bluuebunny/crossref_metadata_2025 huggingface dataset:
Novel gene functions required for melanization of the human pathogen Cryptococcus neoformans
Authors: Walton Felicia J. , Idnurm Alexander , Heitman Joseph
Published: August 2005

The ability to produce melanin is a key virulence factor in many fungal pathogens including the human basidiomycete pathogen Cryptococcus neoformans, a major cause of life‐threatening infections among immunocompromised persons. Despite the significance of melanin biosynthesis in virulence of C. neoformans, the cellular and molecular processes involved in this pathway have not yet been fully elucidated. Here, we used Agrobacterium to isolate insertional mutants and screened 12 000 mutants to uncover genes involved in melanin production in C. neoformans. Four new mutant alleles of the well‐known melanin biosynthesis gene, LAC1, which encodes laccase were identified, and the T‐DNA was shown to have a possible predisposition for insertion into the promoters of genes, in particular LAC1. Melanization in C. neoformans is dependent on five additional genes identified in this screen encoding homologues of the copper transporter Ccc2, the copper chaperone Atx1, the chitin synthase Chs3, the transcriptional coactivator Mbf1 and the chromatin‐remodelling enzyme Snf5. Illumination of the molecular and genetic components of this virulence pathway reveals potential novel targets for drug development against C. neoformans and provides further insight into the intimate relationship between metal ion homeostasis and melanin biosynthesis.
The Dif chemosensory pathway is directly involved in phosphatidylethanolamine sensory transduction in Myxococcus xanthus
Authors: Bonner Pamela J. , Xu Qian , Black Wesley P. , Li Zhuo , Yang Zhaomin , Shimkets Lawrence J.
Published: August 2005

Myxococcus xanthus cells glide on solid surfaces and are chemotactically stimulated by certain phosphatidylethanolamine species. The dif gene cluster consists of six genes, difABCDEG, five of which encode proteins homologous to known chemotaxis proteins. DifA and DifE are required for the biosynthesis of fibrils, an extracellular matrix comprised of polysaccharide and protein. Chemotactic stimulation by 1,2‐O‐Bis[11‐(Z)‐hexadecenoyl]‐sn‐glycero‐3‐phosphatidylethanolamine (16:1 PE) and dilauroyl PE (12:0 PE) requires fibrils. Although previous work has shown that difA and difE mutants are not stimulated by 12:0 PE, these results do not distinguish between a dependence on fibrils or a direct role in chemosensory transduction. Here we provide evidence that the Dif chemosensory pathway directly mediates PE sensory transduction. First, stimulation by and adaptation to 16:1 PE requires all of the dif genes, including difBDG, which are not essential for fibril biogenesis. Second, a specific residue within the first putative methylation domain of DifA is required for stimulation by 16:1 PE but not fibril biogenesis. Transmembrane signalling through a chimeric NarX‐DifA chemoreceptor is required for fibril formation but not for stimulation by or adaptation to 16:1 PE. Third, difD and difE are required for stimulation by dioleoyl PE (18:1 PE) although the response does not require fibrils. Taken together these results argue that the Dif pathway mediates both matrix formation and lipid chemotaxis.
ANTI‐INFECTIVE THERAPY AT END OF LIFE: ETHICAL DECISION‐MAKING IN HOSPICE‐ELIGIBLE PATIENTS
Authors: FORD PAUL J. , FRASER THOMAS G. , DAVIS MELLAR P. , KODISH ERIC
Published: August 2005

Clear guidelines addressing the ethically appropriate use of anti‐infectives in the setting of hospice care do not exist. There is lack of understanding about key treatment decisions related to infection treatment for patients who are eligible for hospice care. Ethical concerns about anti‐infective use at the end of life include: (1) delaying transition to hospice, (2) prolonging a dying process, (3) prescribing regimens incongruent with a short life expectancy and goals of care, (4) increasing the reservoir of potential resistant pathogens, (5) placing unreasonable costs on a capitated hospice system. Although anti‐infectives are thought to be relatively safe, they can place a burden on patients and be inconsistent to particular care plans. The current complex, and at times fragmented, medical care often fails to address these issues in decision‐making. In many ways, the ethics governing the end of life decisions related to dialysis, hydration/nutrition, and hypercalcemia parallel those of anti‐infectives. In this article we articulate important elements in ethical decision‐making in the application of anti‐infectives for patients who are eligible for hospice care, and we point to the need for prospective studies to help refine particular guidelines in these cases.
SOME ETHICAL ISSUES ARISING FROM POLIO ERADICATION PROGRAMMES IN INDIA
Authors: PAUL YASH , DAWSON ANGUS
Published: August 2005

The World Health Organisation's programme for the eradication of poliomyelitis as currently practised in India raises many ethical issues. In this paper we concentrate on just two. The first is the balance to be struck between the risks and benefits generated by the eradication programme itself. The issue of risks and benefits arises in relation to the choice between two different vaccine types available for polio programmes: oral polio vaccine (OPV) and inactivated polio vaccine (IPV). OPV is the vaccine currently used in the eradication campaign in India. We argue that given the current risks/benefits profile of this vaccine, there is an urgent need to review the programme and take remedial action to address existing problems (at least in India). The second issue we discuss is the fact that there is little effort to gain the informed consent of the parents of vaccinated children, as they are not currently told about the potential limitations of OPV or the possibility of vaccine‐induced harm. We suggest that such a policy might be justifiable, given the importance of polio eradication, but only if there is a system of compensation for vaccine‐induced harm as part of the eradication programme itself. There is a real danger that if these issues are not addressed then public trust in the eradication programme and vaccination programmes as a whole will be lost.
PUBLIC COMMUNICATION, RISK PERCEPTION, AND THE VIABILITY OF PREVENTIVE VACCINATION AGAINST COMMUNICABLE DISEASES
Authors: MAY THOMAS
Published: August 2005

Because of the nature of preventive vaccination programs, the viability of these public health interventions is particularly susceptible to public perceptions. This is because vaccination relies on a concept of ‘herd immunity’, achievement of which requires rational public behavior that can only be obtained through full and accurate communication about risks and benefits. This paper describes how irrational behavior that threatens the effectiveness of vaccination programs – both in crisis and non‐crisis situations – can be tied to public perceptions created by media portrayals of health risks. I concentrate on childhood vaccination as an exemplar of ‘non‐crisis’ preventive vaccination, and on the recent flu vaccine shortage as a ‘crisis’ situation. The paper concludes with an examination of the steps necessary to resolve these threats through better public communication.
PREPARING FOR AN INFLUENZA PANDEMIC: ETHICAL ISSUES
Authors: KOTALIK JARO
Published: August 2005

In the near future, experts predict, an influenza pandemic will likely spread throughout the world. Many countries have been creating a contingency plan in order to mitigate the severe health and social consequences of such an event. Examination of the pandemic plans of Canada, the United Kingdom and the United States, from an ethical perspective, raises several concerns. One: scarcity of human and material resources is assumed to be severe. Plans focus on prioritization but do not identify resources that would be optimally required to reduce deaths and other serious consequences. Hence, these plans do not facilitate a truly informed choice at the political level where decisions have to be made on how much to invest now in order to reduce scarcity when a pandemic occurs. Two: mass vaccination is considered to be the most important instrument for reducing the impact of infection, yet pandemic plans do not provide concrete estimates of the benefits and burdens of vaccination to assure everyone that the balance is highly favorable. Three: pandemic plans make extraordinary demands on health care workers, yet professional organizations and unions may not have been involved in the plans’ formulation and they have not been assured that authorities will aim to protect and support health care workers in a way that corresponds to the demands made on them. Four: all sectors of society and all individuals will be affected by a pandemic and everyone's collaboration will be required. Yet, it appears that the various populations have been inadequately informed by occasional media reports. Hence, it is essential that plans are developed and communication programs implemented that will not only inform but also create an atmosphere of mutual trust and solidarity; qualities that at the time of a pandemic will be much needed.
MACROECONOMIC UNCERTAINTY AND MACROECONOMIC PERFORMANCE: ARE THEY RELATED?
Authors: BREDIN DON , FOUNTAS STILIANOS
Published: August 2005

We use a very general bivariate generalized autoregressive conditional heteroskedasticity‐in‐mean model and G7 monthly data covering the 1957–2003 period to test for the impact of real and nominal macroeconomic uncertainty on inflation and output growth. Our evidence supports a number of important conclusions. First, in most countries output growth uncertainty is a positive determinant of the output growth rate. Second, there is mixed evidence regarding the effect of inflation uncertainty on inflation and output growth. Hence, contrary to popular belief, uncertainty about the inflation rate is not necessarily detrimental to economic growth but in some cases it may also enhance growth. Finally, there is mixed evidence on the effect of output uncertainty on inflation. In sum, our results indicate that macroeconomic uncertainty may even improve macroeconomic performance.
MEASURING MONETARY POLICY IN THE UK: A FACTOR‐AUGMENTED VECTOR AUTOREGRESSION MODEL APPROACH
Authors: LAGANÀ GIANLUCA , MOUNTFORD ANDREW
Published: August 2005

This paper investigates the determinants of UK interest rates using a factor‐augmented vector autoregression model (VAR), similar to the one suggested by Bernanke, Boivin and Eliasz (Quarterly Journal of Economics, Vol. 120 (2005), No. 1, pp. 387–422). The method allows impulse response functions to be generated for all the variables in the data set and so is able to provide a more complete description of UK monetary policy than is possible using standard VARs. The results show that the addition of factors to a benchmark VAR generates a more reasonable characterization of the effects of unexpected increases in the interest rate and, in particular, gets rid of a ‘price puzzle’ response present in the benchmark VAR. The extra information generated by this method, however, also brings to light other identification issues, notably house price and stock market ‘puzzles’. Importantly the out‐of‐sample prediction performance of the factor‐augmented VARs is also very good and strongly superior to those of the benchmark VAR and simple autoregression models.
Ideological Typologies of Contemporary British Conservatism
Authors: Heppell Timothy , Hill Michael
Published: August 2005

Prior to the leadership of Margaret Thatcher, traditional academic assumptions about the British Conservative party focused on its emphasis on party unity, the centrality of loyalty to the party, and its ideological pragmatism in the pursuit of power. The leadership of her successor, John Major, was undermined by disunity, disloyalty and ideological conflict, which contributed to the Tory party's removal from power. The ideological implosion of one the most disciplined and electorally successful parties in Western Europe, has stimulated considerable academic appraisal. This article considers the design and utilisation of the ideological typologies of contemporary British conservatism that have been used by academics to help explain the nature of this ideological conflict. By analysing these developments in typological design, we can enhance our understanding of the ideological realignment of contemporary British conservatism in the immediate post-Thatcherite era.
Detection of Helicobacter pylori‐Specific Genes in the Oral Yeast
Authors: Siavoshi Farideh , Salmanian Ali Hatef , Kbari Fereshteh Akbari , Malekzadeh Reza , Massarrat Sadegh
Published: August 2005

Backgrounds.  Until today, human stomach is the only recognized habitat of Helicobacter pylori. However, recruitment of DNA‐based methods has made possible the detection of H. pylori in water and oral cavity, thus suggesting fecal–oral and oral–oral routes for transmission of H. pylori, respectively. In this study, yeast has been proposed as a common vector for transmission of H. pylori. Thus designed primers were recruited to target 16S rDNA and cagA genes in the oral yeasts by PCR.

Materials and methods.  Eighteen yeasts were examined microscopically for the presence of bacterial‐like bodies. DNAs were extracted from oral yeasts using phenol–chloroform method. Amplification conditions were optimized as 33 cycles and annealing temperatures of 63 °C for 16S rDNA and 51 °C and 52 °C for cagA gene which was targeted in two steps. DNAs of H. pylori and Saccharomyces cerevisiae were used as controls. Polymerase chain reaction (PCR) products of two genes from one yeast and from H. pylori were cloned in pCAP and subsequently subcloned in pSK+ and were sequenced.

Results.  Bacterial‐like bodies were observed in all oral yeasts. The amplified products of 16S rDNA from all oral yeasts were homologous in size with those of H. pylori. Fifteen out of eighteen (83%) yeasts contained cagA gene, homologous to H. pylori. CagA was not amplified from three yeasts and S. cerevisiae. Analysis of the sequenced products of 16S rDNA and cagA from one oral yeast showed 98% homology with those of H. pylori.

Conclusions.  The presence of H. pylori inside the yeast was indicated by light microscopy and PCR. It appears that yeasts, which are abundant in nature and thrive the mucosal surfaces of human, might serve as reservoirs and vehicles of H. pylori.
Experimental Helicobacter pylori Infection Induces Antral‐Predominant, Chronic Active Gastritis in Hispid Cotton Rats (Sigmodon hispidus)
Authors: Mähler Michael , Heidtmann Wiebke , Niewiesk Stefan , Gruber Achim , Fossmark Reidar , Beil Winfried , Hedrich Hans , Wagner Siegfried
Published: August 2005

Background.  The hispid cotton rat has proven to be an excellent animal model for a variety of human infectious disease agents. This study was performed to evaluate the use of the cotton rat as a model of Helicobacter pylori infection.

Materials and methods.  Thirty‐eight inbred cotton rats were orogastrically inoculated with a human strain of H. pylori. Twenty‐eight control cotton rats were dosed with vehicle only. Animals were sacrificed at 2, 4, 12, 26, or 38 weeks after inoculation for bacterial and histologic and immunologic examinations.

Results.  Helicobacter pylori was cultured from the glandular stomach of 89% of the infected cotton rats. The level of colonization was consistently high (approximately 104−6 colony‐forming units/g tissue). Histologically, the spiral bacteria were demonstrated on the epithelial surface and in the foveolae of the gastric mucosa with highest numbers in the antrum. H. pylori infection was associated with antral‐predominant, chronic active gastritis which progressively increased in severity over time. By week 26 of infection, moderate antral gastritis had developed with frequent involvement of the submucosa and formation of lymphocytic aggregates. Splenic T cells from infected cotton rats expressed mRNAs for interferon‐γ, interleukin‐4, interleukin‐6, and interleukin‐10 following in vitro stimulation with H. pylori. Serum levels of H. pylori‐specific immunoglobulin G were significantly elevated after 12 weeks of infection.

Conclusions.  The H. pylori‐infected cotton rat represents a novel animal model that should prove useful for studies of H. pylori‐induced chronic active gastritis and factors affecting gastric colonization by this pathogen.
Role of Chronic Infection and Inflammation in the Gastrointestinal Tract in the Etiology and Pathogenesis of Idiopathic Parkinsonism
Authors: Weller Clive , Charlett André , Oxlade Norman L. , Dobbs Sylvia M. , Dobbs R. John , Peterson Dale W. , Bjarnason Ingvar T.
Published: August 2005

Background. EradicatingHelicobactermay convert rapidly progressive idiopathic parkinsonism to quieter disease, however only a minority of probands have evidence of current infection.

Aim. To explore the cross‐sectional fit of parkinsonism as an extra‐alimentary consequence ofHelicobacter pylori, using the serum antibody profile.

Methods. A discriminant index for parkinsonism was based on the Western Blot pattern of IgG antibodies against electrophoretically separatedH. pyloriantigens in 124 subjects with idiopathic parkinsonism, 196 without. In parkinsonism, association was assessed between index and 1, anthropometric measures; 2, current and 3, increase over 4 years in hypokinetic and psychomotor/psychometric disability; and 4, a global score of current severity.

Results. Predicted probability of being labeled parkinsonian was greatest with cytotoxin‐associated‐gene‐product (CagA) positivity and vacuolating‐toxin negativity (p = .03 and .004, respectively, for antibody‐age interactions), and urease‐B negativity (p = .03, irrespective of age). In this circumstance, the odds for parkinsonism increased fivefold by age 80 years (p = .001).Helicobacterstatus, according to anti‐urease enzyme‐linked immunosorbent assay (ELISA), did not complement the model. Gradients, of clinically relevant size, were found between index and disease burden, despite the potentially confounding effect of antiparkinsonian medication. The higher the index 1, the worse was posture, as gauged by forward displacement of occiput (p = .04), 2, the shorter mean stride‐length (p = .003), longer reaction time (= .002) and lesser cognitive efficiency (= .03), 3, the greater their deterioration (p = .006, .002, and .03 respectively), and 4, the greater the overall severity of parkinsonism (< .001).

Conclusion. The apparent importance ofH. pyloriin the etiology/pathogenesis of idiopathic parkinsonism is not confined to those with evidence of current infection.
Role of Chronic Infection and Inflammation in the Gastrointestinal Tract in the Etiology and Pathogenesis of Idiopathic Parkinsonism
Authors: Dobbs R. John , Dobbs Sylvia M. , Weller Clive , Bjarnason Ingua T. , Oxlade Norman L. , Charlett André , Al‐Janabi Mazin A. , Kerwin Robert W. , Mahler Robert F. , Price Ashley B.
Published: August 2005

Background.  Neuronal damage in idiopathic parkinsonism may be in response to ubiquitous occult infection. Since peptic ulceration is prodromal, Helicobacter is a prime candidate.

Aim.  To consider the candidature of Helicobacter in parkinsonism with cachexia.

Methods.  We explore the relationship between being underweight and inflammatory products in 124 subjects with idiopathic parkinsonism and 195 controls, and present the first case‐series evidence of efficacy of Helicobacter eradication, in parkinsonism advanced to the stage of cachexia.

Results.  Association of a low body mass index with circulating interleukin‐6 was specific to parkinsonism (p = .002), unlike that with antibodies against Helicobacter vacuolating‐toxin and cytotoxicity‐associated gene product (p < .04). Marked reversibility in both cachexia and disability of idiopathic parkinsonism followed Helicobacter heilmannii eradication in one case, Helicobacter pylori eradication in another, follow‐up being ≥ 3.5 years. The latter presented with postprandial bloating, and persistent nausea: following eradication, radioisotope gastric‐emptying returned towards normal, and upper abdominal symptoms regressed. Reversibility of their cachexia/disability contrasts with the outcome of anti‐Helicobacter therapy where eradication repeatedly failed (one case), and in non‐Helicobacter gastritis (three cases). Anti‐parkinsonian medication remained constant. Intestinal absorption and barrier function were normal in all.

Conclusion.  Categorization, according to presence or absence of Helicobacter infection, was a useful therapeutic tool in late idiopathic parkinsonism.
Surface Atrial Frequency Analysis in Patients with Atrial Fibrillation: Assessing the Effects of Linear Left Atrial Ablation
Authors: RAINE DAN , LANGLEY PHILIP , MURRAY ALAN , FURNISS STEPHEN S. , BOURKE JOHN P.
Published: August 2005

Introduction: Our group has shown previously that measurements of atrial frequency can be obtained from surface 12‐lead ECG recordings of patients during atrial fibrillation (AF), using a combination of principal component and Fourier transform algorithms. Such measurements are reproducible over time and change with drug manipulation of the arrhythmia.

Aims: To determine whether linear left atrial ablation, using a combination of “roof” and “mitral isthmus” lines results in changes in surface atrial frequency during AF and to assess the contribution of each individual line when sited sequentially.

Methods and Results: Computerized recordings from 26 patients, who had undergone linear ablation procedures for AF, were reviewed. The atrial signal was extracted from the 12‐lead ECG data by principal component analysis and the main frequency component identified using Fourier analysis. Atrial frequency before and after these two standard ablation lines was compared. Atrial frequency decreased significantly after the combination of roof and mitral isthmus lines (5.66 vs 5.15 Hz) and when either roof (5.61 vs 5.13 Hz) or mitral isthmus (5.89 vs 5.75 Hz) lines were sited first. However, only the roof line led to a significant reduction in atrial frequency when sited second (5.64 vs 5.49 Hz).

Conclusions: Measurements of atrial frequency can be obtained from surface 12‐lead ECG recordings during AF and change as predicted in response to linear left atrial ablation. This technique may be useful in assessing antiarrhythmic treatments for AF.
Prolongation of Atrial Effective Refractory Period with Biatrial Nonexcitatory Stimulation
Authors: CHAN JOSEPH Y.S. , FUNG JEFFERY W.H. , CHAN HAMISH C.K. , CHAN WINNIE W.L. , YU CHEUK MAN , SANDERSON JOHN E.
Published: August 2005

Background: A nonexcitatory, nonpropagating atrial extrastimulus delivered in the refractory period of the preceding cycle can prolong the atrial effective refractory period (AERP) and prevent the induction of atrial fibrillation by another AE introduced in the vulnerable period. Whether the effect of this nonexcitatory stimulation (NE) is confined only to its application site is unknown.

Methods and Results: Sixteen consecutive patients were recruited into the study and 2 patients were excluded because of development of more sustained atrial fibrillation. NE was commenced by introduction of a 2.0 msec, 20‐mA impulse at 50 msec after the preceding captured pacing impulse. AERP of right atrial septum, a distant site to NE application, was determined at baseline and after 5 minutes of steady pacing at six different protocols: protocol 1, 2, and 3 were conventional pacing at high right atrium, distal coronary sinus, and biatrial sites, respectively, and protocol 4, 5, and 6 were conventional pacing together with NE applied to the same sites as protocol 1, 2, and 3. Biatrial NE (protocol 6 with median AERP = 212.5 msec) significantly prolonged AERP compared with baseline (median AERP = 202.5 msec and P < 0.05), conventional pacing (protocol 1, 2, and 3 with median AERP = 205.0 msec, 205.0 msec, and 205.0 msec, respectively, and all P < 0.05), and single‐site NE (protocol 4 and 5 with median AERP = 207.5 msec and 207.5 msec, respectively, and both P < 0.05).

Conclusion: Biatrial NE resulted in AERP prolongation even at sites distant to NE application. The study result suggests that by adding NE to multi‐sites pacing for atrial fibrillation prevention may have additional benefit.
Mechanisms for the Maintenance of Ventricular Fibrillation: The Nonuniform Dispersion of Refractoriness, Restitution Properties, or Anatomic Heterogeneities?
Authors: QIN HAO , HUANG JIAN , ROGERS JACK M. , WALCOTT GREGORY P. , ROLLINS DENNIS L. , SMITH WILLIAM M. , IDEKER RAYMOND E.
Published: August 2005

Introduction: The relative importance of nonuniform dispersion of refractoriness, steep restitution slopes, and anatomic heterogeneities in causing conduction block during ventricular fibrillation (VF) remains unknown.

Methods and Results: In six open‐chest pigs, ventricular refractoriness and restitution curves were estimated from activation recovery intervals (ARIs) calculated from 504 (21 × 24) unipolar electrode recordings 2 mm apart in a plaque sutured to the left ventricular (LV) free wall. A steady‐state restitution protocol was performed twice at each of two pacing sites: the LV base and near the left anterior descending artery. VF was electrically induced four times and the incidence of conduction block at each electrode during the first 20 seconds was determined by an automated algorithm. The gradient of the ARI was calculated at each electrode to estimate the spatial dispersion of refractoriness. An exponential curve was fit to the restitution plots of ARIs versus the corresponding diastolic intervals (DIs) for all pacing cycle lengths at each electrode. The locations of epicardial blood vessels were noted after the study. Spatial patterns of conduction block were significantly correlated between the four VF episodes in the same animal (r = 0.66 ± 0.07, P < 0.05). At the shortest pacing cycle length, the spatial distribution of ARIs, ARI gradients, and restitution slopes was not random but formed clusters of similar values. However, none of these variables was significantly correlated with the incidence of conduction block, even though ARI gradients >2 msec/mm were present between many clusters and ∼90% of restitution slopes were >1. Instead, conduction block frequently appeared to cluster along epicardial vessels.

Conclusion: Neither the dispersion of refractoriness nor action potential duration restitution determined during rapid pacing by itself is the major determinant of the location of conduction block during early VF in normal pigs. It may be that these factors interact synergistically with each other as well as with other factors, including anatomic heterogeneities such as those caused by blood vessels, which may be particularly important for the formation of conduction block and maintenance of VF.
Multicenter, Prospective, Randomized Safety and Efficacy Study of a New Atrial‐Based Managed Ventricular Pacing Mode (MVP) in Dual Chamber ICDs
Authors: SWEENEY MICHAEL O. , ELLENBOGEN KENNETH A. , CASAVANT DAVID , BETZOLD ROBERT , SHELDON TODD , TANG FENG , MUELLER MEGAN , LINGLE JOHN ,   The Marquis MVP Download Investigators
Published: August 2005

Background: Ventricular desynchronization caused by right ventricular pacing may impair ventricular function and increase risk of heart failure (CHF), atrial fibrillation (AF), and death. Conventional DDD/R mode often results in high cumulative percentage ventricular pacing (Cum%VP). We hypothesized that a new managed ventricular pacing mode (MVP) would safely provide AAI/R pacing with ventricular monitoring and DDD/R during AV block (AVB) and reduce Cum%VP compared to DDD/R.

Methods: MVP RAMware was downloaded in 181 patients with Marquis DR ICDs. Patients were initially randomized to either MVP or DDD/R for 1 month, then crossed over to the opposite mode for 1 month. ICD diagnostics were analyzed for cumulative percentage atrial pacing (Cum%AP), Cum%VP, and duration of DDD/R pacing for spontaneous AVB.

Results: Baseline characteristics included age 66 ± 12 years, EF 36 ± 14%, and NYHA Class II–III 36%. Baseline PR interval was 190 ± 53 msec and programmed AV intervals (DDD/R) were 216 ± 50 (paced)/189 ± 53 (sensed) msec. Mean Cum%VP was significantly lower in MVP versus DDD/R (4.1 ± 16.3 vs 73.8 ± 32.5, P < 0.0001). The median absolute and relative reductions in Cum%VP during MVP were 85.0 and 99.9, respectively. Mean Cum%AP was not different between MVP versus DDD/R (48.7 ± 38.5 vs 47.3 ± 38.4, P = 0.83). During MVP overall time spent in AAI/R was 89.6% (intrinsic conduction), DDD/R 6.7% (intermittent AVB), and DDI/R 3.7% (AF). No adverse events were attributed to MVP.

Conclusions: MVP safely achieves functional atrial pacing by limiting ventricular pacing to periods of intermittent AVB and AF in ICD patients, significantly reducing Cum%VP compared to DDD/R. MVP is a universal pacing mode that adapts to AVB and AF, providing both atrial pacing and ventricular pacing support when needed.
A comparison of magnetic resonance imaging and cardiac biopsy in the evaluation of heart iron overload in patients with β‐thalassemia major
Authors: Mavrogeni Sophie I. , Markussis Vyron , Kaklamanis Loukas , Tsiapras Dimitrios , Paraskevaidis Ioannis , Karavolias George , Karagiorga Markisia , Douskou Marouso , Cokkinos Dennis V. , Kremastinos Dimitrios T.
Published: August 2005

Abstract:  Objectives: To apply magnetic resonance imaging (MRI) for the assessment of myocardial iron deposition in patients with β‐thalassemia and compare the results with cardiac biopsy data. Background: Myocardial iron accumulation is the main cause for cardiac complications in β‐thalassemia. Methods: Twenty‐five consecutive thalassemic patients were studied using a 0.5‐T (Tesla) system, ECG‐gated, with echo time (TE) = 17–68 ms. T2 relaxation time of the interventricular septum was calculated assuming simple monoexponential decay. A heart T2 relaxation time value of 32 ms was used for the discrimination between high and low iron deposition. Heart biopsy was performed within a week after the MRI study. Patients with stainable iron in more than 50% of the myofibrils were graded as having severe iron deposition. A serum ferritin level below 2000 ng/mL was considered as an indication of successful chelation. Results: Seven of the 25 patients had heart biopsy indicative of low iron deposition (Group L) and the remaining 18 patients had heart biopsy indicative of high iron deposition (Group H). T2 relaxation time of the heart (T2H) was lower in Group H compared to Group L (31.5 ± 3.9 (range: 28–40) ms vs. 35.7 ± 3.7 (range: 29–40) ms, P = 0.026). The T2H was in agreement with heart biopsy in 86% of the patients in Group L and in 78% of the patients in Group H (overall agreement 80%). Similarly, serum ferritin levels were in agreement with heart biopsy in 28% and 88%, respectively (overall agreement 72%). In Group L, MRI was in better agreement with biopsy compared to serum ferritin (86% vs. 28%, P < 0.05). A receiver operating characteristic curve (ROC) analysis confirmed that a T2 relaxation time of 32 ms had the highest discriminating ability for the corresponding biopsy outcome. Conclusions: Heart T2 relaxation time appears in agreement with cardiac biopsy, both in high and low iron deposition, and may become a useful non‐invasive index in β‐thalassemia.
Absence of p16 and p27 gene rearrangements and mutations in de novo myelodysplastic syndromes
Authors: Papageorgiou Sotirios G. , Pappa Vassiliki , Papageorgiou Efstathios , Tsirigotis Panagiotis , Kontsioti Frida , Panani Anna , Dervenoulas John , Economopoulos Theofanis
Published: August 2005

Abstract:  Myelodysplastic syndromes (MDS) represent a group of clonal hematopoietic disorders characterized by dyshemopoiesis and frequent evolution to acute leukemia. Tumor suppressor gene inactivation may be involved in MDS pathogenesis. The two families of cyclin‐dependent kinase inhibitors (CDKIs) (INK4 family of p15, p16, p18 and p19 and CIP/KIP family of p21, p27 and p57) that negatively regulate cell cycle progression are known tumor suppressor genes. To determine whether genetic alterations of p16 and p27 genes play an important role in MDS pathogenesis, we examined DNA from 51 patients classified as 17 refractory anemias (RA), four refractory anemias with ringed sideroblasts (RARS), 19 refractory anemias with an excess of blasts (RAEB), 5 refractory anemias with excess of blasts in transformation (RAEB‐t) and 6 chronic myelomonocytic leukemias (CMML). Southern blot analysis detected no homozygous deletions of p16 and p27. Polymerase chain reaction–single‐strand conformation polymorphism (PCR–SSCP) and sequencing did not reveal point mutations for both genes with the exception of two allelic polymorphisms, namely a C → G transition at 447 bp of p16exon3 and a T → A transition at 791 bp of p27exon1 genes. Our results suggest that mutations of p16 and p27 genes resulting in abnormal p16 and p27 proteins do not represent a mechanism of gene inactivation involved in the pathogenesis of MDS.
Outcome of progressive disease after autologous stem cell transplantation in patients with non‐Hodgkin's lymphoma: a nation‐wide survey
Authors: Kuittinen T. , Wiklund T. , Remes K. , Elonen E. , Lehtinen T. , Kuittinen O. , Leppä S. , Putkonen M. , Räty R. , Turpeenniemi‐Hujanen T. , Nousiainen T. , Jantunen E.
Published: August 2005

Abstract:  Objectives: To analyse outcome and prognostic factors in non‐Hodgkin's lymphoma (NHL) patients who progress after autologous stem cell transplantation (ASCT). Patients: Altogether 115 consecutive NHL patients transplanted in 1991–2000 were studied. Histology included diffuse large B cell (n = 52), follicular (n = 26), mantle cell (n = 15), T cell (n = 16) and other subtypes (n = 6). The median time from ASCT to the progression was 7 months. Ninety‐six patients (83%) received salvage treatment. Results: Twenty‐four patients (25%) achieved complete remission and 30 (31%) partial remission. The median overall survival was 8 months (range 0–98+) and the projected 4‐year survival 21%. In multivariate analysis factors predicting treatment response after the progression included the use of rituximab (P = 0.036), histology other than diffuse large B cell (P = 0.001) and International Prognostic Index ≤2 at progression (P < 0.001). Normal lactate dehydrogenase (LDH) at progression (P = 0.002), response to salvage treatment (P < 0.001) and time from ASCT to progression ≥7 months (P = 0.022) were predictors for overall survival. Conclusions: Although the prognosis of patients who progress after ASCT is generally poor, many patients will respond to current therapies, and some may experience prolonged survival. Normal LDH at time of disease progression and longer time to progression after ASCT were the most powerful predictors for a promising outcome.
Philadelphia‐chromosome positive thrombocythemia in a child
Authors: Mishra Pravas , Mahapatra M. , Kumar Rajat , Dixit Ashish , Chatterjee Tathagat , Tyagi Seema , Choudhry D. R. , Sazawal S. , Choudhry V. P.
Published: August 2005

Abstract:  Philadelphia‐chromosome positive thrombocythemia without features of chronic myeloid leukemia in peripheral blood has been described in adults. It is rare in children. We present a case of Philadelphia positive thrombocythemia in a child who was managed with a combination of imatinib and hydroxyurea. Although a reduction in the BCR‐ABL transcript was documented, the thrombocytosis was refractory to imatinib alone and required the addition of hydroxyurea.
Delineation and molecular characterization of acute myeloid leukemia patients with coduplication of FLT3 and MLL
Authors: Olesen Lene Hyldahl , Nyvold Charlotte Guldborg , Aggerholm Anni , Nørgaard Jan Maxwell , Guldberg Per , Hokland Peter
Published: August 2005

Abstract:  Partial tandem (PTD) and internal tandem duplications (ITD) of the MLL or FLT3 genes respectively, have been demonstrated in acute myeloid leukemia (AML). While occurrence of each of these PTD/ITD seem to confer an unfavorable prognosis, the literature contains only sparse information of the occurrence and the prognosis of simultaneous PTD/ITD of these genes. We have therefore attempted to determine the presence and its consequence in AML and with the further aim of characterizing such patients with respect to other genetic aberrations and to prototype variables in this disease. We analyzed blast cells from 250 adult patients treated at the same institution during a 15‐year period for FLT3 ITD and MLL PTD and the duplications were found in 24% and 4%, respectively. The four co‐duplicated cases (2%) did not differ with respect to sex, age, FAB‐type, or immunophenotype, promoter methylation of p15, E‐cadherin (CDH1), Estrogen receptor, MDR1, expression of apoptosis‐related or multidrug resistance‐related genes, though a trend toward decreased gene expression of MDR1 was observed. Two of the patients had a normal karyotypic analysis, while the remaining two showed aberrations in chromosome 11, one with trisomy 11 and the other with a der (11). The extensive molecular characterization of FLT3/MLL coduplicated patients presented here indicates that, even though they do not differ molecularly from the groups of patients with single ITDs, their prognosis and overall survival is universally poor. More patients are needed to determine whether coduplication has independent clinical implications compared to patients with single ITD/PTD.
Delineation of Regions in the Extracellular Domain of Follicle‐Stimulating Hormone Receptor Involved in Hormone Binding and Signal Transduction
Authors: Kene Pallavi S. , Dighe Rajan R. , Mahale Smita D.
Published: August 2005

Problem:  To use antipeptide antibodies to potential surface‐oriented regions of the extracellular domain (ECD) of the human follicle‐stimulating hormone receptor (hFSHR) to delineate regions involved in FSH binding and FSH‐induced signal transduction.

Method of study:  We developed and characterized antipeptide antibodies to different, potentially surface‐oriented regions of the ECD of hFSHR. The ability of these antibodies to recognize the receptor was studied by sodium dodecyl sulfate–polyacrylamide gel electrophoresis followed by Western blotting. The ability to modulate FSH binding and cAMP generation was studied by the radioreceptor assay and in vitro FSH bioassay respectively.

Results:  Antipeptide antibodies to regions 15–31, 216–235, 285–300 and 327–341 hFSHR inhibited both FSH binding and cAMP production. Regions 15–31 and 216–235 were accessible to their cognate antipeptide antibodies both before and after FSH binding, while regions 285–300 and 327–341 hFSHR were accessible only prior to FSH binding.

Conclusions:  Based on the observations made with respect to accessibility to antipeptide antibodies, ability of antibodies to inhibit FSH binding and the subsequent cAMP generation and kinetics of antibody binding, regions 285–300 and 327–341 hFSHR appear to be the chief FSH‐binding sites, while regions 15–31 and 216–235 hFSHR serve as ancillary FSH‐binding sites.
Mothers in Stress: Consequences for the Offspring
Authors: Knackstedt Maike Katharina , Hamelmann Eckard , Arck Petra Clara
Published: August 2005

No memories exist on one's time before birth. However, this does not imply that the developing fetus is not susceptible to external impulses. On the contrary, the fetus is extremely vulnerable e.g. to environmental challenges, and a wealth of data reveals that conditions in utero affect the health of the fetus before and after birth. Threats for the growing fetus include psychological challenges perceived by the mother, e.g. high levels of stress during pregnancy. However, stress experienced during pregnancy not only leads to pregnancy complications like miscarriage, pre‐eclampsia, preterm parturition, low birth weight or major congenital malformations, stress also increases the risk of the child to develop diseases in the subsequent periods of life. This condition is termed fetal programing of adult disease. Programing agents seem to include growth factors, cytokines and hormones, all of which can be altered by stress. As a consequence, such ‘stress‐modified’ systems of the offspring are more susceptible to environmental influences during later life, e.g. the development of atopic diseases upon exposure to antigens. The present review illuminates the complexity of stress perception on fetal programing focusing predominately on the onset of atopic diseases on the background of published evidence from immunology, endocrinology, neurobiology and neonatology.
Anti‐Phospholipid Antibodies against Phosphatidylinositol, and Phosphatidylserine are More Significant in Reproductive Failure than Antibodies against Cardiolipin only
Authors: Ulcova‐Gallova Zdenka , Krauz Vladimir , Novakova Pavla , Milichovska Lucie , Micanova Zdenka , Bibkova Katerina , Sucha Renata , Turek Jiri , Balvin Miroslav , Rokyta Zdenek
Published: August 2005

Problem

The humoral immune response to phospholipids was investigated in women with reproductive failure [1073 women after one in vitro fertilization (IVF), 853 women after two and more IVF, 627 women after three and more repeated spontaneous miscarriages or missed abortions, 412 women after diagnostic laparoscopy] and compared with that of 391 healthy fertile women.

Method of study

Sera from all women in the study were tested by enzyme‐linked immunosorbent assay (ELISA) for the detection of IgG, IgA, and IgM isotypes of antibodies against seven phospholipids (aPLs), i.e. cardiolipin, L‐phosphatidylserine, phosphatidylglycerol, phosphatidylinositol, phosphatidylethanolamine, phosphatidylacid as well as against β2‐glycoprotein I.

Results

Patients after two and more IVF (48 and 50%, respectively), patients with three and more repeated spontaneous miscarriages (50 and 46.5%, respectively) are associated with significantly higher serum levels of aPLs against inositol, and l‐serine (P < 0.01). A quarter of them were positive for three and more aPLs.

Conclusion

It seems that determination of aPLs only against cardiolipin in reproductive failure is not sufficient for obstetric‐gynecology diagnosis as the primary anti‐phospholipid syndrome. Our long‐ranging study (from 1998 to 2003) shows the necessity to test for a complete aPLs profile. Sera from patients after two and more IVF procedures, and sera from women after three and more repeated abortions are immunologically more active than sera from women after one unsuccessful IVF and sera from women after diagnostic laparoscopy. This important result is very significant for future treatment.
ASRI2005‐86  Ovine Mx1 associates with microtubules during metaphase and with intercellular bridges between dividing cells
Authors: Toyokawa K , Carnahan KG , Ott TL
Published: August 2005

Mx proteins are 70–80 kD intracellular antiviral proteins induced by viruses and type I interferons (IFNs). Mx proteins belong to the dynamin superfamily of large GTPases, thought to regulate endocytosis, intracellular vesicle trafficking and cytokinesis. Although antiviral Mx proteins are highly inducible during early pregnancy by embryo‐derived IFN tau, cellular functions of Mx proteins in uninduced cells are poorly defined. To better understand the physiological role of Mx proteins during early pregnancy, expression and localization of ovine Mx1 (oMx1) protein were determined in a uterine derived cell line (oGE). oMx1 and beta tubulin were immunolabeled in cells at different stages of the cell cycle. oMx1 was uniformly distributed in the cytoplasm during interphase in the absence of roIFN tau, whereas oMx1 aggregated around vacuoles near the surface of the cells in the presence of roIFN. Interestingly, oMx1 co‐localized with mitotic spindles during metaphase. During telophase, oMx1 co‐localized with remnants of mitotic spindles at intercellular bridges between dividing cells. Our findings are consistent with a role for Mx1 in secretion by oGE cells and indicate that oMx1 may be involved in cell division. Supported in part by USDA NRICGP grant 2002‐02398 and NIH NCRR grant P20‐RR15587‐01 to T.L.O.
ASRI2005‐88  Comparable levels of CD4+CD25+ CTLA4+ Treg cells in peripheral blood of pre‐eclampsia and normal pregnant patients
Authors: Paeschke S , Horn N , Fotopoulou C , Zambon‐Bertoja A , Sollwedel A , Zenclussen ML , Casalis P , Dudenhausen J , Volk HD , Chen F , Zenclussen A
Published: August 2005

The acceptance of the semiallogeneic fetus within the maternal environment requires tolerance mechanisms not fully characterized yet. Normal pregnancy is known to be associated with a Th2 profile. Furthermore, T‐regulatory cells were proposed to regulate the Th2/Th1 balance at early stages of pregnancy. Treg may avoid the shift to a Th1 profile preventing miscarriage. Accordingly, spontaneous abortion is characterized by a Th1 dominance and diminished levels of Tregulatory cells (Treg). The major aim of the present work was to investigate if pre‐eclampsia, a late immunological complication of pregnancy, is characterized by similar hallmarks. Therefore, we measured the surface antigens CD4, CD25, CD8, CTLA4 (as well as the secretion of IL‐10) in peripheral blood from patients suffering from pre‐eclampsia (n = 8) and age‐matched patients undergoing normal pregnancies (n = 9) by 4‐colour flow‐cytometry. We were not able to find any significant differences in the levels of CD4+, CD25+, CD8+, CTLA4, CD4+/CD25+, CD4+/CD25bright, CD4+/CTLA4, CD25+/CTLA4, CD4+/CD25+/CTLA4, CD8+/CD25+, CD8+/CTLA4 or CD8+/CD25+/CTLA4 cell subsets. Our data suggest that Treg may not participate in the onset of pre‐eclampsia and suggest other regulatory mechanisms during late pregnancy.
ASRI2005‐91  Reduced semen quality in chronic prostatitis patients that have cellular autoimmune response to prostate antigens
Authors: Motrich RM , Maccioni M , Molina R , Tissera A , Olmedo JJ , Riera CM , Rivero VE
Published: August 2005

Problem:  Acute and chronic infectious prostatitis (CIP) are the best understood of the prostate syndromes but the least frequent. In contrast, although chronic non‐infectious prostatitis (CNIP) is the most frequent syndrome, its cause has proved elusive for decades.

Method of study:  In the present study we analyzed the presence of a possible autoimmune response to prostate antigens (PA) in patients with CIP and CNIP. We also analyzed their semen quality (spermiograms) and levels of seminal inflammatory cytokines.

Results:  We demonstrated the presence of lymphocytes able to proliferate in response to human PA (PSA and PAP) only in a group of patients with CNIP. When INFγ and IL‐10 levels were measured in culture supernatants, significantly elevated levels of INFγ were detected only in patients with positive proliferative response to PA. Interestingly, only these patients showed significantly elevated levels of inflammatory cytokines (IL‐1 and TNF‐α) in seminal plasma and striking alterations in their semen quality.

Conclusions:  We found that INFγ‐secreting lymphocytes specific to PA are detected in 34% of the patients with CNIP and that this fact is associated with a marked alteration of semen quality. These results argue in favor of the importance of prostate functionality for the quality of the semen.