bluuebunny/crossref_metadata_2025 huggingface dataset:
Neural Mechanisms Underlying Selective Attention to Threat
Authors: Bishop Sonia J.
Published: June 2008

Biased competition models of selective attention suggest that attentional competition is influenced both by bottom‐up sensory mechanisms sensitive to stimulus salience and top‐down control mechanisms that support the processing of task‐relevant stimuli. This provides a framework for investigating the neural mechanisms underlying selective attention to threat. Both subcortical regions implicated in threat detection—specifically the amygdala—and prefrontal cortical regions implicated in top‐down attentional control are activated in response to task‐irrelevant threat stimuli. A number of questions including the automaticity of the amygdala response to threat distractors, the modulation by anxiety of the amygdala and prefrontal response to these stimuli, and the impact of genetic and environmental factors upon this circuitry are addressed. The empirical literature is considered in the context of theoretical accounts of the neural substrate of selective attention and conscious awareness. It is suggested that the neural activity provoked by a given visual stimulus is influenced by factors impacting upon the strength of the bottom‐up trace (e.g., presentation time, backward masking), stimulus salience (including threat relatedness), competition with other visual stimuli for perceptual processing resources, and the augmentation of the stimulus trace by allocation of top‐down attentional resources. Individual differences in trait and state anxiety, and in genetic makeup, are thought to modulate the influence of stimulus valence and top‐down attention through their impact upon amygdala and prefrontal function.
Sleep and Wakefulness inDrosophila melanogaster
Authors: Cirelli Chaira , Bushey Daniel
Published: June 2008

Sleep is present and tightly regulated in every vertebrate species in which it has been carefully investigated, but what sleep is for remains a mystery. Sleep is also present in invertebrates, and an extensive analysis in Drosophila melanogaster has shown that sleep in fruit flies shows most of the fundamental features that characterize sleep in mammals. In Drosophila, sleep consists of sustained periods of quiescence associated with an increased arousal threshold. Fly sleep is modulated by several of the same stimulants and hypnotics that affect mammalian sleep. Moreover, like in mammals, fly sleep shows remarkable interindividual variability. The expression of several genes involved in energy metabolism, synaptic plasticity, and the response to cellular stress varies in Drosophila between sleep and wakefulness, and the same occurs in rodents. Brain activity also changes in flies as a function of behavioral state. Furthermore, Drosophila sleep is tightly regulated in a circadian and homeostatic manner, and the homeostatic regulation is largely independent of the circadian regulation. After sleep deprivation, recovery sleep in flies is longer in duration and more consolidated, indicated by an increase in arousal threshold and fewer brief awakenings. Finally, sleep deprivation in flies impairs vigilance and performance. Because of the extensive similarities between flies and mammals, Drosophila is now being used as a promising model system for the genetic dissection of sleep. Over the last few years, mutagenesis screens have isolated several short sleeping mutants, a demonstration that single genes can have a powerful effect on a complex trait like sleep.
Fear Conditioning and Long‐term Potentiation in the Amygdala
Authors: Sah P. , Westbrook R. F. , Lüthi A.
Published: June 2008

The cellular mechanisms that underlie learning and memory formation remain one of the most intriguing unknowns about the mammalian brain. A plethora of experimental evidence over the last 30 years has established that long‐term synaptic plasticity at excitatory synapses is the most likely mechanism that underlies learning and memory formation. Experiments done largely in acute brain slices maintained in vitro have revealed many of the molecular mechanisms in the induction and maintenance of long‐term potentiation (LTP). However, evidence directly liking LTP with learning and memory formation has not been established. Pavlovian fear conditioning is a good candidate to provide such evidence. The relations between events that produce fear conditioning are simple; these relations and their fear products involve circuits in the amygdala that are well understood, as are those circuits in the amygdala that underlie LTP. The evidence that links LTP in the amygdala with fear conditioning is reviewed.
Cholinergic Mediation of Attention
Authors: Parikh Vinay , Sarter Martin
Published: June 2008

Contrary to the classic description of acetylcholine (ACh) as a slowly acting neuromodulator that influences arousal states, results from experiments that employed enzyme‐selective microelectrodes for the real‐time monitoring of ACh release in the cortex of attentional task‐performing rats indicate that cholinergic signals manifesting on multiple timescales (seconds, tens of seconds, and minutes) support, and are necessary for, the mediation of defined cognitive operations. Specifically, in the prefrontal cortex, second‐based cholinergic signals support the detection of behaviorally significant cues. In contrast to these prefrontal cholinergic transients, performance‐associated cholinergic activity that manifested at lower temporal resolution also was observed elsewhere in the cortex. Although tonic cholinergic signal levels were correlated with the amplitudes of cue‐evoked cholinergic transients, and the latter with response latencies, the interrelationships and interactions between the multiple cholinergic signaling modes remains unclear. Hypotheses concerning the afferent circuitry contributing to the regulation of second‐ versus minute‐based cholinergic signals are discussed. The discovery of cholinergic transients and their crucial role in cue detection and attentional performance form the basis for new hypotheses about the nature of cholinergic dysfunction in cognitive disorders and offer new targets for the development of treatments for the cognitive symptoms of neuropsychiatric and neurodegenerative disorders.
Toward a Neurogenetic Theory of Neuroticism
Authors: Canli Turhan
Published: June 2008

Recent advances in neuroscience and molecular biology have begun to identify neural and genetic correlates of complex traits. Future theories of personality need to integrate these data across the behavioral, neural, and genetic level of analysis and further explain the underlying epigenetic processes by which genes and environmental variables interact to shape the structure and function of neural circuitry. In this chapter, I will review some of the work that has been conducted at the cognitive, neural, and molecular genetic level with respect to one specific personality trait—neuroticism. I will focus particularly on individual differences with respect to memory, self‐reference, perception, and attention during processing of emotional stimuli and the significance of gene‐by‐environment interactions. This chapter is intended to serve as a tutorial bridge for psychologists who may be intrigued by molecular genetics and for molecular biologists who may be curious about how to apply their research to the study of personality.
Why Does Consciousness Fade in Early Sleep?
Authors: Tononi Giulio , Massimini Marcello
Published: June 2008

Consciousness fades during deep nonrapid eye movement (NREM) sleep early in the night, yet cortical neurons remain active, keep receiving sensory inputs, and can display patterns of synchronous activity. Why then does consciousness fade? According to the integrated information theory of consciousness, what is critical for consciousness is not firing rates, sensory input, or synchronization per se, but rather the ability of a system to integrate information. If consciousness is the capacity to integrate information, then the brain should be able to generate consciousness to the extent that it has a large repertoire of available states (information), yet it cannot be decomposed into a collection of causally independent subsystems (integration). A key prediction stemming from this hypothesis is that such ability should be greatly reduced in deep NREM sleep; the dreamless brain either breaks down into causally independent modules, shrinks its repertoire of possible responses, or both. In this article, we report the results of a series of experiments in which we employed a combination of transcranial magnetic stimulation and high‐density electroencephalography (TMS/hd‐EEG) to directly test this prediction in humans. Altogether, TMS/hdEEG measurements suggest that the sleeping brain, despite being active and reactive, loses its ability of entering states that are both integrated and differentiated; it either breaks down in causally independent modules, responding to TMS with a short and local activation, or it bursts into an explosive and aspecific response, producing a full‐fledged slow wave.
Placing Neuroanatomical Models of Executive Function in a Developmental Context
Authors: Brocki Karin , Fan Jin , Fossella John
Published: June 2008

Children show gradual and protracted improvement in an array of behaviors involved in the conscious control of thought and emotion. Behavioral research has shown that these abilities, collectively referred to as executive functions (EF), can be dissociated into separable processes, such as inhibition and working memory. Furthermore, noninvasive neuroimaging shows that these component processes often rely on separable neural circuits involving areas of the frontal cortex and nuclei of the basal ganglia. As additional noninvasive methodologies become available, it is increasingly possible to continue to dissect and dissociate components of EF and also test predictions made by a number of theoretical neuroanatomical models. One method of late is genetics, which is noninvasive and readily used in concert with neuroimaging. The biological data obtained with neuroimaging and genetics is particularly able to inform neuroanatomical models that link specific brain systems with higher more abstract process models derived from purely behavioral work. As much progress in this area continues to occur, we seek to evaluate the age dependency and manner in which certain aspects of EF and certain anatomical circuits show changes and interactions as children develop. Some examples are taken from research on children with the developmental disability attention deficit hyperactivity disorder. A review of selected developmental research shows that current cognitive and neuroanatomical models of EF offer a great many system‐ and synaptic‐level hypotheses that can be tested using imaging and imaging genetics in longitudinal and cross‐sectional study designs. Here, we focus on age‐related changes in inhibition and working memory.
Modulation of Cortical Activation and Behavioral Arousal by Cholinergic and Orexinergic Systems
Authors: Jones Barbara E.
Published: June 2008

Multiple neuronal systems contribute to the promotion and maintenance of the wake state, which is characterized by cortical activation and behavioral arousal. Using predominantly glutamate as a neurotransmitter, neurons within the reticular formation of the brainstem give rise to either ascending projections into the forebrain or descending projections into the spinal cord to promote through relays fast cortical activity or motor activity with postural muscle tone. Using acetylcholine, cholinergic neurons in the brainstem project to forebrain relays and others in the basal forebrain to the cortex, by which they stimulate fast gamma activity during waking and during rapid eye movement or paradoxical sleep (PS). Other neuromodulatory systems, such as noradrenergic locus coeruleus neurons, give rise to highly diffuse projections through brain and spinal cord and simultaneously stimulate cortical activation and behavioral arousal. Although such neuromodulatory systems were thought to be redundant, a recently discovered peptide called orexin (Orx) or hypocretin, contained in diffusely projecting neurons of the hypothalamus, was found to be essential for the maintenance of waking with muscle tone, since in its absence narcolepsy with cataplexy occurred. Orx neurons discharge during active waking and cease firing during sleep. Since cholinergic neurons discharge during waking and PS, they would stimulate cortical activation in association with muscle tone when orexinergic neurons are also active but would stimulate cortical activation with muscle atonia when orexinergic neurons are silent, as in natural PS, or absent, as in pathological narcolepsy with cataplexy.
Gene Expression Is Altered in the Lateral Hypothalamus upon Activation of the mu Opioid Receptor
Authors: Befort K. , Filliol D. , Darcq E. , Ghate A. , Matifas A. , Lardenois A. , Muller J. , Thibault C. , Dembele D. , Poch O. , Kieffer B.L.
Published: June 2008

The lateral hypothalamus (LH) is a brain structure that controls hedonic properties of both natural rewards and drugs of abuse. Mu opioid receptors are known to mediate drug reward, but whether overstimulation of these receptors impacts on LH function has not been studied. Here we have used a genome‐wide microarray approach to identify LH responses to chronic mu opioid receptor activation at the transcriptional level. We have subjected wild‐type and mu opioid receptor knockout mice to an escalating morphine regimen, which produces severe physical dependence in wild‐type but not mutant animals. We have analyzed gene profiles in LH samples using the 430A.2 Affymetrix array and identified a set of 25 genes whose expression is altered by morphine in wild‐type mice only. The regulation was confirmed for a subset of these genes using real‐time quantitative PCR on samples from independent treatments. Altered expression of aquaporin 4, apolipoprotein D, and prostaglandin synthase is indicative of modified LH physiology. The regulation of two signaling genes (the serum glucocorticoid kinase and the regulator of G protein signaling 4) suggests that neurotransmission is altered in LH circuitry. Finally, the downregulation of apelin may indicate a potential role for this neuropeptide in opioid signaling and hedonic homeostasis. Altogether, our study shows that chronic mu opioid receptor stimulation induces gene expression plasticity in the LH and provides a unique collection of mu opioid receptor‐dependent genes that potentially contribute to alter reward processes in addictive diseases.
Central Thalamic Contributions to Arousal Regulation and Neurological Disorders of Consciousness
Authors: Schiff Nicholas D.
Published: June 2008

This review focuses on the contributions of the central thalamus to normal mechanisms of arousal regulation and to neurological disorders of consciousness. Forebrain arousal is regulated by ascending influences from brainstem/basal forebrain neuronal populations (“arousal systems”) and control signals descending from frontal cortical systems. These subcortical and cortical systems have converging projections to the central thalamus that emphasize their role in maintaining organized behavior during wakefulness. Central thalamic neurons appear to be specialized both anatomically and physiologically to support distributed network activity that maintains neuronal firing patterns across long‐range cortico–cortical pathways and within cortico–striatopallidal–thalamocortical loop connections. Recruitment of central thalamic neurons occurs in response to increasing cognitive demand, stress, fatigue, and other perturbations that reduce behavioral performance. In addition, the central thalamus receives projections from brainstem pathways evolved to rapidly generate brief shifts of arousal associated with the appearance of salient stimuli across different sensory modalities. Through activation of the central thalamus, neurons across the cerebral cortex and striatum can be depolarized and their activity patterns selectively gated by descending or ascending signals related to premotor attention and alerting stimuli. Direct injury to the central thalamus or prominent deafferentation of these neurons as a result of complex, multifocal, brain insults are both associated with severe impairment of forebrain functional integration and arousal regulation. Interventions targeting neurons within the central thalamus may lead to rational therapeutic approaches to the treatment of impaired arousal regulation following nonprogressive brain injuries. A model accounting for present therapeutic strategies is proposed.
Molecular Mechanisms of Sleep and Wakefulness
Authors: Mackiewicz Miroslaw , Naidoo Nirinjini , Zimmerman John E. , Pack Allan I.
Published: June 2008

Major questions on the biology of sleep include the following: what are the molecular functions of sleep; why can wakefulness only be sustained for defined periods before there is behavioral impairment; what genes contribute to the individual differences in sleep and the response to sleep deprivation? Behavioral criteria to define sleep have facilitated identification of sleep states in a number of different model systems: Drosophila, zebrafish, and Caenorhabditis elegans. Each system has unique strengths. Studies in these model systems are identifying conserved signaling mechanisms regulating sleep that are present in mammals. For example, the PKA‐CREB signaling mechanism promotes wakefulness in Drosophila, mice, and C. elegans. Microarray studies indicate that genes whose expression is upregulated during sleep are involved in macromolecule biosynthesis (proteins, lipids [including cholesterol], heme). Thus, a key function of sleep is likely to be macromolecule synthesis. Moreover, in all species studied to date, there is upregulation of the molecular chaperone BiP with extended wakefulness. Sleep deprivation leads to cellular ER stress in brain and the unfolded protein response. Identification of genes regulating sleep has the potential for translational studies to elucidate the genetics of sleep and response to sleep deprivation in humans.
Mechanisms for the Regulation of State Changes in the Central Nervous System
Authors: Pfaff Donald W. , Kieffer Brigitte L. , Swanson Larry W.
Published: June 2008

Current work on central nervous system (CNS) mechanisms underlying behavior has expanded from consideration of specific sensory codes or motor controls to the analyses of global CNS states. These include states of arousal, alertness, attention, emotional states regarding emotion and motivation, and states of addiction, which carry great importance for medicine and public health. In this brief introduction, orderly neuroanatomical concepts of forebrain pathways regulating motivated behaviors are presented. Neuropeptides often coordinate large sets of responses associated with an individual behavioral state. Here, we emphasize some of the central roles for opioid peptides. We also mention a few outstanding unanswered questions related to this area of neuroscience.
Circadian and Homeostatic Factors in Arousal
Authors: Silver Rae , LeSauter Joseph
Published: June 2008

In the course of evolution, mechanisms have evolved to anticipate the timing of regularly occurring events. These mechanisms are encompassed in a circadian timing system that include a master clock localized to the suprachiasmatic nucleus of the hypothalamus and “slave” oscillators distributed throughout the body. This system serves multiple functions so as to ensure that various physiological processes occur at optimal and nonoverlapping times, to synchronize our activities to local environmental time, and to permit changes required to respond to new environmental circumstances. We suggest that a generalized concept of arousal (which includes alterations in responsiveness to homeostatic pressures, sensory stimuli and emotional reactivity, and to changes in motor activity) serves as a rubric in which to explore the multiple ways in which the circadian system modulates behavior.
Sporadic Epithelial Ovarian Cancer: Clinical Relevance of BRCA1 Inhibition in the DNA Damage and Repair Pathway
Authors: Weberpals Johanne I. , Clark-Knowles Katherine V. , Vanderhyden Barbara C.
Published: June 2008

Among the most promising pathways for molecular targets in sporadic epithelial ovarian cancer (SEOC) are those involving the BRCA1 protein. Because somatic mutations in BRCA1 are rare in SEOC, it was originally postulated that BRCA1 plays a limited role in the pathogenesis of this disease. However, inactivation of BRCA1 through various mechanisms is a relatively frequent event in ovarian cancer. This is important because BRCA1 is involved in the cellular response to DNA damage and repair and has an essential role in the maintenance of genomic stability. The BRCA1 tumor suppressor protein is known to interact with genes and proteins known collectively as the BRCA1 pathway, and defects in this pathway are believed to be a driving force for cancer progression. As a result, there is compelling evidence to suggest that the dysfunction of BRCA1 may be a central mechanism in all ovarian carcinogenesis, and this has clinical and molecular significance beyond the management of patients with hereditary ovarian cancer. The aim of this review is to evaluate the evidence for BRCA1 dysfunction in SEOC and to link this dysfunction to a defective DNA repair pathway and ultimately the promotion of genomic instability and tumorigenesis. Furthermore, we advocate the continued need to study BRCA1 and its pathway by prospectively correlating clinicopathologic data with molecular aberrations. This will determine whether BRCA1 has relevance as a predictive and prognostic marker in SEOC and whether aberrations in the BRCA1 pathway warrant further study as potential therapeutic targets.
Doxorubicin, Cardiac Risk Factors, and Cardiac Toxicity in Elderly Patients With Diffuse B-Cell Non-Hodgkin's Lymphoma
Authors: Hershman Dawn L. , McBride Russell B. , Eisenberger Andrew , Tsai Wei Yann , Grann Victor R. , Jacobson Judith S.
Published: June 2008

Purpose

Anthracycline-based chemotherapy, which improves survival for patients with non-Hodgkin's lymphoma, is often withheld from elderly patients because of its cardiotoxicity. We studied the cardiac effects of doxorubicin in a population-based sample of older patients with diffuse large B-cell lymphoma (DLBCL).

Patients and Methods

Among patients age ≥ 65 years diagnosed with DLBCL from 1991 to 2002 in the Surveillance, Epidemiology, and End Results–Medicare database, we developed logistic regression models of the associations of doxorubicin with demographic, clinical, and cardiac variables. We then developed Cox proportional hazards models of the association between doxorubicin and subsequent congestive heart failure (CHF), taking predictors of CHF into account.

Results

Of 9,438 patients with DLBCL, 3,164 (42%) received doxorubicin-based chemotherapy. Any doxorubicin use was associated with a 29% increase in risk of CHF (95% CI, 1.02 to 1.62); CHF risk increased with number of doxorubicin claims, increasing age, prior heart disease, comorbidities, diabetes, and hypertension; hypertension intensified the effect of doxorubicin on risk of CHF (hazard ratio = 1.8; P < .01). In the 8 years after diagnosis, the adjusted CHF-free survival rate was 74% in doxorubicin-treated patients versus 79% in patients not treated with doxorubicin.

Conclusion

Among patients receiving chemotherapy for DLBCL, those with prior heart disease were less likely than others to be treated with doxorubicin, and those who received doxorubicin were more likely than others to develop CHF. Various cardiac risk factors increased CHF risk, but only hypertension was synergistic with doxorubicin. Doxorubicin has dramatically improved survival of DLBCL patients; nonetheless, some subgroups may benefit from efforts to reduce doxorubicin-related CHF risk.
Current and Future Utilization of Services From Medical Oncologists
Authors: Warren Joan L. , Mariotto Angela B. , Meekins Angela , Topor Marie , Brown Martin L.
Published: June 2008

Purpose

There is limited information on the current use of oncologists and projections of future need. This analysis assesses current utilization patterns and projects the number of people with cancer and their use of oncologists’ services through 2020.

Methods

Data from the Surveillance, Epidemiology, and End Results cancer registries and Medicare physician claims were used to estimate oncologists’ services from 1998 to 2003. We estimated the portion of patients with cancer who saw an oncologist, the mean number of visits, and the clinical setting where care was provided. Care was divided into initial, continuing, and last-year-of-life phases. Projections for future number of patients with cancer and visits were calculated by applying incidence and prevalence rates derived from Surveillance, Epidemiology, and End Results data to census population projections through 2020.

Results

The percentage of patients who saw an oncologist was 47% during the initial-care phase, 36% during the continuing-care phase, and 70% in the last year of life. The number of visits varied by age, sex, cancer site, and phase. The total number of cancer patients in the United States is projected to increase 55%, from 11.8 million in 2005 to 18.2 million in 2020. Total oncology visits are projected to increase from 38 million in 2005 to 57 million in 2020.

Conclusion

Utilization of oncologists’ services will increase appreciably between 2005 and 2020; this will be driven predominantly by an increase in survivors of cancer and by the aging of the population. The United States may face an acute shortage of medical oncologists if efforts are not taken to meet this growing need.
Nonplatinum Topotecan Combinations Versus Topotecan Alone for Recurrent Ovarian Cancer: Results of a Phase III Study of the North-Eastern German Society of Gynecological Oncology Ovarian Cancer Study Group
Authors: Sehouli Jalid , Stengel Dirk , Oskay-Oezcelik Guelten , Zeimet Alain G. , Sommer Harald , Klare Peter , Stauch Martina , Paulenz Axel , Camara Oumar , Keil Elke , Lichtenegger Werner
Published: June 2008

Purpose

The management of recurrent ovarian cancer remains controversial. Single-agent topotecan is an established treatment option, and preliminary evidence suggests improved tumor control by combining topotecan with etoposide or gemcitabine.

Patients and Methods

Women with relapsed ovarian cancer after primary surgery and platinum-based chemotherapy were randomly assigned to topotecan monotherapy 1.25 mg/m2/d, topotecan 1.0 mg/m2 plus oral etoposide 50 mg/d, or topotecan 0.5 mg/m2/d plus gemcitabine 800 mg/m2 on day 1 and 600 mg/m2 on day 8 every 3 weeks. Patients were stratified for platinum-refractory and platinum-sensitive disease according to a recurrence-free interval of less or more than 12 months, respectively. The primary end point was overall survival. Secondary end points included progression-free survival, objective response rates, toxicity, and quality of life (as measured by the European Organisation for Research and Treatment of Cancer [EORTC] 30-item Quality-of-Life Questionnaire).

Results

The trial enrolled 502 patients with a mean age of 60.5 years (± 10.2 years), 208 of whom were platinum resistant. Median overall survival was 17.2 months (95% CI, 13.5 to 21.9 months) with topotecan, 17.8 months (95% CI, 13.7 to 20.0 months) with topotecan plus etoposide (log-rank P = .7647), and 15.2 months (95% CI, 11.3 to 20.9 months) with topotecan plus gemcitabine (log-rank P = .2344). Platinum-sensitive patients lived significantly longer than platinum-refractory patients (21.9 v 10.6 months). The median progression-free survival was 7.0, 7.8, and 6.3 months, respectively. Objective response rates were 27.8%, 36.1%, and 31.6%, respectively. Patients under combined treatment were at higher risk of severe thrombocytopenia.

Conclusion

Nonplatinum topotecan combinations do not provide a survival advantage over topotecan alone in women with relapsed ovarian cancer.
Heteropoly Acid as Efficient, Cost-effective, and Recyclable Solid Acid for the Rapid Synthesis of Substituted Imidazolines
Authors: Yadav J S , Subba Reddy B V , Pandurangam T , Subba Reddy U V
Published: June 2008

Aziridines undergo smooth ring opening with a range of nitriles in the presence of 10 mol % of phosphomolybdic acid supported on silica gel (PMA–SiO2) under mild reaction conditions to afford the corresponding imidazolines in good yields and with high regioselectivity. The use of silica gel as solid support facilitates an easy recovery and reuse of the catalyst thereby making the process quite simple, more convenient, and cost-effective.
Substitution Effects of Cp Ring Benzyl Groups on Photoisomerization of a Rhodium Dithionite Complex in the Crystalline State
Authors: Miyano Yousuke , Nakai Hidetaka , Mizuno Motohiro , Isobe Kiyoshi
Published: June 2008

Crystalline-state photoisomerization of a rhodium dithionite complex with benzyltetramethylcyclopentadienyl ligand, [(CpBnRh)2(μ-CH2)2(μ-O2SSO2)] (CpBn = η5-C5Me4Bn), is studied by X-ray crystallography and CP/MAS 13C NMR spectroscopy. The disorder of the CpBn ring in the crystal and the crystal packing of the molecules of isomers produced by photoreaction play an important role for stabilization of the whole crystal.
A paediatric case of macro aspartate aminotransferase
Authors: Lord Robert , Fahie-Wilson Michael , Suri Sanjay
Published: June 2008

Macroenzymes are enzymes in plasma that have a higher molecular mass than the corresponding enzyme normally present under (patho) physiological conditions. Macro species have been described for most routinely measured enzymes, but with only a few reports of macro species with aspartate aminotransferase (AST), and in particular very few reports in children and adolescents. Routine biochemical analysis in a 15-year-old girl presenting with lower back pain revealed an isolated raised AST as part of a liver function test profile. Polyethylene glycol precipitation and gel filtration chromatography showed this to be a macro species.
Lipid external quality assessment: commutability between external quality assessment and clinical specimens
Authors: Cramb Robert , French Jane , Mackness Michael , G Neely R Dermot , Caslake Muriel , MacKenzie Finlay
Published: June 2008

Background

Targets for cholesterol reduction are part of the Quality Outcomes Framework and general practitioners have to meet these targets to fulfil their remuneration package. By contrast, there are no targets for the accuracy of cholesterol or other lipid measurements and no recent surveys on performance of these assays. We have assessed the performance of lipid measurement of the available methods in the UK.

Methods

Serum samples collected from individual donors attending the national blood service were distributed after values were obtained from a secondary reference laboratory. Samples were sent to participant laboratories to assess different methods' analytical performance on single donation specimens, on routine external quality assessment pooled specimens, on specimens subjected to a range of freeze–thaw cycles and on frozen-stored specimens.

Results

Differences in measured cholesterol were found that were method-dependent and related to triglyceride content. HDL-cholesterol (HDL-C) showed significant positive bias in all assays. Individual donor specimens showed no significant changes with differing numbers of freeze–thaw cycles. Pooled serum was stable for up to six months.

Conclusions

Most cholesterol measurements are accurate but some methods are affected by triglyceride interference. HDL-C methods show significant positive bias. Although there are potential matrix effects introduced as a result of specimen preparation, additional work is needed to show if these effects are present in fresh patient samples.
C-reactive protein and procalcitonin concentrations in bronchoalveolar lavage fluid as a predictor of ventilator-associated pneumonia
Authors: Linssen Catharina F M , Bekers Otto , Drent Marjolein , Jacobs Jan A
Published: June 2008

Background

Diagnosis of ventilator-associated pneumonia (VAP) is difficult. The usefulness of high-sensitivity procalcitonin (ProCa-S) and high-sensitivity C-reactive protein (CRPH) in bronchoalveolar lavage (BAL) fluid and serum in the prediction of VAP was determined.

Methods

The study was conducted over a 28-month period (November 1999–June 2002) at the University Hospital Maastricht. BAL fluid samples were collected from patients admitted to the intensive care unit. Differential cell count and quantitative culture of BAL fluid were performed. C-reactive protein (CRP) and procalcitonin (PCT) on BAL fluid were determined by means of two high-sensitivity kits (CRPH and ProCa-S, respectively). Since both kits were designed for use on serum, validation for use on BAL fluid was performed.

Results

A total of 117 patients were included. 43.6% (51/117) had microbiologically confirmed VAP. Both CRPH and ProCa-S showed good matrix effect, linearity and intra- and inter-assay variation. No significant differences in PCT and CRP concentrations in serum and BAL fluid were found between the VAP and the non-VAP group.

Conclusions

Both the ProCa-S and the CRPH kits can be used for assessing the concentration of PCT and CRP in BAL fluid, respectively. PCT and CRP concentrations in BAL fluid appeared to be of no additional value in the diagnosis of VAP.
Thyrotoxicosis factitia masquerading as recurrent Graves' disease: endogenous antibody immunoassay interference, a pitfall for the unwary
Authors: Jahagirdar V R , Strouhal P , Holder G , Gama R , Singh B M
Published: June 2008

Antibody interference in immunoassays is an underestimated problem, which has the potential to cause patient harm and waste health-care resources. We report a case where thyroglobulin antibodies generated a false-positive thyroglobulin result delaying the diagnosis of thyrotoxicosis factitia masquerading as recurrent Graves' disease. A high index of clinical suspicion and good laboratory-clinician communication underpins effective clinical and laboratory strategies to detect potentially erroneous laboratory results due to endogenous antibody interference in immunoassays.
Interference with serum indices measurement, but not chemical analysis, on the Roche Modular by Patent Blue V
Authors: Darby Denise , Broomhead Christopher
Published: June 2008

Background

Patent Blue V is an inert dye increasingly being used during cancer surgery to identify the sentinel lymph node. We recently discovered three cases with falsely elevated lipaemic indices on the Roche Modular, following intramammary injection of Patent Blue. This, and other potential interferences by Patent Blue, is examined in this study.

Methods

Serum samples which visually appeared normal, haemolysed or icteric were spiked with Patent Blue to a concentration of 7.3 mg/L and the effect on the lipaemic, haemolysis and icteric indices and routine chemical analyses (sodium, potassium, urea, creatinine, bilirubin, alanine aminotransferase, gamma-glutamyltransferase, aspartate aminotransferase, magnesium, creatine kinase, lactate dehydrogenase, amylase, albumin, calcium and phosphate) undertaken. Dose-response curves in the range of 4.9 mg/L to 22.7 mg/L of Patent Blue were established for normal, icteric and haemolysed pooled serum samples.

Results

Significant positive interference by 7.3 mg/L of Patent Blue was observed in the lipaemic index, with an increase of 149 ± 6.3 (mean ± standard deviation [SD]; P < 0.001). Significant negative interference was observed in both the haemolysis and icteric indices, with decreases of 71 ± 9.7 ( P < 0.001) and 46 ± 8.9 ( P < 0.001), respectively. Patent Blue had a linear dose-response effect on the serum indices. No significant differences were observed in the chemical analyses assessed.

Conclusions

The effects observed on the Roche Modular serum index measurements with Patent Blue raises the novel concept of interference in methods routinely used to detect interference. Despite Patent Blue having no direct effect on chemical analysis, failure to reliably detect potential interference, particularly haemolysis, may lead to misleading results being issued.
Overview of human obesity and central mechanisms regulating energy homeostasis
Authors: Crowley Vivion E F
Published: June 2008

Obesity is now regarded as a global epidemic affecting both adults and children, and is associated with significant morbidity and mortality. Thus the effective management of obesity has become an important clinical focus. Therefore, an understanding of the pathways controlling appetite, satiety and food intake is critical for gaining an insight into the pathogenesis of obesity and also for the development of diagnostic tests and therapeutic agents for use in the clinical management of this condition. Over the last decade or more research using both mouse and human genetic models has elucidated the critical role of the leptin-melanocortin pathway in the hypothalamus, in regulating mammalian energy balance. In tandem with this, a clearer understanding of the regulation of gut-derived hormones and their interaction with the central nervous system has further illuminated the complex interplay between central and peripheral aspects of energy regulation. The obesity epidemic and the expanded knowledge base relating to its aetiopathogenesis have specific implications for clinical biochemistry. In particular, an increase in workload may be expected due to biochemical investigation of obesity and its co-morbidities. Moreover, advice on the in-depth investigation of complex cases of obesity may be sought, including information on newer diagnostic tests, such as serum leptin or molecular genetic analysis. There may also be a substantive role for chemical pathologists in establishing and running clinical obesity services. Finally, clinical biochemistry has a role in research pertaining to obesity and cardiometabolic risk.
Performance of the Advia Centaur second-generation troponin assay TnI-Ultra compared with the first-generation cTnI assay
Authors: Kerkhof Daan van de , Peters Berry , Scharnhorst Volkher
Published: June 2008

Background

A cardiac troponin concentration above the 99th percentile limit of a reference population is a sensitive marker of myocardial necrosis. Current guidelines require troponin assays to have a total imprecision of ≤10% at the 99th percentile limit. In this study, the Advia Centaur second-generation TnI-Ultra assay was validated and compared with its predecessor the cardiac troponin I (cTnI) assay, with a focus on the current guidelines for diagnosis of acute myocardial damage.

Methods

An imprecision profile of the TnI-Ultra assay was evaluated by analysing different pools over 20 days. The imprecision of the cTnI assay was used as comparison. The reference range was established based on TnI-Ultra analysis in 221 individuals.

Results

The cTnI concentration that could be determined with a total imprecision of 10% was 0.05 µg/L for the TnI-Ultra assay and 0.3 µg/L for the cTnI assay. The 99th percentile limit in the distribution of a reference population was 0.06 µg/L as determined with the TnI-Ultra assay.

Conclusions

The TnI-Ultra assay provides significantly improved sensitivity when compared with the cTnI assay and a total imprecision of ≤10% is obtained at the 99th percentile limit of value distribution of a reference population. Using the TnI-Ultra assay, slightly increased cTnI concentration can be detected reliably following the current guidelines.
False-positive polyethylene glycol precipitation tests for macroprolactin due to increased serum globulins
Authors: Ram Sweta , Harris Beverley , Fernando Joseph J R , Gama Rousseau , Fahie-Wilson Michael
Published: June 2008

Background

The polyethylene glycol (PEG) precipitation test is widely used to detect hyperprolactinaemia caused by macroprolactin. We report two cases of hyperprolactinaemia in which a low recovery of serum prolactin (PRL) after PEG precipitation indicated the presence of macroprolactin, but no macroprolactin was detected by gel filtration chromatography (GFC). Both cases had elevated concentrations of serum globulin (IgG myeloma and polyclonal hypergammaglobulinaemia due to human immunodeficiency virus [HIV] infection), which prompted us to investigate further the effect of serum globulin on the specificity of the PEG precipitation procedure.

Methods

The effect of increasing concentrations of gamma globulin on the precipitation of PRL by PEG was studied by adding purified human gamma globulin to serum. Ten samples from HIV-infected patients, which showed a low recovery of PRL after PEG precipitation (<60%) were studied with GFC.

Results

Addition of gamma globulin decreased the recovery of PRL following precipitation with PEG and gamma globulin concentrations correlated inversely with PRL concentrations ( r = 0.9429, P < 0.0167) and percentage recovery of PRL ( r = −1.000, P < 0.005). Only one out of 10 samples from HIV-infected patients with PRL recoveries of <60% following PEG precipitation showed a substantial macroprolactin component on GFC.

Conclusions

Monomeric PRL is co-precipitated with serum globulins by PEG. Increased serum globulin concentrations can increase the amount of monomeric PRL precipitated by PEG giving a false estimate of the monomeric PRL and the erroneous impression that macroprolactin is present. The results of the PEG precipitation test should be interpreted with caution in patients with elevated serum globulin concentrations.
Revised national guidelines for analysis of cerebrospinal fluid for bilirubin in suspected subarachnoid haemorrhage
Authors: Cruickshank Anne , Auld Peter , Beetham Robert , Burrows Gillian , Egner William , Holbrook Ian , Keir Geoff , Lewis Emma , Patel Dina , Watson Ian , White Peter
Published: June 2008

It is crucially important to detect subarachnoid haemorrhage (SAH) in all patients in whom it has occurred to select patients for angiography and preventative surgery. A computerized tomography (CT) scan is positive in up to 98% of patients with SAH presenting within 12 h, but is positive in only 50% of those presenting within one week. Cerebrospinal fluid (CSF) bilirubin spectrophotometry can be used to determine the need for angiography in those few CT-negative patients in whom clinical suspicion of SAH remains high; it may remain positive up to two weeks after the event. A lumbar puncture (LP) should only be performed >12 h after the onset of presenting symptoms. Whenever possible collect sequential specimens. Always ensure that the least blood-stained CSF sample taken (usually the last) is sent for bilirubin analysis. Protect the CSF from light and avoid vacuum tube transport systems, if possible. Always use spectrophotometry in preference to visual inspection. All CSF specimens are precious and should always be analysed unless insufficient sample is received. Centrifuge the specimen at >2000 rpm for 5 min as soon as possible after receipt in the laboratory. Store the supernatant at 4°C in the dark until analysis. An increase in CSF bilirubin is the key finding, which supports the occurrence of SAH but is not specific for this. In most positive cases, bilirubin will occur with oxyhaemoglobin.
An eye on sexually transmitted diseases: sexually transmitted diseases and their ocular manifestations
Authors: Lim L T , Nasoodi A , Al-Ani A , Dinsmore W W
Published: June 2008

Ocular examination should be a part of the routine assessment of the patients seen at sexually transmitted diseases (STD) clinics due to the importance of these organs in the general wellbeing of patients. It is essential to keep an open eye on ocular signs and symptoms of patients with a history of exposure to common STD pathogens, to ensure prompt investigation and management of ocular complications of the STDs, which, if left unnoticed, otherwise could subject the patients to a great deal of anxiety and distress.
Changes in Hepatitis a Virus Seroepidemiology in Hiv-Infected Brazilian Patients
Authors: Aloise R , De Almeida A J , Sion F S , Morais-De-SÁ C A , Gaspar A M C , De Paula V S
Published: June 2008

Shifting of hepatitis A virus (HAV) epidemiology from a high towards an intermediate endemicity pattern and use of antiretroviral therapy increased the risk of HIV/HAV coinfection in developing countries. The aim of this study was to investigate the presence of HAV markers in a cohort of HIV-infected patients from 1988 to 2004. The presence of serum anti-HAV antibodies and HAV-RNA by real-time polymerase chain reaction was investigated in 581 patients. Total anti-HAV antibodies was found in 464/581 (79.8%) patients, however, achanging epidemiologic pattern of hepatitis A among HIV-infected patients from 1988 to 2004 was observed. Among patients susceptible to HAV ( n = 117), 5 (4.2%) were co-infected with HAV, all of them had IgM anti-HAV antibodies and were serum HAV-RNA-positive. The high prevalence of anti-HAV antibodies in HIV-infected patients suggests that screening tests for anti-HAV antibodies should be performed before implementation of hepatitis A vaccination, especially in those patients from endemic countries.
The law concerning teenage sex: do we understand it?
Authors: Dunphy Kilian P
Published: June 2008

Recent child protection reports and changes in sexual offences laws in England and Wales have altered the ethical and legal landscape for health professionals working with sexually active young people. This study aimed to identify the educational needs of a sample of those professionals. A true/false questionnaire was developed comprising statements concerning sexual activity in young people. We sent it to a sample of Family Planning staff, genitourinary (GU) medicine nurses and doctors in 102 Family Planning and 261 GU-medicine clinics throughout England and Wales. A total of 168 completed questionnaires were returned. The range of correct responses for the whole group was between 2 and 10 out of 10, with a median of 6. We identified some misunderstanding concerning the term ‘Fraser’ competence and the legal basis on which contraception can be provided to under 16-year olds, as well as some lack of awareness concerning present advice on child protection. In free text responses, many people volunteered educational needs.
Hiv-1 Incidence among Women of Reproductive Age in Malawi
Authors: Kumwenda N I , Kumwenda J , Kafulafula G , Makanani B , Taulo F , Nkhoma C , Li Q , Taha Taha E
Published: June 2008

The aim of this study was to determine HIV-1 incidence among women of reproductive age in Malawi. A prospective study design was followed. HIV-1 uninfected women were followed up for nine visits during a period of 12 months. At baseline, women received HIV-1 counselling and testing. At each visit, venous blood was collected for HIV-1 testing. Incidence rate for HIV-1 was estimated using person-years of follow up (PYFU). Risk factors for HIV acquisition were assessed using Cox proportional hazard models. A total of 842 HIV-1 negative women were enrolled in the study. Of these, 787 had subsequent HIV testing and 31 were found HIV-1 infected; an overall incidence rate of 4.51 (95% confidence interval: 2.96–6.06) per 100 PYFU was obtained. Young age, using hormonal injectable contraceptives and bacterial vaginosis were the main predictors of HIV acquisition. The incidence of HIV continues to be high among women in Malawi, and young women appear to be at higher risk.