bluuebunny/crossref_metadata_2025 huggingface dataset:
Serum immunoglobulin G, M and A response to Cryptosporidium parvum in Cryptosporidium-HIV co-infected patients
Authors: Kaushik Kirti , Khurana Sumeeta , Wanchu Ajay , Malla Nancy
Published: November 2009

Background

Cryptosporidium parvum, the protozoan parasite, causes a significant enteric disease in immunocompromised hosts such as HIV patients. The present study was aimed to compare serum IgG, IgM and IgA responses to crude soluble antigen ofC. parvumin HIV seropositive and seronegative patients co-infected withCryptosporidiumand to correlate the responses with symptomatology.

Methods

Cryptosporidium parvumspecific serum antibody (IgG, IgM and IgA) responses were assessed by ELISA in 11 HIV seropositiveCryptosporidiumpositive (Group I), 20 HIV seropositiveCryptosporidiumnegative (Group II), 10 HIV seronegativeCryptosporidiumpositive (Group III), 20 HIV seronegativeCryptosporidiumnegative healthy individuals (Group IV) and 25 patients with other parasitic diseases (Group V).

Results

A positive IgG and IgA antibody response was observed in significantly higher number ofCryptosporidiuminfected individuals (Gp I and III) compared toCryptosporidiumun-infected individuals (Gp II, IV and V) irrespective of HIV/immune status. Sensitivity of IgG ELISA in our study was found to be higher as compared to IgM and IgA ELISA. The number of patients with positive IgG, IgM and IgA response was not significantly different in HIV seropositiveCryptosporidiumpositive patients with diarrhoea when compared to patients without diarrhoea and in patients with CD4 counts <200 when compared to patients with CD4 counts >200 cells/μl.

Conclusion

The study showed specific serum IgG and IgA production in patients infected withCryptosporidium, both HIV seropositive and seronegative as compared to uninfected subjects suggesting induction ofCryptosporidiumspecific humoral immune response in infected subjects. However, there was no difference in number of patients with positive response in HIV seropositive or seronegative groups indicating that HIV status may not be playing significant role in modulation ofCryptosporidiumspecific antibody responses. The number of patients with positive IgG, IgM and IgA response was not significantly different in patients with or without history of diarrhoea thereby indicating thatCryptosporidiumspecific antibody responses may not be necessarily associated with protection from symptomatology.
Emilin1 gene and essential hypertension: a two-stage association study in northern Han Chinese population
Authors: Shen Chong , Lu Xiangfeng , Li Yun , Zhao Qi , Liu Xiaoli , Hou Liping , Wang Laiyuan , Chen Shufeng , Huang Jianfeng , Gu Dongfeng
Published: November 2009

Background

Elastogenesis of elastic extracellular matrix (ECM) which was recognized as a major component of blood vessels has been believed for a long time to play only a passive role in the dynamic vascular changes of typical hypertension. Emilin1 gene participated in the transcription of ECM's formation and was recognized to modulate links TGF-β maturation to blood pressure homeostasis in animal study. Recently relevant advances urge further researches to investigate the role of Emilin1 gene in regulating TGF-β signals involved in elastogenesis and vascular cell defects of essential hypertension (EH).

Methods

We designed a two-stage case-control study and selected three single nucleotide polymorphisms (SNPs), rs3754734, rs2011616 and rs2304682 from the HapMap database, which covered Emilin1 gene. Totally 2,586 subjects were recruited from the International Collaborative Study of Cardiovascular Disease in Asia (InterASIA). In stage 1, all the three SNPs of the Emilin1 gene were genotyped and tested within a subsample including 503 cases and 490 controls, significant SNPs would enter into stage 2 including 814 cases with hypertension and 779 controls and analyze on the basis of testing total 2,586 subjects.

Results

In stage 1, single locus analyses showed that SNPs rs3754734 and rs2011616 had significant association with EH (P < 0.05). In stage 2, weak association for dominant model were observed by age stratification and odds ratio (ORs) of TG+GG vs. TT of rs3754734 were 0.768 (0.584-1.009), 0.985 (0.735-1.320) and 1.346 (1.003-1.806) in < 50, 50-59 and ≥ 60 years group and ORs of GA+AA vs. GG of rs2011616 were 0.745 (0.568-0.977), 1.013 (0.758-1.353) and 1.437 (1.072-1.926) in < 50, 50-59 and ≥ 60 years group respectively. Accordingly, significant interactions were detected between genotypes of rs3754734 and rs2011616 and age for EH, and ORs were 1.758 (1.180-2.620), P = 0.006 and 1.903 (1.281-2.825), P = 0.001, respectively. Results of haplotypes analysis showed that there weren't any haplotypes associated with EH directly, but the interaction of hap2 (GA) and age-group found to be significant after being adjusted for the covariates, OR was 1.220 (1.031-1.444), P value was 0.020.

Conclusion

Our findings don't support positive association of Emilin1 gene with EH, but the interaction of age and genotype variation of rs3754734 and rs2011616 might increase the risk to hypertension.
Initial activation of EpCAM cleavage viacell-to-cell contact
Authors: Denzel Sabine , Maetzel Dorothea , Mack Brigitte , Eggert Carola , Bärr Gabriele , Gires Olivier
Published: November 2009

Background

Epithelial cell adhesion molecule EpCAM is a transmembrane glycoprotein, which is frequently over-expressed in simple epithelia, progenitors, embryonic and tissue stem cells, carcinoma and cancer-initiating cells. Besides functioning as a homophilic adhesion protein, EpCAM is an oncogenic receptor that requires regulated intramembrane proteolysis for activation of its signal transduction capacity. Upon cleavage, the extracellular domain EpEX is released as a soluble ligand while the intracellular domain EpICD translocates into the cytoplasm and eventually into the nucleus in combination with four-and-a-half LIM domains protein 2 (FHL2) and β-catenin, and drives cell proliferation.

Methods

EpCAM cleavage, induction of the target genes, and transmission of proliferation signals were investigated under varying density conditions using confocal laser scanning microscopy, immunoblotting, cell counting, and conditional cell systems.

Results

EpCAM cleavage, induction of the target genes, and transmission of proliferation signals were dependent on adequate cell-to-cell contact. If cell-to-cell contact was prohibited EpCAM did not provide growth advantages. If cells were allowed to undergo contact to each other, EpCAM transmitted proliferation signals based on signal transduction-related cleavage processes. Accordingly, the pre-cleaved version EpICD was not dependent on cell-to-cell contact in order to induce c-myc and cell proliferation, but necessitated nuclear translocation. For the case of contact-inhibited cells, although cleavage of EpCAM occurred, nuclear translocation of EpICD was reduced, as were EpCAM effects.

Conclusion

Activation of EpCAM's cleavage and oncogenic capacity is dependent on cellular interaction (juxtacrine) to provide for initial signals of regulated intramembrane proteolysis, which then support signalling via soluble EpEX (paracrine).
A sex-role-preference model for HIV transmission among men who have sex with men in China
Authors: Lou Jie , Wu Jianhong , Chen Li , Ruan Yuhua , Shao Yiming
Published: November 2009

Background

Men who have sex with men (MSM) are much more likely to be infected with HIV than the general population. China has a sizable population of MSM, including gay, bisexual men, money boys and some rural workers. So reducing HIV infection in this population is an important component of the national HIV/AIDS prevention and control program.

Methods

We develop a mathematical model using a sex-role-preference framework to predict HIV infection in the MSM population and to evaluate different intervention strategies.

Results

An analytic formula for the basic reproduction ratio R
0 was obtained; this yields R
0 = 3.9296 in the current situation, so HIV will spread very fast in the MSM population if no intervention measure is implemented in a timely fashion. The persistence of HIV infection and the existence of disease equilibrium (or equilibria) are also shown. We utilized our model to simulate possible outcomes of antiretroviral therapy and vaccination for the MSM population. We compared the effects of these intervention measures under different assumptions about MSM behaviour. We also found that R
0 is a decreasing function of the death rate of HIV-infected individuals, following a power law at least asymptotically.

Conclusion

HIV will spread very fast in the MSM population unless intervention measures are implemented urgently. Antiretroviral therapy can have substantial impact on the reduction of HIV among the MSM population, even if disinhibition is considered. The effect of protected sexual behaviour on controlling the epidemic in the MSM population largely depends on the sex-ratio preference of different sub-populations.
CD 9 and vimentin distinguish clear cell from chromophobe renal cell carcinoma
Authors: Williams Ariel A , Higgins John PT , Zhao Hongjuan , Ljungberg Börje , Brooks James D
Published: November 2009

Background

Clear cell renal cell carcinoma (ccRCC) and chromophobe renal cell carcinoma (chRCC) can usually be distinguished by histologic characteristics. Occasionally, diagnosis proves challenging and diagnostic difficulty will likely increase as needle biopsies of renal lesions become more common.

Methods

To identify markers that aid in differentiating ccRCC from chRCC, we used gene expression profiles to identify candidate markers that correlate with histology. 39 antisera and antibodies, including 35 for transcripts identified from gene expression profiling, were evaluated. Promising markers were tested on a tissue microarray (TMA) containing 428 renal neoplasms. Strength of staining of each core on the TMA was formally scored and the distribution of staining across different types of renal neoplasms was analyzed.

Results

Based on results from initial immunohistochemical staining of multitissue titer arrays, 23 of the antisera and antibodies were selected for staining of the TMA. For 7 of these markers, strength of staining of each core on the TMA was formally scored. Vimentin (positive in ccRCC) and CD9 (positive in chRCC) best distinguished ccRCC from chRCC. The combination of vimentin negativity and CD9 positivity was found to distinguish chRCC from ccRCC with a sensitivity of 100.0% and a specificity of 95.2%.

Conclusion

Based on gene expression analysis, we identify CD9 and vimentin as candidate markers for distinguishing between ccRCC and chRCC. In difficult cases and particularly when the amount of diagnostic tissue is limited, vimentin and CD9 staining could serve as a useful adjunct in the differential diagnosis of ccRCC and chRCC.
Population structure analyses and demographic history of the malaria vector Anopheles albimanus from the Caribbean and the Pacific regions of Colombia
Authors: Gutiérrez Lina A , Naranjo Nelson J , Cienfuegos Astrid V , Muskus Carlos E , Luckhart Shirley , Conn Jan E , Correa Margarita M
Published: November 2009

Background

Anopheles albimanusis an important malaria vector in some areas throughout its distribution in the Caribbean and the Pacific regions of Colombia, covering three biogeographic zones of the neotropical region, Maracaibo, Magdalena and Chocó.

Methods

This study was conducted to estimate intra-population genetic diversity, genetic differentiation and demographic history ofAn. albimanuspopulations because knowledge of vector population structure is a useful tool to guide malaria control programmes. Analyses were based on mtDNACOIgene sequences and four microsatellite loci of individuals collected in eight populations from the Caribbean and the Pacific regions of Colombia.

Results

Two distinctive groups were consistently detected corresponding toCOIhaplotypes from each region. A star-shaped statistical parsimony network, significant and unimodal mismatch distribution, and significant negative neutrality tests together suggest a past demographic expansion or a selective sweep inAn. albimanusfrom the Caribbean coast approximately 21,994 years ago during the late Pleistocene. Overall moderate to low genetic differentiation was observed between populations within each region. However, a significant level of differentiation among the populations closer to Buenaventura in the Pacific region was observed. The isolation by distance model best explained genetic differentiation among the Caribbean region localities: Los Achiotes, Santa Rosa de Lima and Moñitos, but it could not explain the genetic differentiation observed between Turbo (Magdalena providence), and the Pacific region localities (Nuquí, Buenaventura, Tumaco). The patterns of differentiation in the populations from the different biogeographic provinces could not be entirely attributed to isolation by distance.

Conclusion

The data provide evidence for limited past gene flow between the Caribbean and the Pacific regions, as estimated by mtDNA sequences and current gene flow patterns amongAn. albimanuspopulations as measured by MS loci which may be mainly influenced by semi-permeable natural barriers in each biogeographical region that lead to the genetic differences and effective population sizes detected. The relatively high genetic differentiation in the port city of Buenaventura may be the result of specific ecological conditions, human migration and activities and/or differences in effective population sizes. This knowledge could serve to evaluate and coordinate vector control strategies in these regions of Colombia.
Gene expression profiles of mouse spermatogenesis during recovery from irradiation
Authors: Shah Fozia J , Tanaka Masami , Nielsen John E , Iwamoto Teruaki , Kobayashi Shinichi , Skakkebæk Niels E , Leffers Henrik , Almstrup Kristian
Published: November 2009

Background

Irradiation or chemotherapy that suspend normal spermatogenesis is commonly used to treat various cancers. Fortunately, spermatogenesis in many cases can be restored after such treatments but knowledge is limited about the re-initiation process. Earlier studies have described the cellular changes that happen during recovery from irradiation by means of histology. We have earlier generated gene expression profiles during induction of spermatogenesis in mouse postnatal developing testes and found a correlation between profiles and the expressing cell types. The aim of the present work was to utilize the link between expression profile and cell types to follow the cellular changes that occur during post-irradiation recovery of spermatogenesis in order to describe recovery by means of gene expression.

Methods

Adult mouse testes were subjected to irradiation with 1 Gy or a fractionated radiation of two times 1 Gy. Testes were sampled every third or fourth day to follow the recovery of spermatogenesis and gene expression profiles generated by means of differential display RT-PCR. In situ hybridization was in addition performed to verify cell-type specific gene expression patterns.

Results

Irradiation of mice testis created a gap in spermatogenesis, which was initiated by loss of A1 to B-spermatogonia and lasted for approximately 10 days. Irradiation with 2 times 1 Gy showed a more pronounced effect on germ cell elimination than with 1 Gy, but spermatogenesis was in both cases completely reconstituted 42 days after irradiation. Comparison of expression profiles indicated that the cellular reconstitution appeared equivalent to what is observed during induction of normal spermatogenesis.

Conclusion

The data indicates that recovery of spermatogenesis can be monitored by means of gene expression, which could aid in designing radiation treatment regimes for cancer patients leading to better restoration of spermatogenesis.
Phylogeographic reconstruction of a bacterial species with high levels of lateral gene transfer
Authors: Pearson Talima , Giffard Philip , Beckstrom-Sternberg Stephen , Auerbach Raymond , Hornstra Heidie , Tuanyok Apichai , Price Erin P , Glass Mindy B , Leadem Benjamin , Beckstrom-Sternberg James S , Allan Gerard J , Foster Jeffrey T , Wagner David M , Okinaka Richard T , Sim Siew Hoon , Pearson Ofori , Wu Zaining , Chang Jean , Kaul Rajinder , Hoffmaster Alex R , Brettin Thomas S , Robison Richard A , Mayo Mark , Gee Jay E , Tan Patrick , Currie Bart J , Keim Paul
Published: November 2009

Background

Phylogeographic reconstruction of some bacterial populations is hindered by low diversity coupled with high levels of lateral gene transfer. A comparison of recombination levels and diversity at seven housekeeping genes for eleven bacterial species, most of which are commonly cited as having high levels of lateral gene transfer shows that the relative contributions of homologous recombination versus mutation for Burkholderia pseudomallei is over two times higher than for Streptococcus pneumoniae and is thus the highest value yet reported in bacteria. Despite the potential for homologous recombination to increase diversity, B. pseudomallei exhibits a relative lack of diversity at these loci. In these situations, whole genome genotyping of orthologous shared single nucleotide polymorphism loci, discovered using next generation sequencing technologies, can provide very large data sets capable of estimating core phylogenetic relationships. We compared and searched 43 whole genome sequences of B. pseudomallei and its closest relatives for single nucleotide polymorphisms in orthologous shared regions to use in phylogenetic reconstruction.

Results

Bayesian phylogenetic analyses of >14,000 single nucleotide polymorphisms yielded completely resolved trees for these 43 strains with high levels of statistical support. These results enable a better understanding of a separate analysis of population differentiation among >1,700 B. pseudomallei isolates as defined by sequence data from seven housekeeping genes. We analyzed this larger data set for population structure and allele sharing that can be attributed to lateral gene transfer. Our results suggest that despite an almost panmictic population, we can detect two distinct populations of B. pseudomallei that conform to biogeographic patterns found in many plant and animal species. That is, separation along Wallace's Line, a biogeographic boundary between Southeast Asia and Australia.

Conclusion

We describe an Australian origin for B. pseudomallei, characterized by a single introduction event into Southeast Asia during a recent glacial period, and variable levels of lateral gene transfer within populations. These patterns provide insights into mechanisms of genetic diversification in B. pseudomallei and its closest relatives, and provide a framework for integrating the traditionally separate fields of population genetics and phylogenetics for other bacterial species with high levels of lateral gene transfer.
Phosphorylation regulates human T-cell leukemia virus type 1 Rex function
Authors: Kesic Matthew , Doueiri Rami , Ward Michael , Semmes O John , Green Patrick L
Published: November 2009

Background

Human T-cell leukemia virus type 1 (HTLV-1) is a pathogenic complex deltaretrovirus, which is the causative agent of adult T-cell leukemia/lymphoma (ATL) and HTLV-1-associated myelopathy/tropical spastic paraparesis. In addition to the structural and enzymatic viral gene products, HTLV-1 encodes the positive regulatory proteins Tax and Rex along with viral accessory proteins. Tax and Rex proteins orchestrate the timely expression of viral genes important in viral replication and cellular transformation. Rex is a nucleolar-localizing shuttling protein that acts post-transcriptionally by binding and facilitating the export of the unspliced and incompletely spliced viral mRNAs from the nucleus to the cytoplasm. HTLV-1 Rex (Rex-1) is a phosphoprotein and general protein kinase inhibition correlates with reduced function. Therefore, it has been proposed that Rex-1 function may be regulated through site-specific phosphorylation.

Results

We conducted a phosphoryl mapping of Rex-1 over-expressed in transfected 293 T cells using a combination of affinity purification and liquid chromatography tandem mass spectrometry. We achieved 100% physical coverage of the Rex-1 polypeptide and identified five novel phosphorylation sites at Thr-22, Ser-36, Thr-37, Ser-97, and Ser-106. We also confirmed evidence of two previously identified residues, Ser-70 and Thr-174, but found no evidence of phosphorylation at Ser-177. The functional significance of these phosphorylation events was evaluated using a Rex reporter assay and site-directed mutational analysis. Our results indicate that phosphorylation at Ser-97 and Thr-174 is critical for Rex-1 function.

Conclusion

We have mapped completely the site-specific phosphorylation of Rex-1 identifying a total of seven residues; Thr-22, Ser-36, Thr-37, Ser-70, Ser-97, Ser-106, and Thr-174. Overall, this work is the first to completely map the phosphorylation sites in Rex-1 and provides important insight into the regulation of Rex-1 function.
Hypothesis of snake and insect venoms against Human Immunodeficiency Virus: a review
Authors: Meenakshisundaram Ramachandran , Sweni Shah , Thirumalaikolundusubramanian Ponniah
Published: November 2009

Background

Snake and insect venoms have been demonstrated to have beneficial effects in the treatment of certain diseases including drug resistant human immunodeficiency virus (HIV) infection. We evaluated and hypothesized the probable mechanisms of venoms against HIV.

Methods

Previous literatures published over a period of 30 years (1979-2009) were searched using the key words snake venom, insect venom, mechanisms and HIV. Mechanisms were identified and discussed.

Results & Conclusion

With reference to mechanisms of action, properties and components of snake venom such as sequence homology and enzymes (protease or L- amino acid oxidase) may have an effect on membrane protein and/or act against HIV at multiple levels or cells carrying HIV virus resulting in enhanced effect of anti-retroviral therapy (ART). This may cause a decrease in viral load and improvement in clinical as well as immunological status. Insect venom and human Phospholipase A2 (PLA2) have potential anti-viral activity through inhibition of virion entry into the cells. However, all these require further evaluation in order to establish its role against HIV as an independent one or as a supplement.
Evidence of recombination in Hepatitis C Virus populations infecting a hemophiliac patient
Authors: Moreno Pilar , Alvarez Macarena , López Lilia , Moratorio Gonzalo , Casane Didier , Castells Matías , Castro Silvia , Cristina Juan , Colina Rodney
Published: November 2009

Background/Aim

Hepatitis C virus (HCV) infection is an important cause of morbidity and mortality in patients affected by hereditary bleeding disorders. HCV, as others RNA virus, exploit all possible mechanisms of genetic variation to ensure their survival, such as recombination and mutation. In order to gain insight into the genetic variability of HCV virus strains circulating in hemophiliac patients, we have performed a phylogenetic analysis of HCV strains isolated from 10 patients with this kind of pathology.

Methods

Putative recombinant sequence was identified with the use of GARD program. Statistical support for the presence of a recombination event was done by the use of LARD program.

Results

A new intragenotypic recombinant strain (1b/1a) was detected in 1 out of the 10 hemophiliac patient studied. The recombination event was located at position 387 of the HCV genome (relative to strain AF009606, sub-type 1a) corresponding to the core gene region.

Conclusion

Although recombination may not appear to be common among natural populations of HCV it should be considered as a possible mechanism for generating genetic diversity in hemophiliacs patients.
Hepatitis A virus (HAV) packaging size limit
Authors: Konduru Krishnamurthy , Nakamura Siham M , Kaplan Gerardo G
Published: November 2009

Background

Hepatitis A virus (HAV), an atypical Picornaviridae that causes acute hepatitis in humans, grows poorly in cell culture and in general does not cause cytopathic effect. Foreign sequences have been inserted into different parts of the HAV genome. However, the packaging size limit of HAV has not been determined. The purpose of the present study is to investigate the maximum size of additional sequences that the HAV genome can tolerate without loosing infectivity.

Results

In vitro T7 polymerase transcripts of HAV constructs containing a 456-nt fragment coding for a blasticidin (Bsd) resistance gene, a 1,098-nt fragment coding for the same gene fused to GFP (GFP-Bsd), or a 1,032-nt fragment containing a hygromycin (Hyg) resistance gene cloned into the 2A-2B junction of the HAV genome were transfected into fetal Rhesus monkey kidney (FRhK4) cells. After antibiotic selection, cells transfected with the HAV construct containing the resistance gene for Bsd but not the GFP-Bsd or Hyg survived and formed colonies. To determine whether this size limitation was due to the position of the insertion, a 606 bp fragment coding for the Encephalomyocarditis virus (EMCV) internal ribosome entry site (IRES) sequence was cloned into the 5' nontranslated (NTR) region of HAV. The resulting HAV-IRES retained the EMCV IRES insertion for 1-2 passages. HAV constructs containing both the EMCV IRES at the 5' NTR and the Bsd-resistance gene at the 2A-2B junction could not be rescued in the presence of Bsd but, in the absence of antibiotic, the rescued viruses contained deletions in both inserted sequences.

Conclusion

HAV constructs containing insertions of approximately 500-600 nt but not 1,000 nt produced viable viruses, which indicated that the HAV particles can successfully package approximately 600 nt of additional sequences and maintain infectivity.
Activation of adenosine A2B receptors enhances ciliary beat frequency in mouse lateral ventricle ependymal cells
Authors: Genzen Jonathan R , Yang Dan , Ravid Katya , Bordey Angelique
Published: November 2009

Background

Ependymal cells form a protective monolayer between the brain parenchyma and cerebrospinal fluid (CSF). They possess motile cilia important for directing the flow of CSF through the ventricular system. While ciliary beat frequency in airway epithelia has been extensively studied, fewer reports have looked at the mechanisms involved in regulating ciliary beat frequency in ependyma. Prior studies have demonstrated that ependymal cells express at least one purinergic receptor (P2X7). An understanding of the full range of purinergic receptors expressed by ependymal cells, however, is not yet complete. The objective of this study was to identify purinergic receptors which may be involved in regulating ciliary beat frequency in lateral ventricle ependymal cells.

Methods

High-speed video analysis of ciliary movement in the presence and absence of purinergic agents was performed using differential interference contrast microscopy in slices of mouse brain (total number of animals = 67). Receptor identification by this pharmacological approach was corroborated by immunocytochemistry, calcium imaging experiments, and the use of two separate lines of knockout mice.

Results

Ciliary beat frequency was enhanced by application of a commonly used P2X7agonist. Subsequent experiments, however, demonstrated that this enhancement was observed in both P2X7+/+and P2X7-/-mice and was reduced by pre-incubation with an ecto-5'-nucleotidase inhibitor. This suggested that enhancement was primarily due to a metabolic breakdown product acting on another purinergic receptor subtype. Further studies revealed that ciliary beat frequency enhancement was also induced by adenosine receptor agonists, and pharmacological studies revealed that ciliary beat frequency enhancement was primarily due to A2Breceptor activation. A2Bexpression by ependymal cells was subsequently confirmed using A2B-/-/β-galactosidase reporter gene knock-in mice.

Conclusion

This study demonstrates that A2Breceptor activation enhances ciliary beat frequency in lateral ventricle ependymal cells. Ependymal cell ciliary beat frequency regulation may play an important role in cerebral fluid balance and cerebrospinal fluid dynamics.
Effective Relief of Neuropathic Pain by Adeno-Associated Virus-Mediated Expression of a Small Hairpin Rna against GTP Cyclohydrolase 1
Authors: Kim Sung Jin , Lee Won Il , Lee Yoon Sun , Kim Dong Hou , Chang Jin Woo , Kim Seong Who , Lee Heuiran
Published: November 2009

Background

Recent studies show that transcriptional activation of GTP cyclohydrolase I (GCH1) in dorsal root ganglia (DRG) is significantly involved in the development and persistency of pain symptoms. We thus hypothesize that neuropathic pain may be attenuated by down-regulation of GCH1 expression, and propose a gene silencing system for this purpose.

Results

To interrupt GCH1 synthesis, we designed a bidirectional recombinant adeno-associated virus encoding both a small hairpin RNA against GCH1 and a GFP reporter gene (rAAV-shGCH1). After rAAV-shGCH1 was introduced into the sciatic nerve prior to or following pain-inducing surgery, therapeutic efficacy and the underlying mechanisms were subsequently validated in animal models. The GFP expression data indicates that rAAV effectively delivered transgenes to DRG. Subsequently reduced GCH1 expression was evident from immunohistochemistry and western-blotting analysis. Along with the down-regulation of GCH1, the von Frey test correspondingly indicated a sharp decline in pain symptoms upon both pre- and post-treatment with rAAV-shGCH1. Interestingly, GCH1 down-regulation additionally led to decreased microglial activation in the dorsal horn, implying an association between pain attenuation and reduced inflammation.

Conclusion

Therefore, the data suggests that GCH1 levels can be reduced by introducing rAAV-shGCH1, leading to pain relief. Based on the results, we propose that GCH1 modulation may be developed as a clinically applicable gene therapy strategy to treat neuropathic pain.
Conditional Gene Deletion Reveals Functional Redundancy of GABABReceptors in Peripheral NociceptorsIn Vivo
Authors: Gangadharan Vijayan , Agarwal Nitin , Brugger Stefan , Tegeder Imgard , Bettler Bernhard , Kuner Rohini , Kurejova Martina
Published: November 2009

Background

γ-aminobutyric acid (GABA) is an important inhibitory neurotransmitter which mainly mediates its effects on neurons via ionotropic (GABAA) and metabotropic (GABAB) receptors. GABABreceptors are widely expressed in the central and the peripheral nervous system. Although there is evidence for a key function of GABABreceptors in the modulation of pain, the relative contribution of peripherally- versus centrally-expressed GABABreceptors is unclear.

Results

In order to elucidate the functional relevance of GABABreceptors expressed in peripheral nociceptive neurons in pain modulation we generated and analyzed conditional mouse mutants lacking functional GABAB(1)subunit specifically in nociceptors, preserving expression in the spinal cord and brain (SNS-GABAB(1)−/−mice). Lack of the GABAB(1)subunit precludes the assembly of functional GABABreceptor. We analyzed SNS-GABAB(1)−/−mice and their control littermates in several models of acute and neuropathic pain. Electrophysiological studies on peripheral afferents revealed higher firing frequencies in SNS-GABAB(1)−/−mice compared to corresponding control littermates. However no differences were seen in basal nociceptive sensitivity between these groups. The development of neuropathic and chronic inflammatory pain was similar across the two genotypes. The duration of nocifensive responses evoked by intraplantar formalin injection was prolonged in the SNS-GABAB(1)−/−animals as compared to their control littermates. Pharmacological experiments revealed that systemic baclofen-induced inhibition of formalin-induced nociceptive behaviors was not dependent upon GABAB(1)expression in nociceptors.

Conclusion

This study addressed contribution of GABABreceptors expressed on primary afferent nociceptive fibers to the modulation of pain. We observed that neither the development of acute and chronic pain nor the analgesic effects of a systematically-delivered GABABagonist was significantly changed upon a specific deletion of GABABreceptors from peripheral nociceptive neurons in vivo. This lets us conclude that GABABreceptors in the peripheral nervous system play a less important role than those in the central nervous system in the regulation of pain.
Social care and changes in occupational accidents and diseases - the situation in Eastern Europe in general and for skin diseases in particular
Authors: von Hirschberg Kathrin R , Kähler Björn , Nienhaus Albert
Published: November 2009

Background

As a consequence of the disintegration of the state systems and the expansion of the European Union, there have been marked changes in the political and social affiliations of the countries of Eastern Europe. Of the 22 countries in Northeastern, Centraleastern, Southeastern and Eastern Europe, 12 are now members and 10 are "new" neighbours of the European Union. The accident insurance systems and changes in occupational accidents and occupational diseases in eastern European countries are described. Changes since EU and visible differences from non-EU countries are analysed. Special emphasis is given to occupational skin diseases.

Methods

The available data from the European Union (MISSOC and MISSCEEC Studies on the Social Protection Systems), the database "Social Security Worldwide" (SSW) of the International Social Security Association (ISSA), the International Labour Office Database (LABORSTA), the World Health Organization (WHO) and the annual statistical reports of the different countries were analysed with respect to changes in occupational accidents and occupational diseases. To find missing data, 128 ministries and authorities in the 22 countries in eastern Europe were researched and 165 persons contacted.

Results

The social insurance systems were very different in the different countries and some were better established than others. Moreover, not all data were available. For these reasons, detailed comparison was not always possible. The occupational accident rates are decreasing in more than half the countries. In contrast, the fatal accident rates have increased in half the countries. The number of newly registered occupational diseases is decreasing in more than half the countries. The rates for occupational skin diseases in 2006 were particularly high in the Czech Republic, Poland and Slovakia. In half the countries (four out of eight), the number of occupational skin diseases is decreasing. A reliable analysis of any correlation between EU membership and the rates of occupational accidents and occupational diseases was not possible, because of missing current data.

Conclusion

Comparison of the social insurance systems and changes in occupational accidents and occupational diseases in 22 countries in eastern Europe makes it clear that further effort is needed to develop registration and notification procedures. Only then will it be possible to analyse changes, to map successes and problems and perhaps to initiate necessary improvements. Standardisation of the documents must also be improved, to allow international comparisons between the systems.
Zebrafish aplnra functions in epiboly
Authors: Nornes Svanhild , Tucker Ben , Lardelli Michael
Published: November 2009

Background

The zebrafish, Danio rerio, possesses the paralogous genes aplnra and aplnrb that are duplicates of an ancestral orthologue of the human APLNR gene encoding a G-protein coupled receptor that binds the peptide ligand APELIN and is required for normal cardiovascular function. aplnrb is required for migration of cells contributing to heart development in zebrafish embryos. aplnra is transcribed in a complex pattern during early development but its function in embryogenesis is largely unknown.

Findings

Blockage of translation of aplnra mRNA in zebrafish embryos results in retarded or failed epiboly with the blastoderm apparently disconnected from the nuclei of the yolk syncytial layer. Gastrulation is also defective. Failure of correct tail extension is observed with ectopic structures resembling somites positioned dorsal to the spinal cord.

Conclusion

aplnra, unlike its duplicate aplnrb, is essential for normal epiboly, although this function appears to be independent of signalling activated by zebrafish Apelin. The defects in epiboly caused by loss of aplnra activity appear, at least partially, to be due to a requirement for aplnra activity in the yolk syncytial layer.
Body fluids and salt metabolism - Part I
Authors: Bianchetti Mario G , Simonetti Giacomo D , Bettinelli Alberto
Published: November 2009

There is a high frequency of diarrhea and vomiting in childhood. As a consequence the focus of the present review is to recognize the different body fluid compartments, to clinically assess the degree of dehydration, to know how the equilibrium between extracellular fluid and intracellular fluid is maintained, to calculate the effective blood osmolality and discuss both parenteral fluid requirments and repair.
Declining recurrence among ductal carcinoma in situ patients treated with breast-conserving surgery in the community setting
Authors: Habel Laurel A , Achacoso Ninah S , Haque Reina , Nekhlyudov Larissa , Fletcher Suzanne W , Schnitt Stuart J , Collins Laura C , Geiger Ann M , Puligandla Balaram , Acton Luana , Quesenberry Charles P
Published: November 2009

Introduction

Randomized trials indicate that adjuvant radiotherapy plus tamoxifen decrease the five-year risk of recurrence among ductal carcinoma in situ patients treated with breast-conserving surgery from about 20% to 8%. The aims of this study were to examine the use and impact of these therapies on risk of recurrence among ductal carcinoma in situ patients diagnosed and treated in the community setting.

Methods

We identified 2,995 patients diagnosed with ductal carcinoma in situ between 1990 and 2001 and treated with breast-conserving surgery at three large health plans. Medical charts were reviewed to confirm diagnosis and treatment and to obtain information on subsequent breast cancers. On a subset of patients, slides from the index ductal carcinoma in situ were reviewed for histopathologic features. Cumulative incidence curves were generated and Cox regression was used to examine changes in five-year risk of recurrence across diagnosis years, with and without adjusting for trends in use of adjuvant therapies.

Results

Use of radiotherapy increased from 25.8% in 1990-1991 to 61.3% in 2000-2001; tamoxifen increased from 2.3% to 34.4%. A total of 245 patients had a local recurrence within five years of their index ductal carcinoma in situ. The five-year risk of any local recurrence decreased from 14.3% (95% confidence interval 9.8 to 18.7) for patients diagnosed in 1990-1991 to 7.7% (95% confidence interval 5.5 to 9.9) for patients diagnosed in 1998-1999; invasive recurrence decreased from 7.0% (95% confidence interval 3.8 to 10.3) to 3.1% (95% confidence interval 1.7 to 4.6). In Cox models, the association between diagnosis year and risk of recurrence was modestly attenuated after accounting for use of adjuvant therapy. Between 1990-1991 and 2000-2001, the proportion of patients with tumors with high nuclear grade decreased from 46% to 32% (P = 0.03) and those with involved surgical margins dropped from 15% to 0% (P = 0.03).

Conclusions

The marked increase in the 1990s in the use of adjuvant therapy for ductal carcinoma in situ patients treated with breast-conserving surgery in the community setting only partially explains the 50% decline in risk of recurrence. Changes in pathology factors have likely also contributed to this decline.
Final Version of 2009 AJCC Melanoma Staging and Classification
Authors: Balch Charles M. , Gershenwald Jeffrey E. , Soong Seng-jaw , Thompson John F. , Atkins Michael B. , Byrd David R. , Buzaid Antonio C. , Cochran Alistair J. , Coit Daniel G. , Ding Shouluan , Eggermont Alexander M. , Flaherty Keith T. , Gimotty Phyllis A. , Kirkwood John M. , McMasters Kelly M. , Mihm Martin C. , Morton Donald L. , Ross Merrick I. , Sober Arthur J. , Sondak Vernon K.
Published: November 2009

Purpose

To revise the staging system for cutaneous melanoma on the basis of data from an expanded American Joint Committee on Cancer (AJCC) Melanoma Staging Database.

Methods

The melanoma staging recommendations were made on the basis of a multivariate analysis of 30,946 patients with stages I, II, and III melanoma and 7,972 patients with stage IV melanoma to revise and clarify TNM classifications and stage grouping criteria.

Results

Findings and new definitions include the following: (1) in patients with localized melanoma, tumor thickness, mitotic rate (histologically defined as mitoses/mm2), and ulceration were the most dominant prognostic factors. (2) Mitotic rate replaces level of invasion as a primary criterion for defining T1b melanomas. (3) Among the 3,307 patients with regional metastases, components that defined the N category were the number of metastatic nodes, tumor burden, and ulceration of the primary melanoma. (4) For staging purposes, all patients with microscopic nodal metastases, regardless of extent of tumor burden, are classified as stage III. Micrometastases detected by immunohistochemistry are specifically included. (5) On the basis of a multivariate analysis of patients with distant metastases, the two dominant components in defining the M category continue to be the site of distant metastases (nonvisceral v lung v all other visceral metastatic sites) and an elevated serum lactate dehydrogenase level.

Conclusion

Using an evidence-based approach, revisions to the AJCC melanoma staging system have been made that reflect our improved understanding of this disease. These revisions will be formally incorporated into the seventh edition (2009) of the AJCC Cancer Staging Manual and implemented by early 2010.
Alternative Antiquarianisms of Scotland and the North
Authors: Sorensen Janet
Published: November 2009

In dominant accounts, the eighteenth-century “ballad revival” brought a dead form back to life by digging up old songs and restoring their force and meaning. It also brought “the people,” as producers or consumers of ballads, to a kind of national public life but relegated them to an anterior temporal space. This essay offers a more differentiated history, examining Scottish and northern song collectors who differed from these formulations and provided distinct understandings of “the people” and of class. David Herd, for instance, used Scottish Enlightenment theories of sense and cognition to reverse the polarity; he did not see the collector revivifying the dead form of the ballad so much as ballads and songs themselves galvanizing the members of a nation. Joseph Ritson, an antiquarian dedicated to the most rigorous standards of authentication, also published “garlands,” collections of songs from various locales in his native northeastern England. Lacking the explanatory prefaces and footnotes that might make meaning available to broader or later audiences, Ritson's garlands targeted a decidedly ephemeral local community in the present. In the face of dominant antiquarian models locating “the people” out of time, Herd and Ritson offered alternative models through which to figure “the people,” rendering them as diverse, only contingently consolidated, but full participants in the here and now.
“On the Borders of Oblivion”: Scott's Historical Novel and the Modern Time of the Remnant
Authors: Ferris Ina
Published: November 2009

This essay contends that Scott's historical novels respond to the widespread sense of displacement in postrevolutionary Europe by activating and rewriting the figure of the remnant. As remnant tales, his novels are less about the loss of the past or its relationship to the present than about a disconnection in the present itself. Belonging neither to the past nor to the present, the remnant draws attention to modernity's temporality as that of the time lag: a suspension of connection and continuity that generates a curiously insubstantial existence in the present. Rereading Scott heroes like Edgar Ravenswood and Henry Morton as remnants, the essay traces the implications of their untimeliness, arguing that the remnant's awkward lingering moves into the foreground the problem of obsolescence and releases in the fictions a meditative-speculative mood answering to the question of how modern cultures live on.
Form inspection using kernel methods
Authors: Gilbert R C , Raman S , Trafalis T B
Published: November 2009

Form inspection of non-linear surfaces is a difficult task as suitable analytical models are often unavailable. This paper presents a mathematical model for surface inspection of face-milled plates and determination of the minimum zone based on a modification of the support vector machine (SVM) technique. The SVM approach is reformulated to regression problems using a different methodology than the ‘largest margin’ paradigm. In addition, this work derives extremely simple quadratic programming (QP) problems that allow for general symbolic solutions to non-linear regression problems. The results obtained from preliminary testing allow identification of processing tendencies so that a selective sampling procedure may be applied for inspecting future plates from that lot.
The adoption of servitization strategies by UK-based manufacturers
Authors: Baines T S , Lightfoot H , Benedettini O , Whitney D , Kay J M
Published: November 2009

Almost all manufacturers offer services, but some use these as the basis for their competitive strategy. This is a growing area of interest among practitioners, policy makers, and academics, yet little is known about the adoption of servitization by UK manufacturers. In this paper a survey is presented that has been used to explore the extent, motivations, challenges, and successes of servitization within the business-to-business sector. The findings indicate, for example, that many manufacturers are succeeding with their service strategies, that they are attracted to these as a source of customer focus and revenue growth, and that such strategies require less organizational change than might be expected. Although the findings from the survey should be treated as preliminary, and further work is needed to confirm their reliability and insight, they indicate that servitization is proving to be a powerful competitive weapon for many companies.
Design and development of a classification system for knowledge management tools and methods
Authors: Barnett T J , Harding J A , Nurse A
Published: November 2009

Mechanical and manufacturing engineering (MME) organizations commonly recognize the value of their knowledge resources, yet most fail effectively to exploit these assets. Knowledge management (KM) solutions should provide the means for appropriate exploitation of the resources, but there are very few published KM implementations in MME contexts compared with the wealth of KM solutions published in other sectors. This paper demonstrates a methodology for the creation of a KM solution space based on the review, analysis, and characterization of 157 sources, including examples of KM problems within 55 companies from 16 different industry sectors. The example KM solution set can be used to identify appropriate tools to solve KM-related problems in many MME contexts.