bluuebunny/crossref_metadata_2025 huggingface dataset:
Comparative effects of aliskiren-based and ramipril-based therapy on the renin system during long-term (6 months) treatment and withdrawal in patients with hypertension
Authors: Andersen Karl , Weinberger Myron H , Constance Christian M , Ali Mohammed A , Jin James , Prescott Margaret F , Keefe Deborah L
Published: July 2009

Introduction. This subgroup analysis assessed the effects of treatment based on the direct renin inhibitor, aliskiren, or the angiotensin-converting enzyme inhibitor, ramipril, on plasma renin activity (PRA), plasma renin concentration (PRC) and other biomarkers in a 26-week randomised, double-blind trial. Changes in PRA and PRC after stopping treatment were also assessed.

Methods. After placebo run-in, 842 patients (mean sitting diastolic blood pressure (BP) 95—109 mmHg) were randomised to aliskiren 150 mg or ramipril 5 mg. Dose titration and hydrochlorothiazide addition were allowed after Week 6 and 12, respectively, for inadequate BP control. Patients completing active treatment were re-randomised to current regimen or placebo during a 4-week posttreatment phase.

Results. BP reductions were independent of baseline PRA at Week 12, were greater with aliskiren- than ramipril-based therapy at Week 26 (17.9/13.3 vs. 15.2/12.0 mmHg, p<0.05) and persisted for longer after stopping aliskiren. Aliskiren-based therapy reduced geometric mean PRA (−63%, p<0.05; n=103), while ramipril-based therapy increased PRA (+143%, p<0.05; n=100) at Week 26; PRC increased in both groups (aliskiren: +224% [n=33], ramipril: +145% [n=39], both p<0.05). Four weeks after stopping aliskiren-based therapy, PRA remained 52% below pre-treatment baseline; PRA returned to baseline 2 weeks after stopping ramipril-based therapy.

Conclusions. Aliskiren-based therapy produced sustained BP and PRA reductions over 26 weeks; ramipril-based therapy lowered BP and increased PRA. PRA reductions persisted 4 weeks after stopping aliskiren, suggesting an inhibitory effect beyond the elimination half-life of the drug.
Combination renin-angiotensin system blockade with the renin inhibitor aliskiren in hypertension
Authors: Doulton Timothy WR , MacGregor Graham A
Published: July 2009

Combining an angiotensin-converting enzyme inhibitor (ACE-I) and angiotensin II receptor blocker (ARB) lowers blood pressure (BP) by 4/3 mmHg compared to either agent alone, although this additive effect may be abolished with maximal monotherapy dosing. The recent ONTARGET study showed no reduction in primary outcomes when an ACE-I-ARB combination was compared to an ACE-I alone, despite 2.4/1.4 mmHg lower BP in the former group. In proteinuric chronic kidney disease, an ACE-I-ARB combination reduces proteinuria and disease progression more than monotherapy, but the ONTARGET study showed an increase in renal endpoints in the combined group. Aliskiren offers a novel approach to renin-angiotensin system (RAS) inhibition. As monotherapy in hypertension, aliskiren is of similar efficacy to thiazides, calcium channel blockers and ARBs. In combination with other RAS inhibitors at maximal dosage aliskiren has a small synergistic effect on BP (additional 4/2 mmHg reduction). Early data suggest a role for aliskiren in preventing end-organ damage but, considering the ONTARGET results with an ACE-I-ARB combination, outcome studies are needed before the use of aliskiren can be recommended in combination with other RAS inhibitors. As monotherapy, aliskiren should probably be reserved for use as an alternative to ACE-Is or ARBs, where these are ineffective or poorly tolerated.
Targeted focal therapy for prostate cancer: a review of the literature
Authors: Sullivan Kathryn F. , Crawford E. David
Published: July 2009

Improvements in prostate cancer diagnosis and treatment have resulted in a decreasing age-adjusted death rate. But improved diagnostic tools have not delivered a proportionate decrease in mortality, primarily because physicians now are diagnosing _ and treating _ more clinically insignificant tumors. Targeted focal therapy (TFT) uses three dimensional (3D) mapping biopsies to guide cryotherapy so that it targets lesions themselves while sparing surrounding healthy tissues, thereby avoiding side effects associated with more invasive treatments. As such, TFT can provide a bridge between active surveillance and more aggressive treatments for patients with low-risk tumors. It is appropriate for men who either do not want or are not good candidates for more aggressive therapies. Identifying patients who are appropriate candidates for TFT is challenging, but the mapping biopsy technique helps identify individuals who have localized disease and could benefit from this treatment. In recent years, improvements in cryotherapy have increased its efficacy while decreasing complications. At the present time using cryotherapy to target and destroy the cancer(s) is appealing. Other approaches to less aggressive therapies are discussed including gland hemi ablation, high intensity ultrasound (HIFU) and others. Going forward, patients will benefit further from development of better imaging technologies and completion of long-term survival studies.
Allogeneic disparities in immunoglobulin-like transcript 5 induce potent antibody responses in hematopoietic stem cell transplant recipients
Authors: Pfistershammer Katharina , Lawitschka Anita , Klauser Christoph , Leitner Judith , Weigl Roman , Heemskerk Mirjam H. M. , Pickl Winfried F. , Majdic Otto , Böhmig Georg A. , Fischer Gottfried F. , Greinix Hildegard T. , Steinberger Peter
Published: July 2009

In hematopoietic stem cell transplant (HSCT) recipients, the recognition of polymorphic antigens by the donor-derived immune system is an important mechanism underlying both graft-versus-host disease and graft-versus-leukemia (GVL) effect. Here we show that a subset of HSCT recipients (13.9%, n = 108) have antibodies directed to surface molecules of dendritic cells. We have used one such serum in conjunction with retroviral expression cloning to identify the highly polymorphic surface molecule immunoglobulin-like transcript 5 (ILT5) as one of the targets of dendritic cell-reactive antibodies. ILT5 reactive antibodies were found in 5.4% of HSCT patients but not in solid organ transplantation recipients, patients with collagen diseases, multiparous women, or polytransfused or healthy persons. We show that ILT5-specific antibodies can mediate killing of ILT5-bearing cells and furthermore demonstrate ILT5 expression in some leukemic cells, indicating that it might be a target for GVL effects. Thus, our results represent the first description of potent allogeneic antibody responses to a non–major histocompatibility complex cell surface molecule in hematopoietic stem cell transplanted patients and warrant further studies to elucidate the role of antibodies to polymorphic cell surface molecules in GVL and graft-versus-host responses.
How I treat amyloidosis
Authors: Comenzo Raymond L.
Published: July 2009

Amyloidosis is an uncommon disorder in which proteins change conformation, aggregate, and form fibrils that infiltrate tissues, leading to organ failure and death. The most frequent types are light-chain (AL) derived from monoclonal B-cell disorders producing amyloidogenic immunoglobulin light chains, and the hereditary and “senile systemic” (ATTR) variants from mutant and wild-type transthyretin (TTR). Diagnosis requires tissue biopsy. AL is more frequent and causes more organ disease than ATTR. Although both can cause cardiomyopathy and heart failure, AL progresses more quickly, so survival depends on timely diagnosis. Typing is usually based on clinical and laboratory findings with monoclonal gammopathy evaluation and, if indicated, TTR gene testing. Direct tissue typing is required when one patient has 2 potential amyloid-forming proteins. In coming years, widespread use of definitive proteomics will improve typing. New therapies are in testing for ATTR, whereas those for AL have followed multiple myeloma, leading to improved survival. Challenges of diagnosing and caring for patients with amyloidosis include determination of type, counseling, and delivery of prompt therapy often while managing multisystem disease. Recent advances grew from clinical research and advocacy in many countries, and global husbandry of such efforts will reap future benefits for families and patients with amyloidosis.
Loss of Kindlin-3 in LAD-III eliminates LFA-1 but not VLA-4 adhesiveness developed under shear flow conditions
Authors: Manevich-Mendelson Eugenia , Feigelson Sara W. , Pasvolsky Ronit , Aker Memet , Grabovsky Valentin , Shulman Ziv , Kilic Sara Sebnem , Rosenthal-Allieri Maria Alessandra , Ben-Dor Shifra , Mory Adi , Bernard Alain , Moser Markus , Etzioni Amos , Alon Ronen
Published: July 2009

Leukocyte adhesion deficiency (LAD)–III is associated with homozygous stop codon mutations in Kindlin-3, the hematopoietic member of the Kindlin family of integrin coactivators. In addition, a subgroup of LAD-III patients has a homozygous splice junction mutation in and reduced expression of the Rap-1 guanine nucleotide exchange factor, CalDAG-GEFI (CDGI). In this study, we compared the adhesive properties of the leukocyte function-associated antigen-1 (LFA-1) and very late activation antigen-4 (VLA-4) integrins in both primary and activated leukocytes derived from these 2 LAD-III subgroups. Primary lymphocytes lacking both Kindlin-3 and CDGI lost all firm T-cell receptor–stimulated LFA-1 adhesiveness, in contrast to LAD-III lymphocytes deficient in Kindlin-3 alone. Effector T cells expanded from all tested LAD-III variants expressed normal CDGI, but lacked Kindlin-3. These Kindlin-3–null effector T cells exhibited total loss of inside-out LFA-1 activation by chemokine signals as well as abrogated intrinsic LFA-1 adhesiveness. Surprisingly, VLA-4 in Kindlin-3–null resting or effector lymphocytes retained intrinsic rolling adhesions to vascular cell adhesion molecule-1 and exhibited only partial defects in chemokine-stimulated adhesiveness to vascular cell adhesion molecule-1. Deletion of the putative β1 Kindlin-3 binding site also retained VLA-4 adhesiveness. Thus, our study provides the first evidence that Kindlin-3 is more critical to LFA-1 than to VLA-4–adhesive functions in human lymphocytes.
Cross-recognition of HLA DR4 alloantigen by virus-specific CD8+ T cells: a new paradigm for self-/nonself-recognition
Authors: Rist Michael , Smith Corey , Bell Melissa J. , Burrows Scott R. , Khanna Rajiv
Published: July 2009

The ability of CD8+ T cells to engage a diverse range of peptide–major histocompatibility complex (MHC) complexes can also lead to cross-recognition of self and nonself peptide-MHC complexes and thus directly contribute toward allograft rejection or autoimmunity. Here we present a novel form of cross-recognition by herpes virus–specific CD8+ cytotoxic T cells that challenges the current paradigm of self/non-self recognition. Functional characterization of a human leukocyte antigen (HLA) Cw*0602-restricted cytomegalovirus-specific CD8+ T-cell response revealed an unusual dual specificity toward a pp65 epitope and the alloantigen HLA DR4. This cross-recognition of HLA DR4 alloantigen was critically dependent on the coexpression of HLA DM and was preferentially directed toward the B-cell lineage. Furthermore, allostimulation of peripheral blood lymphocytes with HLA DRB*0401-expressing cells rapidly expanded CD8+ T cells, which recognized the pp65 epitope in the context of HLA Cw*0602. T-cell repertoire analysis revealed 2 dominant populations expressing T-cell receptor beta variable (TRBV)4-3 or TRBV13, with cross-reactivity exclusively mediated by the TRBV13+ clonotypes. More importantly, cross-reactive TRBV13+ clonotypes displayed markedly lower T-cell receptor binding affinity and a distinct pattern of peptide recognition, presumably mimicking a structure presented on the HLA DR4 allotype. These results illustrate a novel mechanism whereby virus-specific CD8+ T cells can cross-recognize HLA class II molecules and may contribute toward allograft rejection and/or autoimmunity.
Genomic island excisions in Bordetella petrii
Authors: Lechner Melanie , Schmitt Karin , Bauer Susanne , Hot David , Hubans Christine , Levillain Erwan , Locht Camille , Lemoine Yves , Gross Roy
Published: July 2009

Background

Among the members of the genus Bordetella B. petrii is unique, since it is the only species isolated from the environment, while the pathogenic Bordetellae are obligately associated with host organisms. Another feature distinguishing B. petrii from the other sequenced Bordetellae is the presence of a large number of mobile genetic elements including several large genomic regions with typical characteristics of genomic islands collectively known as integrative and conjugative elements (ICEs). These elements mainly encode accessory metabolic factors enabling this bacterium to grow on a large repertoire of aromatic compounds.

Results

During in vitro culture of Bordetella petrii colony variants appear frequently. We show that this variability can be attributed to the presence of a large number of metastable mobile genetic elements on its chromosome. In fact, the genome sequence of B. petrii revealed the presence of at least seven large genomic islands mostly encoding accessory metabolic functions involved in the degradation of aromatic compounds and detoxification of heavy metals. Four of these islands (termed GI1 to GI3 and GI6) are highly related to ICEclc of Pseudomonas knackmussii sp. strain B13. Here we present first data about the molecular characterization of these islands. We defined the exact borders of each island and we show that during standard culture of the bacteria these islands get excised from the chromosome. For all but one of these islands (GI5) we could detect circular intermediates. For the clc-like elements GI1 to GI3 of B. petrii we provide evidence that tandem insertion of these islands which all encode highly related integrases and attachment sites may also lead to incorporation of genomic DNA which originally was not part of the island and to the formation of huge composite islands. By integration of a tetracycline resistance cassette into GI3 we found this island to be rather unstable and to be lost from the bacterial population within about 100 consecutive generations. Furthermore, we show that GI3 is self transmissible and by conjugation can be transferred to B. bronchiseptica thus proving it to be an active integrative and conjugative element

Conclusion

The results show that phenotypic variation of B. petrii is correlated with the presence of genomic islands. Tandem integration of related islands may contribute to island evolution by the acquisition of genes originally belonging to the bacterial core genome. In conclusion, B. petrii appears to be the first member of the genus in which horizontal gene transfer events have massively shaped its genome structure.
Type 2 diabetes gene TCF7L2polymorphism is not associated with fetal and postnatal growth in two birth cohort studies
Authors: Mook-Kanamori Dennis O , de Kort Sandra WK , van Duijn Cornelia M , Uitterlinden Andre G , Hofman Albert , Moll Henriëtte A , Steegers Eric AP , Hokken-Koelega Anita CS , Jaddoe Vincent WV
Published: July 2009

Background

An inverse association between birth weight and the risk of developing type 2 diabetes (T2D) in adulthood has been reported. This association may be explained by common genetic variants related to insulin secretion and resistance, since insulin is the most important growth factor in fetal life. The objective of this study was to examine whether T2D gene polymorphism TCF7L2 rs7903146 is associated with growth patterns from fetal life until infancy.

Methods

This study was performed in two independent birth cohort studies, one prospective population-based (Generation R), and one of subjects born small-for-gestational-age (SGA cohort). Fetal growth was assessed by ultrasounds in second and third trimesters of pregnancy in Generation R. Growth in infancy was assessed in both cohorts at birth and at 6, 12 and 24 months postnatally. TCF7L2 genotype was determined in 3,419 subjects in Generation R and in 566 subjects in the SGA cohort.

Results

Minor allele frequency did not differ significantly (p = 0.47) between Generation R (T-allele: 28.7%) and the SGA cohort (T-allele: 29.8%). No differences at birth were found in gestational age or size (head circumference, length, weight) between the genotypes in either cohort. TCF7L2 genotype was also not associated with any pre- or postnatal growth characteristic in either Generation R or the SGA cohort.

Conclusion

We found no evidence for an association between TCF7L2 genotype and fetal and early postnatal growth. Furthermore, this TCF7L2 polymorphism was not associated with an increased risk of SGA.
No association of CDK5 genetic variants with Alzheimer's disease risk
Authors: Vázquez-Higuera José Luis , Mateo Ignacio , Sánchez-Juan Pascual , Rodríguez-Rodríguez Eloy , Infante Jon , Berciano José , Combarros Onofre
Published: July 2009

Background

As cyclin-dependent kinase 5 (CDK5) has been implicated in the abnormal hyperphosphorylation of tau in Alzheimer's disease (AD) brain, and the development of neurofibrillary tangles, we examined the contribution of this gene to the susceptibility for AD.

Methods

We examined genetic variations of CDK5 by genotyping haplotype tagging SNPs (htSNPs) (rs9278, rs2069459, rs891507, rs2069454, rs1549759 and rs2069442) in a group of 408 Spanish AD cases and 444 controls.

Results

There were no differences in the genotypic, allelic or haplotypic distributions between cases and controls in the overall analysis or after stratification by APOE ε4 allele.

Conclusion

Our negative findings in the Spanish population argue against the hypothesis that CDK5 genetic variations are causally related to AD risk. Still, additional studies using different sets of patients and control subjects deserve further attention, since supporting evidence for association between CDK5 gene and AD risk in the Dutch population exists.
Regulation of MYCNexpression in human neuroblastoma cells
Authors: Jacobs Joannes FM , van Bokhoven Hans , van Leeuwen Frank N , Hulsbergen-van de Kaa Christina A , de Vries I Jolanda M , Adema Gosse J , Hoogerbrugge Peter M , de Brouwer Arjan PM
Published: July 2009

Background

Amplification of the MYCN gene in neuroblastoma (NB) is associated with a poor prognosis. However, MYCN-amplification does not automatically result in higher expression of MYCN in children with NB. We hypothesized that the discrepancy between MYCN gene expression and prognosis in these children might be explained by the expression of either MYCN-opposite strand (MYCNOS) or the shortened MYCN-isoform (ΔMYCN) that was recently identified in fetal tissues. Both MYCNOS and ΔMYCN are potential inhibitors of MYCN either at the mRNA or at the protein level.

Methods

Expression of MYCN, MYCNOS and ΔMYCN was measured in human NB tissues of different stages. Transcript levels were quantified using a real-time reverse transcriptase polymerase chain reaction assay (QPCR). In addition, relative expression of these three transcripts was compared to the number of MYCN copies, which was determined by genomic real-time PCR (gQPCR).

Results

Both ΔMYCN and MYCNOS are expressed in all NBs examined. In NBs with MYCN-amplification, these transcripts are significantly higher expressed. The ratio of MYCN:ΔMYCN expression was identical in all tested NBs. This indicates that ΔMYCN and MYCN are co-regulated, which suggests that ΔMYCN is not a regulator of MYCN in NB. However, the ratio of MYCNOS:MYCN expression is directly correlated with NB disease stage (p = 0.007). In the more advanced NB stages and NBs with MYCN-amplification, relatively more MYCNOS is present as compared to MYCN. Expression of the antisense gene MYCNOS might be relevant to the progression of NB, potentially by directly inhibiting MYCN transcription by transcriptional interference at the DNA level.

Conclusion

The MYCNOS:MYCN-ratio in NBs is significantly correlated with both MYCN-amplification and NB-stage. Our data indicate that in NB, MYCN expression levels might be influenced by MYCNOS but not by ΔMYCN.
Concentration of the genera Aspergillus, Eurotium and Penicillium in 63-μm house dust fraction as a method to predict hidden moisture damage in homes
Authors: Baudisch Christoph , Assadian Ojan , Kramer Axel
Published: July 2009

Background

Quantitative measurements of mould enrichment of indoor air or house dust might be suitable surrogates to evaluate present but hidden moisture damage. Our intent was to develop a house-dust monitoring method to detect hidden moisture damage excluding the influence of outdoor air, accumulated old dust, and dust swirled up from room surfaces.

Methods

Based on standardized measurement of mould spores in the 63-μm fraction of house dust yielded by carpets, the background concentrations were determined and compared to simultaneously obtained colony numbers and total spore numbers of the indoor air in 80 non-mouldy living areas during summer and winter periods. Additionally, sampling with a vacuum-cleaner or manual sieve was compared to sampling with a filter holder or sieving machine, and the evaluative power of an established two-step assessment model (lower and upper limits) was compared to that of a one-step model (one limit) in order to derive concentration limits for mould load in house dust.

Results

Comparison with existing evaluation procedures proved the developed method to be the most reliable means of evaluating hidden moisture damage, yielding the lowest false-positive results (specificity 98.7%). Background measurements and measurements in 14 mouldy rooms show that even by evaluating just the indicator genera in summer and winter, a relatively certain assessment of mould infestation is possible.

Conclusion

A one-step evaluation is finally possible for house dust. The house-dust evaluation method is based on analysis of the indicator genera Aspergillus, Eurotium and Penicillium spp., which depend on the total fungal count. Inclusion of further moisture indicators currently appears questionable, because of outdoor air influence and the paucity of measurements.
Depression during pregnancy: views on antidepressant use and information sources of general practitioners and pharmacists
Authors: Ververs Tessa , van Dijk Liset , Yousofi Somaye , Schobben Fred , Visser Gerard HA
Published: July 2009

Background

The use of antidepressants during pregnancy has increased in recent years. In the Netherlands, almost 2% of all pregnant women are exposed to antidepressants. Although guidelines have been developed on considerations that should be taken into account, prescribing antidepressants during pregnancy is still a subject of debate. Physicians and pharmacists may have opposing views on using medication during pregnancy and may give contradictory advice on whether or not to take medication for depression and anxiety disorders during pregnancy. In this study, we investigated information sources used by general practitioners (GPs) and pharmacists and their common practices.

Methods

A questionnaire on the use of information sources and the general approach when managing depression during pregnancy was sent out to 1400 health care professionals to assess information sources on drug safety during pregnancy and also the factors that influence decision-making. The questionnaires consisted predominantly of closed multiple-choice questions.

Results

A total of 130 GPs (19%) and 144 pharmacists (21%) responded. The most popular source of information on the safety of drug use during pregnancy is the Dutch National Health Insurance System Formulary, while a minority of respondents contacts the Dutch national Teratology Information Service (TIS). The majority of GPs contact the pharmacy with questions concerning drug use during pregnancy. There is no clear line with regard to treatment or consensus between GPs on the best therapeutic strategy, nor do practitioners agree upon the drug of first choice. GPs have different views on stopping or continuing antidepressants during pregnancy or applying alternative treatment options. The debate appears to be ongoing as to whether or not specialised care for mother and child is indicated in cases of gestational antidepressant use.

Conclusion

Primary health care workers are not univocal concerning therapy for pregnant women with depression. Although more research is needed to account for all safety issues, local or national policies are indispensable in order to avoid undesirable practices, such as giving contradictory advice. GPs and pharmacists should address the subject during their regular pharmacotherapeutic consensus meetings, preferably in collaboration with the TIS or other professionals in the field.
An integrated approach of community health worker support for HIV/AIDS and TB care in Angónia district, Mozambique
Authors: Simon Sandrine , Chu Kathryn , Frieden Marthe , Candrinho Baltazar , Ford Nathan , Schneider Helen , Biot Marc
Published: July 2009

Background

The need to scale up treatment for HIV/AIDS has led to a revival in community health workers to help alleviate the health human resource crisis in sub-Saharan Africa. Community health workers have been employed in Mozambique since the 1970s, performing disparate and fragmented activities, with mixed results.

Methods

A participant-observer description of the evolution of community health worker support to the health services in Angónia district, Mozambique.

Results

An integrated community health team approach, established jointly by the Ministry of Health and Médecins Sans Frontières in 2007, has improved accountability, relevance, and geographical access for basic health services.

Conclusion

The community health team has several advantages over 'disease-specific' community health worker approaches in terms of accountability, acceptability, and expanded access to care.
Study of RNA interference inhibiting rat ovarian androgen biosynthesis by depressing 17alpha-hydroxylase/17, 20-lyase activity in vivo
Authors: Li Yi , Liang Xiao-yan , Wei Li-na , Xiong Yong-lao , Yang Xing , Shi Hui-gan , Yang Zi-hong
Published: July 2009

Background

17alpha-hydroxylase/17, 20-lyase encoded by CYP17 is the key enzyme in androgen biosynthesis pathway. Previous studies demonstrated the accentuation of the enzyme in patients with polycystic ovary syndrome (PCOS) was the most important mechanism of androgen excess. We chose CYP17 as the therapeutic target, trying to suppress the activity of 17alpha-hydroxylase/17, 20-lyase and inhibit androgen biosynthesis by silencing the expression of CYP17 in the rat ovary.

Methods

Three CYP17-targeting and one negative control oligonucleotides were designed and used in the present study. The silence efficiency of lentivirus shRNA was assessed by qRT-PCR, Western blotting and hormone assay. After subcapsular injection of lentivirus shRNA in rat ovary, the delivery efficiency was evaluated by GFP fluorescence and qPCR. Total RNA was extracted from rat ovary for CYP17 mRNA determination and rat serum was collected for hormone measurement.

Results

In total, three CYP17-targeting lentivirus shRNAs were synthesized. The results showed that all of them had a silencing effect on CYP17 mRNA and protein. Moreover, androstenedione secreted by rat theca interstitial cells (TIC) in the RNAi group declined significantly compared with that in the control group. Two weeks after rat ovarian subcapsular injection of chosen CYP17 shRNA, the GFP fluorescence of frozen ovarian sections could be seen clearly under fluorescence microscope. It also showed that the GFP DNA level increased significantly, and its relative expression level was 7.42 times higher than that in the control group. Simultaneously, shRNA treatment significantly decreased CYP17 mRNA and protein levels at 61% and 54%, respectively. Hormone assay showed that all the levels of androstenedione, 17-hydroxyprogesterone and testosterone declined to a certain degree, but progesterone levels declined significantly.

Conclusion

The present study proves for the first time that ovarian androgen biosynthesis can be inhibited by silencing CYP17 expression. It may provide a novel strategy for therapy of hyperandrogenism diseases, and also set an example for the use of RNAi technology in endocrine diseases.
Comparing the performance of the EQ-5D and SF-6D when measuring the benefits of alleviating knee pain
Authors: Barton Garry R , Sach Tracey H , Avery Anthony J , Doherty Michael , Jenkinson Claire , Muir Kenneth R
Published: July 2009

Objective

To assess the practicality, validity and responsiveness of using each of two utility measures (the EQ-5D and SF-6D) to measure the benefits of alleviating knee pain.

Methods

Participants in a randomised controlled trial, which was designed to compare four different interventions for people with self-reported knee pain, were asked to complete the EQ-5D, SF-6D, and Western Ontario and McMaster Universities Osteoarthritis Index (WOMAC) at both pre- and post-intervention. For both utility measures, we assessed their practicality (completion rate), construct validity (ability to discriminate between baseline WOMAC severity levels), and responsiveness (ability to discriminate between three groups: those whose total WOMAC score, i) did not improve, ii) improved by <20%, and iii) improved by ≥20%).

Results

The EQ-5D was completed by 97.7% of the 389 participants, compared to 93.3% for the SF-6D. Both the EQ-5D and SF-6D were able to discriminate between participants with different levels of WOMAC severity (p < 0.001). The mean EQ-5D change was -0.036 for group i), 0.091 for group ii), and 0.127 for group iii), compared to 0.021, 0.023 and 0.053 on the SF-6D. These change scores were significantly different according to the EQ-5D (p < 0.001), but not the SF-6D.

Conclusion

The EQ-5D and SF-6D had largely comparable practicality and construct validity. However, in contrast to the EQ-5D, the SF-6D could not discriminate between those who improved post-intervention, and those who did not. This suggests that it is more appropriate to use the EQ-5D in future cost-effectiveness analyses of interventions which are designed to alleviate knee pain.

Trial registration

Current Controlled Trials ISRCTN93206785
Design of a complex virtual reality simulation to train finger motion for persons with hemiparesis: a proof of concept study
Authors: Adamovich Sergei V , Fluet Gerard G , Mathai Abraham , Qiu Qinyin , Lewis Jeffrey , Merians Alma S
Published: July 2009

Background

Current neuroscience has identified rehabilitation approaches with the potential to stimulate adaptive changes in the brains of persons with hemiparesis. These approaches include, intensive task-oriented training, bimanual activities and balancing proximal and distal upper extremity interventions to reduce competition between these segments for neural territory.

Methods

This paper describes the design and feasibility testing of a robotic/virtual environment system designed to train the hand and arm of persons with hemiparesis. The system employs a simulated piano that presents visual, auditory and tactile feedback comparable to an actual piano. Arm tracking allows patients to train both the arm and hand as a coordinated unit, emphasizing the integration of both transport and manipulation phases. The piano trainer includes songs and scales that can be performed with one or both hands. Adaptable haptic assistance is available for more involved subjects. An algorithm adjusts task difficulty in proportion to subject performance. A proof of concept study was performed on four subjects with upper extremity hemiparesis secondary to chronic stroke to establish: a) the safety and feasibility of this system and b) the concurrent validity of robotically measured kinematic and performance measures to behavioral measures of upper extremity function.

Results

None of the subjects experienced adverse events or responses during or after training. As a group, the subjects improved in both performance time and key press accuracy. Three of the four subjects demonstrated improvements in fractionation, the ability to move each finger individually. Two subjects improved their aggregate time on the Jebsen Test of Hand Function and three of the four subjects improved in Wolf Motor Function Test aggregate time.

Conclusion

The system designed in this paper has proven to be safe and feasible for the training of hand function for persons with hemiparesis. It features a flexible design that allows for the use and further study of adjustments in point of view, bilateral and unimanual treatment modes, adaptive training algorithms and haptically rendered collisions in the context of rehabilitation of the hemiparetic hand.
BioGlue and Peri-strips in lung volume reduction surgery: pilot randomised controlled trial
Authors: Rathinam Sridhar , Naidu Babu V , Nanjaiah Prakash , Loubani Mahmoud , Kalkat Maninder S , Rajesh Pala B
Published: July 2009

Background

Both tissue sealants and buttressing have been advocated to reduce alveolar air leaks from staple lines following Lung Volume Reduction Surgery (LVRS). However, the long term detrimental effects of buttressing material are increasingly apparent. We performed a pilot prospective randomised self controlled trial in patients undergoing LVRS comparing BioGlue and Peri-strips as adjuncts in preventing alveolar air-leaks.

Methods

A pilot prospective self controlled clinical trial was conducted in patients undergoing LVRS. Each patient was treated with BioGlue on one side and pericardial buttress on the other side as an adjunct to the staple line. The sides were randomised for adjuncts with each patient acting as his own control. Duration of air leak, intercostal drainage and time to chest drain removal were the study end points.

Results

10 patients undergoing the procedure were recruited between December 2005 and October 2007. There were 6 men and the mean age was 59.8 ± 4.9 years. There was one mortality due to multi-organ failure. The BioGlue treated side had a shorter mean duration of air-leak (3.0 ± 4.6 versus 6.5 ± 6.9 days), lesser chest drainage volume (733 ± 404 ml versus 1001 ± 861) and shorter time to chest drain removal (9.7 ± 10.6 versus 11.5 ± 11.1 days) compared with Peri-strips.

Conclusion

This study demonstrates comparable efficacy of BioGlue and Peri-strips, however there is a trend favouring the BioGlue treated side in terms of reduction in air-leak, chest drainage volumes, duration of chest drainage and significant absence of complications. A larger sample size is needed to validate this result.
An integrative ChIP-chip and gene expression profiling to model SMAD regulatory modules
Authors: Qin Huaxia , Chan Michael WY , Liyanarachchi Sandya , Balch Curtis , Potter Dustin , Souriraj Irene J , Cheng Alfred SL , Agosto-Perez Francisco J , Nikonova Elena V , Yan Pearlly S , Lin Huey-Jen , Nephew Kenneth P , Saltz Joel H , Showe Louise C , Huang Tim HM , Davuluri Ramana V
Published: July 2009

Background

The TGF-β/SMAD pathway is part of a broader signaling network in which crosstalk between pathways occurs. While the molecular mechanisms of TGF-β/SMAD signaling pathway have been studied in detail, the global networks downstream of SMAD remain largely unknown. The regulatory effect of SMAD complex likely depends on transcriptional modules, in which the SMAD binding elements and partner transcription factor binding sites (SMAD modules) are present in specific context.

Results

To address this question and develop a computational model for SMAD modules, we simultaneously performed chromatin immunoprecipitation followed by microarray analysis (ChIP-chip) and mRNA expression profiling to identify TGF-β/SMAD regulated and synchronously coexpressed gene sets in ovarian surface epithelium. Intersecting the ChIP-chip and gene expression data yielded 150 direct targets, of which 141 were grouped into 3 co-expressed gene sets (sustained up-regulated, transient up-regulated and down-regulated), based on their temporal changes in expression after TGF-β activation. We developed a data-mining method driven by the Random Forest algorithm to model SMAD transcriptional modules in the target sequences. The predicted SMAD modules contain SMAD binding element and up to 2 of 7 other transcription factor binding sites (E2F, P53, LEF1, ELK1, COUPTF, PAX4 and DR1).

Conclusion

Together, the computational results further the understanding of the interactions between SMAD and other transcription factors at specific target promoters, and provide the basis for more targeted experimental verification of the co-regulatory modules.
Exploiting gene deletion fitness effects in yeast to understand the modular architecture of protein complexes under different growth conditions
Authors: Pache Roland A , Babu M Madan , Aloy Patrick
Published: July 2009

Background

Understanding how individual genes contribute towards the fitness of an organism is a fundamental problem in biology. Although recent genome-wide screens have generated abundant data on quantitative fitness for single gene knockouts, very few studies have systematically integrated other types of biological information to understand how and why deletion of specific genes give rise to a particular fitness effect. In this study, we combine quantitative fitness data for single gene knock-outs in yeast with large-scale interaction discovery experiments to understand the effect of gene deletion on the modular architecture of protein complexes, under different growth conditions.

Results

Our analysis reveals that genes in complexes show more severe fitness effects upon deletion than other genes but, in contrast to what has been observed in binary protein-protein interaction networks, we find that this is not related to the number of complexes in which they are present. We also find that, in general, the core and attachment components of protein complexes are equally important for the complex machinery to function. However, when quantifying the importance of core and attachments in single complex variations, or isoforms, we observe that this global trend originates from either the core or the attachment components being more important for strain fitness, both being equally important or both being dispensable. Finally, our study reveals that different isoforms of a complex can exhibit distinct fitness patterns across growth conditions.

Conclusion

This study presents a powerful approach to unveil the molecular basis for various complex phenotypic profiles observed in gene deletion experiments. It also highlights some interesting cases of potential functional compensation between protein paralogues and suggests a new piece to fit into the histone-code puzzle.
Identification and characterization of novel amphioxus microRNAs by Solexa sequencing
Authors: Chen Xi , Li Qibin , Wang Jin , Guo Xing , Jiang Xiangrui , Ren Zhiji , Weng Chunyue , Sun Guoxun , Wang Xiuqiang , Liu Yaping , Ma Lijia , Chen Jun-Yuan , Wang Jun , Zen Ke , Zhang Junfeng , Zhang Chen-Yu
Published: July 2009

Background

microRNAs (miRNAs) are endogenous small non-coding RNAs that regulate gene expression at the post-transcriptional level. While the number of known human and murine miRNAs is continuously increasing, information regarding miRNAs from other species such as amphioxus remains limited.

Results

We combined Solexa sequencing with computational techniques to identify novel miRNAs in the amphioxus species B. belcheri (Gray). This approach allowed us to identify 113 amphioxus miRNA genes. Among them, 55 were conserved across species and encoded 45 non-redundant mature miRNAs, whereas 58 were amphioxus-specific and encoded 53 mature miRNAs. Validation of our results with microarray and stem-loop quantitative RT-PCR revealed that Solexa sequencing is a powerful tool for miRNA discovery. Analyzing the evolutionary history of amphioxus miRNAs, we found that amphioxus possesses many miRNAs unique to chordates and vertebrates, and these may thus represent key steps in the evolutionary progression from cephalochordates to vertebrates. We also found that amphioxus is more similar to vertebrates than are tunicates with respect to their miRNA phylogenetic histories.

Conclusions

Taken together, our results indicate that Solexa sequencing allows the successful discovery of novel miRNAs from amphioxus with high accuracy and efficiency. More importantly, our study provides an opportunity to decipher how the elaboration of the miRNA repertoire that occurred during chordate evolution contributed to the evolution of the vertebrate body plan.
Testing the use/disuse hypothesis: pectoral and leg muscle changes in captive barnacle geese Branta leucopsis during wing moult
Authors: Portugal Steven J. , Thorpe Susannah K. S. , Green Jonathan A. , Myatt Julia P. , Butler Patrick J.
Published: July 2009

Previous studies on wild moulting waterfowl have demonstrated that flight and leg muscles experience periods of hypertrophy and atrophy. This is thought to be in response to the change in use of the locomotor muscles as described in the use/disuse hypothesis. We tested this hypothesis using captive barnacle geese. Forty geese were dissected before, during and after wing moult, to determine the changes in mass and functional capacity of the flight and leg muscles. Physiological cross sectional areas (PCSA) and mean fascicle lengths of functional muscle groups were calculated to ascertain the force-producing capabilities of the flight and leg muscles. At the onset of moult, flight muscle mass was at a minimum, having atrophied by 35% compared with pre-moult levels, but it returned to pre-moult levels by the end of wing moult. By contrast, the leg muscles hypertrophied during wing moult by 29%,and the PCSA of individual muscle groups increased substantially. Increases in mass, PCSA and fascicle length of individual leg muscle groups during moult suggest that, when flightless, the leg muscles are functionally adapted to provide greater force and/or manoeuvrability to the birds, to aid ground-based escape from predators. Through studying captive animals that are unable to fly, it has been possible to conclude that the major changes in leg and flight muscle in moulting captive geese cannot be explained through use or disuse. Instead, changes seem to be compensatory or to occur in anticipation of changes in locomotor patterns.
A body composition model to estimate mammalian energy stores and metabolic rates from body mass and body length, with application to polar bears
Authors: Molnár Péter K. , Klanjscek Tin , Derocher Andrew E. , Obbard Martyn E. , Lewis Mark A.
Published: July 2009

Many species experience large fluctuations in food availability and depend on energy from fat and protein stores for survival, reproduction and growth. Body condition and, more specifically, energy stores thus constitute key variables in the life history of many species. Several indices exist to quantify body condition but none can provide the amount of stored energy. To estimate energy stores in mammals, we propose a body composition model that differentiates between structure and storage of an animal. We develop and parameterize the model specifically for polar bears (Ursus maritimus Phipps)but all concepts are general and the model could be easily adapted to other mammals. The model provides predictive equations to estimate structural mass,storage mass and storage energy from an appropriately chosen measure of body length and total body mass. The model also provides a means to estimate basal metabolic rates from body length and consecutive measurements of total body mass. Model estimates of body composition, structural mass, storage mass and energy density of 970 polar bears from Hudson Bay were consistent with the life history and physiology of polar bears. Metabolic rate estimates of fasting adult males derived from the body composition model corresponded closely to theoretically expected and experimentally measured metabolic rates. Our method is simple, non-invasive and provides considerably more information on the energetic status of individuals than currently available methods.
Carbon and nitrogen stable isotope turnover rates and diet–tissue discrimination in Florida manatees (Trichechus manatus latirostris)
Authors: Alves-Stanley Christy D. , Worthy Graham A. J.
Published: July 2009

The Florida manatee (Trichechus manatus latirostris) is a herbivorous marine mammal that occupies freshwater, estuarine and marine habitats. Despite being considered endangered, relatively little is known about its feeding ecology. The present study expands on previous work on manatee feeding ecology by providing critical baseline parameters for accurate isotopic data interpretation. Stable carbon and nitrogen isotope ratios were examined over a period of more than 1 year in the epidermis of rescued Florida manatees that were transitioning from a diet of aquatic forage to terrestrial forage (lettuce). The mean half-life for 13C turnover was 53 and 59 days for skin from manatees rescued from coastal and riverine regions,respectively. The mean half-life for 15N turnover was 27 and 58 days, respectively. Because of these slow turnover rates, carbon and nitrogen stable isotope analysis in manatee epidermis is useful in summarizing average dietary intake over a long period of time rather than assessing recent diet. In addition to turnover rate, a diet–tissue discrimination value of 2.8‰ for 13C was calculated for long-term captive manatees on a lettuce diet. Determining both turnover rate and diet–tissue discrimination is essential in order to accurately interpret stable isotope data.
Intensity of activation and timing of deactivation modulate elastic energy storage and release in a pennate muscle and account for gait-specific initiation of limb protraction in the horse
Authors: Lichtwark Glen A. , Watson Johanna C. , Mavrommatis Sophia , Wilson Alan M.
Published: July 2009

The equine biceps brachii (biceps) initiates rapid limb protraction through a catapult mechanism. Elastic strain energy is slowly stored in an internal tendon and is then rapidly released to protract the forelimb. The muscle fibres are short, have little scope for length change and can therefore only shorten slowly compared with the speed at which the whole muscle must shorten,which makes them poor candidates for driving rapid limb protraction. We suggest that the muscle fibres in the biceps act to modulate the elastic energy output of the muscle–tendon unit (MTU) to meet the demands of locomotion under different conditions. We hypothesise that more elastic strain energy is stored and released from the biceps MTU during higher speed locomotion to accommodate the increase in energy required to protract the limb and that this can be achieved by varying the length change and activation conditions of the muscle. We examined the work performed by the biceps during trot and canter using an inverse dynamics analysis (IDA). We then used excised biceps muscles to determine how much work could be performed by the muscle in active and passive stretch–shorten cycles. A muscle model was developed to investigate the influence of changes in activation parameters on energy storage and energy return from the biceps MTU. Increased biceps MTU length change and increased work performed by the biceps MTU were found at canter compared with at trot. More work was performed by the ex vivo biceps MTU following activation of the muscle and by increasing muscle length change. However, the ratio of active to passive work diminished with increasing length change. The muscle model demonstrated that duration and timing of activation during stretch–shorten cycles could modulate the elastic energy storage and return from the biceps. We conclude that the equine biceps MTU acts as a tuneable spring and the contractile component functions to modulate the energy required for rapid forelimb protraction at different speeds.