bluuebunny/crossref_metadata_2025_split huggingface dataset:
Deficiency of Bim in dendritic cells contributes to overactivation of lymphocytes and autoimmunity
Authors: Chen Min , Huang Li , Wang Jin 
Published: January 2007

AbstractApoptosis in dendritic cells (DCs) can potentially regulate DC homeostasis and immune responses. We have previously observed that inhibition of the Fas signaling pathway in DCs results in spontaneous T-cell activation and the development of systemic autoimmunity in transgenic mice. However, the role for different apoptosis pathways in DCs in regulating DC homeostasis and immune tolerance remains to be determined. Bim, a BH3-only protein of the Bcl-2 family, was expressed at low levels in DCs and was significantly up-regulated by signaling from CD40 or toll-like receptors (TLRs). Because Bim−/− mice develop spontaneous systemic autoimmunity, we investigated whether Bim−/− DCs contributed to lymphoproliferation and autoimmunity in these mice. Bim−/− DCs showed decreased spontaneous cell death, and induced more robust T-cell activation in vitro and in vivo. Moreover, Bim−/− DCs induced autoantibody production after adoptive transfer. Our data suggest that Bim is important for regulating spontaneous cell death in DCs, and Bim-deficient DCs may contribute to the development of autoimmune diseases in Bim−/− mice.
Phenotypes of Myopathy-related Actin Mutants in differentiated C2C12 Myotubes
Authors: Bathe Friederike S , Rommelaere Heidi , Machesky Laura M 
Published: January 2007

Abstract

Background
About 20 % of nemaline myopathies are thus far related to skeletal muscle alpha-actin. Seven actin mutants located in different parts of the actin molecule and linked to different forms of the disease were selected and expressed as EGFP-tagged constructs in differentiated C2C12 mytoubes. Results were compared with phenotypes in patient skeletal muscle fibres and with previous expression studies in fibroblasts and C2C12 myoblasts/myotubes.

Results
Whereas EGFP wt-actin nicely incorporated into endogenous stress fibres and sarcomeric structures, the mutants showed a range of phenotypes, which generally changed upon differentiation. Many mutants appeared delocalized in myoblasts but integrated into endogenous actin structures after 4–6 days of differentiation, demonstrating a poor correlation between the appearance in myotubes and the severity of the disease. However, for some mutants, integration into stress fibres induced aberrant structures in differentiated cells, like thickening or fragmentation of stress fibres. Other mutants almost failed to integrate but formed huge aggregates in the cytoplasm of myotubes. Those did not co-stain with alpha-actinin, a main component of nemaline bodies found in patient muscle. Interestingly, nuclear aggregates as formed by two of the mutants in myoblasts were found less frequently or not at all in differentiated cells.

Conclusion
Myotubes are a suitable system to study the capacity of a mutant to incorporate into actin structures or to form or induce pathological changes. Some of the phenotypes observed in undifferentiated myoblasts may only be in vitro effects. Other phenotypes, like aberrant stress fibres or rod formation may be more directly correlated with disease phenotypes. Some mutants did not induce any changes in the cellular actin system, indicating the importance of additional studies like functional assays to fully characterize the pathological impact of a mutant.
The Francisella pathogenicity island protein IglA localizes to the bacterial cytoplasm and is needed for intracellular growth
Authors: de Bruin Olle M , Ludu Jagjit S , Nano Francis E 
Published: January 2007

Abstract

Background

Francisella tularensis is a gram negative, facultative intracellular bacterium that is the etiological agent of tularemia. F. novicida is closely related to F. tularensis but has low virulence for humans while being highly virulent in mice. IglA is a 21 kDa protein encoded by a gene that is part of an iglABCD operon located on the Francisella pathogenicity island (FPI).

Results
Bioinformatics analysis of the FPI suggests that IglA and IglB are components of a newly described type VI secretion system. In this study, we showed that IglA regulation is controlled by the global regulators MglA and MglB. During intracellular growth IglA production reaches a maximum at about 10 hours post infection. Biochemical fractionation showed that IglA is a soluble cytoplasmic protein and immunoprecipitation experiments demonstrate that it interacts with the downstream-encoded IglB. When the iglB gene was disrupted IglA could not be detected in cell extracts of F. novicida, although IglC could be detected. We further demonstrated that IglA is needed for intracellular growth of F. novicida. A non-polar iglA deletion mutant was defective for growth in mouse macrophage-like cells, and in cis complementation largely restored the wild type macrophage growth phenotype.

Conclusion
The results of this study demonstrate that IglA and IglB are interacting cytoplasmic proteins that are required for intramacrophage growth. The significance of the interaction may be to secrete effector molecules that affect host cell processes.
Prevention, control, and elimination of neglected diseases in the Americas: Pathways to integrated, inter-programmatic, inter-sectoral action for health and development
Authors: Holveck John C , Ehrenberg John P , Ault Steven K , Rojas Rocio , Vasquez Javier , Cerqueira Maria Teresa , Ippolito-Shepherd Josefa , Genovese Miguel A , Periago Mirta Roses 
Published: January 2007

Abstract

Background
In the Latin America and Caribbean region over 210 million people live below the poverty line. These impoverished and marginalized populations are heavily burdened with neglected communicable diseases. These diseases continue to enact a toll, not only on families and communities, but on the economically constrained countries themselves.

Discussion
As national public health priorities, neglected communicable diseases typically maintain a low profile and are often left out when public health agendas are formulated. While many of the neglected diseases do not directly cause high rates of mortality, they contribute to an enormous rate of morbidity and a drastic reduction in income for the most poverty-stricken families and communities. The persistence of this "vicious cycle" between poverty and poor health demonstrates the importance of linking the activities of the health sector with those of other sectors such as education, housing, water and sanitation, labor, public works, transportation, agriculture, industry, and economic development.

Summary
The purpose of this paper is three fold. First, it focuses on a need for integrated "pro-poor" approaches and policies to be developed in order to more adequately address the multi-faceted nature of neglected diseases. This represents a move away from traditional disease-centered approaches to a holistic approach that looks at the overarching causes and mechanisms that influence the health and well being of communities. The second objective of the paper outlines the need for a specific strategy for addressing these diseases and offers several programmatic entry points in the context of broad public health measures involving multiple sectors. Finally, the paper presents several current Pan American Health Organization and other institutional initiatives that already document the importance of integrated, inter-programmatic, and inter-sectoral approaches. They provide the framework for a renewed effort toward the efficient use of resources and the development of a comprehensive integrated solution to neglected communicable diseases found in the context of poverty, and tailored to the needs of local communities.
Methods for peptide identification by spectral comparison
Authors: Liu Jian , Bell Alexander W , Bergeron John JM , Yanofsky Corey M , Carrillo Brian , Beaudrie Christian EH , Kearney Robert E 
Published: January 2007

Abstract

Background
Tandem mass spectrometry followed by database search is currently the predominant technology for peptide sequencing in shotgun proteomics experiments. Most methods compare experimentally observed spectra to the theoretical spectra predicted from the sequences in protein databases. There is a growing interest, however, in comparing unknown experimental spectra to a library of previously identified spectra. This approach has the advantage of taking into account instrument-dependent factors and peptide-specific differences in fragmentation probabilities. It is also computationally more efficient for high-throughput proteomics studies.

Results
This paper investigates computational issues related to this spectral comparison approach. Different methods have been empirically evaluated over several large sets of spectra. First, we illustrate that the peak intensities follow a Poisson distribution. This implies that applying a square root transform will optimally stabilize the peak intensity variance. Our results show that the square root did indeed outperform other transforms, resulting in improved accuracy of spectral matching. Second, different measures of spectral similarity were compared, and the results illustrated that the correlation coefficient was most robust. Finally, we examine how to assemble multiple spectra associated with the same peptide to generate a synthetic reference spectrum. Ensemble averaging is shown to provide the best combination of accuracy and efficiency.

Conclusion
Our results demonstrate that when combined, these methods can boost the sensitivity and specificity of spectral comparison. Therefore they are capable of enhancing and complementing existing tools for consistent and accurate peptide identification.
Skeletal muscle oxygen saturation does not estimate mixed venous oxygen saturation in patients with severe left heart failure and additional severe sepsis or septic shock
Authors: Podbregar Matej , Možina Hugon 
Published: January 2007

Abstract
Introduction
Low cardiac output states such as left heart failure are characterized by preserved oxygen extraction ratio, which is in contrast to severe sepsis. Near infrared spectroscopy (NIRS) allows noninvasive estimation of skeletal muscle tissue oxygenation (StO2). The aim of the study was to determine the relationship between StO2 and mixed venous oxygen saturation (SvO2) in patients with severe left heart failure with or without additional severe sepsis or septic shock.

Methods
Sixty-five patients with severe left heart failure due to primary heart disease were divided into two groups: groups A (n = 24) and B (n = 41) included patients without and with additional severe sepsis/septic shock, respectively. Thenar muscle StO2 was measured using NIRS in the patients and in 15 healthy volunteers.

Results
StO2 was lower in group A than in group B and in healthy volunteers (58 ± 13%, 90 ± 7% and 84 ± 4%, respectively; P < 0.001). StO2 was higher in group B than in healthy volunteers (P = 0.02). In group A StO2 correlated with SvO2 (r = 0.689, P = 0.002), although StO2 overestimated SvO2 (bias -2.3%, precision 4.6%). In group A changes in StO2 correlated with changes in SvO2 (r = 0.836, P < 0.001; ΔSvO2 = 0.84 × ΔStO2 - 0.67). In group B important differences between these variables were observed. Plasma lactate concentrations correlated negatively with StO2 values only in group A (r = -0.522, P = 0.009; lactate = -0.104 × StO2 + 10.25).

Conclusion
Skeletal muscle StO2 does not estimate SvO2 in patients with severe left heart failure and additional severe sepsis or septic shock. However, in patients with severe left heart failure without additional severe sepsis or septic shock, StO2 values could be used to provide rapid, noninvasive estimation of SvO2; furthermore, the trend in StO2 may be considered a surrogate for the trend in SvO2.
Trial Registration: NCT00384644
CpG-B ODNs potently induce low levels of IFN-αβ and induce IFN-αβ-dependent MHC-I cross-presentation in DCs as effectively as CpG-A and CpG-C ODNs
Authors: Gray Reginald C , Kuchtey John , Harding Clifford V 
Published: January 2007

AbstractDeoxycytidyl-deoxyguanosine [(CpG)3] oligodeoxynucleotides (ODNs) signal through TLR9 to induce type-I IFN (IFN-αβ) and IFN-αβ-dependent MHC-I cross-presentation of exogenous antigens by dendritic cells (DCs). A puzzle was presented by our observation that three ODN classes, CpG-A, CpG-B, and CpG-C, had similar efficacy for induction of IFN-αβ-dependent MHC-I antigen cross-presentation by myeloid DCs despite greatly differing for induction of IFN-αβ (CpG-A&gt;CpG-C&gt;&gt;CpG-B). All ODN classes similarly enhanced plasmacytoid DC (pDC) presentation of exogenous MHC-I-restricted peptide, although pDCs did not cross-process protein antigen. MHC-I and the transporter for antigen presentation were induced by all ODN classes or IFN-α. CpG-B ODNs were slightly more potent than CpG-A or CpG-C ODNs for induction of low levels of IFN-αβ but less efficacious at high concentrations than CpG-A or CpG-C ODNs. Low levels of IFN-αβ induced by CpG-B ODNs sufficed for full induction of MHC-I cross-presentation. Thus, CpG-B ODNs are slightly more potent but less efficacious than CpG-A and CpG-C ODNs for induction of IFN-αβ. High sensitivity to IFN-αβ allows CpG-B ODNs to be equally efficacious for induction of MHC-I cross-presentation. CpG-B ODNs may be effective for inducing therapeutic responses that require low levels of IFN-αβ and may avoid unnecessarily high induction of IFN-αβ.
CHOP Alone Compared With CHOP Plus Radiotherapy for Localized Aggressive Lymphoma in Elderly Patients: A Study by the Groupe d’Etude des Lymphomes de l’Adulte
Authors: Bonnet Christophe , Fillet Georges , Mounier Nicolas , Ganem Gérard , Molina Thierry Jo , Thiéblemont Catherine , Fermé Christophe , Quesnel Bruno , Martin Claude , Gisselbrecht Christian , Tilly Hervé , Reyes Félix 
Published: January 2007

Purpose Chemoradiotherapy has been considered standard treatment for patients with limited-stage aggressive lymphoma on the basis of trials conducted before the introduction of the International Prognostic Index. To evaluate this approach in elderly patients with low-risk localized lymphoma, we conducted a trial comparing chemoradiotherapy with chemotherapy alone. Patients and Methods Previously untreated patients older than 60 years with localized stage I or II histologically aggressive lymphoma and no adverse prognostic factors of the International Prognostic Index were randomly assigned to receive either four cycles of cyclophosphamide, doxorubicin, vincristine, and prednisone (CHOP) plus involved-field radiotherapy (299 patients) or chemotherapy alone with four cycles of CHOP (277 patients). Results With a median follow-up time of 7 years, event-free and overall survival did not differ between the two treatment groups (P = .6 and P = .5, respectively). The 5-year estimates of event-free survival were 61% for patients receiving chemotherapy alone and 64% for patients receiving CHOP plus radiotherapy; the 5-year estimates of overall survival were 72% and 68%, respectively. In a multivariate analysis, overall survival was affected by stage II disease (P < .001) and male sex (P = .03). Conclusion In this large prospective study, CHOP plus radiotherapy did not provide any advantage over CHOP alone for the treatment of low-risk localized aggressive lymphoma in elderly patients.
Cisplatin-Induced Long-Term Hearing Impairment Is Associated With Specific Glutathione S-Transferase Genotypes in Testicular Cancer Survivors
Authors: Oldenburg Jan , Kraggerud Sigrid M. , Cvancarova Milada , Lothe Ragnhild A. , Fossa Sophie D. 
Published: January 2007

Purpose Cisplatin, a cornerstone of combination chemotherapy in the treatment of testicular cancer, induces hearing impairment with considerable interindividual variations. These differences might be a result of functional polymorphisms in cisplatin-detoxifying enzymes like glutathione S-transferases (GSTs). Patients and Methods We identified 173 cisplatin-treated testicular cancer survivors (TCSs) who had participated in a long-term survey that included audiometric testing and lymphocyte sampling. The hearing decibel thresholds at 4,000 Hz were categorized into leveled scales by normative decibel percentiles. Known functional polymorphisms (positive or negative) in GSTT1 and GSTM1 and codon 105 A/G (Ile/Val) in GSTP1 were analyzed by multiplex polymerase chain reaction, followed by restriction enzyme cutting, and separated by gel electrophoresis. Results The risk of having an inferior audiometric result was more than four times higher in TCSs with 105Ile/105Ile-GSTP1 or 105Val/105Ile-GSTP1 compared with 105Val/105Val-GSTP1 (odds ratio [OR] = 4.21; 95% CI, 1.99 to 8.88; P < .001 when modeled by ordinal logistic regression [OLR]). GSTM1 positivity was detrimental for hearing ability. Two combined genotypes were associated with hearing ability. The presence of pattern 1 (GSTT1 positive, GSTM1 positive, and 105Ile/105Ile-GSTP1) was associated with hearing impairment (OR = 2.76; 95% CI, 1.35 to 5.64; P = .005, OLR). TCSs with pattern 2 (GSTT1 positive, GSTM1 positive, and 105Val/105Val-GSTP1) had better hearing ability than TCSs without this pattern (OR = 5.35; 95% CI, 2.25 to 12.76; P < .001, OLR). Conclusion The presence of both alleles of 105Val-GSTP1 offered protection against cisplatin-induced hearing impairment. Two genotype patterns with good and poor protection against cisplatin-induced ototoxicity were identified.
Is the Prevalence of Paget's Disease of Bone Decreasing?
Authors: Cundy Tim 
Published: January 2007

Abstract
Secular trends in the severity and prevalence of Paget's disease over a 30-year period are described. Paget's disease has become less prevalent and patients are presenting later, with less severe disease than previously. These data suggest that environmental factors are important in the etiology of Paget's disease.
Introduction: Data from several countries support the view that there are important secular trends in the prevalence and severity of Paget's disease. In this paper, recent trends in the epidemiology of Paget's disease are described.
Materials and Methods: A database of all newly referred patients (n = 1487) with Paget's disease (1973–2002 inclusive, 30 years) was examined. Of these subjects, 56% had scintiscans. Plasma total alkaline phosphatase (total ALP) activity and disease extent on scintiscan were used as indices of severity. A radiographic prevalence survey of 1019 subjects of European origin &gt;55 years of age in Dunedin was undertaken—∼20 years after an earlier survey had shown New Zealand to be a high prevalence area.
Results: The number of new referrals with Paget's disease declined sharply from 1994 onward, to one half the rate seen 20 years earlier, whereas the mean age at presentation increased by 4 years per decade (p &lt; 0.0001). Total ALP at diagnosis, disease extent on scintiscan, and the number of bones involved were all negatively correlated with both date of birth (p &lt; 0.0001) and year of presentation (p &lt; 0.0001), indicating that more recently born and presenting subjects had substantially less severe bone disease. The radiographic survey showed that the current prevalence was only ∼50% of that in the 1983 survey (p = 0.012).
Conclusions: Although there are a number of potential biases, these data are consistent with a continued secular trend to presentation in older subjects with less extensive skeletal involvement and a declining prevalence of Paget's disease.
Paget's Disease of Bone in Italy
Authors: Gennari Luigi , Merlotti Daniela , Martini Giuseppe , Nuti Ranuccio 
Published: January 2007

Abstract
Epidemiological studies of Paget's disease of bone (PDB) suggest a pronounced geographical variation in the prevalence of the disease and a decrease in prevalence and clinical severity over time. To analyze epidemiological and clinical features of PDB in Italy, we recently established a registry of Italian PDB cases and performed radiological, biochemical, and bone scan surveys in the towns of Siena and Turin. The overall prevalence of PDB in Italy varied between 0.7% and 2.4%. Prevalence rates increased with age and were higher in men than in women. We observed clinically confirmed familial aggregation in 15–26% of cases. Pedigree analysis indicated an autosomal dominant pattern of inheritance with variable penetrance. SQSTM1 gene analysis in two Italian studies revealed the presence of at least three different mutations accounting for both familial and sporadic cases. Interestingly, no decrease in the prevalence of PDB over time was observed, the opposite of what is described in populations of British descent. However, clinical severity of PDB cases included in the Registry in 2002–2004 seemed reduced with respect to that of PDB patients from the previous epidemiological studies, including a 1950–1956 Italian study. Of interest, a consistent association between PDB and animal-related factors and a significantly higher prevalence of the disease in rural than in urban districts were observed. These findings are in keeping with an important role of the environment in the pathogenesis of PDB, perhaps facilitating the expression of the disease in genetically susceptible subjects. Finally, there was also preliminary evidence indicating regional clustering of PDB in Italy, with a concentration of cases in rural districts of Campania and Tuscany. These districts may represent high prevalence areas of PDB in Italy, similar to what has been observed in other countries. Extrapolation estimates suggest that ∼150,000–300,000 subjects may be affected with PDB in our country. These results confirm PDB to be the most common bone remodeling disorder in elderly people in Italy, excluding osteoporosis.
Clinical and Cellular Phenotypes Associated With Sequestosome 1 (SQSTM1) Mutations
Authors: Leach Robin J , Singer Frederick R , Ench Yasmin , Wisdom Julie H , Pina Diana S , Johnson-Pais Teresa L 
Published: January 2007

Abstract
Familial Paget's disease of bone has been shown to be associated with mutations in the ubiquitin-associated (UBA) domain of the sequestosome 1 (SQSTM1) gene. We have clinical findings on five families with diverse racial and ethnic backgrounds who all harbor SQSTM1 UBA domain mutations (P387L, P392L, D391fsX394, P392fsX394). Intrafamilial expressivity was highly variable. The probands in two of the families had early-onset disease involving a large number of bones and highly elevated prediagnostic levels of serum alkaline phosphatase. Affected siblings in these same families had limited bone involvement and were only diagnosed by technetium-99m methylene diphosphonate (MDP) bone scans. Furthermore, there was at least one subject in each family with no evidence of Paget's disease, although they carried one mutated copy of the SQSTM1 gene. A total of 18 such individuals were identified across the five kindreds. Thus, the gene seems to have highly variable expressivity, as well as incomplete penetrance, supporting the role of this gene as a predisposition gene for familial Paget's disease of the bone. Molecular studies of the SQSTM1 protein showed different cellular aggregation phenotypes depending on the nature of the mutation. In general, the point mutations formed larger cytoplasmic aggregates than the wildtype or truncation mutations. This aggregation phenotype was not altered on removal of the N-terminal PB1 dimerization domain, implying that aggregate formation is not wholly mediated by interaction through the PB1 domain. Although there was a genotype/phenotype correlation on the cellular level, this was not apparent on the clinical level. This supports the argument that other nongenetic factors play an important role in the pathogenesis of the disease.