bluuebunny/crossref_metadata_2025 huggingface dataset:
In Vitro Activity of Recombinant Lysostaphin against
Staphylococcus aureus
Isolates from Anterior Nares and Blood
Authors: von Eiff Christof , Kokai-Kun John F. , Becker Karsten , Peters Georg
Published: October 2003

The in vitro activity of recombinant lysostaphin was tested against a collection of well-characterized clinical
Staphylococcus aureus
isolates by disk diffusion (429 isolates) and minimum bactericidal concentration (10 isolates) assays. Minimum bactericidal concentrations of 0.16 μg/ml and zones of inhibition ranging between 15 and 21 mm in diameter demonstrate that lysostaphin was highly active against all isolates tested.
Resazurin Microtiter Assay Plate Testing of
Mycobacterium tuberculosis
Susceptibilities to Second-Line Drugs: Rapid, Simple, and Inexpensive Method
Authors: Martin Anandi , Camacho Mirtha , Portaels Françoise , Palomino Juan Carlos
Published: October 2003

The emergence of multidrug-resistant tuberculosis calls for new, rapid drug susceptibility tests. We have tested 150
Mycobacterium tuberculosis
isolates against the second-line drugs ethionamide, kanamycin, capreomycin, ofloxacin, and
para
-aminosalicylic acid by the colorimetric resazurin microtiter assay and the proportion method. By visual reading, MICs were obtained after 8 days. A very good correlation between results by the colorimetric resazurin microtiter assay and the proportion method was obtained. The colorimetric resazurin microtiter assay is inexpensive, rapid, and simple to perform, and implementation of the assay is feasible for low-resource countries.
Rapid Detection and Estimation by Pyrosequencing of 23S rRNA Genes with a Single Nucleotide Polymorphism Conferring Linezolid Resistance in Enterococci
Authors: Sinclair Alistair , Arnold Catherine , Woodford Neil
Published: October 2003

Pyrosequencing was used to detect rapidly and estimate the number of 23S rRNA genes with a G2576T mutation in 43 linezolid-resistant and -susceptible clinical isolates of enterococci. The method showed 100% concordance with PCR-restriction fragment length polymorphism for detecting isolates homozygous for either G2576 or T2576 or heterozygous for this mutation. A good correlation was found between linezolid MICs and the number of 23S rRNA gene copies carrying the mutation.
G484S Amino Acid Substitution in Lanosterol 14-α Demethylase (
ERG11
) Is Related to Fluconazole Resistance in a Recurrent
Cryptococcus neoformans
Clinical Isolate
Authors: Rodero Laura , Mellado Emilia , Rodriguez A. Carolina , Salve Angela , Guelfand Liliana , Cahn Pedro , Cuenca-Estrella Manuel , Davel Graciela , Rodriguez-Tudela Juan L.
Published: October 2003

Five sequential
Cryptococcus neoformans
isolates recovered from an AIDS patient with recurrent meningitis were analyzed. Four isolates were fluconazole susceptible, while the fifth isolate developed fluconazole resistance. Analysis of the 14-α lanosterol demethylase gene (
ERG11
) showed a point mutation in the resistant strain responsible for the amino acid substitution G484S.
Characterization of Chlamydial Genital Infection Resulting from Sexual Transmission from Male to Female Guinea Pigs and Determination of Infectious Dose
Authors: Rank Roger G. , Bowlin Anne K. , Reed Ronald L. , Darville Toni
Published: October 2003

A major problem in the study of chlamydial genital infections in animal models has been the use of varied doses of chlamydiae for infection in different laboratories. It is clearly desirable to use a dose which approximates that of natural sexual infection, but that dose to date has not been determined because of the inability of researchers to quantify chlamydiae in semen. Fortunately, sexual transmission of chlamydiae has been described for the guinea pig model of infection with the chlamydial agent of guinea pig inclusion conjunctivitis (GPIC). In this study, we undertook to determine the approximate infection dose in actual sexual transmission by comparing the kinetics of infection in female guinea pigs acquired via sexual contact to those of genital infections induced artificially with known quantities of chlamydiae. Groups of guinea pigs were infected intravaginally with 10
4
, 10
3
, 10
2
, and 10
1
inclusion-forming units (IFU) of GPIC, and the kinetics of the infection were determined. Infection with 10
2
IFU produced infections with lower peak levels than those in animals receiving 10
4
or 10
3
IFU. Seventy percent of animals receiving 10
2
IFU became infected, while 100 and 79% of animals receiving 10
4
and 10
3
IFU, respectively, became infected. Animals receiving 10
2
IFU also had a longer incubation period. Of 19 animals that mated with infected males, 63.2% became infected, with an infection course which was not significantly different than that of the 10
2
-IFU-infected group. The data suggest that female guinea pigs received approximately 10
2
IFU by sexual transmission. Of interest was the observation that the guinea pigs infected by sexual transmission shed organisms for a significantly shorter time period than that of any group that was artificially infected. This result suggests that there may be factors associated with semen which passively transfer antimicrobial activity to the female or enhance the innate host response in the female. Immunization of females with an inactivated vaccine was also found to elicit a protective immune response against sexual challenge, demonstrating that the model can be used in the evaluation of possible vaccine candidates and/or methodologies. There is currently no other animal model available for any sexually transmitted disease in which the disease or the ability to prevent the disease may be studied in animals infected by the natural means.
Differential Expression of Genes in Uninfected and
Rickettsia
-Infected
Dermacentor variabilis
Ticks as Assessed by Differential-Display PCR
Authors: Macaluso Kevin R. , Mulenga Albert , Simser Jason A. , Azad Abdu F.
Published: October 2003

Ticks serve as both the vector and the reservoir for members of the spotted fever group rickettsiae. The molecular interaction(s) that results from this close relationship is largely unknown. To identify genetic factors associated with the tick response to rickettsial infection, we utilized differential-display PCR. The majority of upregulation appeared in the infected tissue. We cloned and sequenced 54 differentially expressed transcripts and compared the sequences to those in the GenBank database. Nine of the 54 clones were assigned putative identities and included a clathrin-coated vesicle ATPase, peroxisomal farnesylated protein, Ena/vasodilator-stimulated phosphoprotein-like protein, α-catenin, tubulin α-chain, copper-transporting ATPase, salivary gland protein SGS-3 precursor, glycine-rich protein, and Dreg-2 protein. Confirmation of the rickettsial influence on the differential expression in the ovaries for a number of these clones was demonstrated by semiquantitative reverse transcription-PCR and Northern blot analyses, resulting in confirmation of six out of nine and three out of four assessed clones, respectively. Further characterization of the clones identified tissue-dependent expression in the midguts and salivary glands. The potential roles of these molecules in the maintenance and transmission of rickettsiae are discussed.
Genetic Basis for the Structural Difference between
Streptococcus pneumoniae
Serotype 15B and 15C Capsular Polysaccharides
Authors: van Selm Saskia , van Cann Lisette M. , Kolkman Marc A. B. , van der Zeijst Bernard A. M. , van Putten Jos P. M.
Published: October 2003

In a search for the genetic basis for the structural difference between the related
Streptococcus pneumoniae
capsular serotypes 15B and 15C and for the reported reversible switching between these serotypes, the corresponding capsular polysaccharide synthesis (
cps
) loci were investigated by keeping in mind that at the structural level, the capsules differ only in O acetylation. The
cps
locus of a serotype 15B strain was identified, partially PCR amplified with primers based on the related serotype 14 sequence, and sequenced. Sequence analysis revealed, among other open reading frames, an intact open reading frame (designated
cps15bM
) whose product, at the protein level, exhibited characteristics of previously identified acetyltransferases. Genetic analysis of the corresponding region in a serotype15C strain indicated that the same gene was present but had a premature stop in translation. Closer analysis indicated that the serotype 15B gene contained a short tandem TA repeat consisting of eight TA units. In serotype 15C, this gene contained nine TA units that resulted in a frameshift and a truncated product. Genetic analysis of 17 serotype 15B and 15C clinical isolates revealed a perfect correlation between the serotype and the length of the short tandem repeat in the putative
O
-acetyltransferase gene. The number of TA repeating units varied between seven and nine in the various isolates. Together, the data strongly suggest that the structural difference between serotypes 15B and 15C is based on variation in the short tandem TA repeat in the
O
-acetyltransferase gene and that the transition between serotypes is due to slipped-strand mispairing with deletion or insertion of TA units in the
cps15bM
gene.
TheMIC3Gene ofToxoplasma gondiiIs a Novel Potent Vaccine Candidate against Toxoplasmosis
Authors: Ismael Alaa Bassuny , Sekkai Dalila , Collin Christine , Bout Daniel , Mévélec Marie-Noëlle
Published: October 2003

Infection with the intracellular protozoan parasiteToxoplasma gondiicauses serious public health problems and is of great economic importance worldwide. The micronemal protein MIC3, which is a potent adhesin ofT. gondii, could be a significant candidate vaccine against toxoplasmosis. In this study, all CBA/J mice intramuscularly vaccinated with a plasmid encoding the immature form of the MIC3 protein (pMIC3i) produced specific anti-MIC3 immunoglobulin G (IgG) antibodies, and their sera displayed high antibody titers. This response was increased by the coadministration of a plasmid encoding the granulocyte-macrophage colony-stimulating factor (pGM-CSF). Similarly, a specific and significant cellular immune response was obtained in mice immunized with pMIC3i, and this response was markedly enhanced by pGM-CSF coadministration. The cellular immune response was associated with the production of gamma interferon IFN-γ and interleukin-2 (IL-2), indicating that this was a Th1-type response. This was confirmed by the production of large amounts of IgG2a. Mice immunized with pMIC3i displayed significant protection against an oral challenge withT. gondii76K cysts, exhibiting fewer brain cysts than did the control mice. Coadministration of pGM-CSF enhanced this protection. In conclusion, this study describes the design of a potent DNA vaccine encoding the novelT. gondiitarget antigen, MIC3 protein, that elicits a strong specific immune response as well as providing effective protection againstT. gondiiinfection. In the attempt to achieve complete protection against toxoplasmosis, MIC3 is a good candidate vaccine which could be combined with other relevant and previously described candidates, such as SAG1 and GRA4.
DNA Immunization with the Gene Encoding P4 Nuclease ofLeishmania amazonensisProtects Mice against Cutaneous Leishmaniasis
Authors: Campbell Kimberly , Diao Hong , Ji Jiaxiang , Soong Lynn
Published: October 2003

Infection with the protozoan parasiteLeishmania amazonensiscan cause diverse clinical forms of leishmaniasis. Immunization with purified P4 nuclease protein has been shown to elicit a protective response in mice challenged withL. amazonensisandL. pifanoi.To explore the potential of a DNA-based vaccine, we tested theL. amazonensisgene encoding P4 nuclease as well as adjuvant constructs encoding murine interleukin-12 (IL-12) andL. amazonensisHSP70. Susceptible BALB/c mice were immunized with the DNA encoding P4 alone, P4/IL-12, or P4/HSP70 prior to challenge withL. amazonensispromastigotes. Mice given P4/IL-12 exhibited no lesion development and had a 3- to 4-log reduction in tissue parasite burdens compared to controls. This protection corresponded to significant increases in gamma interferon and tumor necrosis factor alpha production and a reduction in parasite-specific immunoglobulin G1, suggesting an enhancement in Th1 responses. Moreover, we immunized mice with theL. amazonensisvaccines to determine if this vaccine regimen could provide cross-protection against a genetically diverse species,L. major. While the P4/HSP70 vaccine led to self-healing lesions, the P4/IL-12 vaccine provided negligible protection againstL. majorinfection. This is the first report of successful use of a DNA vaccine to induce protection againstL. amazonensisinfection. Additionally, our results indicate that different vaccine combinations, including DNA encoding P4, HSP70, or IL-12, can provide significant protection against both Old World and New World cutaneous leishmaniasis.
Autodisplay
Authors: Rizos Konstantin , Lattemann Claus T. , Bumann Dirk , Meyer Thomas F. , Aebischer Toni
Published: October 2003

Live attenuated
Salmonella
strains expressing antigens of pathogens are promising oral vaccine candidates. There is growing evidence that the topology of expression of the foreign antigens can have a dramatic impact on the immunogenicity. We examined the potential of the AIDA-I (
Escherichia coli
adhesin involved in diffuse adherence) autotransporter domain to display antigenic fragments of the urease A subunit of
Helicobacter pylori
for the induction of a protective immune response. In the murine
H. pylori
model, protection is mainly mediated by CD4
+
T cells, and we therefore used the AIDA-I expression system to successfully express both nearly full-length UreA and defined T-helper-cell epitopes on the surface of an attenuated
Salmonella enterica
serovar Typhimurium vaccine strain. Surface exposure of the large UreA fragment or of one UreA T-cell epitope mediated a significant reduction in the level of
H. pylori
in immunized mice after challenge infection, whereas conventional cytoplasmic expression of UreA in
Salmonella
had no effect. These results support the concept that surface display increases the immunogenicity of recombinant antigens expressed on oral live vaccine carriers and further demonstrate the feasibility of immunizing against
H. pylori
with
Salmonella
vaccine strains expressing CD4
+
T-cell epitopes.
Human Neutrophil Chemotaxis Is Modulated by Capsule and O Antigen from an Extraintestinal PathogenicEscherichia coliStrain
Authors: Russo Thomas A. , Davidson Bruce A. , Topolnycky Diana M. , Olson Ruth , Morrill Stacy A. , Knight Paul R. , Murphy Philip M.
Published: October 2003

Gram-negative enteric bacilli, such asEscherichia coli, are common causes of nosocomial pneumonia. The interaction between pulmonary neutrophils and the infecting pathogen is a critical step in determining the outcome. Previous studies from our laboratory, for which a rat model of pneumonia was used, established that pulmonary neutrophil recruitment was modulated by theE. colivirulence factors capsule and O-specific antigen. To begin to understand the mechanism by which this recruitment occurs, we conducted in vitro and ex vivo chemotaxis assays, for which we used a clinically relevantE. coliisolate (CP9) and isogenic derivatives that were deficient in only the O antigen (CP921) or capsule (CP9.137) as chemoattractants with or without the high-affinity N-formylmethionyl-leucyl-phenylalanine receptor antagonistN-tert-butoxycarbonyl-methionine-leucine-phenylalanine (N-t-BOC). Given that only liveE. coliwas used for the initial in vitro chemotaxis assays, it was predicted that onlyN-t-BOC-sensitive chemotaxis would occur. However, bothN-t-BOC-sensitive and -insensitive chemotaxis was observed.N-t-BOC-insensitive chemotaxis was mediated in part by interleukin 8, which was produced by neutrophils that had migrated towardE. coli.N-t-BOC-insensitive chemotaxis was only observed when liveE. colibacteria, not cell-freeE. coliculture supernatants, were used as chemoattractants, suggesting that a directE. coli-neutrophil interaction was necessary. The presence of both capsule and O antigen diminished total,N-t-BOC-sensitive, andN-t-BOC-insensitive neutrophil chemotaxis in vitro. The presence of capsule significantly decreased total,N-t-BOC-sensitive, andN-t-BOC-insensitive neutrophil chemotaxis ex vivo when cell-free bronchoalveolar lavage fluid from infected rats was used as the source of chemotactic factors. These effects ofE. colicapsule and O antigen on neutrophil chemotaxis are novel, and they expand our understanding of the mechanisms by which these virulence traits contribute to the pathogenesis of gram-negative pneumonia and other extraintestinal infections.
Enhanced Expression of Interleukin-1α and Tumor Necrosis Factor Receptor-Associated Protein 1 in Ileal Tissues of Cattle Infected withMycobacterium aviumsubsp.paratuberculosis
Authors: Aho Abraham D. , McNulty Amanda M. , Coussens Paul M.
Published: October 2003

Infection withMycobacterium aviumsubsp. paratuberculosisis associated with high levels of morbidity, decreased production, and early culling in dairy cattle. Clinical symptoms of Johne's disease include persistent diarrhea, inappetence, and resultant weight loss due to chronic inflammation of the small intestine. Although the presence or absence of intestinal lesions cannot be used as a definitive indicator ofM. aviumsubsp.paratuberculosisinfection, most infected cattle exhibit significant changes to intestinal mucosa, with the focus of pathology surrounding the ileal cecal junction. Typical pathology ofM. aviumsubsp.paratuberculosisinfection includes inflammation, thickening of the lumenal wall, and hyperplasia in draining lymph nodes. To further understand the pathology of Johne's disease, we compared the gene expression profiles of ileal tissues from Johne's disease-positive (n= 6), and Johne's disease-negative (n= 5) Holstein cattle. Gene expression profiles were compared with a bovine total leukocyte (BOTL-3) cDNA microarray. Genes that were expressed at significantly higher levels (>1.5-fold;P< 0.05) in tissues from Johne's disease-infected animals relative to noninfected animals included those encoding tumor necrosis factor receptor-associated protein 1 (TRAF1), interleukin-1α (IL-1α), MCP-2, N-cadherin, and β1 integrin (CD29). Dramatic upregulation of IL-1α (21.5-fold) and TRAF1 (27.5-fold) gene expression in tissues of Johne's disease-positive cows relative to tissues from control cows was confirmed by quantitative real-time PCR. Western blot analysis confirmed that IL-1α and TRAF1 mRNA levels resulted in increased protein expression in tissues of Johne's disease-positive cattle relative to tissues from control cattle. High levels of IL-1α can produce symptoms similar to those found in clinical Johne's disease. Taken together, the data presented in this report suggest that many outward symptoms of Johne's disease may be due to IL-1α toxicity. In addition, enhanced levels of TRAF1 could result in cells within the lesions of Johne's disease-positive cattle that are highly resistant to TNF-α-induced signaling.
Correlation betweencagPathogenicity Island Composition andHelicobacter pylori-Associated Gastroduodenal Disease
Authors: Nilsson Christina , Sillén Anna , Eriksson Lena , Strand Mona-Lisa , Enroth Helena , Normark Staffan , Falk Per , Engstrand Lars
Published: October 2003

Helicobacter pyloriinfection is associated with a variety of outcomes ranging from seemingly asymptomatic coexistence to peptic ulcer disease and gastric cancer. Thecagpathogenicity island (PAI) contains genes associated with a more aggressive phenotype and has been suggested to be a determinant of severe disease outcome. ThecagAgene has served as a marker for thecagPAI. However, the presence of this single gene does not necessarily indicate the presence of a complete set ofcagPAI genes. We have analyzed the composition of thecagPAI in 66 clinical isolates obtained from patients with duodenal ulcer, gastric cancer, and nonulcer dyspepsia. Hybridization of DNA to microarrays containing all the genes of thecagPAI showed that 76 and 9% of the strains contained all or none of thecagPAI genes, respectively. Partial deletions of thecagPAI were found in 10 isolates (15%), of which 3 werecagAnegative. The ability to induce interleukin-8 (IL-8) production in AGS cells was correlated to the presence of a completecagPAI. Strains carrying only parts of the island induced IL-8 at levels significantly lower than those induced bycagPAI-positive isolates. The presence of an intactcagPAI correlates with development of more severe pathology, and such strains were found more frequently in patients with severe gastroduodenal disease (odds ratio, 5.13; 95% confidence interval, 1.5 to 17.4). Partial deletions of thecagPAI appear to be sufficient to render the organism less pathogenic.
Mice Deficient in Nuclear Factor of Activated T-Cell Transcription Factor c2 Mount Increased Th2 Responses after Infection withNippostrongylus brasiliensisand Decreased Th1 Responses after Mycobacterial Infection
Authors: Erb Klaus J. , Twardzik Thomas , Palmetshofer Alois , Wohlleben Gisela , Tatsch Ursula , Serfling Edgar
Published: October 2003

Infection of nuclear factor of activated T-cell transcription factor c2 (NFATc2)-deficient mice with the helminthNippostrongylus brasiliensisled to a distinct increase in interleukin-4 (IL-4) and IL-5 protein synthesis by lymph node and spleen cells and to elevated serum immunoglobulin E (IgE) levels in comparison to those seen with infected control mice. While IL-4, IL-5, and IL-13 mRNA expression was also enhanced in lymph node cells from the lungs of infected NFATc2−/−mice, the number of T cells secreting Th2-type lymphokines remained the same in mice infected withN. brasiliensis. In contrast, lymphocytes from NFATc2-deficient mice infected withMycobacterium bovisBCG secreted less gamma interferon than lymphocytes from infected control mice. These findings indicate that NFATc2 is an activator of Th1 responses and a suppressor of Th2 responses in vivo.
Helicobacter pylori cagPathogenicity Island Is Associated with Reduced Expression of Interleukin-4 (IL-4) mRNA and Modulation of the IL-4δ2 mRNA Isoform in Human Gastric Mucosa
Authors: Orsini Barbara , Ottanelli Barbara , Amedei Amedeo , Surrenti Elisabetta , Capanni Marco , Del Prete Gianfranco , Amorosi Andrea , Milani Stefano , D'Elios Mario Milco , Surrenti Calogero
Published: October 2003

Interleukin-4 (IL-4) and IL-4δ2 mRNA gastric expression was evaluated in healthy subjects and patients who did not have ulcers but were infected withHelicobacter pyloriwith or without thecagpathogenicity island (cagPAI). IL-4 mRNA was physiologically expressed by gastric epithelium and negatively influenced byH.pylori. Also, nonepithelial cells in the lamina propria ofH.pylori-infected patients expressed IL-4 mRNA, whereas IL-4δ2 mRNA was found only incagPAI-negative patients. Thus, gastric IL-4 takes part in the local immune response toH.pylori.
Increased Density of Human Immunodeficiency Virus Type 1 Coreceptors CCR5 and CXCR4 on the Surfaces of CD4
+
T Cells and Monocytes of Patients with
Schistosoma mansoni
Infection
Authors: Secor W. Evan , Shah Amil , Mwinzi Pauline M. N. , Ndenga Bryson A. , Watta Caroline O. , Karanja Diana M. S.
Published: October 2003

Distribution of chemokine receptors CCR5 and CXCR4, which are also coreceptors for human immunodeficiency virus type 1 invasion of cells, was measured on the surfaces of CD4
+
T cells and monocytes in peripheral blood samples from a group of Kenyan car washers. Patients with active schistosomiasis displayed higher cell surface densities of these receptors than did cured schistosomiasis patients.
Viral Meningitis-Associated Hospitalizations in the United States, 1988–1999
Authors: Khetsuriani Nino , Quiroz Eva S. , Holman Robert C. , Anderson Larry J.
Published: October 2003

We used the National Hospital Discharge Survey and the Nationwide Inpatient Sample of the Health Care Cost and Utilization Project to estimate disease burden associated with viral meningitis hospitalizations in the United States. During 1988–1999, viral meningitis accounted for an estimated 434,000 hospitalizations (annual average, 36,000; average annual hospitalization rate, 14/100,000), and 2.1 million hospital days (annual average, 175,000). The estimated mean charge for viral meningitis-associated hospitalization during 1993–1997 varied between USD 6,562 and 8,313, resulting in annual estimated hospitalization costs between USD 234 and 310 million and a total estimated cost of nearly USD 1.3 billion for the 5-year period. In summary, viral meningitis remains an important cause of morbidity and financial burden and merits efforts to improve diagnostic, treatment, and prevention options.
Granulocyte Macrophage Colony-Stimulating Factor Regulates Activity of the Nervous System
Authors: Lukashenko Polina V. , Lukashenko Tamara M. , Savanovich Irina I. , Sandakov Dmitry B. , Gerein Valentin
Published: October 2003

Objectives: The peripheral administration of granulocyte macrophage colony-stimulating factor (GM-CSF), widely used for the treatment of cytopenias, is often associated with neurological effects [Lieschke et al., N Engl J Med 1992;327:28–34]. This cytokine has recently been reported to affect neurotransmitter metabolism in the nervous system [Bianchi, Neuroreport 1997;8:3587–3590]. To further investigate the neuromodulatory effect of GM-CSF we studied the influence of GM-CSF on the efferent electric activity in the splenic nerve and the integral neuronal activity in medullary gigantocellular reticular formation (MGRF) in rats. Methods: Anaesthetized (sodium thiopental 70 mg/kg, i.p.) Wistar rats were injected subcutaneously with 1 µg/kg of hr GM-CSF. Efferent electric activity in the splenic nerve and integral electric activity in MGRF were analyzed. The effectiveness of the applied dose of GM-CSF was verified by determining the elevation of the white blood cell count in peripheral blood 60 min after injection. Results: We found that GM-CSF increases efferent electric activity in the splenic nerve and decreases that of MGRF as is evident by the frequency of electric discharges. The latency of both effects was 5–15 min. Conclusions: This data support the view that GM-CSF exerts a neuromodulatory effect and may provide a new link of neuroimmune communication.
The Sympathetic Control of Blood Supply Is Different in the Spleen and Lymph Nodes
Authors: Rogausch Heiner , Böck Thomas , Voigt Karl-Heinz , Besedovsky Hugo
Published: October 2003

Objectives: The noradrenergic innervation of lymphoid organs controls several immune cell functions and local blood perfusion. Considering that cell and antigen uptake depend on the blood supply to lymphoid organs, the hypothesis was tested that feedback signals from activated immune cells control sympathetic vasomotor activity. Methods: We determined the blood flow in spleen and mesenteric lymph nodes (mLN) of Wistar Kyoto rats during immune stimulation with endotoxin (LPS; 10 µg/kg) and following disruption of the noradrenergic transmission. Results: Our data indicate that (a) the splenic noradrenaline content, which reflects the density of the sympathetic innervation, is 5 times higher in the spleen than in other peripheral organs and the spleen receives stronger tonic sympathetic input than mLN; (b) immune stimulation with LPS causes a 4-fold increase in the IL-1β production in the spleen, but only 2-fold in mLN; (c) IL-1β causes an inhibition of the sympathetic vasoconstrictor tonus in the spleen, but has no significant effect on the noradrenergic vascular tonus in mLN, and (d) in mLN, the local hyperemia induced by LPS is attenuated by the degranulation of vesicular stores of histamine and serotonin, indicating that these monoamines participate in the vasodilator effect of LPS in mLN. Conclusions: The present experiments, taken together with our previous studies, indicate that the control of blood supply to the spleen and mLN involves different mechanisms. While blood perfusion in the spleen depends on the inhibition of the noradrenergic vasoconstriction by endogenously produced IL-1β, other vasoactive mediators such as serotonin and histamine play a role in the control of mLN perfusion.
Individualized Pharmacogenetic Therapy: A Critical Analysis
Authors: Schmedders Mechtild , van Aken Jan , Feuerstein Günter , Kollek Regine
Published: October 2003

Objective: Individualized, or personalized, therapy is highlighted as the declared goal of pharmacogenetics. In this paper, the content and significance of the individualization concept are analyzed. Method: Our analysis is based on a systematic reading of the current literature pertinent to pharmacogenetics. Results: This analysis reveals that the pharmacogenetic understanding of individualization is based on a biomechanistic paradigm. In contrast to a notion of individualized therapy based on a biopsychosocial paradigm, this biomechanistic concept does not provide for individualization in psychosocial terms, but instead leads to the stratification and classification of patient populations. This finding does not necessarily cast doubt on the efficacy of pharmacogenetics, but does call its underlying ideology into question. Conclusion: The term ‘individualization of therapy’ does not reflect the real potential of pharmacogenetics, but instead represents a widely used and theoretically unjustified publicity slogan.
A Syndrome of Transient Left Ventricular Apical Wall Motion Abnormality in the Absence of Coronary Disease: A Perspective from the United States
Authors: Seth Paula S. , Aurigemma Gerard P. , Krasnow Joshua M. , Tighe Dennis A. , Untereker William J. , Meyer Theo E.
Published: October 2003

Background: The syndrome of chest pain associated with characteristic anterior electrocardiographic changes, moderate increases in cardiac enzymes, and a reversible apical wall motion abnormality in the absence of coronary artery disease has been documented in Japan, but has received relatively little attention in other countries. Methods: The clinical and echocardiographic data of 12 patients (11 women, mean age 64 ±14 years) who presented with chest symptoms, electrocardiographic (ECG) changes indicative of an acute anteroapical myocardial infarction, abnormal cardiac enzyme levels and echocardiography showing an apical wall motion abnormality were collected. Coronary angiography was performed in 10 patients. A follow-up echocardiogram was obtained within 2 weeks of the initial diagnosis in most cases. Results: An identifiable, precipitating (‘trigger’) event could be identified in all 12 individuals. Respiratory distress was present in 7, the death of a relative in 3, in 4 a surgical or medical procedure had been performed, and in 1 a panic disorder was diagnosed. The echocardiograms showed a characteristic wall motion pattern of significant apical dysfunction. All of the patients who underwent coronary arteriography had noncritical coronary artery disease. Follow-up echocardiography showed normalization of the LV dysfunction in all instances. Conclusion: We identified a syndrome of chest pain, dyspnea, ECG and enzyme changes mimicking acute myocardial infarction, similar to the ‘Takotsubo’ syndrome described in Japan. It is likely that the widespread use of echocardiography, coupled with increased recognition of this syndrome, will result in this diagnosis being made more commonly.
T-Wave Alternans in Patients with Right Ventricular Tachycardia
Authors: Kinoshita Osamu , Tomita Takeshi , Hanaoka Takeshi , Tsutsui Hiroshi , Imamura Hiroshi , Yazaki Yoshikazu , Watanabe Noboru , Hongo Minoru , Kubo Keishi
Published: October 2003

Microvolt T-wave alternans has been proposed as a new risk marker for ventricular arrhythmias. However, the clinical significance of T-wave alternans in patients with ventricular tachycardia (VT) originating from the right ventricle has been unknown. The study population consisted of 20 patients with arrhythmogenic right ventricular cardiomyopathy (ARVC) or idiopathic VT. T-wave alternans was measured during bicycle exercise testing using the CH 2000 system. Of the 7 patients with ARVC, 6 (86%) were positive for T-wave alternans. On the other hand, only 1 (8%) of 13 patients with idiopathic VT originating from the right-ventricular outflow tract was positive for T-wave alternans.
Visual Evoked Potentials in Konzo, a Spastic Paraparesis of Acute Onset in Africa
Authors: Mwanza J.-C. , Lysebo D.E. , Kayembe D.L. , Tshala-Katumbay D. , Nyamabo L.K. , Tylleskär T. , Plant G.T.
Published: October 2003

Aim: To assess whether or not visual evoked potentials (VEPs) are abnormal in konzo, a para/tetraparesis of sudden onset, and to correlate the findings to the clinical picture of the disorder. Methods: VEPs were recorded in 23 patients (9 men and 14 women, mean age: 23 ± 10 years) suffering from konzo, and 38 healthy subjects (20 men and 18 women, mean age: 27 ± 15 years). The mean P100 latencies and peak-to-peak N75-P100 amplitudes of each eye were measured and compared in the two groups. The mean interocular P100 latency and amplitude differences were calculated and also compared. Results: VEPs were abnormal in 11/23 patients (48%) consisting of P100 prolongation (7 subjects), absence of P100 wave (2 subjects) or an atypical waveform (2 subjects). The mean P100 latency value of the konzo group was significantly increased as compared with the mean (+ 2.5 SD) of the reference values from healthy subjects (p < 0.05). There was a statistically significant decrease of amplitude in konzo patients compared to normal subjects (p < 0.05) with, however, only 2 patients outside the 95% confidence limits. Six patients (27%) had abnormal VEPs despite normal visual acuity. These abnormalities were symmetric and a relation could be found between neither the duration nor the severity of the disease and the VEP perturbation. Conclusion: The main features of these abnormalities are delayed P100 latency and decreased amplitude. These findings indicate involvement of visual pathways and seem to suggest the presence of axonal loss in the prechiasmal visual pathways in konzo. This study provides evidence that the neurodamage in konzo extends to the visual pathways.
Long-Term Results of Transscleral Cyclophotocoagulation in Refractory Pediatric Glaucoma Patients
Authors: Autrata R. , Rehurek J.
Published: October 2003

We evaluated efficacy and complications of diode laser cyclophotocoagulation in pediatric patients with refractory glaucomas. The retrospective study comprised 69 eyes of 53 pediatric patients with uncontrolled refractory glaucoma treated by transscleral diode laser cyclophotocoagulation. The mean age was 6.1 ± 4.29 (range 0.9–15) years. The main parameters evaluated were: intraocular pressure (IOP), visual acuity, and complications. The mean follow-up period was 5.6 ± 2.8 (range 2.2–9.5) years. Treatment success was defined as a postoperative IOP of ≤21 mm Hg, with or without adjunctive glaucoma medications. The baseline mean pretreatment IOP was 34.08 ± 7.13 (range 24–47) mm Hg. The final mean postoperative IOP was 20.81 ± 6.38 (range12–33) mm Hg after a mean of 2.13 ± 1.47 (range 1–6) laser procedures. After one treatment session, 66% of the eyes had a successful reduction in IOP (≤21 mm Hg), but this had fallen to 41% by 1 year. With repeat cyclophotocoagulation, 79% of the eyes had a clinically effective reduction in IOP(≤21 mm Hg) for 1 year (mean 7.1-month interval between treatments). Postoperative complications included choroidal detachment in 4 eyes and retinal detachment in 2 eyes with progression of vision loss. All these complications occurred in aphakic patients. Cyclophotocoagulation by diode laser is a useful therapy for the treatment of refractory pediatric glaucomas with uncontrolled IOP. Cyclodiode repeated treatment can provide effective control of IOP with a low risk of severe complications. Aphakic patients may have an increased risk of postoperative complications.
Poikilodermatous Subacute Cutaneous Lupus erythematosus
Authors: Marzano Angelo V. , Facchetti Maura , Alessi Elvio
Published: October 2003

Background: Subacute cutaneous lupus erythematosus (SCLE) is a distinct subset of lupus erythematosus with unique clinical, immunological and genetic features. Among the unusual variants of SCLE, there is a poikilodermic presentation. However, to date, only 1 case of poikilodermatous SCLE has been reported. Objective: Our goal was to summarize the clinical characteristics and course as well as the pathological, laboratory and immunofluorescence findings of 4 patients with poikilodermatous SCLE. Methods: A retrospective study was conducted including 54 patients diagnosed as having SCLE between 1980 and 2002. Results: Four patients (7.4%) had SCLE. All patients were alive, and none developed severe systemic involvement in up to 36 years (median, 24 years) after the onset of disease. The most noteworthy laboratory finding was the cutaneous deposition of amyloid. Conclusion: Poikilodermatous SCLE represents an uncommon variant within the clinicopathological spectrum of SCLE following a favorable course, in spite of extensive cutaneous involvement. Photosensitivity is the pathomechanism explaining, theoretically, the development of both poikiloderma and cutaneous amyloidosis in such cases.
Microsatellite Instability as a Predictor of Survival in Head and Neck Cancer – Is There a Link with Colon Cancer?
Authors: Gleich Lyon L. , Wang Jiang , Gluckman Jack L. , Fenoglio-Preiser Cecilia M.
Published: October 2003

Objective:A reliable genetic marker to predict outcome for head and neck cancer is needed. In colon cancer, microsatellite instability (MSI) predicts response to therapy and improved prognosis. Colon cancer patients with MSI have a 60% improvement in survival as compared to patients without MSI. To assess whether MSI is a predictor of improved prognosis in head and neck cancer we used our tumor registry to find 8 patients treated between 1995 and 1998 with head and neck squamous cell carcinoma and either a history of colon cancer or a parent who had colon cancer. As a control, 15 T2 or T3 oral cavity cancers were used. Methods: The tumor specimens were obtained and laser capture microdissected for analysis using the following microsatellite markers: BAT25, BAT26, BAT40, D1S2883, D2S123, D3S1611, D5S346, D7S501 and D8S25. Results: All 8 patients with head and neck cancer and a colon cancer history exhibited MSI or loss of heterozygosity (LOH) at 1 or more of the markers tested. Three patients had 2 abnormal markers, 1 patient had 3 abnormal markers and 1 had 7 abnormal markers. Only 1 of the patients with a colon cancer history, all of whom had MSI, developed recurrent head and neck cancer. Of the 15 control patients, 5 had MSI or LOH and 1 had MSI or LOH at 2 markers. Three of the 5 patients with MSI or LOH had a recurrence; hence MSI and LOH at these markers were uncommon, and there was no relation between MSI and outcome in patients without a history of colon cancer. Conclusions: These results support a possible alternative mode of carcinogenesis in patients with head and neck cancer and a history of colon cancer and, most significantly, that these cancers are a subgroup of head and neck cancer that may have a better prognosis.
Extensive Tension Pneumocephalus Complicating Continuous Lumbar CSF Drainage for the Management of CSF Rhinorrhoea
Authors: Mirza S. , Saeed S.R. , Ramsden R.T.
Published: October 2003

We report a case of tension pneumocephalus developing after a continuous lumbar CSF drain had been inserted for the treatment of CSF rhinorrhoea following translabyrinthine removal of a vestibular schwannoma. Despite conservative management, the patient developed recurrent CSF rhinorrhoea and hydrocephalus requiring explorations of the petromastoid cavity, an external ventricular drain and eventually a lumbar-peritoneal shunt. The prevention and management of pneumocephalus secondary to continuous lumbar CSF drainage is briefly reviewed.
Natural Killer Cell Lymphoma of the Parotid Gland
Authors: Furukawa Masayuki , Suzuki Hideaki , Tohmiya Yasuo , Matsuura Kazuto , Takahashi Etsu , Ichinohasama Ryo , Kobayashi Toshimitsu
Published: October 2003

The majority of all parotid lymphomas are of the non-Hodgkin type and of B-cell origin. Primary natural killer cell lymphomas of the parotid gland are extremely rare. We present a case of natural killer cell lymphoma in a 34-year-old woman. The disease was refractory to chemotherapy, and the patient eventually succumbed due to lymphoma-associated hemophagocytic syndrome.
Influence of Vagus Nerve Stimulation on Vestibulo-Ocular Reflex
Authors: Gatzonis Stylianos D. , Korres Stavros , Balatsouras Dimitrios G. , Stabulis Eleftherios , Georgakulias Nikolaos , Singunas Evangelos , Siafakas Alexandros , Sakas Damianos
Published: October 2003

Vagus nerve stimulation (VNS), as used for the treatment of intractable epilepsy, may interfere with signals from viscera and modify the integration of autonomic afferent fibers in the brainstem. In order to detect an influence of VNS on vestibular function, the vestibulo-ocular reflex (VOR) of 5 patients was examined before and during VNS. Nonsignificant alterations of the maximum slow-phase velocity of the VOR were found. A significant clinical alteration of the VOR during VNS was not observed.
Pericardial Teratoma: Prenatal Diagnosis and Course
Authors: Tollens M. , Grab D. , Lang D. , Hess J. , Oberhoffer R.
Published: October 2003

We report on a case of primary pericardial teratoma detected in a 29-week-old fetus. Due to cardiac decompensation, pericardiocentesis was performed at 33 weeks of gestation, and surgical excision of the tumor was indicated shortly after birth. The present report draws attention to the impact of fetal echocardiography on perinatal management.
Recurrent Trisomy 21 and Uniparental Disomy 21 in a Family
Authors: Bán Zoltán , Nagy Bálint , Papp Csaba , Beke Artúr , Tóth-Pál Ernő , Papp Zoltán
Published: October 2003

Objective: A 32-year-old pregnant woman was referred to our genetic counselling because of recurrent trisomy 21 in the family. Analysis of amniotic fluid cell culture revealed karyotype 47,XY+21 of the fetus. Methods: Karyotyping and molecular analysis were undertaken in the fetal and parental samples to determine the origin of the extra chromosome 21. Results: Both parents had a normal blood karyotype. Microsatellite marker analysis showed maternal origin of the fetal extra chromosome 21. As the mother showed homozygosity for all investigated markers on chromosome 21, we also tested her family. We detected the same homozygosity in some family members which was consistent with isodisomy of the chromosome 21 caused by uniparental disomy (UPD). Conclusions: Here we report on a family in which multiple aneuploid conceptions occurred with trisomy 21, and molecular analysis showed that the euploidy of the investigated healthy family members is due to UPD21. This observation stresses the importance of prenatal cytogenetic and molecular analysis in case of parental UPD.
Effect of an Increase of the Hematocrit on Middle Cerebral Artery Peak and Umbilical Vein Maximum Velocities in Anemic Fetuses
Authors: Sikkel Esther , Vandenbussche Frank P.H.A. , Oepkes Dick , Klumper Frans J.C.M. , Teunissen Katinka A.K. , Meerman Robertjan H. , Le Cessie Saskia , Kanhai Humphrey H.H.
Published: October 2003

Objective: To measure the effects of acute large increases of the hematocrit on fetal peak arterial and maximum venous blood flow velocities. Methods: Middle cerebral artery peak flow velocities and umbilical vein maximum flow velocities were measured before, immediately after, and 12–24 h after intrauterine transfusions. All measurements were standardized for gestational age. Results: Complete measurements were obtained at 60 intrauterine transfusions. The mean hematocrit before intrauterine transfusion was 0.19 l/l and after 0.40 l/l. The middle cerebral artery peak flow velocity decreased immediately after transfusion in 59 of the 60 cases. There was a rise in umbilical vein maximum flow velocity immediately after intrauterine transfusion in 37 of the 60 cases. The sensitivity of middle cerebral artery peak flow velocity for severe anemia before intrauterine transfusion was 54% and the specificity 57%. The sensitivity of umbilical vein maximum flow velocity for severe anemia before intrauterine transfusion was 67% and the specificity 57%. Conclusions: An acute large increase of the fetal hematocrit significantly decreases middle cerebral artery peak flow velocity. The effect on umbilical vein maximum velocity is, however, unpredictable.
Modeling and E-M Estimation of Haplotype-Specific Relative Risks from Genotype Data for a Case-Control Study of Unrelated Individuals
Authors: Stram Daniel O. , Leigh Pearce Celeste , Bretsky Phillip , Freedman Matthew , Hirschhorn Joel N. , Altshuler David , Kolonel Laurence N. , Henderson Brian E. , Thomas Duncan C.
Published: October 2003

The US National Cancer Institute has recently sponsored the formation of a Cohort Consortium (http://2002.cancer.gov/scpgenes.htm) to facilitate the pooling of data on very large numbers of people, concerning the effects of genes and environment on cancer incidence. One likely goal of these efforts will be generate a large population-based case-control series for which a number of candidate genes will be investigated using SNP haplotype as well as genotype analysis. The goal of this paper is to outline the issues involved in choosing a method of estimating haplotype-specific risk estimates for such data that is technically appropriate and yet attractive to epidemiologists who are already comfortable with odds ratios and logistic regression. Our interest is to develop and evaluate extensions of methods, based on haplotype imputation, that have been recently described (Schaid et al., Am J Hum Genet, 2002, and Zaykin et al., Hum Hered, 2002) as providing score tests of the null hypothesis of no effect of SNP haplotypes upon risk, which may be used for more complex tasks, such as providing confidence intervals, and tests of equivalence of haplotype-specific risks in two or more separate populations. In order to do so we (1) develop a cohort approach towards odds ratio analysis by expanding the E-M algorithm to provide maximum likelihood estimates of haplotype-specific odds ratios as well as genotype frequencies; (2) show how to correct the cohort approach, to give essentially unbiased estimates for population-based or nested case-control studies by incorporating the probability of selection as a case or control into the likelihood, based on a simplified model of case and control selection, and (3) finally, in an example data set (CYP17 and breast cancer, from the Multiethnic Cohort Study) we compare likelihood-based confidence interval estimates from the two methods with each other, and with the use of the single-imputation approach of Zaykin et al. applied under both null and alternative hypotheses. We conclude that so long as haplotypes are well predicted by SNP genotypes (we use the R2h criteria of Stram et al. [1]) the differences between the three methods are very small and in particular that the single imputation method may be expected to work extremely well.