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This review of clinical catecholamine neurochemistry is based on the Streeten Memorial Lecture at the 19th annual meeting of the American Autonomic Society and lectures at a satellite of the 6th Congress of the International Society of Autonomic Neuroscience. Here I provide historical perspective, describe sources and meanings of plasma levels of catecholamines and their metabolites, present a model of a sympathetic noradrenergic neuron that conveys how particular aspects of sympathetic nervous function affect plasma levels of catecholamines and their metabolites, and apply the model to understand plasma neurochemical patterns associated with some drugs and disease states. [ABSTRACT FROM AUTHOR]

Based on concepts proposed by Langley, Cannon, and Selye, adrenal responses to stress occur in a syndrome that reflects activation of the sympathoadrenal system and hypothalamic-pituitary-adrenocortical (HPA) axis; and a 'stress syndrome' maintains homeostasis in emergencies such as 'fight or flight' situations, but if the stress response is excessive or prolonged then any of a variety of clinical disorders can arise. The idea of a unitary sympathoadrenal system does not account for evidence that different stressors elicit different patterns of autonomic responses, with exposure to some stressors differentially affecting sympathetic noradrenergic and adrenomedullary hormonal activities. Instead, adrenomedullary responses to stressors are more closely tied to adrenocortical than to sympathetic noradrenergic responses. Distress involves concurrent activation of the HPA and adrenomedullary neuroendocrine systems. [ABSTRACT FROM AUTHOR]

Cope's gray treefrogs, Hyla chrysoscelis, accumulate glycerol during the period of cold acclimation that leads to the development of freeze tolerance. Glycerol must cross cell membranes in numerous processes during this time, including exit from hepatocytes where glycerol is synthesized and entry into other tissues, where glycerol is cryoprotective. Thus, we hypothesized that erythrocytes from H. chrysoscelis would be permeable to glycerol and that that permeability would be up-regulated during cold acclimation. Further, we hypothesized that glycerol permeability would be associated with the expression of aquaporins, particularly those from the glyceroporin sub-family. Erythrocytes from warm-acclimated treefrogs had high glycerol permeability at 20°C, as assessed by the time required for osmotic lysis following suspension in 0.2 M glycerol. That osmotic lysis, as well as uptake of radio-labeled glycerol, was inhibited by 0.3 mM HgCl. Permeability assessed via osmotic lysis was markedly reduced at 5°C. These properties were similar in animals deriving from northern (Ohio) and southern (Alabama) populations, although suggestive (through statistical interactions) of greater glycerol permeability in northern animals. Erythrocytes expressed mRNA and protein for a previously described glyceroporin, HC-3. In cold-acclimated animals, HC-3 protein expression was up-regulated, but we could not detect a concomitant enhancement of glycerol permeability. [ABSTRACT FROM AUTHOR]

Patients in rural and remote Australia have less access to specialist oncology services and rely more on local health professionals for provision of cancer care. We have developed a 7.5-h online educational program on palliative oncology for health professionals focused on the needs of rural providers. There were 501 active (enrolled) users and 268 ad hoc (non-enrolled) users, with 90 completing evaluation. Eighty-two (91%) indicated that their learning needs were partially or entirely met. Sixty-five (75%) respondents planned to review or change their practice as a result. The online program is effective in meeting learning needs of Australian health providers, reaching high numbers with high acceptability. [ABSTRACT FROM AUTHOR]

One surprising feature of the recently completed waves of genome-wide association studies is the limited impact of common genetic variation in individually detectable polymorphisms on many human traits. This has been particularly pronounced for studies on psychiatric conditions, which have failed to produce clear, replicable associations for common variants. One popular explanation for these negative findings is that many of these traits may be genetically heterogeneous, leading to the idea that relevant endophenotypes may be more genetically tractable. Aspects of cognition may be the most important endophenotypes for psychiatric conditions such as schizophrenia, leading many researchers to pursue large-scale studies on the genetic contributors of cognitive performance in the normal population as a surrogate for aspects of liability to disease. Here, we perform a genome-wide association study with two tests of executive function, Digit Symbol and Stroop Color-Word, in 1086 healthy volunteers and with an expanded cognitive battery in 514 of these volunteers. We show that, consistent with published studies of the psychiatric conditions themselves, no single common variant has a large effect (explaining >4–8% of the population variation) on the performance of healthy individuals on standardized cognitive tests. Given that these are important endophenotypes, our work is consistent with the idea that identifying rare genetic causes of psychiatric conditions may be more important for future research than identifying genetically homogenous endophenotypes. [ABSTRACT FROM AUTHOR]

Although genome-wide association (GWA) studies for common variants have thus far succeeded in explaining only a modest fraction of the genetic components of human common diseases, recent advances in next-generation sequencing technologies could rapidly facilitate substantial progress. This outcome is expected if much of the missing genetic control is due to gene variants that are too rare to be picked up by GWA studies and have relatively large effects on risk. Here, we evaluate the evidence for an important role of rare gene variants of major effect in common diseases and outline discovery strategies for their identification. [ABSTRACT FROM AUTHOR]

Chronic autonomic failure (CAF), as in Parkinson disease (PD), multiple system atrophy (MSA), and pure autonomic failure (PAF), typically entails baroreflex failure, neurogenic orthostatic hypotension (NOH), and supine hypertension. The combination might predispose to cardiac ectopy, which in turn might predispose to syncope and falls during manipulations decreasing venous return to the heart. This study assessed whether CAF is associated with an increased prevalence of cardiac ectopy. Recordings lasting ≥15 min of the electrocardiogram, beat-to-beat heart rate, and continuous blood pressure were reviewed from a total of 97 CAF patients (34 PD + NOH, 48 MSA, 15 PAF) and 82 control subjects (41 PD without NOH, 33 non-parkinsonian patients, 8 healthy volunteers). Cardiac ectopy was considered present if there were at least two premature beats or an arrhythmia. Atrial ectopy was found in 74% of patients with PD + NOH, 68% with MSA, and 63% with PAF, prevalences 2–3 times those in PD without NOH (28%, p < 0.0001) or other controls (24%, p < 0.0001). Atrial ectopy was related to subject age ( p < 0.0001), supine systolic pressure ( p < 0.0001), and the orthostatic fall in systolic pressure ( p = 0.0007) and inversely with baroreflex-cardiovagal gain ( p = 0.005) and the orthostatic increment in plasma norepinephrine ( p = 0.0004). In two PD + NOH patients, atrial ectopy was associated with documented sustained hypotension after the Valsalva maneuver; and in an MSA patient, acute atrial flutter/fibrillation was associated with sudden loss of consciousness. CAF patients have a relatively high frequency of atrial ectopy, which might interact with baroreflex failure to increase morbidity from orthostatic hypotension. [ABSTRACT FROM AUTHOR]

Chronic infection with the hepatitis C virus (HCV) affects 170 million people worldwide and is an important cause of liver-related morbidity and mortality. The standard of care therapy combines pegylated interferon (pegIFN) alpha and ribavirin (RBV), and is associated with a range of treatment-limiting adverse effects. 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. [ABSTRACT FROM AUTHOR]

The objective of this study is to report the long-term outcomes of salvage surgery following local and/or regional failure of tonsillar carcinoma treated with standard fractionation radiotherapy. All cases of carcinoma of the tonsil treated by radical radiotherapy at the Princess Margaret Hospital between January 1970 and December 1990 were reviewed retrospectively. Patients who underwent salvage surgery for local and/or regional recurrent squamous cell carcinoma of the tonsil following radiation therapy were included for analysis. 239 out of 640 patients with tonsillar carcinoma recurred post radiotherapy. 175 patients were deemed candidates for surgical salvage. At the time of the last follow-up, only 13 patients were alive and 162 patients had died. The majority of patients ( n = 96, 59%) died with disease. The median time to death was approximately 1.3 years following salvage surgery. The 5-year overall survival rate was 23%. The 5-year cause-specific survival was 40%. The probability of death due to disease was higher than the probability of death due to other causes. Both N-classification and T-classification were found to be significant predictors of time to death. In conclusion, in spite of the fact that the patients in this study had been treated prior to the widespread introduction of altered fractionation and concurrent chemoradiation for advanced tonsil carcinoma, it demonstrates the poor prognosis of recurrent disease. Despite the poor prognosis, 20% of patients will be alive at 5 years and therefore salvage surgery should be considered when possible. [ABSTRACT FROM AUTHOR]

Because human leukocyte antigen (HLA) associations with various infectious diseases have recently been reported, we examined the role of HLA class I alleles in the development of progressive multifocal leukoencephalopathy (PML) or its outcome in 152 patients, including 123 Caucasians and 29 African Americans. Compared to a human immunodeficiency virus positive (HIV+) control population, we observed decreased frequency of HLA-A3 ( P = 0.03) in the Caucasian PML group, whereas B18 ( P = 0.02), was more frequent. No such difference was found among African American PML patients. We then sought to characterize differences in HLA between PML progressors, whose survival doesn't exceed 1 year, and survivors. Caucasian survivors were less likely to harbor A68 ( P = 0.01), whereas African American survivors less frequently displayed Cw4 ( P = .01). However, none of these differences reached statistical significance after Bonferroni correction for multiple testing. Further investigations are needed to assess the role of genetics in the incidence of PML or its outcome. Physicians may exercise caution in the use of immunomodulatory medications in patients whose genetic background is associated with an increased risk of PML. [ABSTRACT FROM AUTHOR]

Studies of the genetics of gene expression can identify expression SNPs (eSNPs) that explain variation in transcript abundance. Here we address the robustness of eSNP associations to environmental geography and population structure in a comparison of 194 Arab and Amazigh individuals from a city and two villages in southern Morocco. Gene expression differed between pairs of locations for up to a third of all transcripts, with notable enrichment of transcripts involved in ribosomal biosynthesis and oxidative phosphorylation. Robust associations were observed in the leukocyte samples: cis eSNPs (P < 10−08) were identified for 346 genes, and trans eSNPs (P < 10−11) for 10 genes. All of these associations were consistent both across the three sample locations and after controlling for ancestry and relatedness. No evidence of large-effect trans-acting mediators of the pervasive environmental influence was found; instead, genetic and environmental factors acted in a largely additive manner. [ABSTRACT FROM AUTHOR]

A variant 35 kb upstream of the HLA-C gene (-35C/T) was previously shown to associate with HLA-C mRNA expression level and steady-state plasma HIV RNA levels. We genotyped this variant in 1,698 patients of European ancestry with HIV. Individuals with known seroconversion dates were used for disease progression analysis and those with longitudinal viral load data were used for viral load analysis. We further tested cell surface expression of HLA-C in normal donors using an HLA-C-specific antibody. We show that the -35C allele is a proxy for high HLA-C cell surface expression, and that individuals with high-expressing HLA-C alleles progress more slowly to AIDS and control viremia significantly better than individuals with low HLA-C expressing alleles. These data strongly implicate high HLA-C expression levels in more effective control of HIV-1, potentially through better antigen presentation to cytotoxic T lymphocytes or recognition and killing of infected cells by natural killer cells. [ABSTRACT FROM AUTHOR]

Hepatitis C virus (HCV) infection is the most common blood-borne infection in the United States, with estimates of 4 million HCV-infected individuals in the United States and 170 million worldwide. Most (70–80%) HCV infections persist and about 30% of individuals with persistent infection develop chronic liver disease, including cirrhosis and hepatocellular carcinoma. 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. 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. 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. [ABSTRACT FROM AUTHOR]

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 propose research 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. [ABSTRACT FROM AUTHOR]

This case report describes successful treatment of autoimmune autonomic ganglionopathy (AAG) in a 74-year-old woman by total plasma exchanges (PLEX) and rituximab. Two series of PLEX temporarily, but dramatically improved orthostatic intolerance and hypotension and baroreflex function, in a manner inversely related to ganglionic neuronal nicotinic receptor antibody titer. After rituximab treatment, the antibody titer was decreased modestly but persistently, and the patient had symptomatic and clinical laboratory evidence of continued benefit for at least 10 months, supporting the autoimmune pathogenesis of AAG. [ABSTRACT FROM AUTHOR]

Drug-induced liver injury (DILI) is an important cause of serious liver disease. The antimicrobial agent flucloxacillin is a common cause of DILI, but the genetic basis for susceptibility remains unclear. We conducted a genome-wide association (GWA) study using 866,399 markers in 51 cases of flucloxacillin DILI and 282 controls matched for sex and ancestry. The GWA showed an association peak in the major histocompatibility complex (MHC) region with the strongest association (P = 8.7 × 10−33) seen for rs2395029[G], a marker in complete linkage disequilibrium (LD) with HLA-B*5701. Further MHC genotyping, which included 64 flucloxacillin-tolerant controls, confirmed the association with HLA-B*5701 (OR = 80.6, P = 9.0 × 10−19). The association was replicated in a second cohort of 23 cases. In HLA-B*5701 carrier cases, rs10937275 in ST6GAL1 on chromosome 3 also showed genome-wide significance (OR = 4.1, P = 1.4 × 10−8). These findings provide new insights into the mechanism of flucloxacillin DILI and have the potential to substantially improve diagnosis of this serious disease. [ABSTRACT FROM AUTHOR]

The Clinical Antipsychotic Trials of Intervention Effectiveness (CATIE) Phase 1 Schizophrenia trial compared the effectiveness of one typical and four atypical antipsychotic medications. Although trials such as CATIE present important opportunities for pharmacogenetics research, the very richness of the clinical data presents challenges for statistical interpretation, and in particular the risk that data mining will lead to false-positive discoveries. For this reason, it is both misleading and unhelpful to perpetuate the current practice of reporting association results for these trials one gene at a time, ignoring the fact that multiple gene-by-phenotype tests are being carried out on the same data set. On the other hand, suggestive associations in such trials may lead to new hypotheses that can be tested through both replication efforts and biological experimentation. The appropriate handling of these forms of data therefore requires dissemination of association statistics without undue emphasis on select findings. Here we attempt to illustrate this approach by presenting association statistics for 2769 polymorphisms in 118 candidate genes evaluated for 21 pharmacogenetic phenotypes. On current evidence it is impossible to know which of these associations may be real, although in total they form a valuable resource that is immediately available to the scientific community.European Journal of Human Genetics (2009) 17, 946–957; doi:10.1038/ejhg.2008.264; published online 21 January 2009 [ABSTRACT FROM AUTHOR]

The First International Symposium on Cardiac Sympathetic Neuroimaging brought together for the first time clinical and preclinical researchers evaluating autonomic and neurocardiologic disorders by this modality. The invited lectures and posters presented some uses of cardiac sympathetic neuroimaging for diagnosis, prognosis, and monitoring treatments. The Symposium also included a discussion about whether and how to expand the availability of cardiac sympathetic neuroimaging at medical centers in the United States. Here, we review the background for the Symposium, provide an annotated summary of the lectures and posters, discuss some of the take-home points from the roundtable discussion, and propose a plan of action for the future. [ABSTRACT FROM AUTHOR]

Familial dysautonomia (FD) involves incomplete development of the sympathetic nervous system. Whether such loss extends to sympathetic innervation of the heart has been unknown. This study used 6-[18F]fluorodopamine neuroimaging to assess cardiac sympathetic innervation and function in FD. Six adult FD patients underwent thoracic PET scanning for 30 minutes after i.v. 6-[18F]fluorodopamine injection, as did healthy volunteers without ( N = 21) or with ( N = 10) pre-treatment by desipramine, which interferes with neuronal uptake and thereby simulates effects of noradrenergic denervation. Effective rate constants for uptake and loss were calculated using a single compartment pharmacokinetic model. FD patients had decreased uptake and accelerated loss of 6-[18F]fluorodopamine-derived radioactivity in the interventricular myocardial septum ( P = 0.009, P = 0.05) and ventricular free wall ( P = 0.007, P < 0.001), compared to untreated controls. Desipramine-treated subjects had decreased uptake but normal loss of 6-[18F]fluorodopamine-derived radioactivity. FD involves cardiac noradrenergic hypo-innervation. Since accelerated loss of 6-[18F]fluorodopamine-derived radioactivity cannot be explained by decreased neuronal uptake alone, FD may also involve augmented NE loss from extant terminals. [ABSTRACT FROM AUTHOR]

To fully exploit the potential of kinases as drug targets, novel strategies for the efficient discovery of inhibitors are required. In contrast to the traditional, linear process of inhibitor discovery, high-throughput kinase profiling enables a parallel approach by interrogating compounds against hundreds of targets in a single screen. Compound potency and selectivity are determined simultaneously, providing a choice of targets to pursue that is guided by the quality of lead compounds available, rather than by target biology alone. [ABSTRACT FROM AUTHOR]

The past year has witnessed substantial advances in understanding the genetic basis of many common phenotypes of biomedical importance. These advances have been the result of systematic, well-powered, genome-wide surveys exploring the relationships between common sequence variation and disease predisposition. This approach has revealed over 50 disease-susceptibility loci and has provided insights into the allelic architecture of multifactorial traits. At the same time, much has been learned about the successful prosecution of association studies on such a scale. This Review highlights the knowledge gained, defines areas of emerging consensus, and describes the challenges that remain as researchers seek to obtain more complete descriptions of the susceptibility architecture of biomedical traits of interest and to translate the information gathered into improvements in clinical management. [ABSTRACT FROM AUTHOR]

Pure autonomic failure (PAF) and Parkinson’s disease (PD) share several clinical laboratory abnormalities; however, PAF is not associated with parkinsonism. In this study, we tested the hypothesis that preservation of nigrostriatal dopaminergic innervation explains the absence of motor dysfunction in PAF. Patients with PAF ( N = 5) or PD ( N = 21) and control subjects ( N = 14) had brain 6-[18F]fluorodopa positron emission tomographic scanning and cerebrospinal fluid catechol measurements. A patient with PAF and another with PD had rapid postmortem striatal, nigral, and sympathetic ganglion sampling, with assays of catechols and tyrosine hydroxylase activity. The PAF and PD groups had similarly low mean substantia nigra (SN):occipital (OCC) ratios of 6-[18F]fluorodopa-derived radioactivity and similarly low cerebrospinal fluid dihydroxyphenylacetic acid and DOPA levels. Only the PD group, however, had low PUT:OCC, caudate:OCC, or PUT:SN ratios. The PAF and PD cases had similarly low SN tissue concentrations of dopamine and tyrosine hydroxylase activity, but the PD patient had tenfold lower PUT dopamine and the PAF patient 15-fold lower myocardial norepinephrine concentrations. Surprisingly, PAF and PD entail similarly severe nigral and overall central dopaminergic denervation. There is more severe loss of striatal dopaminergic terminals in PD than in PAF and more severe loss of sympathetic noradrenergic terminals in PAF than in PD. These differences explain the distinctive clinical manifestations of the two Lewy body diseases. Parkinsonism appears to reflect striatal dopamine deficiency rather than loss of nigral dopaminergic neurons per se. [ABSTRACT FROM AUTHOR]

Although many studies provide examples of evolutionary processes such as adaptive evolution, balancing selection, deleterious variation and genetic drift, the relative importance of these selective and stochastic processes for phenotypic variation within and among populations is unclear. Theoretical and empirical studies from humans as well as natural animal and plant populations have made progress in examining the role of these evolutionary forces within species. Tentative generalizations about evolutionary processes across species are beginning to emerge, as well as contrasting patterns that characterize different groups of organisms. Furthermore, recent technical advances now allow the combination of ecological measurements of selection in natural environments with population genetic analysis of cloned QTLs, promising advances in identifying the evolutionary processes that influence natural genetic variation. [ABSTRACT FROM AUTHOR]

Maintenance of fluid homeostasis is critical to establishing and maintaining normal physiology. The landmark discovery of membrane water channels (aquaporins; AQPs) ushered in a new area in osmoregulatory biology that has drawn from and contributed to diverse branches of biology, from molecular biology and genomics to systems biology and evolution, and from microbial and plant biology to animal and translational physiology. As a result, the study of AQPs provides a unique and integrated backdrop for exploring the relationships between genes and genome systems, the regulation of gene expression, and the physiologic consequences of genetic variation. The wide species distribution of AQP family members and the evolutionary conservation of the family indicate that the control of membrane water flux is a critical biological process. AQP function and regulation is proving to be central to many of the pathways involved in individual physiologic systems in both mammals and anurans. In mammals, AQPs are essential to normal secretory and absorptive functions of the eye, lung, salivary gland, sweat glands, gastrointestinal tract, and kidney. In urinary, respiratory, and gastrointestinal systems, AQPs are required for proper urine concentration, fluid reabsorption, and glandular secretions. In anurans, AQPs are important in mediating physiologic responses to changes in the external environment, including those that occur during metamorphosis and adaptation from an aquatic to terrestrial environment and thermal acclimation in anticipation of freezing. Therefore, an understanding of AQP function and regulation is an important aspect of an integrated approach to basic biological research. [ABSTRACT FROM AUTHOR]

There is substantial interest in identifying biomarkers to detect early Parkinson disease (PD). Cardiac noradrenergic denervation and attenuated baroreflex-cardiovagal function occur in de novo PD, but whether these abnormalities can precede PD has been unknown. Here we report the case of a patient who had profoundly decreased left ventricular myocardial 6-[18F]fluorodopamine-derived radioactivity and low baroreflex-cardiovagal gain, 4 years before the onset of symptoms and signs of PD. The results lead us to hypothesize that cardiac noradrenergic denervation and decreased baroreflex-cardiovagal function may occur early in the pathogenesis of PD. [ABSTRACT FROM AUTHOR]

Dear Editors, We would like to thank Dr. Blitshteyn for her comments on the American Autonomic Society (AAS) statement on the relationship between human papillomavirus vaccine and autonomic disorder [[1]]. 10.1007/s10286-019-00608-w 2 Blitshteyn S. Human papillomavirus (HPV) vaccines safety concerning POTS, CRPS and related conditions. [Extracted from the article]

In this study we evaluated by indirect immunohistochemistry the prevalence of cerebrospinal fluid (CSF) antibodies reacting with structures of rat pons/medulla in patients with multiple system atrophy (MSA) ( n = 29), Parkinson disease with neurogenic orthostatic hypotension ( n = 13), or pure autonomic failure ( n = 11) and in control subjects without autonomic failure ( n = 33). About 10–20% of CSF samples had positive immunoreactivity to rat locus coeruleus (LC), regardless of clinical diagnosis. The results failed to confirm the previously reported high prevalence of immune binding to rat LC in CSF from patients with MSA. [ABSTRACT FROM AUTHOR]

Genomics is now a core element in the effort to develop a vaccine against HIV-1. Thanks to unprecedented progress in high-throughput genotyping and sequencing, in knowledge about genetic variation in humans, and in evolutionary genomics, it is finally possible to systematically search the genome for common genetic variants that influence the human response to HIV-1. The identification of such variants would help to determine which aspects of the response to the virus are the most promising targets for intervention. However, a key obstacle to progress remains the scarcity of appropriate human cohorts available for genomic research. [ABSTRACT FROM AUTHOR]

A brief review of the concept and practice of providing various services to police employees similar to those in private industry is presented These include Employee Assistance Programs (EAPs) that may be either internal or external in relation to the structure of the organization. Such efforts may also be found in law enforcement organizations. In addition, a hybrid model for law enforcement is examined This involves a working alliance between an internal Peer Support Program and an external EAP. This model may provide immediate assistance to an otherwise resistant population and, in turn, pave the way for additional aid from mental health professionals. Confidentiality issues are presented A brief review of recommended peer supporter characteristics is offered. [ABSTRACT FROM AUTHOR]

Background. The Rural Systemic Adjuvant Therapy Project was initiated to encourage best practice in the treatment of women from rural areas who have breast cancer. Method.We developed an educational program, piloted it and conducted it in 5 regions. In a preevaluation/postevaluation, we assessed participants' perceived knowledge about systemic adjuvant therapy. Results. A statistically significant increase occurred in participants' reported knowledge about all program topics. Improved communication links with the local or visiting medical oncologist were planned. Conclusion. The workshop program was found to be a successful tool for delivering evidence- based information about the use of systemic adjuvant therapy. [ABSTRACT FROM AUTHOR]

Patients with Parkinson’s disease (PD) commonly have clinically significant orthostatic hypotension (OH). In such patients PD+OH might be confused with multiple system atrophy (MSA), in which OH is a frequent finding, or with pure autonomic failure (PAF), if OH preceded clinical manifestations of the movement disorder. This study addressed whether OH can occur as an early finding in PD+OH.Historical data were analyzed from 35 patients with PD+OH evaluated at the NIH. OH was considered early if the patient had OH before, concurrent with, or starting within 1 year after onset of a symptomatic movement disorder. MSA was excluded by myocardial 6-[18F]fluorodopamine-derived radioactivity more than 2 standard deviations below the normal mean. Among the 35 PD+OH patients, 21 (60 %) had documentation of OH as an early finding. In 4 such patients, OH had preceded parkinsonism, and in 4 others, OH had dominated the early clinical picture, even after cessation of levodopa treatment for the movement disorder. In PD, OH can occur early in the disease, occasionally preceding or overshadowing the movement disorder. [ABSTRACT FROM AUTHOR]

Plasma catechols and blood volume were measured in 20 male, native high-altitude residents of Cerro de Pasco, Peru (4338 m), while hypoxic and subsequently while normoxic at sea level. Ten subjects were healthy controls,with hematocrits lower than 61%, and ten had chronic mountain sickness (CMS), a syndrome of maladaptation to altitude, characterized by polycythemia (hematocrit > 61%), profound hypoxemia, and neurologic symptoms. The main aim of the study was to evaluate the chronic effects of hypoxia on plasma catechols and on blood volume, by studying these parameters during hypoxia at high altitude (HA) and shortly after exposure to normoxia at sea level (SL). Subjects were first studied at HA in their habitual hypoxic environment, and measurements were repeated within 4 hours of arrival at SL (Lima, Peru, 150 m). All subjects had higher plasma norepinephrine (NE), dopamine (DA), and dihydroxyphenylglycol (DHPG) levels in HA (NE in controls and CMS: 414±47 and 514±35 pg/mL; DA: 9±1 and 13±1 pg/mL, DHPG: 817±48 and 972±77 pg/mL) than at SL (NE: 164±9 and 243±28 pg/mL; DA: 4±0.5 and 5±1 pg/mL DHPG: 502±23 and 649±39 pg/mL). Group differences were statistically significant only for NE in the CMS group. Plasma volume was higher in HA in both groups (p<0.05); red cell volume was higher in HA only in the CMS group. The results indicate sympathetic nervous stimulation by chronic ambient hypoxia at altitude in Andean natives, independent of maladaptation to their native environment. [ABSTRACT FROM AUTHOR]

The current enthusiasm for pharmacogenetics draws much of its inspiration from the relatively few examples of polymorphisms that have marked and seemingly clinically relevant effects on drug response. In this regard, pharmacogenetic research has paralleled the study of human disease, which has enjoyed success in identifying mutations underlying mendelian conditions. Progress in deciphering the genetics of complex diseases, involving the interaction of multiple genes with each other and with the environment has been considerably less successful. In most instances, drug responses will probably also prove to be complex, influenced by both the environment and multiple genetic factors. For pharmacogenetics to deliver on its potential, this complexity will need to be recognized and accommodated, both in basic research and in clinical application of pharmacogenetics. As the attention of researchers begins to shift toward more systematic pharmacogenetic investigations, we suggest some priorities and standards for pharmacogenetic research. [ABSTRACT FROM AUTHOR]

Dextropropoxyphene, alone or in combination with acetaminophen (paracetamol), is among the most frequently prescribed opioid analgesics in the elderly in the US despite the American Geriatric Society recommendation that its use should be restricted. However, this recommendation is based on expert opinion in an apparent absence of data. Accordingly, we conducted a literature search which identified nine studies that reported efficacy and safety data for dextropropoxyphene in predominantly older patients (≥55 years of age). These studies were evaluated to assess the efficacy and safety of dextropropoxyphene compared with other opioids and to evaluate whether safety and tolerability differed in older versus younger patients. The efficacy of dextropropoxyphene appeared to be similar to that of other analgesics, and its safety was comparable to that of other opioid analgesics. Although the adverse event profile suggests that elderly patients might have more frequent gastrointestinal and CNS complaints than younger patients treated with dextropropoxyphene, the frequency of reports appears similar to that of other opioids. The incidences of dizziness and somnolence were not significantly greater in older patients (1–2% and 0–21%, respectively) than in younger patients (8% and 13%, respectively). The absence of clinical studies directly addressing the safety and tolerability of dextropropoxyphene in elderly patients (>65 years of age) versus younger patients encumbers assessment of the validity of restricting its use in the elderly. Careful outcomes research is needed to assess the effectiveness and safety of dextropropoxyphene in older patients and to develop evidence-based risk/benefit prescribing criteria for use of this drug in this age group. [ABSTRACT FROM AUTHOR]

Interindividual variability in drug response, ranging from no therapeutic benefit to life-threatening adverse reactions, is influenced by variation in genes that control the absorption, distribution, metabolism and excretion of drugs. We genotyped 904 single-nucleotide polymorphisms (SNPs) from 55 such genes in two population samples (European and Japanese) and identified a set of tagging SNPs that represents the common variation in these genes, both known and unknown. Extensive empirical evaluations, including a direct assessment of association with candidate functional SNPs in a new, larger population sample, validated the performance of these tagging SNPs and confirmed their utility for linkage-disequilibrium mapping in pharmacogenetics. The analyses also suggest that rare variation is not amenable to tagging strategies. [ABSTRACT FROM AUTHOR]

Background Oral L-threo-3,4-dihydroxyphenylserine (L-DOPS), a synthetic catechol amino acid, increases standing blood pressure and improves standing ability in patients with neurogenic orthostatic hypotension, by conversion of L-DOPS to norepinephrine (NE) outside the brain. This study assessed the pharmacokinetics of L-DOPS, NE, and dihydroxyphenylglycol (DHPG), the main neuronal metabolite of NE, in patients with primary chronic autonomic failure from pure autonomic failure (PAF) or multiple system atrophy (MSA). Methods In 5 MSA and 4 PAF patients, antecubital venous blood was drawn during supine rest and plasma levels of catechols measured at various times for 48 hours after a single oral dose of 400 mg of L-DOPS. Results Plasma L-DOPS peaked at 1.9 μg/ml (9 μmol/L) about 3 hours after drug administration, followed by a monoexponential decline with a half-time of 2-3 hours in both patient groups. Plasma NE and DHPG also peaked at about 3 hours, but at much lower concentrations (4 and 42 nmol/L). Compared to the MSA group, the PAF group had a smaller calculated volume of distribution of L-DOPS and up to 10-fold lower plasma NE levels at all time points. Plasma NE was above baseline in MSA even at 48 hours after L-DOPS. Conclusions The relatively long half-time for disappearance of L-DOPS compared to that of NE explains their very different attained plasma concentrations. The similar NE and DHPG responses in PAF and MSA suggests production of NE from LDOPS mainly in non-neuronal cells. Persistent elevation of plasma NE in MSA suggests residual release of NE from sympathetic nerves. [ABSTRACT FROM AUTHOR]

The authors located and experimentally reproduced an alcoholic beverage using Schinus molle L. drupes to explain the presence of large quantities of S. molle seeds in archaeological contexts associated with the Middle Horizon (550-1000 C.E.) site of Cerro BaúL Moquegua, Perú. They discuss the production of chicha de molle in the context of the archaeological site, the ecology of the plant, and the ethnobotany associated with S. molle in the Andes. Overall S. molle was and is used today in a variety of ways regionally, and through both ethnobotanical and archaeological fieldwork, they establish a long-standing tradition of human-plant interactions with S. molle. [ABSTRACT FROM AUTHOR]

Rationale: Several lines of evidence suggest that the pathophysiology of schizophrenia may be associated with altered noradrenergic and glucoregulatory function. Objective: The aim of this study was to investigate these alterations during a perturbed homeostatic state. Methods: Fifteen patients with schizophrenia and 13 healthy individuals were given a glucose deprivation challenge through administration of pharmacological doses of 2-deoxyglucose (2DG; 40 mg/kg), and their plasma was assayed over the next 60 min for concentrations of norepinephrine (NE), the intraneuronal NE metabolite dihydroxyphenylglycol (DHPG), epinephrine and glucose. Results: 2DG induced significant increases in plasma NE, epinephrine and glucose levels in both groups with significantly greater NE and glucose increments in patients than in controls. For DHPG, 2DG produced increases in patients and decreases in the control subjects. NE responses correlated positively and significantly with the DHPG and glucose responses in schizophrenics, but not in controls. Conclusions: These findings suggest that patients with schizophrenia have exaggerated NE and glucose responses to an acute metabolic perturbation. [ABSTRACT FROM AUTHOR]

Throughout much of the world, 'race' and 'ethnicity' are key determinants of health. For example, African Americans have, by some estimates, a twofold higher incidence of fatal heart attacks and a 10% higher incidence of cancer than European Americans, and South Asian-or Caribbean-born British are~3.5 times as likely to die as a direct result of diabetes than are British of European ancestry. The health care that people receive also depends on 'race' and 'ethnicity'. African Americans are less likely to receive cancer-screening services and more likely to have late-stage cancer when diagnosed than European Americans. Health disparities such as these are one of the greatest social injustices in the developed world and one of the most important scientific and political challenges. [ABSTRACT FROM AUTHOR]

Purpose: A randomized unblinded controlled trial was used to assess the utility of electronic questionnaires in a survey of Canadian anesthesiologists.Methods: Postal or electronic questionnaires were sent between November 2001 and March 2002 to 1,333 anesthesiologists registered with the Canadian Anesthesiologists' Society. The primary outcome measure was the difference in response rates between electronic and postal questionnaires. Secondary outcome measures included a comparison of demographic characteristics, cost, and knowledge and practice regarding prophylactic perioperative beta blockade.Results: The overall response rate was 52%. E-mail participants were half as likely as postal participants to respond to the questionnaire (35% vs 69%, relative risk = 0.51, 95% confidence interval 0.45-0.58). Respondents who provided an e-mail address were younger and more likely to be affiliated with an academic institution. There were no significant differences in responses to knowledge and practice questions. The electronic arm was faster than the postal arm and the cost per reply was one-third the cost of the postal arm (2.50 dollars vs 8.02 dollars).Conclusions: Electronic surveys are a means of acquiring information from a large number of individuals in a rapid, efficient and cost-effective manner. This methodology may be particularly valid and useful in surveys of participants with similar backgrounds and internet access. However the lower response rates achieved as compared with postal surveys indicates a need to use vigilance when generalizing results to a broader population. [ABSTRACT FROM AUTHOR]

Copyright of Canadian Journal of Anaesthesia / Journal Canadien d'Anesthésie is the property of Springer Nature and its content may not be copied or emailed to multiple sites or posted to a listserv without the copyright holder's express written permission. However, users may print, download, or email articles for individual use. This abstract may be abridged. No warranty is given about the accuracy of the copy. Users should refer to the original published version of the material for the full abstract. (Copyright applies to all Abstracts.)

Copyright of Canadian Journal of Anaesthesia / Journal Canadien d'Anesthésie is the property of Springer Nature and its content may not be copied or emailed to multiple sites or posted to a listserv without the copyright holder's express written permission. However, users may print, download, or email articles for individual use. This abstract may be abridged. No warranty is given about the accuracy of the copy. Users should refer to the original published version of the material for the full abstract. (Copyright applies to all Abstracts.)

Most people in the developed world will sooner or later be given prescription drugs to treat common diseases or to reduce the risk of getting them. Almost everyone who takes medicines will, at some stage, encounter those that do not work as well as they do in other people or even that cause an adverse reaction. Pharmacogenetics seeks to reduce the variation in how people respond to medicines by tailoring therapy to individual genetic make-up. It seems increasingly likely that investment in this field might be the most effective strategy for rapidly delivering the public health benefits that are promised by the Human Genome Project and related endeavours. [ABSTRACT FROM AUTHOR]

Catecholamine-producing tumors are rare neoplasms derived mainly from chromaffin cells of the adrenal medulla (pheochromocytomas) or, in about 10% of cases, from paraganglia (paragangliomas). Diagnosis of these tumors relies heavily on measurements of urinary or plasma catecholamines or catecholamine metabolites. The metabolites are usually thought to be produced after release of catecholamines into the bloodstream. This, however, ignores observations of over 40 yr ago that catecholamines are metabolized within pheochromocytoma tumor cells. Development of improved methods for measurement of catecholamine metabolites, in particular, plasma concentrations of free normetanephrine and metanephrine, has reestablished the importance of intratumoral catecholamine metabolism. In patients with pheochromocytoma, over 90% of the elevations in plasma free normetanephrine and metanephrine result from metabolism of catecholamines within pheochromocytoma tumor cells. This process occurs continuously and independently of variations in catecholamine release. As a consequence, measurements of plasma concentrations and urinary outputs of normetanephrine and metanephrine provide more reliable methods for diagnosis of pheochromocytoma than measurements of the parent amines. Rediscovery of the importance of intratumoral catecholamine metabolism is leading to a reevaluation of the procedures used to diagnose pheochromocytoma. This review provides an update on the diagnosis of pheochromocytoma, with emphasis on identifying and correcting relevant misconceptions about catecholamine metabolism. [ABSTRACT FROM AUTHOR]

Copyright of Canadian Journal of Anaesthesia / Journal Canadien d'Anesthésie is the property of Springer Nature and its content may not be copied or emailed to multiple sites or posted to a listserv without the copyright holder's express written permission. However, users may print, download, or email articles for individual use. This abstract may be abridged. No warranty is given about the accuracy of the copy. Users should refer to the original published version of the material for the full abstract. (Copyright applies to all Abstracts.)

Copyright of Canadian Journal of Anaesthesia / Journal Canadien d'Anesthésie is the property of Springer Nature and its content may not be copied or emailed to multiple sites or posted to a listserv without the copyright holder's express written permission. However, users may print, download, or email articles for individual use. This abstract may be abridged. No warranty is given about the accuracy of the copy. Users should refer to the original published version of the material for the full abstract. (Copyright applies to all Abstracts.)

Background In response to stressors and pathophysiologic conditions, sympathetic neuronal outflows can change heterogeneously among body organs and tissues. This study examined the validity of micro dialysis and measurements of microdialysate concentrations of catechols, to assess local sympathetic function in skeletal muscle and adipose tissue in humans. Methods Based on preliminary experiments, a microdialys ate perfusion rate of 3 μl/mm and collection duration of 30 minutes were chosen. To assess responses to a stimulus that increases sympathetic outflow to skeletal muscle, micro dialysate norepinephrine and dihydroxyphenylglycol concentrations in quadriceps muscle, abdominal subcutaneous adipose tissue, and plasma were measured during orthostasis in 8 healthy normal volunteers. To assess responses to decreased post- ganglionic sympathetic nerve traffic, norepinephrine and dihydroxyphenylglycol concentrations were measured during i. v. infusion of trimethaphan in 5 volunteers. Results All subjects had detectable norepinephrine and dihydroxyphenylglycol in micro- dialysate from both skeletal muscle and adipose tissue. Orthostasis sig- nificantly increased micro dialysate norepinephrine in skeletal muscle (0.38 ± (SEM) 0.07 nmol/L supine to 1.48 ± 0.24 nmol/L standing, p <0.01) and in adipose tissue (0.31 ± 0.02 nmol/L supine to 0.68 ± 0.11 nmol/L standing, p <0.01). Orthostasis also increased microdialysate dihydroxyphenylglycol in both tissues (1.76 ± 0.30 nmol/L to 3.08 ± 0.43 nmol/L,p <0.01; 1.37 ± 0.15 nmol/L supine to 1.99 ± 0.34nmol/L standing,p <0.01). Trimethaphan decreased norepinephrine concentrations in skeletal muscle micro dialysate by 50 %, adipose tissue by 70 %, and antecubital venous plasma 50 %, with non-significant decreases in dihydrox- yphenylglycol concentrations at each site. Conclusions Microdialysate concentrations of nor epinephrine and dihydroxyphenylglycol can be detected reliably and respond appropriately during manipulations that increase or decrease the sympathetically mediated release and turnover of norepinephrine. This approach may provide a means to assess sympathetic neuronal function in skeletal muscle and adipose tissue in humans with known or suspected dysautonomias. [ABSTRACT FROM AUTHOR]

Risperidone is an atypical antipsychotic drug that increases plasma norepinephrine (NE) levels, but the mechanism behind this effect is unclear. We measured arterial plasma levels of NE and other catechols during intravenous infusion of tritium-labeled NE (3H-NE) in risperidone-treated patients and compared their data with those from patients treated with clozapine or placebo. NE levels in risperidone patients were significantly higher than in placebo patients, but lower than in clozapine patients. Neither drug, however, had significant effect on plasma levels of the main neuronal metabolite of NE, dihydroxyphenylglycol (DHPG), suggesting that adrenoceptors blockade alone would not explain the NE findings. The rate of release of endogenous NE into the bloodstream (spillover) was elevated in both risperidone and clozapine patients in a manner that paralleled their NE levels; the NE clearance in both groups did not differ from placebo. Following 3H-NE infusion in risperidone-treated individuals, production of 3H-DHPG was normal, as it was in the clozapine group, suggesting that risperidone does not impede neuronal uptake or intraneuronal metabolism of NE by monoamine oxidase. Our data suggest that both risperidone and clozapine elevate plasma NE levels via enhanced neurotransmitter spillover, with risperidone producing a smaller effect. [Copyright &y& Elsevier]