bluuebunny/crossref_metadata_2025 huggingface dataset:
Modulation of quinpirole-induced compulsive-like behavior in rats by environmental changes: Implications for OCD rituals and for exploration and navigation
Authors: Zadicario Pazit , Ronen Sharon , Eilam David
Published: May 2007

Background

Rats treated chronically with the D2–3dopamine agonist quinpirole were previously proposed as an animal model of obsessive-compulsive disorder (OCD) since their behavior is based on repeated, compulsive-like persistent traveling between a few places in the open field. The aim of the present study was to determine properties of the physical environment that shape such behavior. For this, quinpirole-treated rats were first exposed to an arena with an array of objects (landmarks) and after the development of compulsive-like behavior, the arena was manipulated by multiplying the number of objects, changing their spacing, relocating object array, or removing the objects.

Results

When the number of objects was retained but they were spaced further apart, rat routes converged at 1–2 of the objects and at the corner at which the rats had been introduced into the arena (start corner). When object spacing was retained but their number was increased, the rats traveled between the objects with the routes converging only at the start corner. Finally, when object array was relocated to different places within the arena, the rats extended their routes from the start corner to the object array, regardless of array location.

Conclusion

Quinpirole-treated rats organized and updated their progression primarily according to the proximal layout of landmarks, but did so with excessive repetitions compared with saline-treated rats. The behavior of quinpirole-treated rats paralleled human OCD rituals that are linked to the immediate physical environment, featuring an excessive rate of performance. Finally, when only a few objects were present, they were perceived by the rats as positional cues (beacons) that routes converged at them. In contrast, in the presence of many objects, the routes passed between the objects as if using them as directional cues.
Alternative splicing variations in mouse CAPS2: differential expression and functional properties of splicing variants
Authors: Sadakata Tetsushi , Washida Miwa , Furuichi Teiichi
Published: May 2007

Background

Ca2+-dependent activator protein 2 (CAPS2/CADPS2) is a secretory vesicle-associated protein involved in the release of neurotrophin. We recently reported that an aberrant, alternatively spliced CAPS2 mRNA that lacks exon 3 (CAPS2Δexon3) is detected in some patients with autism. Splicing variations in mouse CAPS2 and their expression and functions remain unclear.

Results

In this study, we defined 31 exons in the mouse CAPS2 gene and identified six alternative splicing variants, CAPS2a-f. CAPS2a is an isoform lacking exons 22 and 25, which encode part of the Munc13-1-homologous domain (MHD). CAPS2b lacks exon 25. CAPS2c lacks exons 11 and 22. CAPS2d, 2e, and 2f have C-terminal deletions from exon 14, exon 12, and exon 5, respectively. On the other hand, a mouse counterpart of CAPS2Δexon3 was not detected in the mouse tissues tested. CAPS2b was expressed exclusively in the brain, and the other isoforms were highly expressed in the brain, but also in some non-neural tissues. In the brain, all isoforms showed predominant expression patterns in the cerebellum. In the developing cerebellum, CAPS2b showed an up-regulated expression pattern, whereas the other isoforms exhibited transiently peaked expression patterns. CAPS2 proteins were mostly recovered in soluble fractions, but some were present in membrane fractions, except for CAPS2c and 2f, both of which lack the PH domain, suggesting that the PH domain is important for membrane association. In contrast to CAPS2a and 2b, CAPS2c showed slightly decreased BDNF-releasing activity, which is likely due to the C-terminal truncation of the PH domain in CAPS2c.

Conclusion

This study indicates that, in mouse, there are six splicing variants of CAPS2 (CAPS2a-f), and that these are subdivided into two groups: a long form containing the C-terminal MHD and a short form lacking the C-terminal MHD. These results demonstrate that the splicing variations correlate with their expression patterns and intracellular distribution, and affect BDNF release; however, whether or not the short forms possess activities other than BDNF release, for example as natural dominant-negative isoforms, remains to be determined.
Clofibrate treatment in pigs: Effects on parameters critical with respect to peroxisome proliferator-induced hepatocarcinogenesis in rodents
Authors: Luci Sebastian , Giemsa Beatrice , Hause Gerd , Kluge Holger , Eder Klaus
Published: May 2007

Background

In rodents treatment with fibrates causes hepatocarcinogenesis, probably as a result of oxidative stress and an impaired balance between apoptosis and cell proliferation in the liver. There is some debate whether fibrates could also induce liver cancer in species not responsive to peroxisome proliferation. In this study the effect of clofibrate treatment on peroxisome proliferation, production of oxidative stress, gene expression of pro- and anti-apoptotic genes and proto-oncogenes was investigated in the liver of pigs, a non-proliferating species.

Results

Pigs treated with clofibrate had heavier livers (+16%), higher peroxisome counts (+61%), higher mRNA concentration of acyl-CoA oxidase (+66%), a higher activity of catalase (+41%) but lower concentrations of hydrogen peroxide (-32%) in the liver than control pigs (P < 0.05); concentrations of lipid peroxidation products (thiobarbituric acid-reactive substances, conjugated dienes) and total and reduced glutathione in the liver did not differ between both groups. Clofibrate treated pigs also had higher hepatic mRNA concentrations of bax and the proto-oncogenes c-myc and c-jun and a lower mRNA concentration of bcl-XL than control pigs (P < 0.05).

Conclusion

The data of this study show that clofibrate treatment induces moderate peroxisome proliferation but does not cause oxidative stress in the liver of pigs. Gene expression analysis indicates that clofibrate treatment did not inhibit but rather stimulated apoptosis in the liver of these animals. It is also shown that clofibrate increases the expression of the proto-oncogenes c-myc and c-jun in the liver, an event which could be critical with respect to carcinogenesis. As the extent of peroxisome proliferation by clofibrate was similar to that observed in humans, the pig can be regarded as a useful model for investigating the effects of peroxisome proliferators on liver function and hepatocarcinogenesis.
Isolation and functional characterization of a cDNA coding a hydroxycinnamoyltransferase involved in phenylpropanoid biosynthesis in Cynara cardunculus L
Authors: Comino Cinzia , Lanteri Sergio , Portis Ezio , Acquadro Alberto , Romani Annalisa , Hehn Alain , Larbat Romain , Bourgaud Frédéric
Published: May 2007

Background

Cynara cardunculus L. is an edible plant of pharmaceutical interest, in particular with respect to the polyphenolic content of its leaves. It includes three taxa: globe artichoke, cultivated cardoon, and wild cardoon. The dominating phenolics are the di-caffeoylquinic acids (such as cynarin), which are largely restricted to Cynara species, along with their precursor, chlorogenic acid (CGA). The scope of this study is to better understand CGA synthesis in this plant.

Results

A gene sequence encoding a hydroxycinnamoyltransferase (HCT) involved in the synthesis of CGA, was identified. Isolation of the gene sequence was achieved by using a PCR strategy with degenerated primers targeted to conserved regions of orthologous HCT sequences available. We have isolated a 717 bp cDNA which shares 84% aminoacid identity and 92% similarity with a tobacco gene responsible for the biosynthesis of CGA from p-coumaroyl-CoA and quinic acid. In silico studies revealed the globe artichoke HCT sequence clustering with one of the main acyltransferase groups (i.e. anthranilate N-hydroxycinnamoyl/benzoyltransferase). Heterologous expression of the full length HCT (GenBank accession DQ104740) cDNA in E. coli demonstrated that the recombinant enzyme efficiently synthesizes both chlorogenic acid and p-coumaroyl quinate from quinic acid and caffeoyl-CoA or p-coumaroyl-CoA, respectively, confirming its identity as a hydroxycinnamoyl-CoA: quinate HCT. Variable levels of HCT expression were shown among wild and cultivated forms of C. cardunculus subspecies. The level of expression was correlated with CGA content.

Conclusion

The data support the predicted involvement of the Cynara cardunculus HCT in the biosynthesis of CGA before and/or after the hydroxylation step of hydroxycinnamoyl esters.
Conifer R2R3-MYB transcription factors: sequence analyses and gene expression in wood-forming tissues of white spruce (Picea glauca)
Authors: Bedon Frank , Grima-Pettenati Jacqueline , Mackay John
Published: May 2007

Background

Several members of the R2R3-MYB family of transcription factors act as regulators of lignin and phenylpropanoid metabolism during wood formation in angiosperm and gymnosperm plants. The angiosperm Arabidopsis has over one hundred R2R3-MYBs genes; however, only a few members of this family have been discovered in gymnosperms.

Results

We isolated and characterised full-length cDNAs encoding R2R3-MYB genes from the gymnosperms white spruce, Picea glauca (13 sequences), and loblolly pine, Pinus taeda L. (five sequences). Sequence similarities and phylogenetic analyses placed the spruce and pine sequences in diverse subgroups of the large R2R3-MYB family, although several of the sequences clustered closely together. We searched the highly variable C-terminal region of diverse plant MYBs for conserved amino acid sequences and identified 20 motifs in the spruce MYBs, nine of which have not previously been reported and three of which are specific to conifers. The number and length of the introns in spruce MYB genes varied significantly, but their positions were well conserved relative to angiosperm MYB genes. Quantitative RTPCR of MYB genes transcript abundance in root and stem tissues revealed diverse expression patterns; three MYB genes were preferentially expressed in secondary xylem, whereas others were preferentially expressed in phloem or were ubiquitous. The MYB genes expressed in xylem, and three others, were up-regulated in the compression wood of leaning trees within 76 hours of induction.

Conclusion

Our survey of 18 conifer R2R3-MYB genes clearly showed a gene family structure similar to that of Arabidopsis. Three of the sequences are likely to play a role in lignin metabolism and/or wood formation in gymnosperm trees, including a close homolog of the loblolly pine PtMYB4, shown to regulate lignin biosynthesis in transgenic tobacco.
Impact of AtNHX1, a vacuolar Na+/H+ antiporter, upon gene expression during short- and long-term salt stress in Arabidopsis thaliana
Authors: Sottosanto Jordan B , Saranga Yehoshua , Blumwald Eduardo
Published: May 2007

Background

AtNHX1, the most abundant vacuolar Na+/H+ antiporter in Arabidopsis thaliana, mediates the transport of Na+ and K+ into the vacuole, influencing plant development and contributing to salt tolerance. In this report, microarray expression profiles of wild type plants, a T-DNA insertion knockout mutant of AtNHX1 (nhx1), and a 'rescued' line (NHX1::nhx1) were exposed to both short (12 h and 48 h) and long (one and two weeks) durations of a non-lethal salt stress to identify key gene transcripts associated with the salt response that are influenced by AtNHX1.

Results

147 transcripts showed both salt responsiveness and a significant influence of AtNHX1. Fifty-seven of these genes showed an influence of the antiporter across all salt treatments, while the remaining genes were influenced as a result of a particular duration of salt stress. Most (69%) of the genes were up-regulated in the absence of AtNHX1, with the exception of transcripts encoding proteins involved with metabolic and energy processes that were mostly down-regulated.

Conclusion

While part of the AtNHX1-influenced transcripts were unclassified, other transcripts with known or putative roles showed the importance of AtNHX1 to key cellular processes that were not necessarily limited to the salt stress response; namely calcium signaling, sulfur metabolism, cell structure and cell growth, as well as vesicular trafficking and protein processing. Only a small number of other salt-responsive membrane transporter transcripts appeared significantly influenced by AtNHX1.
Discovery of chemically induced mutations in rice by TILLING
Authors: Till Bradley J , Cooper Jennifer , Tai Thomas H , Colowit Peter , Greene Elizabeth A , Henikoff Steven , Comai Luca
Published: May 2007

Background

Rice is both a food source for a majority of the world's population and an important model system. Available functional genomics resources include targeted insertion mutagenesis and transgenic tools. While these can be powerful, a non-transgenic, unbiased targeted mutagenesis method that can generate a range of allele types would add considerably to the analysis of the rice genome. TILLING (Targeting Induced Local Lesions in Genomes), a general reverse genetic technique that combines traditional mutagenesis with high throughput methods for mutation discovery, is such a method.

Results

To apply TILLING to rice, we developed two mutagenized rice populations. One population was developed by treatment with the chemical mutagen ethyl methanesulphonate (EMS), and the other with a combination of sodium azide plus methyl-nitrosourea (Az-MNU). To find induced mutations, target regions of 0.7–1.5 kilobases were PCR amplified using gene specific primers labeled with fluorescent dyes. Heteroduplexes were formed through denaturation and annealing of PCR products, mismatches digested with a crude preparation of CEL I nuclease and cleaved fragments visualized using denaturing polyacrylamide gel electrophoresis. In 10 target genes screened, we identified 27 nucleotide changes in the EMS-treated population and 30 in the Az-MNU population.

Conclusion

We estimate that the density of induced mutations is two- to threefold higher than previously reported rice populations (about 1/300 kb). By comparison to other plants used in public TILLING services, we conclude that the populations described here would be suitable for use in a large scale TILLING project.
Chinese and white Canadian satisfaction and compliance with physicians
Authors: Liu Richard , So Lawrence , Quan Hude
Published: May 2007

Background

Patient satisfaction has become an important indicator of primary care and healthcare system performance. Ethnic disparities in patient satisfaction and compliance with physician care have been studied in several countries. However, this issue has not received significant attention in Canada. The unique characteristics of the Canadian healthcare system and ethnic population make it worthwhile to examine this issue in this population. Therefore, we conducted a survey among Chinese and Whites in a Canadian city to determine their reported satisfaction, and perceptions of physicians.

Methods

The survey was conducted in English, Mandarin and Cantonese in 2005 among Chinese and White Canadians, 18 years of age or older, who had visited at least one physician in Canada.

Results

We analyzed 746 Chinese and 711 Whites in the general practitioner (GP) visit group and 485 Chinese and 637 Whites in the specialist visit group. A lower proportion of Chinese compared to Whites reported that they were very satisfied or satisfied with GP (73.7% vs. 92.8%) and specialist care (75.5% vs. 85.6%) and the differences between the two groups remained after adjustment for demographic variables and chronic conditions (risk adjusted OR: 0.70, 95%CI: 0.42–1.18 for the GP visit group and OR: 0.77, 95%CI: 0.48–1.23 for the specialist visit group). A similar proportion of Chinese and Whites reported that they always followed a physician's advice (59.4% vs. 59.6% for the GP visit group and 67.2% vs. 62.8% for the specialist visit group). Non-English speaking Chinese and recent arrivals in Canada were less likely to be satisfied with GPs than Chinese born in Canada [risk adjusted OR: 0.5, 95%CI: 0.3–0.9, 0.2 and 0.1–0.7, respectively].

Conclusion

Chinese Canadians reported lower satisfaction with physicians and perceived physicians slightly more negatively than White Canadians. Particularly, Chinese with limited English and short length of stay in Canada were less satisfied than Canadian born Chinese.
Sex- and age-dependent association of SLC11A1polymorphisms with tuberculosis in Chinese: a case control study
Authors: Leung Kim Hung , Yip Shea Ping , Wong Wa Sang , Yiu Lap San , Chan Kam Keung , Lai Wai Man , Chow Eudora YD , Lin Che Kit , Yam Wing Cheong , Chan Kin Sang
Published: May 2007

Background

Host genetic factors are important determinants in tuberculosis (TB). TheSLC11A1(orNRAMP1) gene has been studied extensively for genetic association with TB, but with inconsistent findings. In addition, no study has yet looked into the effect of sex and age on the relationship betweenSLC11A1polymorphisms and TB.

Methods

A case-control study was conducted. In total, 278 pulmonary TB patients and 282 sex- and age-matched controls without TB were recruited. All subjects were ethnic Chinese. On the basis of linkage disequilibrium pattern, three genetic markers fromSLC11A1and one from the nearbyIL8RBlocus were selected and examined for association with TB susceptibility. These markers were genotyped using single strand conformation polymorphism analysis or fragment analysis of amplified products.

Results

Statistically significant differences in allele (P= 0.0165, OR = 1.51) and genotype (P= 0.0163, OR = 1.59) frequencies of the linked markers SLC6a/b (classically called D543N and 3'UTR) of theSLC11A1locus were found between patients and controls. With stratification by sex, positive associations were identified in the female group for both allele (P= 0.0049, OR = 2.54) and genotype (P= 0.0075, OR = 2.74) frequencies. With stratification by age, positive associations were demonstrated in the young age group (age ≤65 years) for both allele (P= 0.0047, OR = 2.52) and genotype (P= 0.0031, OR = 2.92) frequencies. All positive findings remained significant even after correction for multiple comparisons. No significant differences were noted in either the male group or the older age group. No significant differences were found for the other markers (oneSLC11A1marker and oneIL8RBmarker) either.

Conclusion

This study confirmed the association betweenSLC11A1and TB susceptibility and demonstrated for the first time that the association was restricted to females and the young age group.
Empirical use of antibiotics and adjustment of empirical antibiotic therapies in a university hospital: a prospective observational study
Authors: Mettler Julian , Simcock Mathew , Sendi Pedram , Widmer Andreas F , Bingisser Roland , Battegay Manuel , Fluckiger Ursula , Bassetti Stefano
Published: May 2007

Background

Several strategies to optimise the use of antibiotics have been developed. Most of these interventions can be classified as educational or restrictive. Restrictive measures are considered to be more effective, but the enforcement of these measures may be difficult and lead to conflicts with prescribers. Any intervention should be aimed at targets with the highest impact on antibiotic prescribing. The aim of the present study was to assess the adequacy of empirical and adjusted antibiotic therapies in a Swiss university hospital where no antibiotic use restrictions are enforced, and to identify risk factors for inadequate treatment and targets for intervention.

Methods

A prospective observational study was performed during 9 months. All patients admitted through the emergency department who received an antibiotic therapy within 24 hours of admission were included. Data on demographic characteristics, diagnoses, comorbidities, systemic inflammatory response syndrome (SIRS) parameters, microbiological tests, and administered antibiotics were collected prospectively. Antibiotic therapy was considered adequate if spectrum, dose, application modus, and duration of therapy were appropriate according to local recommendations or published guidelines.

Results

2943 admitted patients were evaluated. Of these, 572 (19.4%) received antibiotics within 24 hours and 539 (94%) were analysed in detail. Empirical antibiotic therapy was inadequate in 121 patients (22%). Initial therapy was adjusted in 168 patients (31%). This adjusted antibiotic therapy was inadequate in 46 patients (27%). The main reason for inadequacy was the use of antibiotics with unnecessarily broad spectrum (24% of inadequate empirical, and 52% of inadequate adjusted therapies). In 26% of patients with inadequate adjusted therapy, antibiotics used were either ineffective against isolated pathogenic bacteria or antibiotic therapy was continued despite negative results of microbiological investigations.

Conclusion

The rate of inadequate antibiotic therapies was similar to the rates reported from other institutions despite the absence of a restrictive antibiotic policy. Surprisingly, adjusted antibiotic therapies were more frequently inappropriate than empirical therapies. Interventions aiming at improving antibiotic prescribing should focus on both initial empirical therapy and streamlining and adjustment of therapy once microbiological results become available.
Trends of Hepatitis A hospitalization and risk factors in Quebec, Canada, between 1990 and 2003
Authors: Canuel Magalie , De Serres Gaston , Duval Bernard , Gilca Rodica , De Wals Philippe , Gilca Vladimir
Published: May 2007

Background

In Canada, targeted vaccination of at risk groups for hepatitis A (HA) is done since the mid 1990s resulting in declining incidence. This study estimated the year and age specific hospitalization rates and distribution of risk factors for HA in Quebec, Canada, between 1990 and 2003.

Methods

Records of patients hospitalized with HA-related diagnostic codes were retrieved from the provincial database. Hospital charts of all deceased cases and a random sample of all other records were reviewed.

Results

From 1503 hospitalization records, 573 charts were reviewed including 49 (91%) of the 54 deceased patients. Confirmed acute HA was present in 79% of records where HA was the primary diagnosis, and in 3%–8% of records where HA was a secondary diagnosis. From the total estimated number of hospitalizations, 96% had HA as the primary diagnosis. The hospitalization rate decreased from 1.06 per 100 000 person-years between 1990 and 1997 to 0.36 between 1998 and 2003. During the study period, 54% HA hospitalizations were in 20–39 year-olds. The overall case fatality ratio among hospitalized patients was 1.4%, increasing from 0.4% in those < 40 years old to 12.5% in those ≥60 years. By decreasing order, reported risk factors were travel to HA endemic countries (30%), MSM (18%) and household contacts (11%).

Conclusion

HA hospitalization rates have been low since 1998 but the cause of this is unclear given the cyclical pattern of HA. Travel to endemic countries remains the most important risk factor and improved control of HA will require better strategies to vaccinate travelers.
Analysis of meiotic recombination in 22q11.2, a region that frequently undergoes deletions and duplications
Authors: Torres-Juan Laura , Rosell Jordi , Sánchez-de-la-Torre Manuel , Fibla Joan , Heine-Suñer Damià
Published: May 2007

Background

The 22q11.2 deletion syndrome is the most frequent genomic disorder with an estimated frequency of 1/4000 live births. The majority of patients (90%) have the same deletion of 3 Mb (Typically Deleted Region, TDR) that results from aberrant recombination at meiosis between region specific low-copy repeats (LCRs).

Methods

As a first step towards the characterization of recombination rates and breakpoints within the 22q11.2 region we have constructed a high resolution recombination breakpoint map based on pedigree analysis and a population-based historical recombination map based on LD analysis.

Results

Our pedigree map allows the location of recombination breakpoints with a high resolution (potential recombination hotspots), and this approach has led to the identification of 5 breakpoint segments of 50 kb or less (8.6 kb the smallest), that coincide with historical hotspots. It has been suggested that aberrant recombination leading to deletion (and duplication) is caused by low rates of Allelic Homologous Recombination (AHR) within the affected region. However, recombination rate estimates for 22q11.2 region show that neither average recombination rates in the 22q11.2 region or within LCR22-2 (the LCR implicated in most deletions and duplications), are significantly below chromosome 22 averages. Furthermore, LCR22-2, the repeat most frequently implicated in rearrangements, is also the LCR22 with the highest levels of AHR. In addition, we find recombination events in the 22q11.2 region to cluster within families. Within this context, the same chromosome recombines twice in one family; first by AHR and in the next generation by NAHR resulting in an individual affected with the del22q11.2 syndrome.

Conclusion

We show in the context of a first high resolution pedigree map of the 22q11.2 region that NAHR within LCR22 leading to duplications and deletions cannot be explained exclusively under a hypothesis of low AHR rates. In addition, we find that AHR recombination events cluster within families. If normal and aberrant recombination are mechanistically related, the fact that LCR22s undergo frequent AHR and that we find familial differences in recombination rates within the 22q11.2 region would have obvious health-related implications.
Association of TGFβ1, TNFα, CCR2 and CCR5 gene polymorphisms in type-2 diabetes and renal insufficiency among Asian Indians
Authors: Prasad Pushplata , Tiwari Arun K , Kumar KM Prasanna , Ammini AC , Gupta Arvind , Gupta Rajeev , Thelma BK
Published: May 2007

Background

Cytokines play an important role in the development of diabetic chronic renal insufficiency (CRI). Transforming growth factor β1 (TGF β1) induces renal hypertrophy and fibrosis, and cytokines like tumor necrosis factor-alpha (TNFα), chemoattractant protein-1 (MCP-1), and regulated upon activation and normal T cell expressed and secreted (RANTES) mediate macrophage infiltration into kidney. Over expression of these chemokines leads to glomerulosclerosis and interstitial fibrosis. The effect of MCP-1 and RANTES on kidney is conferred by their receptors i.e., chemokine receptor (CCR)-2 and CCR-5 respectively. We tested association of nine single nucleotide polymorphisms (SNPs) from TGFβ1, TNFα, CCR2 and CCR5 genes among individuals with type-2 diabetes with and without renal insufficiency.

Methods

Type-2 diabetes subjects with chronic renal insufficiency (serum creatinine ≥ 3.0 mg/dl) constituted the cases, and matched individuals with diabetes of duration ≥ 10 years and normoalbuminuria were evaluated as controls from four centres in India. Allelic and genotypic contributions of nine SNPs from TGFβ1, TNFα, CCR2 and CCR5 genes to diabetic CRI were tested by computing odds ratio (OR) and 95% confidence intervals (CI). Sub-analysis of CRI cases diabetic retinopathy status as dependent variable and SNP genotypes as independent variable in a univariate logistic regression was also performed.

Results

SNPs Tyr81His and Thr263Ile in TGF β1 gene were monomorphic, and Arg25Pro in TGF β1 gene and Δ32 polymorphism in CCR5 gene were minor variants (minor allele frequency <0.05) and therefore were not considered for case-control analysis. A significant allelic association of 59029G>A SNP of CCR5 gene has been observed and the allele 59029A seems to confer predisposition to development of diabetic CRI (OR 1.39; CI 1.04–1.84). In CRI subjects a compound group of genotypes "GA and AA" of SNP G>A -800 was found to confer predisposition for proliferative retinopathy (OR 3.03; CI 1.08–8.50, p = 0.035).

Conclusion

Of the various cytokine gene polymorphisms tested, allele 59029A of CCR5 gene is significantly associated with diabetic renal insufficiency among Asian Indians. Result obtained for 59029G>A SNP of CCR5 gene is in conformity with reports from a Japanese population but due to sub-optimal power of the sample, replication in larger sample set is warranted.
Theory of obstetrics: An epidemiologic framework for justifying medically indicated early delivery
Authors: Joseph K S
Published: May 2007

Background

Modern obstetrics is faced with a serious paradox. Obstetric practice is becoming increasingly interventionist based on empirical evidence but without a theoretical basis for such intervention. Whereas obstetric models of perinatal death show that mortality declines exponentially with increasing gestational duration, temporal increases in medically indicated labour induction and cesarean delivery have resulted in rising rates of preterm birth and declining rates of postterm birth. Other problems include a disconnection between patterns of gestational age-specific growth restriction (constant across gestation) and gestational age-specific perinatal mortality (exponential decline with increasing duration) and the paradox of intersecting perinatal mortality curves (low birth weight infants of smokers have lower neonatal mortality rates than the low birth weight infants of non-smokers).

Discussion

The fetuses at risk approach is a causal model that brings coherence to the various perinatal phenomena. Under this formulation, pregnancy complications (such as preeclampsia), labour induction/cesarean delivery, birth, revealed small-for-gestational age and death show coherent patterns of incidence. The fetuses at risk formulation also provides a theoretical justification for medically indicated early delivery, the cornerstone of modern obstetrics. It permits a conceptualization of the number needed to treat (e.g., as low as 2 for emergency cesarean delivery in preventing perinatal death given placental abruption and fetal bradycardia) and a calculation of the marginal number needed to treat (i.e., the number of additional medically indicated labour inductions/cesarean deliveries required to prevent one perinatal death). Data from the United States showed that between 1995–96 and 1999–2000 rates of labour induction/cesarean delivery increased by 45.1 per 1,000 and perinatal mortality decreased by 0.31 per 1,000 total births among singleton pregnancies at > = 28 weeks of gestation. The marginal number needed to treat was 145 (45.1/0.31), showing that 145 excess labour inductions/cesarean deliveries in 1999–2000 (relative to 1995–96) were responsible for preventing 1 perinatal death among singleton pregnancies at > = 28 weeks gestation.

The fetuses at risk approach, with its focus on incidence measures, provides a coherent view of perinatal phenomena. It also provides a theoretical justification for medically indicated early delivery and reconciles the contemporary divide between obstetric theory and obstetric practice.
Tyrosine kinase inhibitor SU6668 represses chondrosarcoma growth via antiangiogenesis in vivo
Authors: Klenke Frank M , Abdollahi Amir , Bertl Elisabeth , Gebhard Martha-Maria , Ewerbeck Volker , Huber Peter E , Sckell Axel
Published: May 2007

Background

As chondrosarcomas are resistant to chemotherapy and ionizing radiation, therapeutic options are limited. Radical surgery often cannot be performed. Therefore, additional therapies such as antiangiogenesis represent a promising strategy for overcoming limitations in chondrosarcoma therapy. There is strong experimental evidence that SU6668, an inhibitor of the angiogenic tyrosine kinases Flk-1/KDR, PDGFRbeta and FGFR1 can induce growth inhibition of various primary tumors. However, the effectiveness of SU6668 on malignant primary bone tumors such as chondrosarcomas has been rarely investigated. Therefore, the aim of this study was to investigate the effects of SU6668 on chondrosarcoma growth, angiogenesis and microcirculation in vivo.

Methods

In 10 male severe combined immunodeficient (SCID) mice, pieces of SW1353 chondrosarcomas were implanted into a cranial window preparation where the calvaria serves as the site for the orthotopic implantation of bone tumors. From day 7 after tumor implantation, five animals were treated with SU6668 (250 mg/kg body weight, s.c.) at intervals of 48 hours (SU6668), and five animals with the equivalent amount of the CMC-based vehicle (Control). Angiogenesis, microcirculation, and growth of SW 1353 tumors were analyzed by means of intravital microscopy.

Results

SU6668 induced a growth arrest of chondrosarcomas within 7 days after the initiation of the treatment. Compared to Controls, SU6668 decreased functional vessel density and tumor size, respectively, by 37% and 53% on day 28 after tumor implantation. The time course of the experiments demonstrated that the impact on angiogenesis preceded the anti-tumor effect. Histological and immunohistochemical results confirmed the intravital microscopy findings.

Conclusion

SU6668 is a potent inhibitor of chondrosarcoma tumor growth in vivo. This effect appears to be induced by the antiangiogenic effects of SU6668, which are mediated by the inhibition of the key angiogenic receptor tyrosine kinases Flk-1/KDR, PDGFRbeta and FGFR1. The experimental data obtained provide rationale to further develop the strategy of the use of the angiogenesis inhibitor SU6668 in the treatment of chondrosarcomas in addition to established therapies such as surgery.
Silencing of the XAF1 gene by promoter hypermethylation in cancer cells and reactivation to TRAIL-sensitization by IFN-β
Authors: Micali O Cristina , Cheung Herman H , Plenchette Stéphanie , Hurley Sandra L , Liston Peter , LaCasse Eric C , Korneluk Robert G
Published: May 2007

Background

XIAP-associated factor 1 (XAF1) is a putative tumor suppressor that exerts its proapoptotic effects through both caspase-dependent and – independent means. Loss of XAF1 expression through promoter methylation has been implicated in the process of tumorigenesis in a variety of cancers. In this report, we investigated the role of basal xaf1 promoter methylation in xaf1 expression and assessed the responsiveness of cancer cell lines to XAF1 induction by IFN-β.

Methods

We used the conventional bisulfite DNA modification and sequencing method to determine the methylation status in the CpG sites of xaf1 promoter in glioblastoma (SF539, SF295), neuroblastoma (SK-N-AS) and cervical carcinoma (HeLa) cells. We analysed the status and incidence of basal xaf1 promoter methylation in xaf1 expression in non-treated cells as well as under a short or long exposure to IFN-β. Stable XAF1 glioblastoma knock-down cell lines were established to characterize the direct implication of XAF1 in IFN-β-mediated sensitization to TRAIL-induced cell death.

Results

We found a strong variability in xaf1 promoter methylation profile and responsiveness to IFN-β across the four cancer cell lines studied. At the basal level, aberrant promoter methylation was linked to xaf1 gene silencing. After a short exposure, the IFN-β-mediated reactivation of xaf1 gene expression was related to the degree of basal promoter methylation. However, in spite of continued promoter hypermethylation, we find that IFN-β induced a transient xaf1 expression, that in turn, was followed by promoter demethylation upon a prolonged exposure. Importantly, we demonstrated for the first time that IFN-β-mediated reactivation of endogenous XAF1 plays a critical role in TRAIL-induced cell death since XAF1 knock-down cell lines completely lost their IFN-β-mediated TRAIL sensitivity.

Conclusion

Together, these results suggest that promoter demethylation is not the sole factor determining xaf1 gene induction under IFN-β treatment. Furthermore, our study provides evidence that XAF1 is a crucial interferon-stimulated gene (ISG) mediator of IFN-induced sensitization to TRAIL in cancer.
Novel markers for differentiation of lobular and ductal invasive breast carcinomas by laser microdissection and microarray analysis
Authors: Turashvili Gulisa , Bouchal Jan , Baumforth Karl , Wei Wenbin , Dziechciarkova Marta , Ehrmann Jiri , Klein Jiri , Fridman Eduard , Skarda Jozef , Srovnal Josef , Hajduch Marian , Murray Paul , Kolar Zdenek
Published: May 2007

Background

Invasive ductal and lobular carcinomas (IDC and ILC) are the most common histological types of breast cancer. Clinical follow-up data and metastatic patterns suggest that the development and progression of these tumors are different. The aim of our study was to identify gene expression profiles of IDC and ILC in relation to normal breast epithelial cells.

Methods

We examined 30 samples (normal ductal and lobular cells from 10 patients, IDC cells from 5 patients, ILC cells from 5 patients) microdissected from cryosections of ten mastectomy specimens from postmenopausal patients. Fifty nanograms of total RNA were amplified and labeled by PCR and in vitro transcription. Samples were analysed upon Affymetrix U133 Plus 2.0 Arrays. The expression of seven differentially expressed genes (CDH1, EMP1, DDR1, DVL1, KRT5, KRT6, KRT17) was verified by immunohistochemistry on tissue microarrays. Expression of ASPN mRNA was validated by in situ hybridization on frozen sections, and CTHRC1, ASPN and COL3A1 were tested by PCR.

Results

Using GCOS pairwise comparison algorithm and rank products we have identified 84 named genes common to ILC versus normal cell types, 74 named genes common to IDC versus normal cell types, 78 named genes differentially expressed between normal ductal and lobular cells, and 28 named genes between IDC and ILC. Genes distinguishing between IDC and ILC are involved in epithelial-mesenchymal transition, TGF-beta and Wnt signaling. These changes were present in both tumor types but appeared to be more prominent in ILC. Immunohistochemistry for several novel markers (EMP1, DVL1, DDR1) distinguished large sets of IDC from ILC.

Conclusion

IDC and ILC can be differentiated both at the gene and protein levels. In this study we report two candidate genes, asporin (ASPN) and collagen triple helix repeat containing 1 (CTHRC1) which might be significant in breast carcinogenesis. Besides E-cadherin, the proteins validated on tissue microarrays (EMP1, DVL1, DDR1) may represent novel immunohistochemical markers helpful in distinguishing between IDC and ILC. Further studies with larger sets of patients are needed to verify the gene expression profiles of various histological types of breast cancer in order to determine molecular subclassifications, prognosis and the optimum treatment strategies.
Matrix-comparative genomic hybridization from multicenter formalin-fixed paraffin-embedded colorectal cancer tissue blocks
Authors: Fensterer Heiko , Radlwimmer Bernhard , Sträter Jörn , Buchholz Malte , Aust Daniela E , Julié Catherine , Radvanyi François , Nordlinger Bernard , Belluco Claudio , Van Cutsem Eric , Köhne Claus-Henning , Kestler Hans A , Schwaenen Carsten , Nessling Michelle , Lutz Manfred P , Lichter Peter , Gress Thomas M ,   the EORTC Gastrointestinal (GI) Group
Published: May 2007

Background

The identification of genomic signatures of colorectal cancer for risk stratification requires the study of large series of cancer patients with an extensive clinical follow-up. Multicentric clinical studies represent an ideal source of well documented archived material for this type of analyses.

Methods

To verify if this material is technically suitable to perform matrix-CGH, we performed a pilot study using macrodissected 29 formalin-fixed, paraffin-embedded tissue samples collected within the framework of the EORTC-GI/PETACC-2 trial for colorectal cancer. The scientific aim was to identify prognostic genomic signatures differentiating locally restricted (UICC stages II-III) from systemically advanced (UICC stage IV) colorectal tumours.

Results

The majority of archived tissue samples collected in the different centers was suitable to perform matrix-CGH. 5/7 advanced tumours displayed 13q-gain and 18q-loss. In locally restricted tumours, only 6/12 tumours showed a gain on 13q and 7/12 tumours showed a loss on 18q. Interphase-FISH and high-resolution array-mapping of the gain on 13q confirmed the validity of the array-data and narrowed the chromosomal interval containing potential oncogenes.

Conclusion

Archival, paraffin-embedded tissue samples collected in multicentric clinical trials are suitable for matrix-CGH analyses and allow the identification of prognostic signatures and aberrations harbouring potential new oncogenes.
Enhanced NFκB and AP-1 transcriptional activity associated with antiestrogen resistant breast cancer
Authors: Zhou Yamei , Yau Christina , Gray Joe W , Chew Karen , Dairkee Shanaz H , Moore Dan H , Eppenberger Urs , Eppenberger-Castori Serenella , Benz Christopher C
Published: May 2007

Background

Signaling pathways that converge on two different transcription factor complexes, NFκB and AP-1, have been identified in estrogen receptor (ER)-positive breast cancers resistant to the antiestrogen, tamoxifen.

Methods

Two cell line models of tamoxifen-resistant ER-positive breast cancer, MCF7/HER2 and BT474, showing increased AP-1 and NFκB DNA-binding and transcriptional activities, were studied to compare tamoxifen effects on NFκB and AP-1 regulated reporter genes relative to tamoxifen-sensitive MCF7 cells. The model cell lines were treated with the IKK inhibitor parthenolide (PA) or the proteasome inhibitor bortezomib (PS341), alone and in combination with tamoxifen. Expression microarray data available from 54 UCSF node-negative ER-positive breast cancer cases with known clinical outcome were used to search for potential genes signifying upregulated NFκB and AP-1 transcriptional activity in association with tamoxifen resistance. The association of these genes with patient outcome was further evaluated using node-negative ER-positive breast cancer cases identified from three other published data sets (Rotterdam, n = 209; Amsterdam, n = 68; Basel, n = 108), each having different patient age and adjuvant tamoxifen treatment characteristics.

Results

Doses of parthenolide and bortezomib capable of sensitizing the two endocrine resistant breast cancer models to tamoxifen were capable of suppressing NFκB and AP-1 regulated gene expression in combination with tamoxifen and also increased ER recruitment of the transcriptional co-repressor, NCoR. Transcript profiles from the UCSF breast cancer cases revealed three NFκB and AP-1 upregulated genes – cyclin D1, uPA and VEGF – capable of dichotomizing node-negative ER-positive cases into early and late relapsing subsets despite adjuvant tamoxfien therapy and most prognostic for younger age cases. Across the four independent sets of node-negative ER-positive breast cancer cases (UCSF, Rotterdam, Amsterdam, Basel), high expression of all three NFκB and AP-1 upregulated genes was associated with earliest metastatic relapse.

Conclusion

Altogether, these findings implicate increased NFκB and AP-1 transcriptional responses with tamoxifen resistant breast cancer and early metastatic relapse, especially in younger patients. These findings also suggest that agents capable of preventing NFκB and AP-1 gene activation may prove useful in restoring the endocrine responsiveness of such high-risk ER-positive breast cancers.
Potential cost savings with terrestrial rabies control
Authors: Recuenco Sergio , Cherry Bryan , Eidson Millicent
Published: May 2007

Background

The cost-benefit of raccoon rabies control strategies such as oral rabies vaccination (ORV) are under evaluation. As an initial quantification of the potential cost savings for a control program, the collection of selected rabies cost data was pilot tested for five counties in New York State (NYS) in a three-year period.

Methods

Rabies costs reported to NYS from the study counties were computerized and linked to a human rabies exposure database. Consolidated costs by county and year were averaged and compared.

Results

Reported rabies-associated costs for all rabies variants totalled $2.1 million, for human rabies postexposure prophylaxes (PEP) (90.9%), animal specimen preparation/shipment to laboratory (4.7%), and pet vaccination clinics (4.4%). The proportion that may be attributed to raccoon rabies control was 37% ($784,529). Average costs associated with the raccoon variant varied across counties from $440 to $1,885 per PEP, $14 to $44 per specimen, and $0.33 to $15 per pet vaccinated.

Conclusion

Rabies costs vary widely by county in New York State, and were associated with human population size and methods used by counties to estimate costs. Rabies cost variability must be considered in developing estimates of possible ORV-related cost savings. Costs of PEPs and specimen preparation/shipments, as well as the costs of pet vaccination provided by this study may be valuable for development of more realistic scenarios in economic modelling of ORV costs versus benefits.
Acute hepatitis C virus infection assessment among chronic hemodialysis patients in the Southwest Parana State, Brazil
Authors: Engel Maricea , Malta Fernanda M , Gomes Michele MS , Mello Isabel MVGC , Pinho João RR , Ono-Nita Suzane K , Carrilho Flair J
Published: May 2007

Background

Chronic hemodialysis patients are at higher risk for acquiring hepatitis C virus (HCV). The prevalence varies among different countries and hemodialysis centers. Although guidelines for a comprehensive infection control program exist, the nosocomial transmission still accounts for the new cases of infection. The aim of this study was analyze the follow up of newly acquired acute hepatitis C cases, during the period from January 2002 to May 2005, in the Hemodialysis Center, located in the Southwest region of Parana State, Brazil and to analyze the effectiveness of the measures to restrain the appearance of new cases of acute hepatitis C.

Methods

Patients were analyzed monthly with anti-HCV tests and ALT measurements. Patients with ALT elevations were monitored for possible acute hepatitis C.

Results

During this period, 32 new cases were identified with acute hepatitis C virus infection. Blood screening showed variable ALT levels preceding the anti-HCV seroconversion. HCV RNA viremia by PCR analysis was intermittently and even negative in some cases. Ten out of 32 patients received 1 mcg/kg dose of pegylated interferon alfa-2b treatment for 24 weeks. All dialysis personnel were re-trained to strictly follow the regulations and recommendations regarding infection control, proper methods to clean and disinfect equipment were reviewed and HCV-positive patients were isolated.

Conclusion

Laboratory tests results showed variable ALT preceding anti-HCV seroconversion and intermittent viremia. The applied recommendations contributed importantly to restrain the appearance of new cases of acute hepatitis C in this center and the last case was diagnosed in May 2004.