bluuebunny/crossref_metadata_2025 huggingface dataset:
Sapropterin hydrochloride: enzyme enhancement therapy for phenylketonuria
Authors: Lachmann Robin
Published: March 2011

Phenylketonuria (PKU) is an inherited disorder of amino acid metabolism caused by deficiency of the enzyme phenylalanine hydroxylase (PAH). Historically PKU was a common genetic cause of severe learning difficulties and developmental delay, but with the introduction of newborn screening and early dietary management, it has become a treatable disease and people born with PKU should now have IQs and achievements similar to their peers. Dietary treatment, however, involves lifestyle changes that pervade most aspects of daily life for an individual and their family. A simple pharmacological treatment for PKU would have a great appeal. Sapropterin hydrochloride is a synthetic form of tetrahydrobiopterin, the cofactor for PAH. A proportion of mutant PAH enzymes show enhanced activity in the presence of pharmacological doses of sapropterin and, for some patients with milder forms of PKU, sapropterin can effectively lower plasma phenylalanine levels. This article discusses the potential place for sapropterin in the management of PKU and how this expensive orphan drug is being integrated into patient care in different healthcare systems.
Establishment and characterization of a novel Waldenström macroglobulinemia cell line, MWCL-1
Authors: Hodge Lucy S. , Novak Anne J. , Grote Deanna M. , Braggio Esteban , Ketterling Rhett P. , Manske Michelle K. , Price Troska Tammy L. , Ziesmer Steven C. , Fonseca Rafael , Witzig Thomas E. , Morice William G. , Gertz Morie A. , Ansell Stephen M.
Published: March 2011

Waldenström macroglobulinemia (WM) is a rare, lymphoplasmacytic lymphoma characterized by hypersecretion of immunoglobulin M (IgM) protein and tumor infiltration into the bone marrow and lymphatic tissue. Our understanding of the mechanisms driving the development and progression of WM is currently by the shortage of representative cell models available for study. We describe here the establishment of a new WM cell line, MWCL-1. Comprehensive genetic analyses have unequivocally confirmed a clonal relationship between this novel cell line and the founding tumor. MWCL-1 cells exhibit an immunophenotype consistent with a diverse, tumor clone composed of both small B lymphocytes and larger lymphoplasmacytic cells and plasma cells: CD3−, CD19+, CD20+, CD27+, CD38+, CD49D+, CD138+, cIgM+, and κ+. Cytogenetic studies identified a monoallelic deletion of 17p13 (TP53) in both the cell line and the primary tumor. Direct DNA resequencing of the remaining copy of TP53 revealed a missense mutation at exon 5 (V143A, GTG>GCG). In accordance with primary WM tumors, MWCL-1 cells retain the ability to secrete high amounts of IgM protein in the absence of an external stimulus. The genetic, immunophenotypic, and biologic data presented here confirm the validity of the MWCL-1 cell line as a representative model of WM.
Clonal analysis of hematopoietic progenitor cells in the zebrafish
Authors: Stachura David L. , Svoboda Ondrej , Lau Ryan P. , Balla Keir M. , Zon Leonard I. , Bartunek Petr , Traver David
Published: March 2011

Identification of hematopoietic progenitor cells in the zebrafish (Danio rerio) has been hindered by a lack of functional assays to gauge proliferative potential and differentiation capacity. To investigate the nature of myeloerythroid progenitor cells, we developed clonal methylcellulose assays by using recombinant zebrafish erythropoietin and granulocyte colony-stimulating factor. From adult whole kidney marrow, erythropoietin was required to support erythroid colony formation, and granulocyte colony-stimulating factor was required to support the formation of colonies containing neutrophils, monocytes, and macrophages. Myeloid and erythroid colonies showed distinct morphologies and were easily visualized and scored by their expression of lineage-specific fluorescent transgenes. Analysis of the gene-expression profiles after isolation of colonies marked by gata1:DsRed or mpx:eGFP transgenes confirmed our morphological erythroid and myeloid lineage designations, respectively. The majority of progenitor activity was contained within the precursor light scatter fraction, and more immature precursors were present within the lymphoid fraction. Finally, we performed kinetic analyses of progenitor activity after sublethal irradiation and demonstrated that recovery to preirradiation levels occurred by 14 days after irradiation. Together, these experiments provide the first report of clonal hematopoietic progenitor assays in the zebrafish and establish the number, characteristics, and kinetics of myeloerythroid progenitors during both steady-state and stress hematopoiesis.
Small RNA profiling of Dengue virus-mosquito interactions implicates the PIWI RNA pathway in anti-viral defense
Authors: Hess Ann M , Prasad Abhishek N , Ptitsyn Andrey , Ebel Gregory D , Olson Ken E , Barbacioru Catalin , Monighetti Cinna , Campbell Corey L
Published: March 2011

Background

Small RNA (sRNA) regulatory pathways (SRRPs) are important to anti-viral defence in mosquitoes. To identify critical features of the virus infection process in Dengue serotype 2 (DENV2)-infected Ae. aegypti, we deep-sequenced small non-coding RNAs. Triplicate biological replicates were used so that rigorous statistical metrics could be applied.

Results

In addition to virus-derived siRNAs (20-23 nts) previously reported for other arbovirus-infected mosquitoes, we show that PIWI pathway sRNAs (piRNAs) (24-30 nts) and unusually small RNAs (usRNAs) (13-19 nts) are produced in DENV-infected mosquitoes. We demonstrate that a major catalytic enzyme of the siRNA pathway, Argonaute 2 (Ago2), co-migrates with a ~1 megadalton complex in adults prior to bloodfeeding. sRNAs were cloned and sequenced from Ago2 immunoprecipitations. Viral sRNA patterns change over the course of infection. Host sRNAs were mapped to the published aedine transcriptome and subjected to analysis using edgeR (Bioconductor). We found that sRNA profiles are altered early in DENV2 infection, and mRNA targets from mitochondrial, transcription/translation, and transport functional categories are affected. Moreover, small non-coding RNAs (ncRNAs), such as tRNAs, spliceosomal U RNAs, and snoRNAs are highly enriched in DENV-infected samples at 2 and 4 dpi.

Conclusions

These data implicate the PIWI pathway in anti-viral defense. Changes to host sRNA profiles indicate that specific cellular processes are affected during DENV infection, such as mitochondrial function and ncRNA levels. Together, these data provide important progress in understanding the DENV2 infection process in Ae. aegypti.
miR-449 inhibits cell proliferation and is down-regulated in gastric cancer
Authors: Bou Kheir Tony , Futoma-Kazmierczak Ewa , Jacobsen Anders , Krogh Anders , Bardram Linda , Hother Christoffer , Grønbæk Kirsten , Federspiel Birgitte , Lund Anders H , Friis-Hansen Lennart
Published: March 2011

Background

Gastric cancer is the fourth most common cancer in the world and the second most prevalent cause of cancer related death. The development of gastric cancer is mainly associated with H. Pylori infection leading to a focus in pathology studies on bacterial and environmental factors, and to a lesser extent on the mechanistic development of the tumour. MicroRNAs are small non-coding RNA molecules involved in post-transcriptional gene regulation. They are found to regulate genes involved in diverse biological functions and alterations in microRNA expression have been linked to the pathogenesis of many malignancies. The current study is focused on identifying microRNAs involved in gastric carcinogenesis and to explore their mechanistic relevance by characterizing their targets.

Results

Invitrogen NCode miRNA microarrays identified miR-449 to be decreased in 1-year-old Gastrin KO mice and in H. Pylori infected gastric tissues compared to tissues from wild type animals. Growth rate of gastric cell lines over-expressing miR-449 was inhibited by 60% compared to controls. FACS cell cycle analysis of miR-449 over-expressing cells showed a significant increase in the sub-G1 fraction indicative of apoptosis. ß-Gal assays indicated a senescent phenotype of gastric cell lines over-expressing miR-449. Affymetrix 133v2 arrays identified GMNN, MET, CCNE2, SIRT1 and CDK6 as miR-449 targets. Luciferase assays were used to confirm GMNN, MET, CCNE2 and SIRT1 as direct targets. We also show that miR-449 over-expression activated p53 and its downstream target p21 as well as the apoptosis markers cleaved CASP3 and PARP. Importantly, qPCR analyses showed a loss of miR-449 expression in human clinical gastric tumours compared to normal tissues.

Conclusions

In this study, we document a diminished expression of miR-449 in Gastrin KO mice and further confirmed its loss in human gastric tumours. We investigated the function of miR-449 by identifying its direct targets. Furthermore we show that miR-449 induces senescence and apoptosis by activating the p53 pathway.
Biological and immunological characterization of recombinant Yellow Fever 17D Viruses expressing a Trypanosoma cruzi Amastigote Surface Protein-2 CD8+T cell epitope at two distinct regions of the genome
Authors: Nogueira Raquel T , Nogueira Alanderson R , Pereira Mirian CS , Rodrigues Maurício M , Galler Ricardo , Bonaldo Myrna C
Published: March 2011

Background

The attenuated Yellow fever (YF) 17D vaccine virus is one of the safest and most effective viral vaccines administered to humans, in which it elicits a polyvalent immune response. Herein, we used the YF 17D backbone to express aTrypanosoma cruziCD8+T cell epitope from the Amastigote Surface Protein 2 (ASP-2) to provide further evidence for the potential of this virus to express foreign epitopes. The TEWETGQI CD8+T cell epitope was cloned and expressed based on two different genomic insertion sites: in thefgloop of the viral Envelope protein and the protease cleavage site between the NS2B and NS3. We investigated whether the site of expression had any influence on immunogenicity of this model epitope.

Results

Recombinant viruses replicated similarly to vaccine virus YF 17D in cell culture and remained genetically stable after several serial passages in Vero cells. Immunogenicity studies revealed that both recombinant viruses elicited neutralizing antibodies to the YF virus as well as generated an antigen-specific gamma interferon mediated T-cell response in immunized mice. The recombinant viruses displayed a more attenuated phenotype than the YF 17DD vaccine counterpart in mice. Vaccination of a mouse lineage highly susceptible to infection byT. cruziwith a homologous prime-boost regimen of recombinant YF viruses elicited TEWETGQI specific CD8+T cells which might be correlated with a delay in mouse mortality after a challenge with a lethal dose ofT. cruzi.

Conclusions

We conclude that the YF 17D platform is useful to expressT. cruzi(Protozoan) antigens at different functional regions of its genome with minimal reduction of vector fitness. In addition, the modelT. cruziepitope expressed at different regions of the YF 17D genome elicited a similar T cell-based immune response, suggesting that both expression sites are useful. However, the epitope as such is not protective and it remains to be seen whether expression of larger domains of ASP-2, which include the TEWETGQI epitope, will elicit better T-CD8+ responses to the latter. It is likely that additional antigens and recombinant virus formulations will be necessary to generate a protective response.
The transcription factor Foxg1 regulates telencephalic progenitor proliferation cell autonomously, in part by controlling Pax6 expression levels
Authors: Manuel Martine N , Martynoga Ben , Molinek Mike D , Quinn Jane C , Kroemmer Corinne , Mason John O , Price David J
Published: March 2011

Background

The transcription factor Foxg1 is an important regulator of telencephalic cell cycles. Its inactivation causes premature lengthening of telencephalic progenitor cell cycles and increased neurogenic divisions, leading to severe hypoplasia of the telencephalon. These proliferation defects could be a secondary consequence of the loss of Foxg1 caused by the abnormal expression of several morphogens (Fibroblast growth factor 8, bone morphogenetic proteins) in the telencephalon of Foxg1 null mutants. Here we investigated whether Foxg1 has a cell autonomous role in the regulation of telencephalic progenitor proliferation. We analysed Foxg1

+/+
↔Foxg1

-/-
chimeras, in which mutant telencephalic cells have the potential to interact with, and to have any cell non-autonomous defects rescued by, normal wild-type cells.

Results

Our analysis showed that the Foxg1

-/-
cells are under-represented in the chimeric telencephalon and the proportion of them in S-phase is significantly smaller than that of their wild-type neighbours, indicating that their under-representation is caused by a cell autonomous reduction in their proliferation. We then analysed the expression of the cell-cycle regulator Pax6 and found that it is cell-autonomously downregulated in Foxg1

-/-
dorsal telencephalic cells. We went on to show that the introduction into Foxg1

-/-
embryos of a transgene designed to reverse Pax6 expression defects resulted in a partial rescue of the telencephalic progenitor proliferation defects.

Conclusions

We conclude that Foxg1 exerts control over telencephalic progenitor proliferation by cell autonomous mechanisms that include the regulation of Pax6, which itself is known to regulate proliferation cell autonomously in a regional manner.
Gene amplification in human cells knocked down for RAD54
Authors: Ruiz-Herrera Aurora , Smirnova Alexandra , Khouriauli Lela , Nergadze Solomon G , Mondello Chiara , Giulotto Elena
Published: March 2011

Background

In mammalian cells gene amplification is a common manifestation of genome instability promoted by DNA double-strand breaks (DSBs). The repair of DSBs mainly occurs through two mechanisms: non-homologous end-joining (NHEJ) and homologous recombination (HR). We previously showed that defects in the repair of DSBs via NHEJ could increase the frequency of gene amplification. In this paper we explored whether a single or a combined defect in DSBs repair pathways can affect gene amplification.

Results

We constructed human cell lines in which the expression of RAD54 and/or DNA-PKcs was constitutively knocked-down by RNA interference. We analyzed their radiosensitivity and their capacity to generate amplified DNA. Our results showed that both RAD54 and DNA-PKcs deficient cells are hypersensitive to γ-irradiation and generate methotrexate resistant colonies at a higher frequency compared to the proficient cell lines. In addition, the analysis of the cytogenetic organization of the amplicons revealed that isochromosome formation is a prevalent mechanism responsible for copy number increase in RAD54 defective cells.

Conclusions

Defects in the DSBs repair mechanisms can influence the organization of amplified DNA. The high frequency of isochromosome formation in cells deficient for RAD54 suggests that homologous recombination proteins might play a role in preventing rearrangements at the centromeres.
A Rising, Emboldened China
Authors: Williamson Richard S.
Published: March 2011

The essay offers an in-depth account of China's assertiveness in world affairs, an analysis of its own emerging contradictions, and how it must reconcile economic development and the inevitable growth of the middle class that will, sooner or later, demand political freedoms. China's influence in the global financial system constitutes the core of the author's analysis. The author also describes the challenges faced by the US from China as a rising competitor for superpower status.
Historical Greek-Albanian Relations: Some Mysteries and Riddles
Authors: Abadzi Helen
Published: March 2011

Since the nineteenth century, Greece and Albania have been separate countries, but for about twenty-two centuries they belonged to the same state in its various forms. The ancient Greeks and Illyrians were Indo-European tribes who intermarried with pre-Hellenic populations after arriving in the Balkans about four thousand years ago. Multiple migration events occurred to and from one another's lands; in ancient years Greek cities like Corinth established colonies on the Illyrian coast, while in the Middle Ages Albanian speakers (known as Arvanites) migrated across Greece. Hundreds of years later, another five hundred thousand Albanian speakers had immigrated to Greece after 1985. The data show that Greeks and Albanians have a long-term kinship, but this is obscured by linguistic and religious differences. Understanding this common past may strengthen contemporary political relationships.
From Dictatorship to Democracy: Us-Greek Relations at a Critical Turning Point (1974–1975)
Authors: Klapsis Antonis
Published: March 2011

The essay examines the way US-Greek relations evolved during the first critical year after the collapse of the seven-year military dictatorship in Greece. It is argued that the new prime minister of Greece, Konstantinos Karamanlis, wished to promote cooperation between Athens and Washington but on condition that this cooperation would be equally beneficial for Greece and the United States. That the Americans did not seem prepared to undertake any serious initiative to promote a solution of the Cyprus question or to relieve Ankara's pressures on Athens in the Aegean Sea made relations more complicated.
An investigation on the influence of glycerin on sclerosant foam stability
Authors: Peterson J D , Goldman M P
Published: March 2011

Background

Foam sclerotherapy is an increasingly popular modality in the treatment of varicose veins. Foam stability varies according to foam composition, volume and injection technique.

Materials and methods

A disposable plastic connector was used to create foam from 0.50% sodium tetradecyl sulphate (STS) mixed with varying volumes of glycerin. As a measure of foam stability, the half liquid time was defined as the time required for half of the original volume of sclerosing solution to settle. Three recordings were determined for each of the three mixtures of sclerosant foam.

Results

The time for sclerosing solution to settle to half of its initial volume was found to be 89 seconds for 0.50% STS alone, 117.7 seconds with the addition of 0.1 mL of 72% glycerin, and 114.7 seconds with the addition of 0.2 mL of 72% glycerin.

Conclusion

The small volumes of glycerin added to STS prolonged the half liquid time of STS foam up to 35%. As glycerin alone is unable to be foamed with the double-syringe system technique there may be a point at which further addition of glycerin has a negative effect on the half-life of foam.
Echocardiography in low-resource rural tropical hospitals
Authors: Bregani Enrico Rino , Van Tien Tu , Occhipinti Michele
Published: March 2011

Cardiopathies are common in tropical regions and echocardiography could be of substantial value. However, it is difficult to practice. We suggest simple techniques with conventional instruments that are available in many rural hospitals, and describe the most common echocardiographic procedures and findings that can be undertaken with short training by non-cardiologist physicians.
Results of infertility investigations and follow-up among 312 infertile women and their partners in Kigali, Rwanda
Authors: Dhont Nathalie , van de Wijgert Janneke , Vyankandondera Joseph , Busasa Rosette , Gasarabwe Ammiel , Temmerman Marleen
Published: March 2011

The objectives of this study were to assess the outcome of infertility investigations and an 18-month follow-up of 312 infertile women and their partners in Rwanda. Between November 2007 and May 2009, an infertility research clinic was opened. Infertile couples received basic infertility investigations, the available treatment was provided and couples were followed up over an 18-month period. The infertility remained unexplained in 3%, was due to a female factor in 31%, due to a male factor in 16% or due to a combination of male and female causes in 50% of fully investigated couples ( n = 224). A tubal factor was found in 69% of women, a male factor in 64% of men. Predictors for tubal infertility in women included a history of high-risk sexual behaviour, HIV infection and a history of sexually transmitted infection (STI) symptoms in the male partner. After 12–18 months of follow-up, 40 pregnancies (16%) had occurred in 244 women. Our study shows high rates of tubal and male factor infertility in Rwanda. Pregnancy rates were low after conventional therapy. In order to provide effective and affordable treatment for infertility in resource-poor countries the development of low-cost assisted reproductive technologies are needed.
Early Breast Cancer in the Older Woman
Authors: Gandhi Sonal , Verma Sunil
Published: March 2011

Background.

Women aged ≥65 are generally underrepresented in early breast cancer studies. Therefore, the optimal management of this group of women remains less certain.

Methods.

A literature review of recently published trials, reviews, and practice guidelines outlining the surgical and adjuvant management of early breast cancer in older women was performed.

Results.

Surgery remains as the cornerstone treatment for early breast cancer in the elderly. Adjuvant radiation is generally considered if the projected lifespan is >5 years. Hormone receptor–positive disease is best treated with adjuvant endocrine treatment; aromatase inhibitors and tamoxifen are both options. Evidence for the use of adjuvant chemotherapy and trastuzumab for high-risk disease in the elderly is more limited. Polychemotherapy is still preferred in fit older women. Certain toxicities from systemic treatments can be more pronounced and should be carefully managed. Treatment with systemic agents should be individualized, with consideration of patient preference, performance status, comorbidities, and projected lifespan. Molecular tumor signatures may help better select patients for treatment in the future.

Conclusions.

Age in itself should not be an absolute contraindication to any breast cancer therapy. Comprehensive, multidisciplinary assessment of elderly patients is imperative in evaluating eligibility for beneficial therapies.
An insight into the water retention properties of compacted clayey soils
Authors: ROMERO E. , DELLA VECCHIA G. , JOMMI C.
Published: March 2011

Experimental data from different testing methodologies on different compacted clayey soils, with dominant bimodal pore size distribution, are presented and analysed, to provide a comprehensive picture of the evolution of the aggregated fabric along hydraulic and mechanical paths. Fabric changes are analysed both from the porous network viewpoint, by means of careful mercury intrusion porosimetry investigation, and from the soil skeleton viewpoint, by quantifying swelling and shrinkage of the aggregates in an environmental scanning electron microscopy study. The consequences of the aggregated fabric evolution on the water retention properties of compacted soils are analysed and discussed. A new model for water retention domain is proposed, which introduces a dependence of the intra-aggregate pore volume on water content. The model succeeds in tracking correctly the evolution of the hydraulic state of the different soils investigated along generalised hydromechanical paths. The proposed approach brings to light coupling between intra-aggregate and inter-aggregate pores in the retention properties of compacted clayey soils. Dependence of the air entry and the air occlusion values on swelling and shrinking of aggregates, besides void ratio, is introduced and discussed.
Experimental observations of the stress regime in unsaturated compacted clay when laterally confined
Authors: BOYD J.L. , SIVAKUMAR V.
Published: March 2011

Construction processes often involve reformation of the landscape, which will inevitably encompass compaction of artificially placed soils. A common application of fill materials is their use as backfill in many engineering applications, for example behind a retaining wall. The post-construction behaviour of clay fills is complex with respect to stresses and deformation when the fills become saturated over time. Heavily compacted fills swells significantly more than the lightly compacted fills. This will produce enhanced lateral stresses if the fill is laterally restrained. The work presented in this paper examines how the stress regime in unsaturated clay fills changes with wetting under laterally restrained conditions. Specimens of compacted kaolin, with different initial conditions, were wetted to various values of suction under zero lateral strain at constant net overburden pressure which allowed the concept of K0 (the ratio between the net horizontal stress and the net vertical stress) to be examined. Tests were also carried out to examine the traditional concept of the earth pressure coefficient ‘at rest' under loading and unloading and its likely effects on the stress–strain properties. The results have shown that the stress regime (i.e. the lateral stress) changes significantly during wetting under laterally restrained conditions. The magnitude of the change is affected by the initial condition of the soil. The results have also indicated that the earth pressure coefficient ‘at rest' during loading (under the normally consolidated condition) is unaffected by suction and such loading conditions inevitably lead to the development of anisotropic stress–strain properties
A Critical Review of the U.S. EPA's Risk Assessment for the Land Application of Sewage Sludge
Authors: Mathney Jennifer M. J.
Published: March 2011

Sewage sludge is a complex mixture of inorganic and organic materials and pathogens generated by the treatment of domestic sewage. Section 40 of the Code of Federal Regulations Part 503 regulates the land application of sewage sludge based on pathogen content and sets standards for nine inorganic chemicals. It is believed that the Part 503 standards are protective of human health and the environment and that sewage sludge applied to land poses little risk. A critical inspection of the pertinent literature, however, reveals that the standards were based on outdated methods, outdated data, inaccurate data, and flawed assumptions, leading to underestimation of risk. The standards are not sufficiently protective, and even if changes were made, sewage sludge is so complex that it is very unlikely it could be monitored to ensure the protection of human health and the environment. For these reasons, the practice of land application of sewage sludge must be discontinued.
Occupational Health Nursing and the Quest for Professional Authority
Authors: Draper Elaine , Ladou Joseph , Tennenhouse Dan J.
Published: March 2011

Occupational health nurses provide most of the in-plant health care services in U.S. industry but have dubious credentials to provide care for many of the injuries and illnesses they encounter. The nurses work directly for the employer in an atmosphere designed to control employer costs and employee benefits. Their loyalty to the company and limited autonomy make it unlikely that they will represent the workers' interests. They generally embrace any expansion of their roles within the company. However, employers and government have made no serious effort to determine whether nurses can adequately take on these new functions and advance occupational health. A nurse-directed model carries the risk that nurses who are not knowledgeable enough about the law, or are overly committed to reducing costs, may overdelegate responsibilities, thereby aiding and abetting the unlicensed practice of nursing. This overreaching is part of an ill-conceived effort to establish nursing as a profession with the greater independence, expertise, and control over training that longstanding professions such as medicine and law have achieved. An extensive literature devoted to the approval and acceptance of occupational health nursing exists, yet constructive criticism of occupational health nursing is almost nonexistent. Occupational health and safety is much too important to be largely relegated to an inadequately defined semi-profession, striving to attain higher professional status and control while lacking the expertise, power, professional standards, and autonomy required of a profession.
The Differing Perspectives of Workers and Occupational Medicine Physicians on the Ethical, Legal and Social Issues of Genetic Testing in the Workplace
Authors: Brandt-Rauf Sherry I. , Brandt-Rauf Elka , Gershon Robyn , Brandt-Rauf Paul W.
Published: March 2011

Genetic testing in the workplace holds the promise of improving worker health but also raises ethical, legal, and social issues. In considering such testing, it is critical to understand the perspectives of workers, who are most directly affected by it, and occupational health professionals, who are often directly involved in its implementation. Therefore, a series of focus groups of unionized workers (n=25) and occupational medicine physicians (n=23) was conducted. The results demonstrated strikingly different perspectives of workers and physicians in several key areas, including the goals and appropriateness of genetic testing, and methods to minimize its risks. In general, workers were guided by a profound mistrust of the employer, physician, and government, while physicians were guided primarily by scientific and medical concerns, and, in many cases, by the business concerns distrusted by the workers.
Clinical Utility of Genetic Testing in Children and Adults with Steroid-Resistant Nephrotic Syndrome
Authors: Santín Sheila , Bullich Gemma , Tazón-Vega Bárbara , García-Maset Rafael , Giménez Isabel , Silva Irene , Ruíz Patricia , Ballarín José , Torra Roser , Ars Elisabet
Published: March 2011

Background and objectives

The increasing number of podocyte-expressed genes implicated in steroid-resistant nephrotic syndrome (SRNS), the phenotypic variability, and the uncharacterized relative frequency of mutations in these genes in pediatric and adult patients with SRNS complicate their routine genetic analysis. Our aim was to compile the clinical and genetic data of eight podocyte genes analyzed in 110 cases (125 patients) with SRNS (ranging from congenital to adult onset) to provide a genetic testing approach.

Design, setting, participants, & measurements

Mutation analysis was performed by sequencing the NPHS1, NPHS2, TRPC6, CD2AP, PLCE1, INF2, WT1 (exons 8 and 9), and ACTN4 (exons 1 to 10) genes.

Results

We identified causing mutations in 34% (37/110) of SRNS patients, representing 67% (16/24) familial and 25% (21/86) sporadic cases. Mutations were detected in 100% of congenital-onset, 57% of infantile-onset, 24 and 36% of early and late childhood-onset, 25% of adolescent-onset, and 14% of adult-onset patients. The most frequently mutated gene was NPHS1 in congenital onset and NPHS2 in the other groups. A partial remission was observed in 7 of 26 mutation carriers treated with immunosuppressive agents and/or angiotensin-converting enzyme inhibitors. Patients with NPHS1 mutations showed a faster progression to ESRD than patients with NPHS2 mutations. None of these mutation carriers relapsed after kidney transplantation.

Conclusions

We propose a genetic testing algorithm for SRNS based on the age at onset and the familial/sporadic status. Mutation analysis of specific podocyte-genes has a clinical value in all age groups, especially in children.
Trace elements and antioxidants in Astragalus onobrychis L. var. chlorocarpus (Griseb.) S. Kozuharov et D.K. Pavlova
Authors: Miladinovic Dragoljub , Ilic Budimir , Milosavljevic Violeta
Published: March 2011

Leaves of growing-wild species Astragalus onobrychis L. var. chlorocarpus
(Griseb.) S. Kozuharov et D. K. Pavlova were collected during the different
stages of growth and analyzed for iron (Fe), copper (Cu), zinc (Zn),
manganese (Mn), soluble proteins, reduced glutathione (GSH), total flavonoid
and total carotenoid contents. Iron, copper and manganese have shown similar
seasonal pattern, increasing of metal content in leaves during the vegetative
period. The highest values of the examined elements were in seed forming
stage, except zinc. The highest value of this element was recorded in initial
stage of vegetation. Antioxidant compounds have the highest values in
blooming stage of vegetation. The results from the present study suggest that
researched plant species represent a good source of trace elements and
antioxidant compounds.
Multi-criteria analysis of soil pollution by heavy metals in the vicinity of the copper smelting plant in Bor (Serbia)
Authors: Nikolic Djordje , Milosevic Novica , Zivkovic Zivan , Mihajlovic Ivan , Kovacevic Renata , Petrovic Nevenka
Published: March 2011

This study highlights the consequences on soil pollution of one hundred years
of manufacturing in the Copper Mining and Smelting Complex RTB-Bor (Serbia).
Soil sediments were taken via a probe from the surface layer of the soil at
twelve different measuring points. The measuring points were all within 20 km
of the smelting plant, which included both urban and rural zones. Soil
sampling was performed using a soil core sampler in such way that a core of a
soil of radius 5 cm and depth of 30 cm was removed. Subsequently, the samples
were analyzed for pH and heavy metal concentrations (Cu, Pb, As, Cd, Mn, Ni
and Hg) using different spectrometric methods. The obtained results for the
heavy metal contents in the samples show high values: 2,540 mg kg-1 Cu; 230
mg kg-1 Pb; 6 mg kg-1 Cd; 530 mg kg-1 Ni; 1,300 mg kg-1 Mn; 260 mg kg-1 As
and 0.3 mg kg-1 Hg. In this study, critical zones of polluted soil were
identified and ranked according to their metal contents by the multicriteria
decision method PROMETHEE/GAIA, which is the preferred multivariate method
commonly used in chemometric studies. The ranking results clearly showed that
the most polluted zones are at locations holding the vital functions of the
town. Therefore, due to the high bioavailability of heavy metals through
complex reactions with organic species in the sediments, consequences for
human health could drastically emerge if these metals enter the food chain.
Preliminary report: rapid prototyping models for Dysplastic hip surgery
Authors: Dhakshyani R. , Nukman Y. , Abu Osman N. , Vijay C.
Published: March 2011

Rapid prototyping (RP) is a technology used to produce physical models. The RP application is applied in the medical field to build anatomy models from high resolution multiplanar data such as Computed tomography (CT). CT of a female patient diagnosed with hip dysplasia was obtained prior to surgery. Specific software was used to prepare the physical model of the patient and was produced using fused deposition machine. Pre fused deposition models (FDM) were given to the orthopaedic surgeon to plan for the dysplastic hip dysplasia. The patient was scanned again using CT after surgery and a post model was produced. The outcome of the surgery was seen clearly by viewing the post model. Orthopaedic surgeon commented on his experience of using the models for the hip dysplasia surgery. These models were found to be very useful for pre surgery planning, determining procedure, implant sizes, positioning, bone grafting which also reduced surgery time by forty percent and increased surgeon confidence as rehearsal prior to actual surgery was made possible. This paper provides an understanding of the benefits of using RP models in hip dysplasia surgery as a good way to enhance both orthopaedic surgeon skill and knowledge.
Correlations between left ventricular mass index and cerebrovascular lesion
Authors: Kang Kyusik , Lee Seung-Hoon , Kim Beom , Lim Jae-Sung , Yoon Byung-Woo
Published: March 2011

Left ventricular (LV) mass and LV geometry are well-established measures of hypertension chronicity and severity, have a prognostic value on cardiovascular morbidity and mortality, and are related to asymptomatic cerebral small-artery disease (SAD) and largeartery disease (LAD). The aim of the present study was to clarify the different effects of LV mass and LV geometry on underlying SAD compared with its effects on underlying LAD in ischemic stroke patients. Four hundred three ischemic stroke patients underwent echocardiography to determine LV mass index and relative wall thickness. Brain magnetic resonance imaging, angiography, and carotid magnetic resonance angiography were preformed to detect LAD (≥50% stenosis) and SAD (leukoaraiosis, microbleeds, and old lacunar infarction) in the brain. Multivariate analyses showed that the LV mass index was highly associated with underlying SAD but not with underlying LAD. Among the various subtypes of SAD, only cerebral microbleeds were closely related to the LV mass index. Concentric LV hypertrophy was not related to the presence of either SAD or LAD. Subgroup analyses revealed that, among the various subtypes of SAD, only cerebral microbleeds were associated with concentric LV hypertrophy. In conclusion, cerebral microbleeds may imply more advanced target organ damage than underlying LAD and ischemic subtypes of SAD.
Heart-rate changes in asphyxic preconditioning in rats depend on light-dark cycle
Authors: Svorc Pavol , Bacova Ivana , Benacka Roman , Svorc Pavol , Galanova Ruzena , Fulton Benjamin
Published: March 2011

Generally, it is assumed that heart-rhythm disorders during hypoxia result from the interplay between the autonomic nervous system (ANS) and the direct effect of hypoxia on cardiorespiratory structures of the central nervous system and on the myocardium. Circadian variability in the ANS may substantially influence the electrical stability of the myocardium, and thus it is associated with the preconditioning protective mechanism. We designed our study using anaesthetized Wistar rats (ketamine/xylazine 100 mg/15 mg/kg, i.m., open chest experiments) to evaluate the effect of preconditioning (PC) induced by 1 to 3 cycles (1 PC–3 PC) of asphyxia (5 min. of artificial hypoventilation, VT = 0.5 ml/100 g of b.w., 20 breaths/min.) and reoxygenation (5 min. of artificial ventilation, VT = 1 ml/100 g of b.w., 50 breaths/min.) on the heart rate (HR) during followed exposure 20 minutes of hypoventilation after adaptation to a light-dark (LD) cycle of 12 hours:12 hours. Hypoxic HR increases were only minimally prevented by 1 to 2 PC pre-treatment, particularly during the dark part of the day. A statistically significant HR increase required 3 PC and was seen only in the light part of the day. We concluded that possible ANS participation in asphyxic preconditioning depends not only on the number of preconditioned cycles but also on the LD cycle, when the ANS participation in preconditioning can be effective only in the light (nonactive) period.
Accountability Under Constraint
Authors: Strunk Katharine O. , McEachin Andrew
Published: March 2011

The authors examine how the collective bargaining agreement (CBA) negotiated between teachers’ unions and districts is associated with schools’ and districts’ performance under accountability pressures in California. They find that CBA restrictiveness is associated with the increased likelihood that districts will be in Program Improvement (PI) and at higher levels of PI, and with lower school- and district-level proficiency and graduation rates. They also show that strong contract schools and districts that have higher proportions of minority, low-income, and low-achieving student are even less likely to meet performance targets and have even lower proficiency rates.
Prospective evaluation of a clinical decision guideline to diagnose spinal epidural abscess in patients who present to the emergency department with spine pain
Authors: Davis Daniel P. , Salazar Anthony , Chan Theodore C. , Vilke Gary M.
Published: March 2011

Object

A spinal epidural abscess (SEA) is rare but potentially devastating if not diagnosed early. Unfortunately, diagnostic delays and associated neurological deficits are common. The objectives of this analysis were to explore the use of a novel clinical decision guideline to screen patients who present to the emergency department (ED) with spine pain for SEA and to determine the diagnostic test characteristics of the erythrocyte sedimentation rate (ESR) and C-reactive protein (CRP) level in patients at risk for SEA.

Methods

This was a prospective, cohort analysis comparing the incidence of diagnostic delays and presence of motor deficits at the time of diagnosis before and after implementation of a novel decision guideline using risk factor assessment followed by ESR and CRP testing prior to definitive imaging. A delay was defined as either multiple ED visits or admission to a nonsurgical service without a diagnosis of SEA. A 9-month substudy was performed in all patients who presented to the ED with spine pain so that the diagnostic test characteristics of the ESR and CRP level could be defined.

Results

A total of 55 patients with an SEA in the 9-year control period and 31 patients with an SEA in the 5-year study period were identified. Diagnostic delays were observed in 46 (83.6%) of 55 patients before guideline implementation versus 3 (9.7%) of 31 after guideline implementation (p < 0.001). Motor deficits were present at the time of diagnosis in 45 (81.8%) of 55 patients before guideline implementation versus 6 (19.4%) of 31 after guideline implementation (p < 0.001). The sensitivity and specificity of ESR in patients with an SEA risk factor were 100% and 67%, respectively. The receiver operating characteristic curve analysis revealed better test characteristics for ESR (area under curve 0.96) than for CRP (area under curve 0.81).

Conclusions

A treatment guideline incorporating risk factor assessment followed by ESR and CRP testing was highly sensitive and moderately specific in identifying ED patients with SEA. A decrease in diagnostic delays and a lower incidence of motor deficits at the time of diagnosis was observed.
Attenuation of hematoma size and neurological injury with curcumin following intracerebral hemorrhage in mice
Authors: King Melanie D. , McCracken D. Jay , Wade F. Marlene , Meiler Steffen E. , Alleyne Cargill H. , Dhandapani Krishnan M.
Published: March 2011

Object

Intracerebral hemorrhage (ICH) is associated with significant morbidity and mortality. Acute hematoma enlargement is an important predictor of neurological injury and poor clinical prognosis; but neurosurgical clot evacuation may not be feasible in all patients and treatment options remain largely supportive. Thus, novel therapeutic approaches to promote hematoma resolution are needed. In the present study, the authors investigated whether the curry spice curcumin limited neurovascular injury following ICH in mice.

Methods

Intracerebral hemorrhage was induced in adult male CD-1 mice by intracerebral administration of collagenase or autologous blood. Clinically relevant doses of curcumin (75–300 mg/kg) were administered up to 6 hours after ICH, and hematoma volume, inflammatory gene expression, blood-brain barrier permeability, and brain edema were assessed over the first 72 hours. Neurological assessments were performed to correlate neurovascular protection with functional outcomes.

Results

Curcumin increased hematoma resolution at 72 hours post-ICH. This effect was associated with a significant reduction in the expression of the proinflammatory mediators, tumor necrosis factor–α, interleukin-6, and interleukin-1β. Curcumin also reduced disruption of the blood-brain barrier and attenuated the formation of vasogenic edema following ICH. Consistent with the reduction in neuroinflammation and neurovascular injury, curcumin significantly improved neurological outcome scores after ICH.

Conclusions

Curcumin promoted hematoma resolution and limited neurological injury following ICH. These data may indicate clinical utility for curcumin as an adjunct therapy to reduce brain injury and improve patient outcome.
An extent of resection threshold for newly diagnosed glioblastomas
Authors: Sanai Nader , Polley Mei-Yin , McDermott Michael W. , Parsa Andrew T. , Berger Mitchel S.
Published: March 2011

Object

The value of extent of resection (EOR) in improving survival in patients with glioblastoma multiforme (GBM) remains controversial. Specifically, it is unclear what proportion of contrast-enhancing tumor must be resected for a survival advantage and how much survival improves beyond this threshold. The authors attempt to define these values for the patient with newly diagnosed GBM in the modern neurosurgical era.

Methods

The authors identified 500 consecutive newly diagnosed patients with supratentorial GBM treated at the University of California, San Francisco between 1997 and 2009. Clinical, radiographic, and outcome parameters were measured for each case, including MR imaging–based volumetric tumor analysis.

Results

The patients had a median age of 60 years and presented with a median Karnofsky Performance Scale (KPS) score of 80. The mean clinical follow-up period was 15.3 months, and no patient was unaccounted for. All patients underwent resection followed by chemotherapy and radiation therapy. The median postoperative tumor volume was 2.3 cm3, equating to a 96% EOR. The median overall survival was 12.2 months. Using Cox proportional hazards analysis, age, KPS score, and EOR were predictive of survival (p < 0.0001). A significant survival advantage was seen with as little as 78% EOR, and stepwise improvement in survival was evident even in the 95%–100% EOR range. A recursive partitioning analysis validated these findings and provided additional risk stratification parameters related to age, EOR, and tumor burden.

Conclusions

For patients with newly diagnosed GBMs, aggressive EOR equates to improvement in overall survival, even at the highest levels of resection. Interestingly, subtotal resections as low as 78% also correspond to a survival benefit.