bluuebunny/crossref_metadata_2025 huggingface dataset:
Cleavage of sphingosine kinase 2 by caspase-1 provokes its release from apoptotic cells
Authors: Weigert Andreas , Cremer Sarah , Schmidt Martina Victoria , von Knethen Andreas , Angioni Carlo , Geisslinger Gerd , Brüne Bernhard
Published: March 2010

Execution of physiologic cell death known as apoptosis is tightly regulated and transfers immunologically relevant information. This ensures efficient clearance of dying cells and shapes the phenotype of their “captors” toward anti-inflammatory. Here, we identify a mechanism of sphingosine-1-phosphate production by apoptotic cells. During cell death, sphingosine kinase 2 (SphK2) is cleaved at its N-terminus in a caspase-1–dependent manner. Thereupon, a truncated but enzymatically active fragment of SphK2 is released from cells. This step is coupled to phosphatidylserine exposure, which is a hallmark of apoptosis and a crucial signal for phagocyte/apoptotic cell interaction. Our data link signaling events during apoptosis to the extracellular production of a lipid mediator that affects immune cell attraction and activation.
Occurrence of minimal change nephrotic syndrome in classical Hodgkin lymphoma is closely related to the induction of c-mip in Hodgkin-Reed Sternberg cells and podocytes
Authors: Audard Vincent , Zhang Shao-yu , Copie-Bergman Christiane , Rucker-Martin Catherine , Ory Virginie , Candelier Marina , Baia Maryse , Lang Philippe , Pawlak André , Sahali Djillali
Published: March 2010

It is currently considered that idiopathic minimal change nephrotic syndrome is an immune-mediated glomerular disease. Its association with classical Hodgkin lymphoma minimal change nephrotic syndrome (cHL-MCNS) suggests a molecular link, which remains to be elucidated. We analyzed the expression of cmaf inducing protein (c-mip) in lymphomatous tissues and kidney biopsy samples of patients with cHL-MCNS (n = 8) and in lymphomatous tissues of patients with isolated cHL (n = 9). Because c-mip affects the regulatory loop involving Fyn, we investigated possible structural defects in this signaling pathway, using laser capture microdissection, reverse transcription polymerase chain reaction, and Western blotting. We found that c-mip was selectively expressed in Hodgkin and Reed-Sternberg (HRS) cells and podocytes of patients with cHL-MCNS but is undetectable in patients with isolated cHL. We demonstrated that c-mip was specifically involved in the negative regulation of early proximal signaling through its interaction with phosphoprotein associated with glycosphingolipid-enriched microdomains and Fyn. We showed that the up-regulation of c-mip in cHL-MCNS was associated with a possible Fyn defect in HRS cells and podocytes. Moreover, we showed that c-mip was up-regulated in Fyn-deficient podocytes. c-mip may be a useful marker of cHL-MCNS and its induction reflects the dysregulation of proximal signaling.
MicroRNAs of Bombyx mori identified by Solexa sequencing
Authors: Liu Shiping , Li Dong , Li Qibin , Zhao Ping , Xiang Zhonghuai , Xia Qingyou
Published: March 2010

Background

MicroRNA (miRNA) and other small regulatory RNAs contribute to the modulation of a large number of cellular processes. We sequenced three small RNA libraries prepared from the whole body, and the anterior-middle and posterior silk glands of Bombyx mori, with a view to expanding the repertoire of silkworm miRNAs and exploring transcriptional differences in miRNAs between segments of the silk gland.

Results

With the aid of large-scale Solexa sequencing technology, we validated 257 unique miRNA genes, including 202 novel and 55 previously reported genes, corresponding to 324 loci in the silkworm genome. Over 30 known silkworm miRNAs were further corrected in their sequence constitutes and length. A number of reads originated from the loop regions of the precursors of two previously reported miRNAs (bmo-miR-1920 and miR-1921). Interestingly, the majority of the newly identified miRNAs were silkworm-specific, 23 unique miRNAs were widely conserved from invertebrates to vertebrates, 13 unique miRNAs were limited to invertebrates, and 32 were confined to insects. We identified 24 closely positioned clusters and 45 paralogs of miRNAs in the silkworm genome. However, sequence tags showed that paralogs or clusters were not prerequisites for coordinated transcription and accumulation. The majority of silkworm-specific miRNAs were located in transposable elements, and displayed significant differences in abundance between the anterior-middle and posterior silk gland.

Conclusions

Conservative analysis revealed that miRNAs can serve as phylogenetic markers and function in evolutionary signaling. The newly identified miRNAs greatly enrich the repertoire of insect miRNAs, and provide insights into miRNA evolution, biogenesis, and expression in insects. The differential expression of miRNAs in the anterior-middle and posterior silk glands supports their involvement as new levels in the regulation of the silkworm silk gland.
Neuroprotective effects of bis(7)-tacrine against glutamate-induced retinal ganglion cells damage
Authors: Fang Jia Hua , Wang Xing Hua , Xu Zhi Rong , Jiang Fa Gang
Published: March 2010

Background

Glutamate-mediated excitotoxicity, primarily through N-methyl-D-aspartate (NMDA) receptors, may be an important cause of retinal ganglion cells (RGCs) death in glaucoma and several other retinal diseases. Bis(7)-tacrine is a noncompetitive NMDA receptors antagonist that can prevent glutamate-induced hippocampal neurons damage. We tested the effects of bis(7)-tacrine against glutamate-induced rat RGCs damage in vitro and in vivo.

Results

In cultured neonatal rats RGCs, the MTT assay showed that glutamate induced a concentration- and time-dependent toxicity. Bis(7)-tacrine and memantine prevented glutamate-induced cell death in a concentration-dependent manner with IC50 values of 0.028 μM and 0.834 μM, respectively. The anti-apoptosis effects of bis(7)-tacrine were confirmed by annexin V-FITC/PI staining. In vivo, TUNEL analysis and retrograde labeling analysis found that pretreatment with bis(7)-tacrine(0.2 mg/kg) induced a significant neuroprotective effect against glutamate-induced RGCs damage.

Conclusions

Our results showed that bis(7)-tacrine had neuroprotective effects against glutamate-induced RGCs damage in vitro and in vivo, possibly through the drug's anti-NMDA receptor effects. These findings make bis(7)-tacrine potentially useful for treating a variety of ischemic or traumatic retinopathies inclusive of glaucoma.
Complementary genetic and genomic approaches help characterize the linkage group I seed protein QTL in soybean
Authors: Bolon Yung-Tsi , Joseph Bindu , Cannon Steven B , Graham Michelle A , Diers Brian W , Farmer Andrew D , May Gregory D , Muehlbauer Gary J , Specht James E , Tu Zheng Jin , Weeks Nathan , Xu Wayne W , Shoemaker Randy C , Vance Carroll P
Published: March 2010

Background

The nutritional and economic value of many crops is effectively a function of seed protein and oil content. Insight into the genetic and molecular control mechanisms involved in the deposition of these constituents in the developing seed is needed to guide crop improvement. A quantitative trait locus (QTL) on Linkage Group I (LG I) of soybean (Glycine max (L.) Merrill) has a striking effect on seed protein content.

Results

A soybean near-isogenic line (NIL) pair contrasting in seed protein and differing in an introgressed genomic segment containing the LG I protein QTL was used as a resource to demarcate the QTL region and to study variation in transcript abundance in developing seed. The LG I QTL region was delineated to less than 8.4 Mbp of genomic sequence on chromosome 20. Using Affymetrix® Soy GeneChip and high-throughput Illumina® whole transcriptome sequencing platforms, 13 genes displaying significant seed transcript accumulation differences between NILs were identified that mapped to the 8.4 Mbp LG I protein QTL region.

Conclusions

This study identifies gene candidates at the LG I protein QTL for potential involvement in the regulation of protein content in the soybean seed. The results demonstrate the power of complementary approaches to characterize contrasting NILs and provide genome-wide transcriptome insight towards understanding seed biology and the soybean genome.
Medically unexplained pain complaints are associated with underlying unrecognized mood disorders in primary care
Authors: Agüera Luis , Failde Inmaculada , Cervilla Jorge A , Díaz-Fernández Paula , Mico Juan Antonio
Published: March 2010

Background

Patients with chronic pain frequently display comorbid depression, but the impact of this concurrence is often underestimated and mistreated. The aim of this study was to determine the prevalence of unrecognized major depression and other mood disorders and comorbid unexplained chronic pain in primary care settings and to explore the associated factors.

Also, to compare the use of health services by patients with unexplained chronic pain, both with and without mood disorder comorbidity.

Methods

A cross-sectional study was carried out in a sample of primary care centers. 3189 patients consulting for "unexplained chronic pain" were assessed by the Visual Analogue Scales (VAS) and the Primary Care Evaluation of Mental Disorders (PRIME-MD) questionnaire.

Results

We report: a) a high prevalence of unrecognized mood disorders in patients suffering from unexplained chronic pain complaints (80.4%: CI 95%: 79.0%; 81.8%); b) a greater susceptibility of women to mood disorders (OR adjusted = 1.48; CI 95%:1.22; 1.81); c) a direct relationship between the prevalence of mood disorders and the duration of pain (OR adjusted = 1.01; CI 95%: 1.01; 1.02) d) a higher comorbidity with depression if the pain etiology was unknown (OR adjusted = 1.74; CI 95%: 1.45; 2.10) and, e) an increased use of health care services in patients with such a comorbidity (p < 0.0001).

Conclusions

The prevalence of undiagnosed mood disorders in patients with unexplained chronic pain in primary care is very high, leading to dissatisfaction with treatment processes and poorer outcomes. Consequently, it seems necessary to explore this condition more regularly in general practice in order to reach accurate diagnoses and to select the appropriate treatment.
PARP-1 Val762Ala polymorphism is associated with reduced risk of non-Hodgkin lymphoma in Korean males
Authors: Jin Xue Mei , Kim Hee Nam , Lee Il-Kwon , Park Kyeong-Soo , Kim Hyeoung-Joon , Choi Jin-Su , Juhng Sang Woo , Choi Chan
Published: March 2010

Background

Poly(ADP-ribose) polymerase-1 (PARP-1) is a nuclear enzyme that plays a role in DNA repair, differentiation, proliferation, and cell death. The polymorphisms ofPARP-1have been associated with the risk of various carcinomas, including breast, lung, and prostate. We investigated whetherPARP-1polymorphisms are associated with the risk of non-Hodgkin lymphoma (NHL).

Methods

Subjects from a Korean population consisting of 573 NHL patients and 721 controls were genotyped for 5PARP-1polymorphisms (Asp81Asp, Ala284Ala, Lys352Lys, IVS13+118A>G, and Val762Ala) using High Resolution Melting polymerase chain reaction (PCR) and an automatic sequencer.

Results

None of the 5 polymorphisms were associated with overall risk for NHL. However, the Val762Ala polymorphism was associated with reduced risk for NHL in males [odds ratio (OR), 0.62; 95% confidence interval (CI), 0.41-0.93 for CC genotype and OR, 0.84; 95% CI, 0.60-1.16 for TC genotype] with a trend toward a gene dose effect (p for trend, 0.02). The Asp81Asp (p for trend, 0.04) and Lys352Lys (p for trend, 0.03) polymorphisms revealed the same trend. In an association study ofPARP-1haplotypes, the haplotype-ACAAC was associated with decreased risk of NHL in males (OR, 0.75; 95% CI, 0.59-0.94).

Conclusion

The present data suggest that Val762Ala, Asp81Asp, and Lys352Lys polymorphisms and the haplotype-ACAAC inPARP-1are associated with reduced risk of NHL in Korean males.
Chronic infection during placental malaria is associated with up-regulation of cycloxygenase-2
Authors: Sarr Demba , Aldebert Delphine , Marrama Laurence , Frealle Emilie , Gaye Alioune , Brahim Hamoud O , Niang Makhtar , Dangou Jean Marie , Mercereau-Puijalon Odile , Lehesran Jean Yves , Jambou Ronan
Published: March 2010

Background

Placental malaria (PM) is associated with poor foetal development, but the pathophysiological processes involved are poorly understood. Cyclooxygenase (COX) and lipoxygenase (LOX) which convert fatty acids to prostaglandins and leukotrienes, play important roles in pregnancy and foetal development. COX-2, currently targeted by specific drugs, plays a dual role as it associates with both pre-eclampsia pathology and recovery during infection. The role of COX during PM was questioned by quantifying at delivery COX-1, COX-2, 15-LOX, and IL-10 expression in two groups of malaria infected and uninfected placenta.

Methods

Placental biopsies were collected at delivery for mRNA isolation and quantification, using real time PCR.

Results

COX-2 and IL-10 mRNAs increased mainly during chronic infections (nine- and five-times, respectively), whereas COX-1 transcripts remained constant. COX-2 over-expression was associated with a higher birth weight of the baby, but with a lower rate of haemoglobin of the mother. It was associated with a macrophage infiltration of the placenta and with a low haemozoin infiltration. In the opposite way, placental infection was associated with lower expression of 15-LOX mRNA. A high degree of haemozoin deposition correlates with low birth weight and decreased expression of COX-2.

Conclusion

These data provide evidence that COX-2 and IL-10 are highly induced during chronic infection of the placenta, but were not associated with preterm delivery or low birth weight. The data support the involvement of COX-2 in the recovery phase of the placental infection.
Markers of anti-malarial drug resistance in Plasmodium falciparum isolates from Swaziland: identification of pfmdr1-86F in natural parasite isolates
Authors: Dlamini Sabelo V , Beshir Khalid , Sutherland Colin J
Published: March 2010

Background

The development of Plasmodium falciparum resistance to chloroquine (CQ) has limited its use in many malaria endemic areas of the world. However, despite recent drug policy changes to adopt the more effective artemisinin-based combination (ACT) in Africa and in the Southern African region, in 2007 Swaziland still relied on CQ as first-line anti-malarial drug.

Methods

Parasite DNA was amplified from P. falciparum isolates from Swaziland collected in 1999 (thick smear blood slides) and 2007 (filter paper blood spots). Markers of CQ and sulphadoxine-pyrimethamine (SP) resistance were identified by probe-based qPCR and DNA sequencing.

Results

Retrospective microscopy, confirmed by PCR amplification, found that only six of 252 patients treated for uncomplicated malaria in 2007 carried detectable P. falciparum. The pfcrt haplotype 72C/73V/74I/75E/76T occurred at a prevalence of 70% (n = 64) in 1999 and 83% (n = 6) in 2007. Prevalence of the pfmdr1-86N allele was 24% in 1999 and 67% in 2007. A novel substitution of phenylalanine for asparagine at codon 86 of pfmdr1 (N86F) occurred in two of 51 isolates successfully amplified from 1999. The pfmdr1-1246Y allele was common in 1999, with a prevalence of 49%, but was absent among isolates collected in 2007. The 86N/184F/1246D pfmdr1 haplotype, associated with enhanced parasite survival in patients treated with artemether-lumefantrine, comprised 8% of 1999 isolates, and 67% among 2007 isolates. The pfdhfr triple-mutant 16C/51I/59R/108N/164I haplotype associated with pyrimethamine resistance was common in both 1999 (82%, n = 34) and 2007 (50%, n = 6), as was the wild-type 431I/436S/437A/540K/581A/613A haplotype of pfdhps (100% and 93% respectively in 1999 and 2007). The quintuple-mutant haplotype pfdhfr/pfdhps-CIRNI/ISGEAA, associated with high-level resistance to SP, was rare (9%) among 1999 isolates and absent among 2007 isolates.

Conclusions

The prevalence of pfcrt and pfmdr1 alleles reported in this study is consistent with a parasite population under sustained CQ drug pressure. The low prevalence of dhps-437G and dhps-540E mutations (ISGEAA) and the rarity of quintuple-mutant haplotype pfdhfr/pfdhps-CIRNI/ISGEAA suggest that SP retains some efficacy in Swaziland. Anti-malarial policy changes in neighbouring countries may have had an impact on the prevalence of molecular markers of anti-malarial resistance in Swaziland, and it is hoped that this new information will add to understanding of the regional anti-malarial resistance map.
Identification and characterization of Dlc1 isoforms in the mouse and study of the biological function of a single gene trapped isoform
Authors: Sabbir Mohammad G , Wigle Nichola , Loewen Shauna , Gu Yuan , Buse Cordula , Hicks Geoffrey G , Mowat Michael RA
Published: March 2010

Background

The Dlc1 (deleted in liver cancer 1) tumour suppressor gene codes for a RhoGTPase activating protein that is found inactivated in many tumour types. Several transcriptional isoforms have been described but the functional significance and tissue distribution of each form is presently poorly understood. Also, differences in the number of isoforms and splice variants reported still exist between different mammalian species. In order to better understand the number and function of the different variants of the Dlc1 gene in the mouse, we have carried out a detailed analysis. Extensive 3' RACE experiments were carried out in order to identify all possible Dlc1 isoforms and splice variants in the mouse. In addition, we have generated a gene trapped mouse that targets one of these isoforms in order to study its biological function. The effect of this gene trap insertion on the splicing of other isoforms has also been studied.

Results

In addition to the known 6.1 and 6.2 Kb transcripts of Dlc1, our study revealed the existence of a novel 7.6 Kb transcriptional isoform in the mouse, which corresponds to the human 7.4 Kb (KIAA1723) cDNA transcript. A gene trapped embryonic cell line, with an insertion between Exon 1 and 2 of the 6.1 Kb transcriptional isoform, was used to generate a transgenic mouse. This line showed a significant reduction in the expression of the trapped isoform. However, reduced expression of the other isoforms was not seen. Mice heterozygous for the gene trapped allele were phenotypically normal, but homozygous mutant embryos did not survive beyond 10.5 days post coitum. Dlc1gt/gt embryos showed defects in the brain, heart, and placental blood vessels. Cultured serum-free mouse embryo cells from Dlc1 deficient embryos had elevated RhoA activity and displayed alterations in the organization of actin filaments and focal adhesions. The Dlc1 deficient cells also exhibited increased wound closure in an in vitro scratch assay.

Conclusions

The mouse has three major transcriptional isoforms of the Dlc1 gene that are differentially expressed in various tissues. A mouse with exon 1 of the 6.1 Kb transcript gt resulted in hypomorphic expression of Dlc1 protein and an embryonic lethal phenotype in the homozygous condition, which indicates that this isoform plays a major role in mouse development. The Dlc1 deficient cells showed altered cytoskeleton structure, increased RhoA activity and cellular migration.
Multifunctional Nanocarriers for diagnostics, drug delivery and targeted treatment across blood-brain barrier: perspectives on tracking and neuroimaging
Authors: Bhaskar Sonu , Tian Furong , Stoeger Tobias , Kreyling Wolfgang , de la Fuente Jesús M , Grazú Valeria , Borm Paul , Estrada Giovani , Ntziachristos Vasilis , Razansky Daniel
Published: March 2010

Nanotechnology has brought a variety of new possibilities into biological discovery and clinical practice. In particular, nano-scaled carriers have revolutionalized drug delivery, allowing for therapeutic agents to be selectively targeted on an organ, tissue and cell specific level, also minimizing exposure of healthy tissue to drugs. In this review we discuss and analyze three issues, which are considered to be at the core of nano-scaled drug delivery systems, namely functionalization of nanocarriers, delivery to target organs andin vivoimaging. The latest developments on highly specific conjugation strategies that are used to attach biomolecules to the surface of nanoparticles (NP) are first reviewed. Besides drug carrying capabilities, the functionalization of nanocarriers also facilitate their transport to primary target organs. We highlight the leading advantage of nanocarriers, i.e. their ability to cross the blood-brain barrier (BBB), a tightly packed layer of endothelial cells surrounding the brain that prevents high-molecular weight molecules from entering the brain. The BBB has several transport molecules such as growth factors, insulin and transferrin that can potentially increase the efficiency and kinetics of brain-targeting nanocarriers. Potential treatments for common neurological disorders, such as stroke, tumours and Alzheimer's, are therefore a much sought-after application of nanomedicine. Likewise any other drug delivery system, a number of parameters need to be registered once functionalized NPs are administered, for instance their efficiency in organ-selective targeting, bioaccumulation and excretion. Finally, directin vivoimaging of nanomaterials is an exciting recent field that can provide real-time tracking of those nanocarriers. We review a range of systems suitable forin vivoimaging and monitoring of drug delivery, with an emphasis on most recently introduced molecular imaging modalities based on optical and hybrid contrast, such as fluorescent protein tomography and multispectral optoacoustic tomography. Overall, great potential is foreseen for nanocarriers in medical diagnostics, therapeutics and molecular targeting. A proposed roadmap for ongoing and future research directions is therefore discussed in detail with emphasis on the development of novel approaches for functionalization, targeting and imaging of nano-based drug delivery systems, a cutting-edge technology poised to change the ways medicine is administered.
Construction of an Yucatec Maya soil classification and comparison with the WRB framework
Authors: Bautista Francisco , Zinck J Alfred
Published: March 2010

Background

Mayas living in southeast Mexico have used soils for millennia and provide thus a good example for understanding soil-culture relationships and for exploring the ways indigenous people name and classify the soils of their territory. This paper shows an attempt to organize the Maya soil knowledge into a soil classification scheme and compares the latter with the World Reference Base for Soil Resources (WRB).

Methods

Several participative soil surveys were carried out in the period 2000-2009 with the help of bilingual Maya-Spanish-speaking farmers. A multilingual soil database was built with 315 soil profile descriptions.

Results

On the basis of the diagnostic soil properties and the soil nomenclature used by Maya farmers, a soil classification scheme with a hierarchic, dichotomous and open structure was constructed, organized in groups and qualifiers in a fashion similar to that of the WRB system. Maya soil properties were used at the same categorical levels as similar diagnostic properties are used in the WRB system.

Conclusions

The Maya soil classification (MSC) is a natural system based on key properties, such as relief position, rock types, size and quantity of stones, color of topsoil and subsoil, depth, water dynamics, and plant-supporting processes. The MSC addresses the soil properties of surficial and subsurficial horizons, and uses plant communities as qualifier in some cases. The MSC is more accurate than the WRB for classifying Leptosols.
The value of SPECT in the detection of stress injury to the pars interarticularis in patients with low back pain
Authors: Zukotynski Katherine , Curtis Christine , Grant Frederick D , Micheli Lyle , Treves S Ted
Published: March 2010

The medical cost associated with back pain in the United States is considerable and growing. Although the differential diagnosis of back pain is broad, epidemiological studies suggest a correlation between adult and adolescent complaints. Injury of the pars interarticularis is one of the most common identifiable causes of ongoing low back pain in adolescent athletes. It constitutes a spectrum of disease ranging from bone stress to spondylolysis and spondylolisthesis. Bone stress may be the earliest sign of disease. Repetitive bone stress causes bone remodeling and may result in spondylolysis, a non-displaced fracture of the pars interarticularis. A fracture of the pars interarticularis may ultimately become unstable leading to spondylolisthesis. Results in the literature support the use of bone scintigraphy to diagnose bone stress in patients with suspected spondylolysis. Single photon emission computed tomography (SPECT) provides more contrast than planar bone scintigraphy, increases the sensitivity and improves anatomic localization of skeletal lesions without exposing the patient to additional radiation. It also provides an opportunity for better correlation with other imaging modalities, when necessary. As such, the addition of SPECT to standard planar bone scintigraphy can result in a more accurate diagnosis and a better chance for efficient patient care. It is our expectation that by improving our ability to correctly diagnose bone stress in patients with suspected injury of the posterior elements, the long-term cost of managing this condition will be lowered.
Detection of siRNA induced mRNA silencing by RT-qPCR: considerations for experimental design
Authors: Holmes Katherine , Williams Catrin M , Chapman Elinor A , Cross Michael J
Published: March 2010

Background

RNA interference (RNAi) has been one of the most rapidly expanding areas of biological research in the past decade, revolutionizing the ability to analyze gene function. Thorough validation of siRNA duplexes is required prior to use in experimental systems, ideally by western blotting to show a reduction in protein levels. However, in many cases good antibodies are not available, and researchers must rely on RT-qPCR to detect knockdown of the mRNA species.

Findings

We have observed a phenomenon that gives a disparity between analyzing small interfering RNA (siRNA) efficacy by western blotting of the protein levels and real-time quantitative PCR (RT-qPCR) measurement of mRNA levels. Detection of this phenomenon was dependent upon the location of the target amplicon for PCR primers within the mRNA.

Conclusions

Our data suggests that for certain mRNAs, degradation of the 3' mRNA fragment resulting from siRNA mediated cleavage is blocked, leaving an mRNA fragment that can act as a template for cDNA synthesis, giving rise to false negative results and the rejection of a valid siRNA duplex. We show that this phenomenon may be avoided by the careful design of RT-qPCR primers for each individual siRNA experiment.
Summary of 615 patients of chronic myeloid leukemia in Shanghai from 2001 to 2006
Authors: Wang Ai-Hua , Wang Yan-Yan , Yao Yu , Xu Zi-Zhen , Zhou Li , Wang Li , Zhang Li , Chen Yu , Shen Zhi-Xiang , Hu Jiong , Li Jun-Min
Published: March 2010

Background

To retrospectively review the incidence, treatment efficacy, we followed up newly diagnosed chronic myelogenous leukemia (CML) patients residing in Shanghai during 2001-2006.

Methods

All eligible cases were reviewed with the data of efficacy responses as well as overall survival (OS) and progression-free survival (PFS) time.

Results

A total of 615 cases entered the study. CML mainly afflicted those aged 40-60 years old and was slightly more frequent in males than females. More than 85% of the patients were in chronic phase (CP) when diagnosed. All patients were divided into four groups based on the main regimens - hydroxyurea, interferon alpha (IFN-α), imatinib, and hemopoietic stem cell transplantation (HSCT). With the median follow-up of 18 months, imatinib treatment induced 92.2% complete hematologic responses, and 64.3% complete cytogenetic responses among CML-CP patients. Overall the therapeutic efficacy in the imatinib group was higher than that in the hydroxyurea or IFN-α group. Meanwhile, in the imatinib group, all response rates of patients in CP were significantly greater than that in accelerated or blastic crisis phase. The patients treated with imatinib also showed the most promising results regarding OS and PFS. Patients receiving HSCT decreased markedly in number with the introduction of imatinib.

Conclusions

The number of new patients arising in Shanghai increased from 2001 to 2006. There were still patients receiving hydroxyurea and IFN-α. As the first-line regime for CML, imatinib was less administered in Shanghai before, but has received considerable development and great responses since 2003.
Short-term nutritional counseling reduces body mass index, waist circumference, triceps skinfold and triglycerides in women with metabolic syndrome
Authors: Pimentel Gustavo D , Arimura Silvia T , de Moura Bruno M , Silva Maria ER , de Sousa Maysa V
Published: March 2010

Background

It is recognized that the growing epidemic of metabolic syndrome is related to dietary and lifestyle changes.

Objective

The purpose of this study was to evaluate short-term application of nutritional counseling in women with metabolic syndrome.

Methods

This follow-up study was conducted from September to November 2008 with thirty three women ≥35 years old screened clinically for nutritional counseling. Dietary intake was reported, and biochemical and body composition measures were taken at baseline and after three months of follow-up.

Results

Of the 33 women evaluated, 29 patients completed the study. The prevalence of type 2 diabetes mellitus, hypertension, dyslipidemia, and obesity was high at 38%, 72.4%, 55.2%, and 75.8%, respectively. At the end of three-months of follow-up, a significant decline in body mass index, waist circumference, triceps skinfold, and triglycerides was observed, as was an increase in calcium and vitamin D intake. The multiple regression analysis showed that changes in body mass index, triceps skinfold, waist circumference and triglyceride levels after nutritional intervention were positively associated with changes in anthropometric (loss of body weight) and biochemical (decrease of TG/HDL-c ratio) parameters. Moreover, waist circumference changes were negatively associated with changes in calcium and vitamin D intake.

Conclusion

Short-term nutritional counseling improved some factors of metabolic syndrome. Moreover, the increases in calcium and vitamin D consumption can be associated with the improvement in markers of metabolic syndrome.
Urokinase-type plasminogen activator and arthritis progression: role in systemic disease with immune complex involvement
Authors: Cook Andrew D , De Nardo Christine M , Braine Emma L , Turner Amanda L , Vlahos Ross , Way Kerrie J , Beckman S Kaye , Lenzo Jason C , Hamilton John A
Published: March 2010

Introduction

Urokinase-type plasminogen activator (u-PA) has been implicated in fibrinolysis, cell migration, latent cytokine activation, cell activation, T-cell activation, and tissue remodeling, all of which are involved in the development of rheumatoid arthritis. Previously, u-PA has been reported to play a protective role in monoarticular arthritis models involving mBSA as the antigen, but a deleterious role in the systemic polyarticular collagen-induced arthritis (CIA) model. The aim of the current study is to determine how u-PA might be acting in systemic arthritis models.

Methods

The CIA model and bone marrow chimeras were used to determine the cellular source of u-PA required for the arthritis development. Gene expression of inflammatory and destructive mediators was measured in joint tissue by quantitiative PCR and protein levels by ELISA. The requirement for u-PA in the type II collagen mAb-induced arthritis (CAIA) and K/BxN serum transfer arthritis models was determined using u-PA-/- mice. Neutrophilia was induced in the peritoneal cavity using either ovalbumin/anti-ovalbumin or the complement component C5a.

Results

u-PA from a bone marrow-derived cell was required for the full development of CIA. The disease in u-PA-/- mice reconstituted with bone marrrow from C57BL/6 mice was indistinguishable from that in C57BL/6 mice, in terms of clincal score, histologic features, and protein and gene expression of key mediators. u-PA-/- mice were resistant to both CAIA and K/BxN serum transfer arthritis development. u-PA-/- mice developed a reduced neutrophilia and chemokine production in the peritoneal cavity following ovalbumin/anti-ovalbumin injection; in contrast, the peritoneal neutrophilia in response to C5a was u-PA independent.

Conclusions

u-PA is required for the full development of systemic arthritis models involving immune complex formation and deposition. The cellular source of u-PA required for CIA is bone marrow derived and likely to be of myeloid origin. For immune complex-mediated peritonitis, and perhaps some other inflammatory responses, it is suggested that the u-PA involvement may be upstream of C5a signaling.
Adrenocortical Zonation in Humans under Normal and Pathological Conditions
Authors: Nishimoto Koshiro , Nakagawa Ken , Li Dan , Kosaka Takeo , Oya Mototsugu , Mikami Shuji , Shibata Hirotaka , Itoh Hiroshi , Mitani Fumiko , Yamazaki Takeshi , Ogishima Tadashi , Suematsu Makoto , Mukai Kuniaki
Published: March 2010

Context: Aldosterone synthase (CYP11B2) and steroid 11β-hydroxylase (CYP11B1) catalyze the terminal steps for aldosterone and cortisol syntheses, respectively, thereby determining the functional differentiation of human adrenocortical cells. Little is known, however, about how the cells expressing the enzymes are actually distributed in the adrenals under normal and pathological conditions.

Objective: The objective of the study was to determine the localization of CYP11B2 and -B1 in human adrenal specimens by using developed antibodies capable of distinguishing the two enzymes from each other.

Results: Under normal conditions, CYP11B2 was sporadically detected in the zona glomerulosa, whereas CYP11B1 was entirely detected in the zonae fasciculata-reticularis. Adrenocortical cells lacking both enzymes were observed in the outer cortical regions. In addition to conventional zonation, we found a variegated zonation consisting of a subcapsular cell cluster expressing CYP11B2, which we termed aldosterone-producing cell cluster, and a CYP11B1-expressing area. Aldosterone-producing adenomas differed in cell populations expressing CYP11B2 from one another, whereas CYP11B1-expressing and double-negative cells were also intermingled. Adenomas from patients with Cushing’s syndrome expressed CYP11B1 entirely but not CYP11B2, resulting in atrophic nontumor glands. The nontumor portions of both types of adenomas bore frequently one or more aldosterone-producing cell clusters, which sustained CYP11B2 expression markedly under the conditions of the suppressed renin-angiotensin system.

Conclusion: Immunohistochemistry of the human normal adrenal cortex for CYP11B2 and CYP11B1 revealed a variegated zonation with cell clusters constitutively expressing CYP11B2. This technique may provide a pathological confirmatory diagnosis of adrenocortical adenomas.
Ascidians: an invertebrate chordate model to study Alzheimer’s disease pathogenesis
Authors: Virata Michael J. , Zeller Robert W.
Published: March 2010

Here we present the ascidian Ciona intestinalis as an alternative invertebrate system to study Alzheimer’s disease (AD) pathogenesis. Through the use of AD animal models, researchers often attempt to reproduce various aspects of the disease, particularly the coordinated processing of the amyloid precursor protein (APP) by α-, β- and γ-secretases to generate amyloid beta (Aβ)-containing plaques. Recently, Drosophila and C. elegans AD models have been developed, exploiting the relative simplicity of these invertebrate systems, but they lack a functional Aβ sequence and a β-secretase ortholog, thus complicating efforts to examine APP processing in vivo. We propose that the ascidian is a more appropriate invertebrate AD model owing to their phylogenetic relationship with humans. This is supported by bioinformatic analyses, which indicate that the ascidian genome contains orthologs of all AD-relevant genes. We report that transgenic ascidian larvae can properly process human APP695 to generate Aβ peptides. Furthermore, Aβ can rapidly aggregate to form amyloid-like plaques, and plaque deposition is significantly increased in larvae expressing a human APP695 variant associated with familial Alzheimer’s disease. We also demonstrate that nervous system-specific Aβ expression alters normal larval behavior during attachment. Importantly, plaque formation and alterations in behavior are not only observed within 24 hours post-fertilization, but anti-amyloid drug treatment improves these AD-like pathologies. This ascidian model for AD provides a powerful and rapid system to study APP processing, Aβ plaque formation and behavioral alterations, and could aid in identifying factors that modulate amyloid deposition and the associated disruption of normal cellular function and behaviors.
Loss of fibulin-5 binding to β1 integrins inhibits tumor growth by increasing the level of ROS
Authors: Schluterman Marie K. , Chapman Shelby L. , Korpanty Grzegorz , Ozumi Kiyoshi , Fukai Tohru , Yanagisawa Hiromi , Brekken Rolf A.
Published: March 2010

Tumor survival depends in part on the ability of tumor cells to transform the surrounding extracellular matrix (ECM) into an environment conducive to tumor progression. Matricellular proteins are secreted into the ECM and impact signaling pathways that are required for pro-tumorigenic activities such as angiogenesis. Fibulin-5 (Fbln5) is a matricellular protein that was recently shown to regulate angiogenesis; however, its effect on tumor angiogenesis and thus tumor growth is currently unknown. We report that the growth of pancreatic tumors and tumor angiogenesis is suppressed in Fbln5-null (Fbln5−/−) mice compared with wild-type (WT) littermates. Furthermore, we observed an increase in the level of reactive oxygen species (ROS) in tumors grown in Fbln5−/− animals. Increased ROS resulted in elevated DNA damage, increased apoptosis of endothelial cells within the tumor, and represented the underlying cause for the reduction in angiogenesis and tumor growth. In vitro, we identified a novel pathway by which Fbln5 controls ROS production through a mechanism that is dependent on β1 integrins. These results were validated in Fbln5RGE/RGE mice, which harbor a point mutation in the integrin-binding RGD motif of Fbln5, preventing its interaction with integrins. Tumor growth and angiogenesis was reduced in Fbln5RGE/RGE mice, however treatment with an antioxidant rescued angiogenesis and elevated tumor growth to WT levels. These findings introduce a novel function for Fbln5 in the regulation of integrin-induced ROS production and establish a rationale for future studies to examine whether blocking Fbln5 function could be an effective anti-tumor strategy, alone or in combination with other therapies.
The Puf-family RNA-binding protein PfPuf2 regulates sexual development and sex differentiation in the malaria parasitePlasmodium falciparum
Authors: Miao Jun , Li Jinfang , Fan Qi , Li Xiaolian , Li Xinyi , Cui Liwang
Published: March 2010

Translation regulation plays an important role during gametocytogenesis in the malaria parasite, a process that is obligatory for the transmission of the parasite through mosquito vectors. In this study we determined the function of PfPuf2, a member of the Puf family of translational repressors, in gametocytogenesis of Plasmodium falciparum. Tagging of the endogenous PfPuf2 protein with green fluorescent protein showed that PfPuf2 was expressed in both male and female gametocytes, and the protein was localized in the cytoplasm of the parasite. Targeted disruption of the PfPuf2 gene did not affect asexual growth of the parasite, but promoted the formation of gametocytes and differentiation of male gametocytes. Complementation studies were performed to confirm that the resultant phenotypic changes were due to disruption of the PfPuf2 gene. Episomal expression of PfPuf2 under its cognate promoter almost restored the gametocytogenesis rate in a PfPuf2 disruptant to the level of the wild-type parasite. It also partially restored the effect of PfPuf2 disruption on male-female sex ratio. In addition, episomal overexpression of PfPuf2 under its cognate promoter but with a higher concentration of the selection drug or under the constitutive hsp86 promoter in both the PfPuf2-disruptant and wild-type 3D7 lines, further dramatically reduced gametocytogenesis rates and sex ratios. These findings suggest that in this early branch of eukaryotes the function of PfPuf2 is consistent with the ancestral function of suppressing differentiation proposed for Puf-family proteins.
Early initiation of a replication origin tethered at the nuclear periphery
Authors: Ebrahimi Hani , Robertson E. Douglas , Taddei Angela , Gasser Susan M. , Donaldson Anne D. , Hiraga Shin-ichiro
Published: March 2010

Peripheral nuclear localization of chromosomal loci correlates with late replication in yeast and metazoan cells. To test whether peripheral positioning can impose late replication, we examined whether artificial tethering of an early-initiating replication origin to the nuclear periphery delays its replication in budding yeast. We tested the effects of three different peripheral tethering constructs on the time of replication of the early replication origin ARS607. Using the dense-isotope transfer method to assess replication time, we found that ARS607 still replicates early when tethered to the nuclear periphery using the Yif1 protein or a fragment of Sir4, whereas tethering using a Yku80 construct produces only a very slight replication delay. Single-cell microscopic analysis revealed no correlation between peripheral positioning of ARS607 in individual cells and delayed replication. Overall, our results demonstrate that a replication origin can initiate replication early in S phase, even if artificially relocated to the nuclear periphery.
CXCR7 is an active component of SDF-1 signalling in astrocytes and Schwann cells
Authors: Ödemis Veysel , Boosmann Karina , Heinen André , Küry Patrick , Engele Jürgen
Published: March 2010

The alternative SDF-1 (stromal cell derived factor-1) receptor, CXCR7, has been suggested to act as either a scavenger of extracellular SDF-1 or a modulator of the primary SDF-1 receptor, CXCR4. CXCR7, however, also directly affects the function of various tumor-cell types. Here, we demonstrate that CXCR7 is an active component of SDF-1 signalling in astrocytes and Schwann cells. Cultured cortical astrocytes and peripheral nerve Schwann cells exhibit comparable total and cell-surface levels of expression of both SDF-1 receptors. Stimulation of astrocytes with SDF-1 resulted in the temporary activation of Erk1/2, Akt and PKCζ/λ, but not p38 and PKCα/β. Schwann cells showed SDF-1-induced activation of Erk1/2, Akt and p38, but not PKCα/β and PKCζ/λ. The respective signalling pattern remained fully inducible in astrocytes from CXCR4-deficient mice, but was abrogated following depletion of astrocytic CXCR7 by RNAi. In Schwann cells, RNAi-mediated depletion of either CXCR4 or CXCR7 silenced SDF-1 signalling. The findings of the astrocytic receptor-depletion experiments were reproduced by CXCR7 antagonist CCX754, but not by CXCR4 antagonist AMD3100, both of which abolished astrocytic SDF-1 signalling. Further underlining the functional importance of CXCR7 signalling in glial cells, we show that the mitogenic effects of SDF-1 on both glial cell types are impaired upon depleting CXCR7.
Trends in the epidemiology of asthma in England: a national study of 333,294 patients
Authors: Simpson Colin R , Sheikh Aziz
Published: March 2010

Summary

Background

Observations in the UK at the end of the last century found increasing trends of asthma prevalence over time. However, it has been reported that the number of new cases of asthma presenting to general practice has declined, especially among younger children.

Aim

To study national trends in the epidemiology of asthma.

Methods

A cross-sectional observation analysis was performed using the QRESEARCH database, which is one of the world's largest national aggregated health databases containing records from 422 English practices yielding 30 million patient-years of observation. Data was extracted on 333,294 individuals with a recorded diagnosis of asthma and calculated annual age–sex standardized incidence, lifetime period prevalence and asthma-related prescribing rates for each year from 2001–2005.

Results

The incidence rate of asthma decreased in all patients (2001: 6.9 (95% confidence intervals [CI] 6.8–7.0); 2005: 5.2 (95% CI 5.1–5.3) per 1000 patient-years, p<0.001), but most particularly in children under 5 years of age (–38.4%) where a decrease in the lifetime prevalence of asthma (–34.3%) was also found. However, the lifetime prevalence rate of asthma for adults increased (15–44 years: 23.3%; 45–64 years: 27.7%; >65 years: 21.5%) with an estimated 5,658,900 (95% CI 5,639,700–5,678,200) or approximately one person in nine having being diagnosed with asthma in England. The number of asthma-related prescriptions also increased over the study period (17.1%), such that in 2005 an estimated 32,577,300 (95%CI 32,531,600–32,623,000) prescriptions were issued.

Conclusions

This large national study reveals that the rate of new diagnoses of asthma appears to have passed its peak; however, the number of adults with a lifetime asthma diagnosis continues to rise. Whether these trends are genuine or are a result of the introduction of incentives and guidelines to improve identification and recording of asthma or changing diagnostic trends is a question with important public health implications and one, therefore, that warrants detailed further enquiry.
Medicolegal reports in asylum applications: a framework for addressing the practical and ethical challenges
Authors: Pitman Alexandra
Published: March 2010

Summary

The clinical care of asylum-seekers may bring clinicians in contact with the immigration authorities. A request for a medicolegal report usually requires the responsible clinician to state their opinion on the risks involved in returning an applicant to their country of origin, taking into account their current condition, the treatments available in that country, and the risks involved in travel. This review draws on clinical experience and a review of the literature to describe the work involved in preparing a medical report requested by immigration authorities. Although the starting point chosen is the psychiatric report, the principles described apply to the preparation of immigration reports in any medical discipline.