data implicated 16p13.11 and possibly other large deletions as risk factors for a wide range of epilepsy disorders and appear to point toward haploinsufficiency as a contributor to the pathogenicity of deletions.

A more in-depth analysis of key scientific and non-scientific aspects of genetic ancestry inference in academia and industry is summarized based on the data from the 2008 ASHG Ancestry Testing. It concludes with recommendations for advancing the current debate and facilitating the development of scientifically based, ethically sound, and socially attentive guidelines concerning the use of these continually evolving technologies.

Using DNA from consenting participants of the IDEAL study (2),we performed a genome-wide association study (GWAS) of determinants of treatment-related anaemia in individuals with chronic genotype 1 hepatitis C. A [...], Chronic infection with the hepatitis C virus (HCV) affects 170 million people worldwide and is an important cause of liver-related morbidity and mortality (1). The standard of care therapy combines pegylated interferon (pegIFN) alpha and ribavirin (RBV), and is associated with a range of treatment-limiting adverse effects (2). One of the most important of these is RBV-induced haemolytic anaemia, which affects most patients and is severe enough to require dose modification in up to 15% of patients. Here we show that genetic variants leading to inosine triphosphatase deficiency, a condition not thought to be clinically important, protect against haemolytic anaemia in hepatitis-C-infected patients receiving RBV.

Many common human diseases and traits are known to cluster in families and are believed to be influenced by several genetic and environmental factors, but until recently the identification of [...], Genome-wide association studies have identified hundreds of genetic variants associated with complex human diseases and traits, and have provided valuable insights into their genetic architecture. Most variants identified so far confer relatively small increments in risk, and explain only a small proportion of familial clustering, leading many to question how the remaining, 'missing' heritability can be explained. Here we examine potential sources of missing heritability and search strategies, including and extending beyond current genome-wide association approaches, to illuminate the genetics of complex diseases and enhance its potential to enable effective disease prevention or treatment.

Approximately 30% of individuals spontaneously clear acute HCV infection. Host genetic variation is assumed to explain the heterogeneity in HCV clearance across individuals because such differences occur even after exposure [...], Hepatitis C virus (HCV) infection is the most common bloodborne infection in the United States, with estimates of 4 million HCV-infected individuals in the United States and 170 million Worldwide (1). Most (70-80%) HCV infections persist and about 30% of individuals with persistent infection develop chronic liver disease, including cirrhosis and hepatocellular carcinoma (2). Epidemiological, viral and host factors have been associated with the differences in HCV clearance or persistence, and studies have demonstrated that a strong host immune response against HCV favours viral clearance (3,4). Thus, variation in genes involved in the immune response may contribute to the ability to clear the virus. In a recent genome-wide association study, a single nucleotide polymorphism (rs12979860) 3 kilobases upstream of the IL28B gene, which encodes the type III interferon IFN-λ3, was shown to associate strongly with more than a twofold difference in response to HCV drug treatment (5). To determine the potential effect of rs12979860 variation on outcome to HCV infection in a natural history setting, we genotyped this variant in HCV cohorts comprised of individuals who spontaneously cleared the virus (n = 388) or had persistent infection (n = 620). We show that the C/C genotype strongly enhances resolution of HCV infection among individuals of both European and African ancestry. To our knowledge, this is the strongest and most significant genetic effect associated with natural clearance of HCV, and these results implicate a primary role for IL28B in resolution of HCV infection.

The game of basketball serves as a fitting metaphor for the conflicts and tensions of life. It involves both cooperation and competition, selflessness and ego. In the hands of a [...]

IN ANY DISCUSSION OF SHAKESPEARE and the New World, it seems The Tempest 'must follow, as the night the day.' I propose instead to analyze the use of American exploration [...]

A study to examine if neonatal diagnosis of Menkes disease, a fatal degenerative disorder in infancy and treatment with copper injections can help prevent fatalities is conducted. Results confirm the hypothesis showing neurochemical profiles to have high sensitivity and specificity for detecting disease.

Direct effects of vasoactive substances on blood pressure can be examined in individuals with tetraplegia due to disruption of descending spinal pathways to sympathetic preganglionic neurons, as cervical lesions interfere with baroreceptor reflex buffering of sympathetic outflow. In this study, we assessed effects of the nitric oxide synthase inhibitor nitro-L-arginine methyl ester (L-NAME) on mean arterial pressure, heart rate, and plasma norepinephrine concentrations in individuals with tetraplegia vs. effects shown in a neurologically intact control group. Seven individuals with tetraplegia and seven age-matched controls received, on separate visits and in the following order, placebo (30 ml normal saline) and 0.5, 1, 2, and 4 mg/kg L-NAME intravenously over 60 min. Supine hemodynamic data were collected, and blood was sampled at the end of each infusion and at 120, 180, and 240 min thereafter. L-NAME increased mean arterial pressure, and the relative increase was greater in the tetraplegia group than in the control group. Heart rate was reduced after L-NAME administration in both groups. L-NAME decreased plasma norepinephrine in the control group but not in the group with tetraplegia. These findings suggest that reflexive sympathoinhibition normally buffers the pressor response to nitric oxide synthase inhibition, an effect that is not evident in individuals with tetraplegia as a result of decentralized sympathetic vasomotor control. spinal cord injury; nitro-L-arginine methyl ester; norepinephrine; sympathetic nervous system

In young adults, having a relatively long time perspective has been associated with a more abstract, holistic approach to cognitive tasks, as opposed to the more concrete, detailed approach associated with having a more limited or near-future focus (Trope & Liberman, 2003). Here we studied the impact of age differences in temporal perspective on performance on a classic visual attention task (Navon, 1977) that allowed for an orientation toward either detailed or holistic processing. Consistent with views on temporal perspective and cognition (Liberman, Sagristano, & Trope, 2002), we found that younger adults were more likely than older adults to orient toward holistic processing.

Purpose: We examined whether written emotional disclosure reduces stress and improves health outcomes for family caregivers of physically frail and cognitively impaired older adults, as it has been shown to do for certain student and clinical populations. Design and Methods: Primary caregivers of older adults attending a day program were randomly assigned to expressive-writing (n = 14), time-management (n = 13), or history-writing (n = 13) conditions. Participants wrote for 20 minutes on four occasions over a 2-week period, and they completed self-report measures of caregiver burden and health prior to the intervention, immediately afterward, and at 1-month follow-up. Results: Contrary to expectations, expressive-writing and history-writing participants performed similarly across outcomes. Only caregiver participants in the time-management condition experienced significant mental and physical health improvements after writing. Implications: The results of this study add to a growing body of research demonstrating equivocal effects of expressive writing with clinical samples, and they suggest the potential benefit of written time management for stressed caregivers. Key Words: Expressive writing, Written disclosure, Caregiver stress, Time management, Randomized clinical trial

A study is conducted to characterize functional effects of the intronic polymorphism on alternative splicing of SCN1A and to explore the potential for modulating the drug response in the pharmacologically unfavorable genotype by identification of a splice modifier acting on SCN1A. The findings of the study emphasize the emerging role of genetic polymorphisms in modulation of drug effect and illustrate the alternative splicing as a potential therapeutic target.

Cope's gray tree frog Hyla chrysoscelis accumulates glycerol during cold acclimation. We hypothesized that, during this process, gray tree frogs adjust renal filtration and/or reabsorption rates to retain accumulated glycerol. During cold acclimation, plasma concentrations of glycerol rose >200-fold, to 51 mmol/1. Although fractional water reabsorption decreased, glomerular filtration rate (GFR) and, consequently, urine flow were kidney; Xenopus oocyte; glomerular filtration rate; aquaglyceroporin; anuran

A growing literature on decision making in older adults suggests that they are more likely to use heuristic processing than are younger adults. We assessed this tendency in the context of a framing effect, a decision-making phenomenon whereby the language used to describe options greatly influences the decision maker's choice. We compared decision making under a standard ('heuristic') condition and also under a 'justification' condition known to reduce reliance on heuristics. In the standard condition, older adults were more susceptible than younger adults to framing hut the two groups did not differ when participants were asked to provide a justification. Thus, although older adults may spontaneously rely more on heuristic processing than younger adults, they can be induced to take a more systematic approach to decision making.

The mortality of chronic heart failure (CHF) doubles either when CHF patients are depressed or when their plasma norepinephrine (NE) level exceeds those of controls by [approximately equal to] 40%. We hypothesized that patients with major depression had centrally driven, sustained, stress-related, and treatment-reversible increases in plasma NE capable of increasing mortality in CHF patients with depression. We studied 23 controls and 22 medication-free patients with melancholic depression. In severely depressed patients before and after electroconvulsive therapy (ECT), we measured cerebrospinal fluid (CSF) NE, plasma NE, plasma epinephrine (EPI), and plasma cortisol hourly for 30 h. In mildly-to-moderately depressed melancholic patients, we assessed basal and stress-mediated arterial NE appearance. Severely depressed patients had significant increases in mean around-the-clock levels of CSF NE (P < 0.02), plasma NE (P < 0.02), plasma EPI (P < 0.02), and plasma cortisol (P < 0.02). CSF NE, plasma NE, and cortisol all rose together throughout the night and peaked in the morning. Each fell to control values after ECT. Mildly-to-moderately melancholic patients also had increased basal (P < 0.05) and stress-related (P < 0.03) arterial NE-appearance rates. Severely melancholic depressed, medication-free patients had around-the-clock increases in plasma NE levels capable of increasing mortality in CHF. Twenty-four-hour indices of central noradrenergic, adrenomedullary, and adrenocortical secretion were also elevated. Concurrent diurnal rhythms of these secretions could potentiate their cardiotoxicity. Even mildly-to-moderately depressed melancholic patients had clinically relevant increases in the arterial NE-appearance rate. These findings will not apply to all clinical subtypes of major depression. cerebrospinal fluid | epinephrine | major depression | cardiovascular disease | chronic heart failure

Phenytoin and carbamazepine are effective and inexpensive anti-epileptic drugs (AEDs). As with many AEDs, a broad range of doses is used, with the final 'maintenance' dose normally determined by trial and error. Although many genes could influence response to these medicines, there are obvious candidates. Both drugs target the [alpha]-subunit of the sodium channel, encoded by the SCN family of genes. Phenytoin is principally metabolized by CYP2C9, and both are probable substrates of the drug transporter P-glycoprotein. We therefore assessed whether variation in these genes associates with the clinical use of carbamazepine and phenytoin in cohorts of 425 and 281 patients, respectively. We report that a known functional polymorphism in CYP2C9 is highly associated with the maximum dose of phenytoin (P = 0.0066). We also show that an intronic polymorphism in the SCN1A gene shows significant association with maximum doses in regular usage of both carbamazepine and phenytoin (P = 0.0051 and P = 0.014, respectively). This polymorphism disrupts the consensus sequence of the 5' splice donor site of a highly conserved alternative exon (5N), and it significantly affects the proportions of the alternative transcripts in individuals with a history of epilepsy. These results provide evidence of a drug target polymorphism associated with the clinical use of AEDs and set the stage for a prospective evaluation of how pharmacogenetic diagnostics can be used to improve dosing decisions in the use of phenytoin and carbamazepine. Although the case made here is compelling, our results cannot be considered definitive or ready for clinical application until they are confirmed by independent replication. association study | epilepsy | pharmacogenetics

Hereditary cancer is about families, and clinicians and genetic counsellors need to understand the cultural beliefs of patients and families about cancer and inheritance. In the light of their kinship patterns Chinese-Australians were chosen for the present study, which aims to determine the explanatory models of inheritance, cancer, and inherited cancer, with a view to identifying the relationship between these culture-specific lay attributions and help-seeking behaviour, and to identify possible barriers to genetic counselling and testing. Qualitative ethnographically informed methodology involving semi-structured interview was used as a method to uncover latent beliefs held by the families who are represented by the subjects. In-depth interviews were conducted with 16 informants of Chinese ethnicity, who had been recruited through two major Sydney familial cancer clinics. We report the attributions of cancer in general, then on inheritance, kinship, genes and genetics and then focus on the way in which these beliefs come together around hereditary cancer. The majority of informants, despite high acculturation and belief in biomedical explanations about hereditary cancer, also acknowledged the influence of traditional family Chinese beliefs, where 'inheritance' and 'genetics' were related to retribution for ancestral misdeeds and offending ancestors. Extensive mismatch of attributes and beliefs were identified in those who attended the clinic and senior family members, creating barriers to optimal service utilisation. Three traditional patterns of beliefs were identified: (a) father and mother contributed in equal share to one's genetic makeup, linked to the ying-yang theory; (b) the dominance of life force (yang chi) and the shaping of genes were transmitted through the paternal line; and (c) natural and supernatural forces operated in the cause of hereditary cancer. The study provided guidance for clinical practice. Exploration and acknowledgement of family beliefs, regardless of cultural background and therefore avoiding stereotyping, can enable the clinician to work with the whole family--those who hold Western attributions, those who maintain traditional notions of genetics and inheritance, and those who incorporate both into their belief systems--and provide effective clinical services. Further ethnographic studies are needed, focusing on the Chinese groups who do not attend the clinic and those with lower acculturation and educational levels. Keywords: Hereditary cancer; Kinship; Family history; Cultural competence; Australia; Chinese-Australian culture

The abundance of cis-regulatory polymorphisms in humans suggests that many may have been important in human evolution, but evidence for their role is relatively rare. Four common polymorphisms in the 5' promoter region of factor VII (F7), a coagulation factor, have been shown to affect its transcription and protein abundance both in vitro and in vivo. Three of these polymorphisms have low-frequency alleles that decrease expression of F7 and may provide protection against myocardial infarction (heart attacks). The fourth polymorphism has a minor allele that increases the level of transcription. To look for evidence of natural selection on the cis-regulatory variants flanking F7, we genotyped three of the polymorphisms in six Old World populations for which we also have data from a group of putatively neutral SNPs. Our population genetic analysis shows evidence for selection within humans; surprisingly, the strongest evidence is due to a large increase in frequency of the high-expression variant in Singaporean Chinese. Further characterization of a Japanese population shows that at least part of the increase in frequency of the high-expression allele is found in other East Asian populations. In addition, to examine interspecific patterns of selection we sequenced the homologous 5' noncoding region in chimpanzees, bonobos, a gorilla, an orangutan, and a baboon. Analysis of these data reveals an excess of fixed differences within transcription factor binding sites along the human lineage. Our results thus further support the hypothesis that regulatory mutations have been important in human evolution.

Prion diseases are invariably fatal, transmissible neurodegenerative conditions, which include Creutzfeldt-Jakob disease (CJD) and kuru in humans and bovine spongiform encephalopathy (BSE) and scrapie in animals. According to the protein-only [...], Kuru is an acquired prion disease largely restricted to the Fore linguistic group of the Papua New Guinea Highlands, which was transmitted during endocannibalistic feasts. Heterozygosity for a common polymorphism in the human prion protein gene (PRNP) confers relative resistance to prion diseases. Elderly survivors of the kuru epidemic, who had multiple exposures at mortuary feasts, are, in marked contrast to younger unexposed Fore, predominantly PRNP 129 heterozygotes. Kuru imposed strong balancing selection on the Fore, essentially eliminating PRNP 129 homozygotes. Worldwide PRNP haptotype diversity and coding allele frequencies suggest that strong balancing selection at this locus occurred during the evolution of modern humans.

People with epilepsy that cannot be treated with drugs may have a gene variation that affects drug metabolism. In a study of 315 people with epilepsy, those with drug-resistant epilepsy were more than twice as likely to have the CC variation of the ABCB1 gene than the TT variation compared to patients who were successfully treated. The ABCB1 gene codes for a protein that can pump at least four different anticonvulsants out of the cell.

Incorporating pharmacogenetics data into clinical practice will be time-consuming and expensive. Pharmacogenetics is the study of how certain gene variations influence the metabolism of drugs. Once a doctor knows a patient's genetic profile, the doctor can create specific drug treatment plans for that particular patient.

We explored aspects of renal function in American Kestrels (Falco sparverius), birds that habitually eat high-protein meals. In particular, we hypothesized that, like granivorous birds switched to high-protein food, kestrels would have high urine flows with high proportions of waste N as urate. In nestlings in the field, 80-93% of urinary N was in the form of urate, though concentrations of ammonia and urea were higher in older nestlings. Feeding resulted in reduced osmotic and ion concentrations in urine, but concentrations and proportions of nitrogenous wastes were unaffected. In adult kestrels in the laboratory, urine flow rate in fed animals, ~1 mL [h.sup.-1], was similar to that previously measured in avian granivores. Urine flow declined with fasting, accomplished by both a reduction in glomerular filtration rate (significant after 24 h fast) and a rise in tubular water reabsorption (significant after 48 h). During the course of a 48 h fast, proportion of urinary N excreted as urate fell and that as ammonia rose. Both filtration and secretion of urate dropped during fasting, so that tubular secretion remained responsible for ~90% of urinary urate. Composition of fluid voided from the cloaca differed little from that of the ureteral urine.

Measuring the amount of plasma free metanephrines appears to be the best diagnostic test for identifying patients who have an adrenal gland tumor called a pheochromocytoma. This was the conclusion of researchers who measured plasma free metanephrines, plasma catecholamines, urinary catecholamines, urinary total and fractionated metanephrines, and urinary vanillylmandelic acid in a study of 858 patients., Context Diagnosis of pheochromocytoma depends on biochemical evidence of catecholamine production by the tumor. However, the best test to establish the diagnosis has not been determined. Objective To determine the biochemical test or combination of tests that provides the best method for diagnosis of pheochromocytoma. Design, Setting, and Participants Multicenter cohort study of patients tested for pheochromocytoma at 4 referral centers between 1994 and 2001. The analysis included 214 patients in whom the diagnosis of pheochromocytoma was confirmed and 644 patients who were determined to not have the tumor. Main Outcome Measures Test sensitivity and specificity, receiver operating characteristic curves, and positive and negative predictive values at different pretest prevalences using plasma free metanephrines, plasma catecholamines, urinary catecholamines, urinary total and fractionated metanephrines, and urinary vanillylmandelic acid. Results Sensitivities of plasma free metanephrines (99% [95% confidence interval (CI), 96%-100%]) and urinary fractionated metanephrines (97% [95% CI, 92%-99%]) were higher than those for plasma catecholamines (84% [95% CI, 78%-89%]), urinary catecholamines (86% [95% CI, 80%-91 %]), urinary total metanephrines (77% [95% CI, 68%-85%]), and urinary vanillylmandelic acid (64% 1195% CI, 55%-71 %]). Specificity was highest for urinary vanillylmandelic acid (95% [95% CI, 93%-97%]) and urinary total metanephrines (93% [95% CI, 89%-97%]); intermediate for plasma free metanephrines (89% [95% CI, 87%-92%]), urinary catecholamines (88% [95% Cl, 85%91%]), and plasma catecholamines (81 % [95% CI, 78%-84%]); and lowest for urinary fractionated metanephrines (69% [95% Cl, 64%-72%]). Sensitivity and specificity values at different upper reference limits were highest for plasma free metanephrines using receiver operating characteristic curves. Combining different tests did not improve the diagnostic yield beyond that of a sin gle test of plasma free metanephrines. Conclusion Plasma free metanephrines provide the best test for excluding or confirming pheochromocytoma and should be the test of first choice for diagnosis of the tumor.