bluuebunny/crossref_metadata_2025 huggingface dataset:
Complete absence of Cockayne syndrome group B gene product gives rise to UV-sensitive syndrome but not Cockayne syndrome
Authors: Horibata Katsuyoshi , Iwamoto Yuka , Kuraoka Isao , Jaspers Nicolaas G. J. , Kurimasa Akihiro , Oshimura Mitsuo , Ichihashi Masamitsu , Tanaka Kiyoji
Published: October 2004

UV-sensitive syndrome (UV
s
S) is a rare autosomal recessive disorder characterized by photosensitivity and mild freckling but without neurological abnormalities or skin tumors. UV
s
S cells show UV hypersensitivity and defective transcription-coupled DNA repair of UV damage. It was suggested that UV
s
S does not belong to any complementation groups of known photosensitive disorders such as xeroderma pigmentosum and Cockayne syndrome (CS). To identify the gene responsible for UV
s
S, we performed a microcell-mediated chromosome transfer based on the functional complementation of UV hypersensitivity. We found that one of the UV
s
S cell lines, UV
s
1KO, acquired UV resistance when human chromosome 10 was transferred. Because the gene responsible for CS group B (CSB), which involves neurological abnormalities and photosensitivity as well as a defect in transcription-coupled DNA repair of UV damage, is located on chromosome 10, we sequenced the CSB gene from UV
s
1KO and detected a homozygous null mutation. Our results indicate that previous complementation analysis of UV
s
1KO was erroneous. This finding was surprising because a null mutation of the CSB gene would be expected to result in CS features such as severe developmental and neurological abnormalities. On the other hand, no mutation in the CSB cDNA and a normal amount of CSB protein was detected in Kps3, a UV
s
S cell line obtained from an unrelated patient, indicating genetic heterogeneity in UV
s
S. Possible explanations for the discrepancy in the genotype-phenotype relationship in UV
s
1KO are presented.
The beginnings of mucin biosynthesis: The crystal structure of UDP-GalNAc:polypeptide α-
N
-acetylgalactosaminyltransferase-T1
Authors: Fritz Timothy A. , Hurley James H. , Trinh Loc-Ba , Shiloach Joseph , Tabak Lawrence A.
Published: October 2004

UDP-GalNAc:polypeptide α-
N
-acetylgalactosaminyltransferases (ppGaNTases) initiate the formation of mucin-type,
O
-linked glycans by catalyzing the transfer of α-
N
-acetylgalactosamine from UDP-GalNAc to Ser or Thr residues of core proteins to form the Tn antigen (GalNAc-α-1-
O
-Ser/Thr). ppGaNTases are unique among glycosyltransferases in containing a C-terminal lectin domain. We present the x-ray crystal structure of a ppGaNTase, murine ppGaNTase-T1, and show that it folds to form distinct catalytic and lectin domains. The association of the two domains forms a large cleft in the surface of the enzyme that contains a Mn
2+
ion complexed by invariant D209 and H211 of the “DXH” motif and by invariant H344. Each of the three potential lectin domain carbohydrate-binding sites (α, β, and γ) is located on the active-site face of the enzyme, suggesting a mechanism by which the transferase may accommodate multiple conformations of glycosylated acceptor substrates. A model of a mucin 1 glycopeptide substrate bound to the enzyme shows that the spatial separation between the lectin α site and a modeled active site UDP-GalNAc is consistent with the
in vitro
pattern of glycosylation observed for this peptide catalyzed by ppGaNTase-T1. The structure also provides a template for the larger ppGaNTase family, and homology models of several ppGaNTase isoforms predict dramatically different surface chemistries consistent with isoform-selective acceptor substrate recognition.
Origin of icosahedral symmetry in viruses
Authors: Zandi Roya , Reguera David , Bruinsma Robijn F. , Gelbart William M. , Rudnick Joseph
Published: October 2004

With few exceptions, the shells (capsids) of sphere-like viruses have the symmetry of an icosahedron and are composed of coat proteins (subunits) assembled in special motifs, the
T
-number structures. Although the synthesis of artificial protein cages is a rapidly developing area of materials science, the design criteria for self-assembled shells that can reproduce the remarkable properties of viral capsids are only beginning to be understood. We present here a minimal model for equilibrium capsid structure, introducing an explicit interaction between protein multimers (capsomers). Using Monte Carlo simulation we show that the model reproduces the main structures of viruses
in vivo
(
T
-number icosahedra) and important nonicosahedral structures (with octahedral and cubic symmetry) observed
in vitro
. Our model can also predict capsid strength and shed light on genome release mechanisms.
Obesity epidemic in India: intrauterine origins?
Authors: Yajnik C. S.
Published: October 2004

The epidemic of ‘obesity’ in India is not appreciated because BMI underestimates the adiposity of Indians. Specific adiposity measurements are necessary for recognition of the adiposity of ‘thin’ Indians. The origin of this adiposity is only beginning to be understood. In addition to a possible genetic predisposition, intrauterine ‘programming’ might be responsible, although in the ‘thrifty phenotype’ hypothesis the adiposity of the ‘thin’ fetus has not been appreciated. Dutch men who faced ‘winter hunger’ during the first trimester of their in utero life have become more obese as adults. Low birth weight predicts central obesity in some studies, including studies in urban children. It has also been shown that small and thin Indian newborns (weight 2·7?kg and ponderal index 2·4?kg\m3) have poor muscle and visceral mass but higher adiposity for a given weight compared with white Caucasian babies. This body composition is influenced by maternal adiposity before pregnancy and by aspects of maternal nutritional intake and circulating nutrient concentrations during pregnancy. There are no strong paternal determinants of adiposity at birth. Adiposity may be an integral part of the orchestrated adjustments made to support ‘brain preservation’ during intrauterine growth, because brain tissue is predominantly fat. Increased nutrition in the face of a genetic predisposition or multigenerational undernutrition increases maternal insulin resistance in late pregnancy and promotes fetal adiposity even in absence of marked hyperglycaemia. Further research is necessary to define the role of specific nutrients and metabolites in the intrauterine processes promoting adiposity before maternal interventions to curtail the epidemic of obesity and diabetes are planned.
How are genes measured? Examples from studies on iron metabolism in pregnancy
Authors: Andersen Henriette S. , McArdle Harry J.
Published: October 2004

As the 21st century moves forward, it is becoming more and more apparent that the genetic makeup of any individual strongly influences the way they metabolise nutrients. It is very important, therefore, to understand the techniques and technologies used to assess the contribution genes make to the physiology of an individual. Clearly, it is not possible to provide a comprehensive overview, but in the present review an attempt will be made to show, using examples from the authors' research, how these methods have contributed to this understanding. Studies are being undertaken into Fe transport across the placenta, from the mother to the fetus, and the consequences of maternal anaemia on pregnancy outcome. Levels of gene transcript and protein have been measured using Northern and Western blotting respectively. During the course of this work a new protein has been identified using the available human genome database. Following this ‘in silico’ or ‘cyber biology’, techniques such as real-time RT–PCR and RNA interference have been used to examine expression of this gene and its protein. The methods used, briefly how they work and some of their limitations will be explained. The objective of the present review is primarily to give a better perception of how molecular biology can be used in research and to help gain a clearer understanding of some of the techniques used.
Endocrine modifications and interventions during critical illness
Authors: Weekers Frank , Berghe Greet Van den
Published: October 2004

The ongoing hypermetabolic response in patients with prolonged critical illness leads to the loss of lean tissue mass. Since the cachexia of prolonged illness is usually associated with low concentrations of anabolic hormones, hormonal intervention has been thought to be beneficial. However, most interventions have been shown to be ineffective and their indiscriminate use even causes harm. Before considering endocrine intervention in these frail patients, a detailed understanding of the neuroendocrinology of the stress response is warranted. It is now clear that the acute phase and the later phase of critical illness behave differently from an endocrinological point of view. The acute stress reponse consists primarily of an actively-secreting pituitary in the presence of low circulating peripheral anabolic hormones, suggesting resistance of the peripheral tissues to the effects of anterior pituitary hormones. However, when the disease process becomes prolonged, there is a uniformly-reduced pulsatile secretion of anterior pituitary hormones with proportionally reduced concentrations of peripheral anabolic hormones. The origin of this suppressed pituitary secretion is located in the hypothalamus, as hypothalamic secretagogues can reactivate the anterior pituitary and restore pulsatile secretion. The reactivated pituitary secretion is accompanied by an increase in peripheral target hormones, indicating at least partial sensitivity of these tissues to anterior pituitary hormones in this chronic phase of illness. Thus, endocrine intervention with a combination of hypothalamic secretagogues that more completely reactivate the anterior pituitary could be a more physiological and effective strategy for inducing anabolism in patients with prolonged critical illness.
Anti-cytokine and anti-inflammatory therapies for the treatment of severe sepsis: progress and pitfalls
Authors: Minnich Douglas J. , Moldawer Lyle L.
Published: October 2004

The medical care of patients with sepsis or severe inflammatory response syndromes has seen tremendous technological advancements in recent years; yet, several clinical studies with anti-cytokine therapies targetted to this population have met with disappointing results. Four primary factors have been identified that represent potential pitfalls involving the use of biological response modifiers in critically-ill patients. First, the physiological response in the stressed patient is complex. Redundancy within this system may not allow a single intervention to produce a clinical response. Second, the critically-ill patient population is heterogenous and important factors including the age of the patient, associated co-morbidities, the nature of the original injury and the presence or absence of an ongoing injury can modulate the effectiveness of a specific therapy. Third, the timing of the therapeutic intervention can be difficult to standardize among patients and can often produce differing results. A greater understanding of the physiological response to injury has shown that there are both proinflammatory and anti-inflammatory processes ongoing simultaneously. Determining the optimal time to intervene within this framework can be problematic. Fourth, the presence of genetic polymorphisms within the general population has identified subsets of individuals who may have different physiological responses to similar stresses. The relative proportions of patients with these polymorphisms within clinical trials may affect outcome and data analysis. Thus, a better understanding of these issues will result in improvement of the experimental design of clinical trials involving anti-cytokine therapies and critically-ill patients. Avoidance of these pitfalls will enhance the quality and utility of outcomes research in this subset of patients.
A predictive model for dormancy loss in Polygonum aviculare L. seeds based on changes in population hydrotime parameters
Authors: Batlla Diego , Benech-Arnold Roberto Luis
Published: October 2004

Changes in population hydrotime parameters were determined during stratification inPolygonum aviculareL. seeds in order to model dormancy loss. Seeds buried in pots were stored at three temperatures (1.6, 7 and 12°C) for 110 d and were exhumed at regular intervals during the storage period. Exhumed seeds were incubated at different water potentials at 15°C and germination time courses were analysed to determine hydrotime parameters. The population mean base water potential (Ψb(50)) decreased concomitantly with seed dormancy, while the hydrotime constant (θH) and the standard deviation of base water potential (θΨb) displayed only minor changes. Based on these results, a model for simulatingP. aviculareseed dormancy loss in relation to low temperature was developed. The model employs Ψb(50) as an index of mean seed population dormancy status. While Ψb(50) was allowed to vary as seeds were released from dormancy, θHand θΨbwere held constant. Changes in Ψb(50) were related to the time and temperature, using a previously developed thermal stratification time index (Stt), which quantifies the accumulation of thermal time units below a threshold temperature required for dormancy loss to occur. Therefore, Ψb(50) varied in relation to the accumulation ofSttaccording to time and temperature. Model performance showed acceptable prediction of timing and percentage of germination of seeds buried in irrigated plots, but did not accurately predict germination of seeds exhumed from rain-fed plots. Thus, environmental factors other than temperature could also be involved in the regulation of dormancy status of buried seeds under field conditions.
Orthogonal versus linear models of acculturation among immigrant Chinese Canadians: A comparison of mothers, fathers, and children
Authors: Costigan Catherine L. , Su Tina F.
Published: October 2004

A multidimensional model of acculturation was examined among 96 immigrant Chinese families living in Canada. All parents were foreign-born, as were 75% of children (average age 12). Each family member completed measures of cultural orientation (behavioural practices), identity, and cultural values. An orthogonal model of acculturation (e.g., host and ethnic culture affiliations are independent rather than linear) was clearly supported for fathers and children. For fathers and foreign-born children, greater involvement in Canadian culture was not associated with a diminishment of ethnic identity or values. For Canadian-born children, this involvement seemed to foster, rather than reduce, the endorsement of ethnic identity and traditional values. For mothers, ethnic and host cultural domains were modestly negatively correlated, providing less support for the orthogonal model. Results are discussed in relation to the conditions that may foster orthogonal versus linear models of acculturation.
Indole-3-Acetic Acid Induces Microencephaly in Rat Fetuses
Authors: Furukawa Satoshi , Abe Masayoshi , Usuda Koji , Ogawa Izumi
Published: October 2004

Indole-3-acetic acid (IAA), known as natural auxin, induces cleft palate in rodents. However, there has been no report about the neurodevelopmental toxicity of IAA in rats. In the present study, we found microencephaly in the fetuses from the rats exposed to IAA. The purpose of this work was to examine the effects of IAA administration in pregnant rats on neuroepithelial cells in the embryos/fetuses. IAA was administered at 500 and 1,000 mg/kg on gestation days (days) 12, 13, and 14, and then embryos/fetuses were harvested on days 14.5, 15, 16, and 21. Cleft palate was induced at 1,000 mg/kg. The brain in treated groups exhibited reduction in the size and weight on day 21 in a dose-dependent manner. Histopathologically, apoptotic cells were observed mainly in the medial and dorsal layer of the neuroepithelium at 500 and 1,000 mg/kg on day 14.5. On day 15, they were observed in the medial and dorsal layer of the neuroepithelium, and preplate at 1,000 mg/kg. On day 16, they existed in the dorsal layer of the neuroepithelium and intermediate zone in the embryos from 1 dam at 1,000 mg/kg. On day 21, an increase in cell proliferative activity was observed in the neuroepithelium at 500 and 1,000 mg/kg. The reduction of the cortical plate, the enlargement of the neuroepithelium and a slight increase in neuron density in the intermediate zone were observed at 1,000 mg/kg. These findings indicated IAA might induce the neuronal apoptosis in the S phase and lead to microencephaly.
Modeling Compromise at the International Table
Authors: Butler Christopher K.
Published: October 2004

A number of people have modeled Putnam's (1988) analogy of the two-level game to better understand the interaction between domestic and international politics. Milner and Rosendorff's model (1997) has taken on particular significance in this area of research. By applying a Nash bargaining solution to a standard spatial model, they were able to make specific predictions of bargaining behavior with and without domestic constraints. In this paper, I argue that some compromise should be expected in the bargaining, compromise that the Nash bargaining solution does not allow when paired with a linear utility assumption. I present a number of theoretical alternatives for which some degree of compromise is predicted. General solutions are derived given the unidimensional spatial model for the Nash (1950), the Kalai—Smorodinsky (1975), and the Felsenthal—Diskin (1982) bargaining solutions with linear and with quadratic equations. Given the unidimensional spatial context, more compromise is proposed under a given bargaining solution when using quadratic utilities rather than linear utilities. The most compromise is proposed by the Felsenthal—Diskin bargaining solution, followed by the Kalai—Smorodinsky, and then the Nash bargaining solutions.
Bargaining, War, and Alliances
Authors: Harrison Wagner R.
Published: October 2004

As a way of clarifying and evaluating competing claims made by writers on alliances and the balance of power, I extend recent work on the relation between bargaining and war to a three-state setting where coalitions are possible. I show that if what is commonly called “balancing” occurs at all, it is because it is seen as a way of reducing the risk associated with possible exogenous changes in the distribution of military capabilities. It is therefore not necessarily inconsistent with what is called “bandwagoning,” but can actually make bandwagoning more likely. Moreover, balancing need not occur for international systems to be stable.
The Not‐So‐Simple Process of Sickle Cell Vasoocclusion
Authors: EMBURY STEPHEN H.
Published: October 2004

Traditional concepts of sickle cell disease as a monogenically inherited disorder that is understood completely on the basis of polymerization based pathophysiology are more simple that what clinical observations allow. Detailed explications of the determinants of polymerization can be counted, but these do not account for all aspects of sickle cell disease. Neither can all perturbations that count in the course of sickle cell disease be counted as determinants of polymerization. The polymerization based theory that has been extrapolated to describe clinical disease often is not identical to clinical reality. Although contemporary understandings of sickle cell pathophysiology have been described as crazy by those bound to traditional polymerization based understandings, increasingly iconoclastic, seemingly crazy notions are regularly providing important new understandings of sickle cell disease. One of the major challenges to contemporary investigators is to describe new scientific insights in a way that can be understood by others, particularly those reluctant to afford polymerization independent discoveries validity among the interdependent processes that account for sickle cell disease.
Polymerization and Sickle Cell Disease: A Molecular View
Authors: FERRONE FRANK A.
Published: October 2004

The present molecular‐level understanding of polymerization and sickling is reviewed for 2 central questions in sickle hemoglobin pathophysiology, viz., what determines when cells sickle, and what determines when cells get stuck. The description of sickling includes the central aspects of the double nucleation mechanism, as well as recent results on the effects of crowding, with an emphasis on the physiological applicability of this fundamental knowledge. In considering when cells get stuck, new measurements of individual fiber stiffness and the processes of depolymerization are also considered. Finally, a fundamental connection is shown between thermodynamics and rheology.
The Endothelial Biology of Sickle Cell Disease: Inflammation and a Chronic Vasculopathy
Authors: HEBBEL ROBERT P. , OSAROGIAGBON RAYMOND , KAUL DHANANJAY
Published: October 2004

A single amino acid substitution in hemoglobin comprises the molecular basis for sickle cell anemia, but evolution of the corresponding clinical disease is extraordinarily complicated and likely involves multiple pathogenic factors. Sickle disease is fundamentally an inflammatory state, with activation of the endothelium, probably through proximate effects of reperfusion injury physiology and chronic molestation by adherent red cells and white cells. The disease also involves enhanced angiogenic propensity, activation of coagulation, disordered vasoregulation, and a component of chronic vasculopathy. Sickle cell anemia is truly an endothelial disease, and it is likely that genetic differences in endothelial function help govern its astonishing phenotypic diversity.
In Vivo Studies of Sickle Red Blood Cells
Authors: KAUL DHANANJAY K. , FABRY MARY E.
Published: October 2004

The defining clinical feature of sickle cell anemia is periodic occurrence of painful vasoocclusive crisis. Factors that promote trapping and sickling of red cells in the microcirculation are likely to trigger vasoocclusion. The marked red cell heterogeneity in sickle blood and abnormal adhesion of sickle red cells to vascular endothelium would be major disruptive influences. Using ex vivo and in vivo models, the authors show how to dissect the relative contribution of heterogeneous sickle red cell classes to adhesive and obstructive events. These studies revealed that (1) both rheological abnormalities and adhesion of sickle red cells contribute to their abnormal hemodynamic behavior, (2) venules are the sites of sickle cell adhesion, and (3) sickle red cell deformability plays an important role in adhesive and obstructive events. Preferential adhesion of deformable sickle red cells in postcapillary venules followed by selective trapping of dense sickle red cells could result in vasoocclusion. An updated version of this 2‐step model is presented. The multifactorial nature of sickle red cell adhesion needs to be considered in designing antiadhesive therapy in vivo.
Pathophysiology of Stroke in Sickle Cell Disease
Authors: HILLERY CHERYL A. , PANEPINTO JULIE A.
Published: October 2004

Stroke affects both motor and cognitive function in patients with sickle cell disease (SCD). Symptomatic stroke is associated with intimal disease of the large cerebral arteries. Silent stroke, defined as cerebral infarction in the absence of overt clinical neurologic symptoms, is often due to microinfarcts suggestive of microvascular disease. While the natural history of stroke in SCD is well described, the pathophysiology remains poorly understood and probably varies with the site of vascular injury. Increased red cell adhesion, oxidative injury of the vessel wall, inflammation, abnormal vasomotor tone regulation, and increased activity of the coagulation system all may contribute to cerebral vasopathology in SCD.
Sickle Red Cell Microrheology and Sickle Blood Rheology
Authors: BALLAS SAMIR K. , MOHANDAS NARLA
Published: October 2004

The hallmark of the phenotypic expression of sickle cell disease is the remarkable degree of heterogeneity in the clinical manifestations. They vary latitudinally among patients and longitudinally in the same patient. The pathogenesis of sickle cell anemia centers on the sequence of events that occur between polymerization of deoxy hemoglobin S and increased red cell destruction, vasoocclusion, and end organ damage. Cellular dehydration, changes in sickle red blood cell rheology, adhesion of sickle red cells to vascular endothelium, inflammatory response, and tissue injury are some of the factors that contribute to hemolytic anemia, vasoocclusion, and eventual multiorgan damage. The focus of this review is on the rheology of sickle blood and microrheology of sickle RBC. Determinants of sickle RBC rheology and the factors that modulate its severity are discussed.
DictyosteliumPAKc Is Required for Proper Chemotaxis
Authors: Lee Susan , Rivero Francisco , Park Kyung Chan , Huang Emerald , Funamoto Satoru , Firtel Richard A.
Published: October 2004

We have identified a new Dictyostelium p21-activated protein kinase, PAKc, that we demonstrate to be required for proper chemotaxis. PAKc contains a Rac-GTPase binding (CRIB) and autoinhibitory domain, a PAK-related kinase domain, an N-terminal phosphatidylinositol binding domain, and a C-terminal extension related to the Gβγ binding domain of Saccharomyces cerevisiae Ste20, the latter two domains being required for PAKc transient localization to the plasma membrane. In response to chemoattractant stimulation, PAKc kinase activity is rapidly and transiently activated, with activity levels peaking at ∼10 s. pakc null cells exhibit a loss of polarity and produce multiple lateral pseudopodia when placed in a chemoattractant gradient. PAKc preferentially binds the Dictyostelium Rac protein RacB, and point mutations in the conserved CRIB that abrogate this binding result in misregulated kinase activation and chemotaxis defects. We also demonstrate that a null mutation lacking the PAK family member myosin I heavy chain kinase (MIHCK) shows mild chemotaxis defects, including the formation of lateral pseudopodia. A null strain lacking both PAKc and the PAK family member MIHCK exhibits severe loss of cell movement, suggesting that PAKc and MIHCK may cooperate to regulate a common chemotaxis pathway.
Coregulation of Fibronectin Signaling and Matrix Contraction by Tenascin-C and Syndecan-4
Authors: Midwood Kim S. , Valenick Leyla V. , Hsia Henry C. , Schwarzbauer Jean E.
Published: October 2004

Syndecan-4 is a ubiquitously expressed heparan sulfate proteoglycan that modulates cell interactions with the extracellular matrix. It is transiently up-regulated during tissue repair by cells that mediate wound healing. Here, we report that syndecan-4 is essential for optimal fibroblast response to the three-dimensional fibrin-fibronectin provisional matrix that is deposited upon tissue injury. Interference with syndecan-4 function inhibits matrix contraction by preventing cell spreading, actin stress fiber formation, and activation of focal adhesion kinase and RhoA mediated-intracellular signaling pathways. Tenascin-C is an extracellular matrix protein that regulates cell response to fibronectin within the provisional matrix. Syndecan-4 is also required for tenascin-C action. Inhibition of syndecan-4 function suppresses tenascin-C activity and overexpression of syndecan-4 circumvents the effects of tenascin-C. In this way, tenascin-C and syndecan-4 work together to control fibroblast morphology and signaling and regulate events such as matrix contraction that are essential for efficient tissue repair.
Reconstructing biological networks using conditional correlation analysis
Authors: Rice John Jeremy , Tu Yuhai , Stolovitzky Gustavo
Published: October 2004

Motivation: One of the present challenges in biological research is the organization of the data originating from high-throughput technologies. One way in which this information can be organized is in the form of networks of influences, physical or statistical, between cellular components. We propose an experimental method for probing biological networks, analyzing the resulting data and reconstructing the network architecture.

Methods: We use networks of known topology consisting of nodes (genes), directed edges (gene–gene interactions) and a dynamics for the genes' mRNA concentrations in terms of the gene–gene interactions. We proposed a network reconstruction algorithm based on the conditional correlation of the mRNA equilibrium concentration between two genes given that one of them was knocked down. Using simulated gene expression data on networks of known connectivity, we investigated how the reconstruction error is affected by noise, network topology, size, sparseness and dynamic parameters.

Results: Errors arise from correlation between nodes connected through intermediate nodes (false positives) and when the correlation between two directly connected nodes is obscured by noise, non-linearity or multiple inputs to the target node (false negatives). Two critical components of the method are as follows: (1) the choice of an optimal correlation threshold for predicting connections and (2) the reduction of errors arising from indirect connections (for which a novel algorithm is proposed). With these improvements, we can reconstruct networks with the topology of the transcriptional regulatory network in Escherichia coli with a reasonably low error rate.

Contact:  gustavo@us.ibm.com

Supplementary information: Available from our website: www.research.ibm.com/FunGen
Respiratory and cardiovascular function at rest and during exercise testing in a
healthy working population: effects of outdoor traffic air pollution
Authors: Volpino P. , Tomei F. , La Valle C. , Tomao E. , Rosati M. V. , Ciarrocca M. , De Sio S. , Cangemi B. , Vigliarolo R. , Fedele F.
Published: October 2004

Background

There is controversy regarding long-term adverse effects of urban pollutants in urban workers.

Aim

The aim of this study was to evaluate the effects of urban pollutants on respiratory and cardiovascular function in exposed traffic policemen compared to a control group.

Methods

Sixty-eight traffic policemen and 62 controls (all male) were investigated at rest and during symptom-limited incremental exercise test (performed with a cycle ergometer). The data were statistically evaluated.

Results

There were no significant differences in the mean values of resting ventilatory capacity, the forced spirometric test, or in blood gas parameters between the groups. The traffic exposed group demonstrated a number of significant changes in cardiorespiratory measures on exercise testing. Twenty-six traffic policemen and none of the controls experienced exercise-induced ECG abnormalities, hypertension or oxyhaemoglobin desaturation; 80% of the 26 had resting PaO2 values <80 mmHg.

Conclusion

The findings suggest that chronic occupational exposure to urban pollutants reduces resistance to physical effort and increases the risk of cardiovascular and respiratory changes including slight hypoxemia.
The Search for Genes Contributing to the Low Level of Response to Alcohol: Patterns of Findings Across Studies
Authors: Schuckit Marc A. , Smith Tom L. , Kalmijn Jelger
Published: October 2004

Background: Alcoholism is a complex genetically influenced disorder in which multiple phenotypes [e.g., disinhibition, alcohol‐metabolizing patterns, and the low level of response (LR) to alcohol] contribute to the risk. A low LR to alcohol is one of the more thoroughly studied risk phenotypes; data indicate that LR relates to the risk status, predicts future alcoholism, and has a heritability as high as 60%. This article reviews data from animal and human studies regarding the LR to alcohol, searching for a convergence of results that might lead to the identification of relevant genes.

Methods: A literature search was performed regarding animal and human genetic studies focusing on genes that might affect the LR to alcohol as a risk factor for alcoholism. The goal was to synthesize these results and highlight potential patterns.

Results: Focusing on both genetic linkage and association studies, a number of chromosomal regions and genes potentially relevant to findings across two or more sources were identified. The genes of potential interest fell into several categories, including second‐messenger systems (e.g., G proteins, adenylyl cyclase, and protein kinases); neurotransmitters or drug‐related receptors (e.g., γ‐aminobutyric acid‐A, glutamate, serotonin, and cannabinoid and opioid receptors); genes that affect alcohol metabolism; and genes that might relate to an overlap in the risk for alcoholism and some psychiatric conditions (e.g., catechol‐O‐methyltransferase regarding schizophrenia and bipolar disorder).

Conclusions: The review identifies several genes that may contribute to a low LR to alcohol and, thus, to an increased risk for alcohol use disorders. The chromosomal regions and genes highlighted here may form the basis for more focused genetic studies of alcohol use disorders, with the goals of developing more specific and effective prevention and treatment approaches.
National and State Estimates of the Mean Ethanol Content of Beer Sold in the US and Their Impact on Per Capita Consumption Estimates: 1988 to 2001
Authors: Kerr William C. , Brown Stephan , Greenfield Thomas K.
Published: October 2004

Background: The average ethanol content of the beer sold in the US is a key factor in determining the per capita consumption of ethanol, the standard measure of alcohol use in aggregate‐level research. To address the lack of empirically based estimates of beer ethanol content, we have calculated national estimates for the years 1988 to 2001 and state‐specific estimates for 1993 to 2001.

Methods: These estimates are based on the ethanol content by volume of leading brands in each year, the national market share of each leading brand by type, and state‐specific market shares of each beer type.

Results: The national mean ethanol content of beer was higher than the 4.5% figure typically used, ranging from 4.58% in 1993 to 4.75% in 1996. State‐specific mean ethanol content estimates were also found to vary by state and over time. Application of mean ethanol content estimates to the per capita consumption of beer led to higher consumption estimates than those with the 4.5% conversion. For example, in 2000, the national estimate indicates that nearly 10 more drinks (containing 0.6 oz of ethanol) were consumed per person aged 14 years and older during that year.

Conclusions: This may indicate that a larger than previously estimated share of the alcohol consumed in the US is in the form of beer. However, the results also indicate that empirically based estimates of wine and spirits mean that ethanol content may modify their consumption estimates as well.
Inward Rectifier Potassium Channels in the Basilar Artery During Chronic Alcohol Consumption
Authors: Sun Hong , Fang Qin , Mayhan William G.
Published: October 2004

Background: The goals of this study were to determine whether chronic alcohol consumption alters potassium channel–mediated reactivity in the basilar artery and to determine a potential mechanism that might account for the effects of alcohol on the basilar artery.

Methods: Sprague‐Dawley rats were fed liquid diets with or without alcohol for 2 to 3 months. We measured diameter of the basilar artery in response to potassium channel inhibitors and activators. Protein level of inward rectifier potassium channel subunit Kir2.1 in the basilar artery was determined by Western blot.

Results: Topical application of glibenclamide (1 and 10 μM) significantly constricted the basilar artery at high dose; iberiotoxin (10 and 100 nM), 4‐AP (0.1 and 1 mM), and BaCl2 (1 and 10 μM) produced dose‐related constriction in both non–alcohol‐fed and alcohol‐fed rats. However, the magnitude of constriction in response to BaCl2 was significantly less in alcohol‐fed rats compared with non–alcohol‐fed rats. Topical application of KCl (1 and 3 mM), cromakalim (0.1 and 0.3 μM), and NS1619 (10 and 30 μM) induced dose‐related dilation in non–alcohol‐fed and alcohol‐fed rats. However, the magnitude of vasodilation in response to KCl was significantly less in alcohol‐fed rats compared with non–alcohol‐fed rats. In addition, Kir2.1 protein level in the basilar artery was significantly reduced in alcohol‐fed compared with non–alcohol‐fed rats.

Conclusions: These findings suggest that chronic alcohol consumption reduces expression of inward rectifier potassium channels and inhibits KIR channel–mediated dilation in the basilar artery.
Predictors of High Ethanol Consumption in RIIβ Knock‐Out Mice: Assessment of Anxiety and Ethanol‐Induced Sedation
Authors: Fee Jon R. , Sparta Dennis R. , Knapp Darin J. , Breese George R. , Picker Mitchell J. , Thiele Todd E.
Published: October 2004

Background: Genetic and pharmacological evidence suggests that the cyclic adenosine monophosphate–dependent protein kinase A pathway modulates neurobiological responses to ethanol. Mutant mice lacking the RIIβ subunit of protein kinase A (RIIβ−/−) are resistant to ethanol‐induced sedation and drink significantly more ethanol than littermate wild‐type mice (RIIβ+/+). We determined whether high ethanol intake by the RIIβ−/− mice on alternate genetic backgrounds is reliably predicted by high basal levels of anxiety or resistance to the sedative effects of ethanol.

Methods: Two‐bottle choice procedures and a battery of behavioral tests (elevated plus maze, open‐field activity, and zero maze) were used to assess voluntary ethanol consumption and basal levels of anxiety in RIIβ−/− and RIIβ+/+ mice on either a C57BL/6J or a 129/SvEv × C57BL/6J genetic background. Additionally, ethanol‐induced sedation and blood ethanol levels were determined in RIIβ−/− and RIIβ+/+ mice after intraperitoneal injection of ethanol (3.8 g/kg).

Results: RIIβ−/− mice on both genetic backgrounds consumed more ethanol and had a greater preference for ethanol relative to RIIβ+/+ mice. However, RIIβ−/− mice showed reduced basal levels of anxiety when maintained on the C57BL/6J background but showed increased anxiety when maintained on the 129/SvEv × C57BL/6J background. Consistent with prior research, RIIβ−/− mice were resistant to the sedative effects of ethanol, regardless of the genetic background. Finally, RIIβ−/− and RIIβ+/+ mice showed similar blood ethanol levels.

Conclusions: These results indicate that high ethanol consumption is associated with resistance to the sedative effects of ethanol but that basal levels of anxiety, as well as ethanol metabolism, do not reliably predict high ethanol drinking by RIIβ−/− mice.
Blood Oxygen Level Dependent Response and Spatial Working Memory in Adolescents With Alcohol Use Disorders
Authors: Tapert Susan F. , Schweinsburg Alecia D. , Barlett Valerie C. , Brown Sandra A. , Frank Lawrence R. , Brown Gregory G. , Meloy M J.
Published: October 2004

Background: Previous studies have suggested neural disruption and reorganization in young and older adults with alcohol use disorders (AUD). However, it remains unclear at what age and when in the progression of AUD changes in brain functioning might occur.

Methods: Alcohol use disordered (n= 15) and nonabusing (n= 19) boys and girls aged 15 to 17 were recruited from local high schools. Functional magnetic resonance imaging data were collected after a minimum of 5 days’ abstinence as participants performed spatial working memory and simple motor tasks.

Results: Adolescents with AUD showed greater brain response to the spatial working memory task in bilateral parietal cortices and diminished response in other regions, including the left precentral gyrus and bilateral cerebellar areas (clusters ≥943 μl; p < 0.05), although groups did not differ on behavioral measures of task performance. No brain response differences were observed during a simple finger‐tapping task. The degree of abnormality was greater for teens who reported experiencing more withdrawal or hangover symptoms and who consumed more alcohol.

Conclusions: Adolescents with AUD show abnormalities in brain response to a spatial working memory task, despite adequate performance, suggesting that subtle neuronal reorganization may occur early in the course of AUD.
Rapid and Chronic: Two Distinct Forms of Ethanol Tolerance in Drosophila
Authors: Berger Karen H. , Heberlein Ulrike , Moore Monica S.
Published: October 2004

Background: Ethanol tolerance, defined as a reduction in the intensity of the effects of ethanol upon continuous or repeated exposure, is a hallmark of alcoholism. Tolerance may develop at the cellular or neural systems levels. The molecular changes underlying ethanol tolerance are not well understood. We therefore explored the utility of Drosophila, with its accessibility to genetic, molecular, and behavioral analyses, as a model organism to study tolerance development in response to different ethanol‐exposure regimens.

Methods: We describe a new assay that quantifies recovery from ethanol intoxication in Drosophila. Using this recovery assay, we define ethanol pre‐exposure paradigms that lead to the development of tolerance. We also use the inebriometer, an assay that measures the onset of intoxication, to study the effects of pharmacological and genetic manipulations on tolerance development.

Results: We show that flies develop different forms of ethanol tolerance: rapid tolerance, induced by a single short exposure to a high concentration of ethanol, and chronic tolerance, elicited by prolonged exposure to a low concentration of the drug. Neither rapid nor chronic tolerance involves changes in ethanol pharmacokinetics, implying that they represent functional rather than dispositional tolerance. Chronic and rapid tolerance can be distinguished mechanistically: chronic tolerance is disrupted by treatment with the protein synthesis inhibitor cycloheximide, whereas rapid tolerance is resistant to this treatment. Furthermore, rapid and chronic tolerance rely on distinct genetic pathways: a mutant defective for octopamine biosynthesis shows reduced rapid tolerance but normal chronic tolerance.

Conclusions: Flies, like mammals, develop tolerance in response to different ethanol‐exposure regimens, and this tolerance affects both the onset of and the recovery from acute intoxication. Two forms of tolerance, rapid and chronic, are mechanistically distinct, because they can be dissociated genetically and pharmacologically.
Genetic and Environmental Effects on Conduct Disorder and Alcohol Dependence Symptoms and Their Covariation at Age 14
Authors: Rose Richard J. , Dick Danielle M. , Viken Richard J. , Pulkkinen Lea , Kaprio Jaakko
Published: October 2004

Background: Alcohol misuse and conduct disorder (CD) are strongly associated in adolescents. Is their association due to shared genetic and environmental liabilities? We addressed that question with data obtained from structured interviews of 14‐year‐old Finnish twins.

Methods: A total of 1854 twins completed face‐to‐face interviews. Univariate models, allowing for sex limitation, were fit to symptom counts for Diagnostic and Statistical Manual of Mental Disorders, Third Edition, Revised diagnoses of CD and alcoholism to examine their genetic and environmental influences. Then, bivariate models evaluated the extent to which genetic and environmental influences contributed to the covariation between symptom counts for the two disorders.

Results: A total of 822 twins (44% of the sample) reported one or more symptoms of CD; alcohol dependence symptoms were much less common, reported by only 12%. The correlation between the two symptom counts was 0.50. Models fit to the twin data demonstrated that CD symptoms were under significant genetic influence in both boys and girls, although those influences were predominantly sex specific. In contrast, alcohol dependence symptoms were, at this age, under sex‐specific effects of common environments, with no evidence of genetic influences. Accordingly, the substantial covariation between alcohol dependence symptoms and those of CD was attributed entirely to shared environmental effects.

Conclusions: At age 14, genetic influences on alcohol dependence symptoms are negligible, and the correlated liabilities between these symptoms and those of CD are to be found in environmental factors that are common to both.
The University of California, San Francisco Family Alcoholism Study. I. Design, Methods, and Demographics
Authors: Vieten Cassandra , Seaton Kimberly L. , Feiler Heidid S. , Wilhelmsen Kirk C.
Published: October 2004

Background: The University of California, San Francisco (UCSF) Family Alcoholism Study is a project designed to identify genetic loci that influence susceptibility to alcohol dependence and related phenotypes. Evidence supports a substantial genetic contribution to alcoholism susceptibility. However, the genetic epidemiology of alcoholism is complex, and its clinical manifestation is heterogeneous, making phenotype definition and demonstration of linkage difficult. Despite these challenges, some progress has been made toward identifying genes.

Methods: The UCSF Family Alcoholism Study used a small family design, focusing primarily on sibling pairs and parent‐child trios for linkage and association studies. Alcoholism‐related phenotypes were assessed through interview and self‐report questionnaires, with a focus on unidimensional and subphenotypical traits. Data‐driven approaches to determining the most promising phenotypes for genetic analysis are being used. Both genome‐wide scan and candidate gene approaches were used.

Results: The study enrolled 2154 individuals from 970 families from December 1995 through January 2003. Test‐retest and interrater reliability for clinical data are very good, and power estimates suggest that this study will have adequate power by linkage analysis to detect loci with moderate effects. Design, methods, and sample demographics of the UCSF Family Study are presented, along with intrafamilial correlations for primary diagnostic phenotypes.

Conclusions: Plans for genetic analysis, novel approaches to phenotype refinement, and the implications of ascertainment bias for heritability estimates are discussed.
Intermittent Ethanol Exposure in Adolescent Rats: Dose‐Dependent Impairments in Trace Conditioning
Authors: Yttri Eric A. , Burk Joshua A. , Hunt Pamela S.
Published: October 2004

Background: Recent studies have revealed that the adolescent brain may be especially vulnerable to ethanol‐induced toxicity. Corticolimbic regions are more severely damaged following ethanol exposure during adolescence than during adulthood. The consequences of adolescent ethanol exposure on cognition however, have only recently begun to be explored.

Methods: Male and female rats were administered 0, 1.5, 2.5 or 4.5 g/kg ethanol (20% v/v) by acute intragastric gavage during adolescence (postnatal days [PD] 28, 30, 32 and 34). On PD 40, half of the subjects in each dose group were given 5 pairings of a 10‐sec flashing light (CS; conditioned stimulus) immediately followed by mild footshock (US; unconditioned stimulus), a procedure known as delay conditioning. The other half were also given 5 CS‐US pairings, but the US was presented 10 sec after CS offset, a procedure known as trace conditioning. All subjects were tested for CS‐elicited freezing 24 h later.

Results: There was no effect of adolescent ethanol exposure on delay conditioned responding, with all subjects demonstrating comparable levels of CS‐elicited freezing. In contrast, the amount of freezing in the trace conditioned subjects was negatively correlated with prior ethanol dose. Specifically, exposure to 2.5 or 4.5 g/kg during adolescence resulted in a deficit in trace conditioned responding.

Conclusions: These data indicate that intermittent exposure to ethanol during adolescence results in impairment in hippocampal‐dependent trace conditioning that persists beyond the period of ethanol exposure. Delay conditioning was unaffected by prior ethanol treatment, indicating that there was no difficulty in detecting the CS or US, or in the ability to engage in freezing behavior. These results suggest that the adolescent brain may be particularly vulnerable to the effects of repeated exposure to ethanol that can have consequences for nonspatial, hippocampal‐dependent cognitive abilities.