bluuebunny/crossref_metadata_2025 huggingface dataset:
Transcriptional Regulation of the
Staphylococcus aureus
Thioredoxin and Thioredoxin Reductase Genes in Response to Oxygen and Disulfide Stress
Authors: Uziel Orit , Borovok Ilya , Schreiber Rachel , Cohen Gerald , Aharonowitz Yair
Published: December 2003

In this report we describe the cloning, organization, and promoter analysis of the
Staphylococcus aureus
thioredoxin (
trxA
) and thioredoxin reductase (
trxB
) genes and their transcription in response to changes in oxygen concentration and to oxidative stress compounds. Northern analysis showed that the
S. aureus trxA
and
trxB
genes were transcribed equally well in aerobic and anaerobic conditions. Several oxidative stress compounds were found to rapidly induce transcription of the
trxA
and
trxB
genes. The most pronounced effects were seen with diamide, a thiol-specific oxidant that promotes disulfide bond formation; menadione, a redox cycling agent; and τ-butyl hydroperoxide, an organic peroxide. In each case the induction was independent of the general stress sigma factor σ
B
. These studies show that the
S. aureus trxA
and
trxB
genes are upregulated following exposure to these oxidative stress agents, resulting in increased disulfide bond formation. In contrast, no effect of hydrogen peroxide on induction of the
trxA
and
trxB
genes was seen. We also show that the
S. aureus
thioredoxin reductase appears to be essential for growth. This observation, coupled with structural differences between the bacterial and mammalian thioredoxin reductases, suggests that it may serve as a target for the development of new antimicrobials.
Identification of the LIV-I/LS System as the Third Phenylalanine Transporter in
Escherichia coli
K-12
Authors: Koyanagi Takashi , Katayama Takane , Suzuki Hideyuki , Kumagai Hidehiko
Published: December 2003

In
Escherichia coli
, the active transport of phenylalanine is considered to be performed by two different systems, AroP and PheP. However, a low level of accumulation of phenylalanine was observed in an aromatic amino acid transporter-deficient
E. coli
strain (Δ
aroP
Δ
pheP
Δ
mtr
Δ
tna
Δ
tyrP
). The uptake of phenylalanine by this strain was significantly inhibited in the presence of branched-chain amino acids. Genetic analysis and transport studies revealed that the LIV-I/LS system, which is a branched-chain amino acid transporter consisting of two periplasmic binding proteins, the LIV-binding protein (LIV-I system) and LS-binding protein (LS system), and membrane components, LivHMGF, is involved in phenylalanine accumulation in
E. coli
cells. The

K
m

values for phenylalanine in the LIV-I and LS systems were determined to be 19 and 30 μM, respectively. Competitive inhibition of phenylalanine uptake by isoleucine, leucine, and valine was observed for the LIV-I system and, surprisingly, also for the LS system, which has been assumed to be leucine specific on the basis of the results of binding studies with the purified LS-binding protein. We found that the LS system is capable of transporting isoleucine and valine with affinity comparable to that for leucine and that the LIV-I system is able to transport tyrosine with affinity lower than that seen with other substrates. The physiological importance of the LIV-I/LS system for phenylalanine accumulation was revealed in the growth of phenylalanine-auxotrophic
E. coli
strains under various conditions.
Participation of
fad
and
mbt
Genes in Synthesis of Mycobactin in
Mycobacterium smegmatis
Authors: LaMarca B. Babbette D. , Zhu Wenming , Arceneaux Jean E. L. , Byers B. Rowe , Lundrigan Michael D.
Published: December 2003

Colonies of
Mycobacterium smegmatis
LR222 on iron-limiting (0.1 μM Fe) minimal medium agar fluoresce under UV light due to the accumulation in the cells of the deferri form of the siderophore mycobactin. Two mutants with little or no fluorescence, designated LUN8 and LUN9, were isolated by screening colonies of transposon (Tn
611
)-mutagenized
M. smegmatis
. Ferrimycobactin prepared from iron-restricted cells of the wild type had an
R

f

of 0.62 on high-performance thin-layer chromatography (HPTLC) and a characteristic visible absorption spectrum with a peak near 450 nm. Similar extracts from LUN8 cells contained a small amount of ferrimycobactin with an
R

f

of 0.58 on HPTLC and an absorption spectrum with the peak shifted to a wavelength lower than that of the wild-type ferrimycobactin. Nuclear magnetic resonance spectroscopy studies suggested that the LUN8 mycobactin may have an altered fatty acid side chain. Mutant strain LUN9 produced no detectable mycobactin. Neither mutant strain produced measurable amounts of excreted mycobactin, although both excreted exochelin (the mycobacterial peptido-hydroxamate siderophore), and both mutants were more sensitive than the wild-type strain to growth inhibition by the iron chelator ethylenediamine-di(
o
-hydroxyphenylacetic acid). The transposon insertion sites were identified, and sequence analyses of the cloned flanking chromosome regions showed that the mutated gene in LUN9 was an orthologue of the
Mycobacterium tuberculosis
mycobactin biosynthetic gene
mbtE
. The mutated gene in LUN8 had homology with
M. tuberculosis fadD33
(
Rv1345
), a gene that may encode an acyl-coenzyme A synthase and which previously was not known to participate in synthesis of mycobactin.
Structural and Genetic Characterization of the
Shigella boydii
Type 13 O Antigen
Authors: Feng Lu , Senchenkova Sof'ya N. , Yang Jinghua , Shashkov Alexander S. , Tao Jiang , Guo Hongjie , Zhao Guang , Knirel Yuriy A. , Reeves Peter , Wang Lei
Published: December 2003

Shigella
is an important human pathogen. It is generally agreed that
Shigella
and
Escherichia coli
constitute a single species; the only exception is
Shigella boydii
type 13, which is more distantly related to
E. coli
and other
Shigella
forms and seems to represent another species. This gives
S. boydii
type 13 an important status in evolution. O antigen is the polysaccharide part of the lipopolysaccharide in the outer membrane of gram-negative bacteria and plays an important role in pathogenicity. The chemical structure and genetic organization of the
S. boydii
type 13 O antigen were investigated. The O polysaccharide was found to be acid labile owing to the presence of a glycosyl phosphate linkage in the main chain. The structure of the linear pentasaccharide phosphate repeating unit (O unit) was established by nuclear magnetic resonance spectroscopy, including two-dimensional COSY, TOCSY, ROESY, and H-detected
1
H,
13
C and
1
H,
31
P HMQC experiments, along with chemical methods. The O antigen gene cluster of
S. boydii
type 13 was located and sequenced. Genes for synthesis of UDP-2-acetamido-2,6-dideoxy-
l
-glucose and genes that encode putative sugar transferases, O unit flippase, and O antigen polymerase were identified. Seven genes were found to be specific to
S. boydii
type 13. The
S. boydii
type 13 O antigen gene cluster has higher levels of sequence similarity with
Vibrio cholerae
gene clusters and may be evolutionarily related to these gene clusters.
Complete Sequence and Evolutionary Genomic Analysis of the
Pseudomonas aeruginosa
Transposable Bacteriophage D3112
Authors: Wang Pauline W. , Chu Linda , Guttman David S.
Published: December 2003

Bacteriophage D3112 represents one of two distinct groups of transposable phage found in the clinically relevant, opportunistic pathogen
Pseudomonas aeruginosa
. To further our understanding of transposable phage in
P. aeruginosa
, we have sequenced the complete genome of D3112. The genome is 37,611 bp, with an overall G+C content of 65%. We have identified 53 potential open reading frames, including three genes (the c repressor gene and early genes A and B) that have been previously characterized and sequenced. The organization of the putative coding regions corresponds to published genetic and transcriptional maps and is very similar to that of enterobacteriophage Mu. In contrast, the International Committee on Taxonomy of Viruses has classified D3112 as a λ-like phage on the basis of its morphology. Similarity-based analyses identified 27 open reading frames with significant matches to proteins in the NCBI databases. Forty-eight percent of these were similar to Mu-like phage and prophage sequences, including proteins responsible for transposition, transcriptional regulation, virion morphogenesis, and capsid formation. The tail proteins were highly similar to prophage sequences in
Escherichia coli
and phage Phi12 from
Staphylococcus aureus
, while proteins at the right end were highly similar to proteins in
Xylella fastidiosa
. We performed phylogenetic analyses to understand the evolutionary relationships of D3112 with respect to Mu-like versus λ-like bacteriophages. Different results were obtained from similarity-based versus phylogenetic analyses in some instances. Overall, our findings reveal a highly mosaic structure and suggest that extensive horizontal exchange of genetic material played an important role in the evolution of D3112.
The HWE Histidine Kinases, a New Family of Bacterial Two-Component Sensor Kinases with Potentially Diverse Roles in Environmental Signaling
Authors: Karniol Baruch , Vierstra Richard D.
Published: December 2003

Two-component signal transduction pathways play a major role in the response of bacteria to external cues. These pathways are initiated by large collection of histidine kinases (HKs) containing a sensor domain that perceives the environmental signal followed by an HK domain that triggers a histidine-aspartate phosphorelay. Previous phylogenetic analyses identified 11 major families of two-component HKs by comparing signature motifs within the HK domain. Here we describe a new family with homology to
Agrobacterium tumefaciens
BphP2, an HK first discovered by the presence of a phytochrome sensor domain involved in light perception. Members of this sensor HK family differ from most others by the absence of a recognizable F box and the presence of several uniquely conserved residues, including a histidine in the N box and a tryptophan-X-glutamic acid sequence in the G1 box, which we have used to define the family (HWE). At least 81 members were identified in a variety of α- and γ-proteobacteria, with a significant enrichment in the
Rhizobiaceae
family. Several representatives were shown to have HK activity in vitro, supporting their proposed participation in phosphorelays. One or more domains related to signal transduction were evident N-terminal to the HK domain, including chemotactic methyltransferase domains, suggesting that this family has multiple roles in environmental signaling. The discovery of the HWE family further extends the diversity within the HK superfamily and expands the importance of two-component signaling in bacteria.
TheacnDGenes ofShewenella oneidensisandVibrio choleraeEncode a New Fe/S-Dependent 2-Methylcitrate Dehydratase Enzyme That RequiresprpFFunction In Vivo
Authors: Grimek Tracey L. , Escalante-Semerena Jorge C.
Published: December 2003

The propionate utilization operons of several bacteria differ from each other in the occurrence of two genes,acnDandprpF, in place of or in addition to theprpDgene encoding an Fe/S-independent 2-methylcitrate dehydratase enzyme. We cloned theacnDandprpFgenes from two organisms,Shewanella oneidensisandVibrio cholerae, and found that, together, the AcnD and PrpF proteins restored the ability of aprpDmutant strain ofSalmonella entericato grow on propionate as a source of carbon and energy. However, neitheracnDnorprpFalone was able to substitute forprpD. The AcnD and PrpF proteins were isolated and biochemically analyzed. The AcnD protein required reconstitution of an Fe/S cluster for activity. All detectable AcnD activity was lost after incubation with iron-chelating agents, and no AcnD activity was observed after attempted reconstitution without iron. Nuclear magnetic resonance spectroscopy and in vitro activity assay data showed that AcnD dehydrated 2-methylcitrate and citrate to 2-methyl-cis-aconitate andcis-aconitate, respectively; AcnD also hydratedcis-aconitate. However, 2-methylisocitrate and isocitrate were not substrates for AcnD, indicating that AcnD only catalyzes the first half of the aconitase-like dehydration reactions. No aconitase-like activity was found for PrpF. It is hypothesized that, in vivo, PrpF is an accessory protein required to prevent oxidative damage of the Fe/S center of active AcnD enzyme or that it may be involved in synthesis or repair of the Fe/S cluster present in AcnD.
Genetic Analysis of the Cell Division Protein FtsI (PBP3): Amino Acid Substitutions That Impair Septal Localization of FtsI and Recruitment of FtsN
Authors: Wissel Mark C. , Weiss David S.
Published: December 2003

FtsI (also called PBP3) of
Escherichia coli
is a transpeptidase required for synthesis of peptidoglycan in the division septum and is one of several proteins that localize to the septal ring. FtsI comprises a small cytoplasmic domain, a transmembrane helix, a noncatalytic domain of unknown function, and a catalytic (transpeptidase) domain. The last two domains reside in the periplasm. We used PCR to randomly mutagenize
ftsI
, ligated the products into a green fluorescent protein fusion vector, and screened ∼7,500 transformants for
gfp-ftsI
alleles that failed to complement an
ftsI
null mutant. Western blotting and penicillin-binding assays were then used to weed out proteins that were unstable, failed to insert into the cytoplasmic membrane, or were defective in catalysis. The remaining candidates were tested for septal localization and ability to recruit another division protein, FtsN, to the septal ring. Mutant proteins severely defective in localization to the septal ring all had lesions in one of three amino acids—R23, L39, or Q46—that are in or near the transmembrane helix and implicate this region of FtsI in septal localization. Mutant FtsI proteins defective in recruitment of FtsN all had lesions in one of eight residues in the noncatalytic domain. The most interesting of these mutants had lesions at G57, S61, L62, or R210. Although separated by ∼150 residues in the primary sequence, these amino acids are close together in the folded protein and might constitute a site of FtsI-FtsN interaction.
EXCHANGE FREQUENCIES IN THE 2D WIGNER CRYSTAL
Authors: BERNU B. , GIANINETTI P. , CÂNDIDO LADIR , CEPERLEY D. M.
Published: December 2003

Path Integral Monte Carlo is used to calculate exchange frequencies as electrons undergo ring exchanges in a "clean" 2d Wigner crystal as a function of density. Agreement with WKB calculations is found at very low density, but the results show an enhanced increase with density near melting. Remarkably, the exchange Hamiltonian closely resembles the measured exchanges in 2d3 He . Using the resulting multi-spin exchange model we find the spin Hamiltonian for rs ≥ 175 ± 10 is a frustrated antiferromagnetic, with a spin liquid ground state. For lower density the ground state will be ferromagnetic. Some effects of a magnetic field are presented.
FINITE TEMPERATURE DYNAMICS NEAR QUANTUM PHASE TRANSITIONS
Authors: SACHDEV SUBIR
Published: December 2003

We review the non-zero temperature relaxational dynamics of quantum systems near a zero temperature, second-order phase transition. We begin with the quantum Ising chain, for which universal and exact results for the relaxation rates can be obtained in all the distinct limiting regimes of the phase diagram. Next, we describe the crossovers in the electron spectral function near a transition involving a change in the pairing symmetry of BCS superconductors in two dimensions. Finally, we consider dynamic spin models which may provide a mean-field description of magnetic ordering transitions in the heavy fermion compounds.
HIDDEN UNITY IN THE QUANTUM DESCRIPTION OF MATTER
Authors: ORTIZ G. , BATISTA C. D.
Published: December 2003

We introduce an algebraic framework for interacting quantum systems that enables studying complex phenomena, characterised by the coexistence and competition of various broken symmetry states of matter. The approach unveils the hidden unity behind seemingly unrelated physical phenomena, thus establishing exact connections between them. This leads to the fundamental concept of universality of physical phenomena, a general concept not restricted to the domain of critical behaviour. Key to our framework is the concept of languages and the construction of dictionaries relating them.
ISOTHERMAL QUANTUM DYNAMICS: NOSÉ–HOOVER DYNAMICS FOR COHERENT STATES
Authors: MENTRUP D. , SCHNACK J.
Published: December 2003

The method of Nosé and Hoover1,2 to create canonically distributed positions and momenta in classical molecular dynamics simulations is frequently used. Hamilton's equations of motion are supplemented by time-dependent pseudofriction terms that convert the microcanonical isoenergetic time evolution into a canonical isothermal time evolution, thus permitting the calculation of canonical ensemble averages by time averaging. We show that for one quantum particle in an external harmonic oscillator, the equations of motion in terms of coherent states can easily be modified in an analogous manner to mimic the coupling of the system to a thermal bath and create a quantum canonical ensemble.3 The method is generalised to a system of two identical quantum particles. In the resulting equations of motion, one obtains an additional attractive term for bosons and a repulsive term for fermions in the dynamics of the pseudofriction coefficients, leading to a correctly sampled thermal weight.
CARTILAGE-SPECIFIC OVEREXPRESSION OF C-PROPEPTIDE OF TYPE II COLLAGEN AFFECTED MATRIX MINERALIZATION IN TRANSGENIC MICE
Authors: Matsui Yoshito , Nakata Ken , Adachi Eijiro , Tsumaki Noriyuki , Kimura Tomoatsu , Yasui Natsuo , Kataoka Eiichiro , Fujita Yoshi , Tsuboi Hideki , Yoshikawa Hideki
Published: December 2003

The C-propeptide of type II collagen (CppII) is cleaved from the procollagen molecule at the time of extracellular secretion from chondrocytes, and was reported to localize in the lower hypertrophic zone of the growth plate cartilage. In the present study, the in vivo role of CppII in the process of endochondral bone formation was investigated by cartilage-specific overexpression of CppII in transgenic mice. Two independent lines of transgenic mice were obtained and they showed mild skeletal dysplasia, as evidenced by morphometric measurement of skeletal bones. Whole body staining revealed delayed mineralization of embryonic endochondral bones, including occipital bone and vertebral bodies. Histological sections showed reduced area of mineralization and scattered chondrocyte hypertrophy in the lower part of growth plate cartilage in the embryonic long bones. Immuno-electron micrographs demonstrated that CppII co-localized with collagen fibrils in the extracellular matrix of the cartilage. Taken together, these results indicate that overexpression of CppII affected endochondral bone formation by negatively regulating the matrix mineralization.
TREATMENT OF NECK PAIN AFTER WHIPLASH INJURIES WITH BOTULINUM TOXIN-A INJECTIONS
Authors: Juan Francisco J.
Published: December 2003

Objective: Botulinum toxin has demonstrated efficacy in a variety of conditions associated with muscle spasm. We report our experience with botulinum toxin-A in patients with neck pain after whiplash associated disorders.

Methods: A descriptive epidemiology study and case reports of patients treated with botulinum toxin type-A (Botox®) for neck pain after whiplash injuries were performed over a three-year period. A total of 31 patients who had received botulinum toxin-A for neck pain were studied. Patients were treated with 50–75 units of Botox®. Clinical follow-up evaluation was performed with repeated examinations that included range of movement (ROM), visual analogue scale (VAS), and neck pain disability index (NPDI). After initial assessment and treatment patients were followed-up 8 weeks.

Results: Of 31 patients, 67.7% had excellent response rates. There was a significant reduction in pain as well as improvement in the ROM. 77.4% of patients responded significantly (p<0.05) to botulinum toxin-A injection with reduction in pain.

Conclusion: The use of botulinum toxin type-A in patients with neck pain associated to whiplash injury resulted in significant improvement in subjective pain. This therapy is safe. These results suggest the need for a double-blind trial on the use of botulinum toxin during chronic phase. Also, the treatment of the subacute or acute phase of whiplash associated disorders should be investigated.
Putting Clinical Pharmacology in Context: The Use of Popular Movies
Authors: Farré Magí , Bosch Fèlix , Roset Pere N. , Baños Josep‐E.
Published: December 2003

The usefulness of movies to illustrate the psychological and sociological conflicts of medical practice is widely recognized. However, the use of popular movies to teach less oriented medical sciences, such as pharmacology is not so common. In the present review, we report the use of three films (Awakenings, Lorenzo's Oil, and Miss Evers' Boys) as a teaching tool to allow students to better understand some conflicts which appear in the domain of clinical pharmacology. These movies may help to introduce some relevant topics such as the difficulties of planning and performing clinical research with new drugs, the need of considering bioethical principles when doing research with human beings, and the social and psychological aspects of drug therapy. The films may increase the motivation of students to understand clinical pharmacology principles and may become a driving force for an increased desire to learn.
Effect of St. John's Wort on the Pharmacokinetics of Theophylline in Healthy Volunteers
Authors: Morimoto Takuya , Kotegawa Tsutomu , Tsutsumi Kimiko , Ohtani Yasukiyo , Imai Hiromitsu , Nakano Shigeyuki
Published: December 2003

The objective of this study was to investigate the effect of St. John's wort (SJW, Hypericum perforatum) on the pharmacokinetics of theophylline in healthy volunteers. Twelve healthy Japanese male volunteers participated in this randomized, open‐labeled, crossover study. The subjects took an SJW caplet (300 mg) three times a day for 15 days. On day 14, they received a single oral dose of 400 mg of theophylline. They took the same dose of theophylline without SJW treatment on another occasion. Plasma and urine samples were obtained during a 48‐hour period after theophylline administration. Theophylline concentrations in plasma and urine, as well as the major metabolites (13U, 1U, 3X) in urine, were measured. SJW caused no significant changes in the pharmacokinetics of theophylline in plasma. SJW administration tended to increase the ratio of 1U/the total amount excreted in urine. However, no changes in the ratio of unchanged theophylline, 13U, and 3X were observed. It is unlikely that the effect of 15 days of treatment with SJW on CYPs is sufficient to cause a change in plasma theophylline concentrations.
A genome-wide scan to identify loci for smoking rate in the Framingham Heart Study population
Authors: Li Ming D , Ma Jennie Z , Cheng Rong , Dupont Randolph T , Williams Nancy J , Crews Karen M , Payne Thomas J , Elston Robert C
Published: December 2003

Background

Although many years of genetic epidemiological studies have demonstrated that genetics plays a significant role in determining smoking behavior, little information is available on genomic loci or genes affecting nicotine dependence. Several susceptibility chromosomal regions for nicotine dependence have been reported, but few have received independent confirmation. To identify susceptibility loci for nicotine dependence, 313 extended pedigrees selected from the Framingham Heart Study population were analyzed by both the GENEHUNTER and S.A.G.E. programs.

Results

After performing linkage analyses on the 313 extended Framingham Heart Study families, the EM Haseman-Elston method implemented in GENEHUNTER provided evidence for significant linkage of smoking rate to chromosome 11 and suggestive linkage to chromosomes 9, 14, and 17. Multipoint sib-pair regression analysis using the SIBPAL program of S.A.G.E. on 1389 sib pairs that were split from the 313 extended families identified suggestive linkage of smoking rate to chromosomes 4, 7, and 17. Of these identified positive regions for nicotine dependence, loci on chromosomes 7, 11, and 17 were identified by both GENEHUNTER and S.A.G.E. programs.

Conclusion

Our genome-wide scan results on the Framingham Heart Study data provide evidence for significant linkage of smoking rate to chromosome 11 and suggestive linkage to chromosomes 4, 7, 9, 14, and 17. These findings suggest that some of these regions may harbor susceptibility loci for nicotine dependence, and warrant further investigation in this and other populations.
Genome-wide linkage analysis of longitudinal phenotypes using σ2
A random effects (SSARs) fitted by Gibbs sampling
Authors: Palmer Lyle J , Scurrah Katrina J , Tobin Martin , Patel Sanjay R , Celedon Juan C , Burton Paul R , Weiss Scott T
Published: December 2003

The study of change in intermediate phenotypes over time is important in genetics. In this paper we explore a new approach to phenotype definition in the genetic analysis of longitudinal phenotypes. We utilized data from the longitudinal Framingham Heart Study Family Cohort to investigate the familial aggregation and evidence for linkage to change in systolic blood pressure (SBP) over time. We used Gibbs sampling to derive sigma-squared-A-random-effects (SSARs) for the longitudinal phenotype, and then used these as a new phenotype in subsequent genome-wide linkage analyses.

Additive genetic effects (σ2A.time) were estimated to account for ~9.2% of the variance in the rate of change of SBP with age, while additive genetic effects (σ2A) were estimated to account for ~43.9% of the variance in SBP at the mean age. The linkage results suggested that one or more major loci regulating change in SBP over time may localize to chromosomes 2, 3, 4, 6, 10, 11, 17, and 19. The results also suggested that one or more major loci regulating level of SBP may localize to chromosomes 3, 8, and 14.

Our results support a genetic component to both SBP and change in SBP with age, and are consistent with a complex, multifactorial susceptibility to the development of hypertension. The use of SSARs derived from quantitative traits as input to a conventional linkage analysis appears to be valuable in the linkage analysis of genetically complex traits. We have now demonstrated in this paper the use of SSARs in the context of longitudinal family data.
Sibling recurrence risk ratio analysis of the metabolic syndrome and its components over time
Authors: Chen Wei J , Liu Pi-Hua , Ho Yen-Yi , Chien Kuo-Liong , Lo Min-Tzu , Shih Wei-Liang , Yen Yu-Chun , Lee Wen-Chung
Published: December 2003

Background

The purpose of this study was to estimate both cross-sectional sibling recurrence risk ratio (λ
s
) and lifetime λ
s
for the metabolic syndrome and its individual components over time among sibships in the prospectively followed-up cohorts provided by the Genetic Analysis Workshop 13. Five measures included in the operational criteria of the metabolic syndrome by the Adult Treatment Panel III were examined. A method for estimating sibling recurrence risk with correction for complete ascertainment was used to estimate the numerator, and the prevalence in the whole cohort was used as the denominator of λ
s
.

Results

Considerable variability in the λ
s
was found in terms of different time-points for the cross-sectional definition, the times of fulfilling the criterion for lifetime definition, and different components. Obesity and hyperglycemia had the highest cross-sectional λ
s
of the five components. Both components also had the largest slopes in the linear trend of the lifetime λ
s
. However, the magnitudes of the lifetime λ
s
were similar to that of the mean cross-sectional λ
s
, which were <2. The results of nonparametric linkage analysis showed only suggestive evidence of linkage between one marker and lifetime diagnosis of low high-density lipoprotein cholesterol and metabolic syndrome, respectively.

Conclusion

The λ
s
of the metabolic syndrome and its components varies substantially across time, and the λ
s
of lifetime diagnosis was not necessarily larger than that of a cross-sectional diagnosis. The magnitude of λ
s
does not predict well the maximum LOD score of linkage analysis.
Lack of reproducibility of linkage results in serially measured blood pressure data
Authors: Patel Sanjay R , Celedon Juan C , Weiss Scott T , Palmer Lyle J
Published: December 2003

Background

Using the longitudinal Framingham Heart Study data on blood pressure, we analyzed the reproducibility of linkage measures from serial cross-sectional surveys of a defined population by performing genome-wide model-free linkage analyses to systolic blood pressure (SBP) and history of hypertension (HTN) measured at five separate time points.

Results

The heritability of SBP was relatively stable over time, ranging from 11.6 to 23.5% (coefficient of variation = 25.7%). However, the variability in linkage results was much greater. The average correlation in LOD scores at any pair of time points was 0.46 for HTN (NPL All LOD) and 0.17 for SBP (Variance Components LOD). No evidence of reproducible linkage results was found, with a mean κ of 0.02 for linkage to HTN and -0.03 for SBP linkage. At loci with potential evidence for linkage (LOD > 1.0 at one or more time points), the correlation was even lower. The coefficient of variation at loci with potential evidence of linkage was 126% for HTN and 135% for SBP. None of 15 chromosomal regions for HTN and only one of 28 regions for SBP with potential evidence for linkage had a LOD > 1.0 at more than two of the five time points.

Conclusion

These data suggest that, although heritability estimates at different time points are relatively robust, the reproducibility of linkage results in serial cross-sectional samples of a geographically defined population at successive time points is poor. This may explain in part the difficulty encountered in replicating linkage studies of complex phenotypes.
Adjusting for covariates on a slippery slope: linkage analysis of change over time
Authors: Rampersaud Evadnie , Allen Andrew , Li Yi-Ju , Shao Yujun , Bass Meredyth , Haynes Carol , Ashley-Koch Allison , Martin Eden R , Schmidt Silke , Hauser Elizabeth R
Published: December 2003

Background

We analyzed the Genetic Analysis Workshop 13 (GAW13) simulated data to contrast and compare different methods for the genetic linkage analysis of hypertension and change in blood pressure over time. We also examined methods for incorporating covariates into the linkage analysis. We used methods for quantitative trait loci (QTL) linkage analysis with and without covariates and affected sib-pair (ASP) analysis of hypertension followed by ordered subset analysis (OSA), using variables associated with change in blood pressure over time.

Results

Four of the five baseline genes and one of the three slope genes were not detected by any method using conventional criteria. OSA detected baseline gene b35 on chromosome 13 when using the slope in blood pressure to adjust for change over time. Slope gene s10 was detected by the ASP analysis and slope gene s11 was detected by QTL linkage analysis as well as by OSA analysis. Analysis of null chromosomes, i.e., chromosomes without genes, did not reveal significant increases in type I error. However, there were a number of genes indirectly related to blood pressure detected by a variety of methods.

Conclusions

We noted that there is no obvious first choice of analysis software for analyzing a complicated model, such as the one underlying the GAW13 simulated data. Inclusion of covariates and longitudinal data can improve localization of genes for complex traits but it is not always clear how best to do this. It remains a worthwhile task to apply several different approaches since one method is not always the best.
Genome-wide linkage scan on estimated breeding values for a quantitative trait
Authors: Zabaneh Delilah , Mackay Ian J
Published: December 2003

Background

A genome-wide linkage scan was performed on Replicate 1 of the simulated data for fasting triglyceride levels. The aim of this study was to implement mixed-model methodology to estimate breeding values for each individual for this trait and to assess the merit of these breeding values in linkage analysis. These breeding values utilize all the pedigree information, and the genetic and phenotypic correlations with other measured traits across the two cohorts. A genome-wide linkage scan was run on both the new breeding value traits and the original traits.

Results

Using breeding values, a maximum LOD of 7.78 was found on chromosome 5 at a position very close to a gene underlying the triglyceride levels. This effect was not detected using the original trait.

Conclusion

The results imply that estimating breeding values may be a suitable method of deriving traits for use in genome-wide scans.
Linkage analysis of the simulated data – evaluations and comparisons of methods
Authors: Biswas Swati , Papachristou Charalampos , Irwin Mark E , Lin Shili
Published: December 2003

The goal of this study is to evaluate, compare, and contrast several standard and new linkage analysis methods. First, we compare a recently proposed confidence set approach with MAPMAKER/SIBS. Then, we evaluate a new Bayesian approach that accounts for heterogeneity. Finally, the newly developed software SIMPLE is compared with GENEHUNTER. We apply these methods to several replicates of the Genetic Analysis Workshop 13 simulated data to assess their ability to detect the high blood pressure genes on chromosome 21, whose positions were known to us prior to the analyses. In contrast to the standard methods, most of the new approaches are able to identify at least one of the disease genes in all the replicates considered.
Segregation analysis comparing liability and quantitative trait models for hypertension using the Genetic Analysis Workshop 13 simulated data
Authors: Crockford GP , Bishop DT , Barrett JH
Published: December 2003

Discrete (qualitative) data segregation analysis may be performed assuming the liability model, which involves an underlying normally distributed quantitative phenotype. The appropriateness of the liability model for complex traits is unclear. The Genetic Analysis Workshop 13 simulated data provides measures on systolic blood pressure, a highly complex trait, which may be dichotomized into a discrete trait (hypertension). We perform segregation analysis under the liability model of hypertensive status as a qualitative trait and compare this with results using systolic blood pressure as a quantitative trait (without prior knowledge at that stage of the true underlying simulation model) using 1050 pedigrees ascertained from four replicates on the basis of at least one affected member. Both analyses identify models with major genes and polygenic components to explain the family aggregation of systolic blood pressure. Neither of the methods estimates the true parameters well (as the true model is considerably more complicated than those considered for the analysis), but both identified the most complicated model evaluated as the preferred model. Segregation analysis of complex diseases using relatively simple models is unlikely to provide accurate parameter estimates but is able to indicate major gene and/or polygenic components in familial aggregation of complex diseases.
Age-of-onset of hypertension vs. a single measurement of systolic blood pressure in a combined linkage and segregation analysis
Authors: Daw E Warwick , Liu Xiaoming , Wu Chih-Chieh
Published: December 2003

Background

Often, multiple measures of a trait are available in a genetic linkage analysis. We compare Monte Carlo Markov chain analysis of two very different measures of hypertension in the simulated Genetic Analysis Workshop 13 data to examine how choice of measure affects the results. The measures selected were age-of-onset of hypertension and systolic blood pressure at first visit.

Results

In combined segregation and linkage analysis of the complete pedigrees using the first replicate of the simulated data with missing values, we found that the age-of-onset analysis was better at identifying "slope" genes, while the systolic blood pressure analysis was better at identifying "baseline" genes.

Conclusion

Analysis of different trait measures may identify different trait-related genes. When linkage analysis is conducted on multiple trait measures, a linkage signal found for only one measure can represent a true trait locus.
Bivariate variance-component analysis, with application to systolic blood pressure and total cholesterol levels in the Framingham Heart Study
Authors: Cui Jisheng S , Sheffield Leslie J
Published: December 2003

Background

The correlations between systolic blood pressure (SBP) and total cholesterol levels (CHOL) might result from genetic or environmental factors that determine variation in the phenotypes and are shared by family members. Based on 330 nuclear families in the Framingham Heart Study, we used a multivariate normal model, implemented in the software FISHER, to estimate genetic and shared environmental components of variation and genetic and shared environmental correlation between the phenotypes. The natural logarithm of the phenotypes measured at the last visit in both Cohort 1 and 2 was used in the analyses. The antihypertensive treatment effect was corrected before adjustment of the systolic blood pressure for age, sex, and cohort.

Results

The univariate correlation coefficient was statistically significant for sibling pairs and parent-offspring pairs, but not significant for spouse pairs. In the bivariate analysis, the cross-trait correlation coefficients were not statistically significant for all relative pairs. The shared environmental correlation was statistically significant, but the genetic correlation was not significant.

Conclusion

There is no significant evidence for a close genetic correlation between systolic blood pressure and total cholesterol levels. However, some shared environmental factors may determine the variation of both phenotypes.
Using an age-at-onset phenotype with interval censoring to compare methods of segregation and linkage analysis in a candidate region for elevated systolic blood pressure
Authors: Kopciuk Karen A , Briollais Laurent , Demenais Florence , Bull Shelley B
Published: December 2003

Background

Genetic studies of complex disorders such as hypertension often utilize families selected for this outcome, usually with information obtained at a single time point. Since age-at-onset for diagnosed hypertension can vary substantially between individuals, a phenotype based on long-term follow up in unselected families can yield valuable insights into this disorder for the general population.

Methods

Genetic analyses were conducted using 2884 individuals from the largest 330 families of the Framingham Heart Study. A longitudinal phenotype was constructed using the age at an examination when systolic blood pressure (SBP) first exceeds 139 mm Hg. An interval for age-at-onset was created, since the exact time of onset was unknown. Time-fixed (sex, study cohort) and time-varying (body mass index, daily cigarette and alcohol consumption) explanatory variables were included.

Results

Segregation analysis for a major gene effect demonstrated that the major gene effect parameter was sensitive to the choice for age-at-onset. Linkage analyses for age-at-onset were conducted using 1537 individuals in 52 families. Evidence for putative genes identified on chromosome 17 in a previous linkage study using a quantitative SBP phenotype for these data was not confirmed.

Conclusions

Interval censoring for age-at-onset should not be ignored. Further research is needed to explain the inconsistent segregation results between the different age-at-onset models (regressive threshold and proportional hazards) as well as the inconsistent linkage results between the longitudinal phenotypes (age-at-onset and quantitative).
A cautionary note on the appropriateness of using a linkage resource for an association study
Authors: Allen-Brady Kristina , Farnham James M , Weiler Jeff , Camp Nicola J
Published: December 2003

Background

Utilizing a linkage resource for association analysis requires consideration both of the marker data used and correlations among relatives in pedigrees. We previously developed a method for association testing in pedigrees. We applied our method to 50 replicates of microsatellite data surrounding five genes involved in high-density lipoprotein (HDL) in the Genetic Analysis Workshop 13 (GAW13) simulated data and examined association with HDL as well as linkage disequilibrium (LD) between markers.

Results

Although no association was intentionally simulated, we found significant evidence of weak LD between microsatellite markers (flanking/~5 cM from the genes), in some but not all replicates. This level of LD compared well to that observed in the real GAW13 Framingham data. Only one region had sufficient replicates to assess power, and this was low (12.5–20.8%). More power was attained using all individuals and accounting for relationships, compared with one independent individual/pedigree, although this was not significant due to small sample sizes. Not accounting for relatedness inflated statistical significance (p < 0.0001).

Conclusion

A correction for dependence is necessary in association studies to avoid an inflation of significance probabilities. Our results further illustrate that use of microsatellite marker data is not an effective approach for association testing.
HDL cholesterol in females in the Framingham Heart Study is linked to a region of chromosome 2q
Authors: North Kari E , Martin Lisa J , Dyer Tom , Comuzzie Anthony G , Williams Jeff T
Published: December 2003

Background

Despite strong evidence for a genetic component to variation in high-density lipoprotein cholesterol levels (HDL-C), specific polymorphisms associated with normal variation in HDL-C have not been identified. It is known, however, that HDL-C levels are influenced in complex ways by factors related to age and sex. In this paper, we examined the evidence for age- and sex-specific linkage of HDL-C in a longitudinal sample of participants from the Framingham Heart Study.

To determine if aging could influence our ability to detect linkage, we explored the evidence for linkage of HDL-C at three time points, t1, t2, and t3, spaced approximately 8 years apart and corresponding respectively to visits 11, 15, and 20 for the original cohort and 1, 2, and 4 for the offspring and spouses. Additionally, to examine the effects of sex on linkage at each time point, we estimated the heritability and genetic correlation of HDL-C, performed linkage analysis of HDL-C, tested for genotype-by-sex interaction at a QTL, and performed linkage analysis of HDL-C in males and females separately.

Results and Conclusion

In women, we found evidence for a QTL on chromosome 2q influencing HDL-C variation. Although the QTL could be detected in the combined sample of males and females at the first time point, the linkage was not significant at subsequent time points.
Endotoxin neutralization and anti-inflammatory effects of tobramycin and ceftazidime in porcine endotoxin shock
Authors: Goscinski Gunilla , Lipcsey Miklos , Eriksson Mats , Larsson Anders , Tano Eva , Sjölin Jan
Published: December 2003

Introduction

Antibiotics used for treatment of severe bacterial infections have been shown to exert effects on the inflammatory response in addition to their antibacterial effects. The aim of the present study was to investigate whether the biological effects of endotoxin in a porcine model could be neutralized by tobramycin, and whether tobramycin or ceftazidime was able to modulate the inflammatory response.

Method

Thirteen piglets were subjected to endotoxin infusion at an initial rate of 4 μg/kg per hour, which was reduced to 1 μg/kg per hour after 30 min. Before endotoxin infusion, the animals received saline (n = 4), ceftazidime (n = 5), or tobramycin (n = 4) at clinically relevant doses. Physiological parameters were measured and blood samples were taken hourly for 6 hours for analysis of tumour necrosis factor-α, IL-6 and endotoxin concentrations.

Results

All of the animals exhibited physiological signs of severe sepsis without major differences between the groups. Plasma endotoxin concentration was stable after 1 hour. There were no differences in endotoxin concentration or initial tumour necrosis factor-α and IL-6 concentrations between the groups. At 6 hours the IL-6 concentration was significantly lower in the ceftazidime group than in the saline group (P < 0.05), and in both the ceftazidime and the tobramycin groups there were significantly greater reductions from peak values (P < 0.05).

Conclusion

There was no neutralization of the biological effects of endotoxin in this porcine model. However, our data indicate a possible anti-inflammatory effect exerted by both ceftazidime and tobramycin, which manifested as a significantly greater reduction in IL-6 in comparison with the untreated group.
The rediscovery of recovery: open to all
Authors: Roberts Glenn , Wolfson Paul
Published: December 2003

‘Recovery’ is usually taken as broadly equivalent to ‘getting back to normal’ or ‘cure’, and by these standards few people with severe mental illness recover. At the heart of the growing interest in recovery is a radical redefinition of what recovery means to those with severe mental health problems. Redefinition of recovery as a process of personal discovery, of how to live (and to live well) with enduring symptoms and vulnerabilities opens the possibility of recovery to all. The ‘recovery movement’ argues that this reconceptualisation is personally empowering, raising realistic hope for a better life alongside whatever remains of illness and vulnerability. This paper explores the background and defining features of the international recovery movement, its influence and impact on contemporary psychiatric practice, and steps towards developing recovery-based practice and services.
Psychotropic medication in pregnancy
Authors: Kohen Dora
Published: December 2003

The risks and benefits of psychopharmacological treatment in pregnancy need careful consideration. Conventional antipsychotics and tricyclic antidepressants are relatively safe for the foetus. Selective serotonin reuptake inhibitors appear to be safe, but mood stabilisers such as lithium, sodium valproate and carbamazepine are associated with increased foetal malformations. Benzodiazepines in the first trimester are teratogenic, and in high dosage can also cause withdrawal symptoms, hypotonia and agitation in the newborn. Women taking atypical antipsychotics should be switched to conventional antipsychotics before they conceive. In women with long-term mental illness necessitating psychotropic medication, effort should be made to stop polypharmacy and non-essential medication (e.g. benzodiazepines) and to decrease the dose of essential drugs, after full assessment. There is rarely a valid reason to stop essential drug treatment during pregnancy.
Globalisation and mental disorders
Authors: Bhugra Dinesh , Mastrogianni Anastasia
Published: December 2003

Background

Globalisation is the process by which traditional boundaries of cultures are changing. Industrialisation, urbanisation and influence of the media are influencing idioms of distress across cultures.

Aims

To discuss the role of globalisation, using the epidemiology, diagnosis, clinical presentation and treatment of depression across various cultures as an example.

Method

Recent studies focusing on transcultural aspects of depression were reviewed and summarised.

Results

Cultural, social and religious mores account for variations in the presentation of depression across cultures. Somatic symptoms are common presenting features throughout the world and may serve as cultural idioms of distress, but psychological symptoms can usually be found when probed. Feelings of guilt and suicide rates vary across cultures and depression may be underdiagnosed.

Conclusions

Training packages could enhance clinicians' cultural competency in multicultural settings. However, globalisation is likely to influence idioms of distress and pathways to care in ways that are difficult to predict.