bluuebunny/crossref_metadata_2025 huggingface dataset:
Evidence for Pyronaridine as a Highly Effective Partner Drug for Treatment of Artemisinin-Resistant Malaria in a Rodent Model
Authors: Henrich Philipp P. , O'Brien Connor , Sáenz Fabián E. , Cremers Serge , Kyle Dennis E. , Fidock David A.
Published: October 2013

The increasing prevalence in Southeast Asia of
Plasmodium falciparum
infections with delayed parasite clearance rates, following treatment of malaria patients with the artemisinin derivative artesunate, highlights an urgent need to identify which of the currently available artemisinin-based combination therapies (ACTs) are most suitable to treat populations with emerging artemisinin resistance. Here, we demonstrate that the rodent
Plasmodium berghei
SANA strain has acquired artemisinin resistance following drug pressure, as defined by reduced parasite clearance and early recrudescence following daily exposure to high doses of artesunate or the active metabolite dihydroartemisinin. Using the SANA strain and the parental drug-sensitive N strain, we have interrogated the antimalarial activity of five ACTs, namely, artemether-lumefantrine, artesunate-amodiaquine, artesunate-mefloquine, dihydroartemisinin-piperaquine, and the newest combination artesunate-pyronaridine. By monitoring parasitemia and outcome for 30 days following initiation of treatment, we found that infections with artemisinin-resistant
P. berghei
SANA parasites can be successfully treated with artesunate-pyronaridine used at doses that are curative for the parental drug-sensitive N strain. No other partner drug combination was as effective in resolving SANA infections. Of the five partner drugs tested, pyronaridine was also the most effective at suppressing the recrudescence of SANA parasites. These data support the potential benefit of implementing ACTs with pyronaridine in regions affected by artemisinin-resistant malaria.
Occurrence of
rpoB
Mutations in Isoniazid-Resistant but Rifampin-Susceptible Mycobacterium tuberculosis Isolates from Germany
Authors: Andres Sönke , Hillemann Doris , Rüsch-Gerdes Sabine , Richter Elvira
Published: October 2013

Four out of 143 phenotypically isoniazid-resistant but rifampin-susceptible
Mycobacterium tuberculosis
strains that were isolated from patients in Germany in 2011 had mutations in the rifampin resistance-determining region of
rpoB
. After performing drug susceptibility testing (DST) with two methods, the proportion method on Löwenstein-Jensen medium and using the Bactec 960 Mycobacteria Growth Indicator Tube system, we conclude that the two methods are equally reliable for phenotypic DST and MIC determination.
Streptococcus pyogenes Arginine and Citrulline Catabolism Promotes Infection and Modulates Innate Immunity
Authors: Cusumano Zachary T. , Watson Michael E. , Caparon Michael G.
Published: October 2013

A bacterium's ability to acquire nutrients from its host during infection is an essential component of pathogenesis. For the Gram-positive pathogen
Streptococcus pyogenes
, catabolism of the amino acid arginine via the arginine deiminase (ADI) pathway supplements energy production and provides protection against acid stress
in vitro
. Its expression is enhanced in murine models of infection, suggesting an important role
in vivo
. To gain insight into the function of the ADI pathway in pathogenesis, the virulence of mutants defective in each of its enzymes was examined. Mutants unable to use arginine (ΔArcA) or citrulline (ΔArcB) were attenuated for carriage in a murine model of asymptomatic mucosal colonization. However, in a murine model of inflammatory infection of cutaneous tissue, the ΔArcA mutant was attenuated but the ΔArcB mutant was hyperattenuated, revealing an unexpected tissue-specific role for citrulline metabolism in pathogenesis. When mice defective for the arginine-dependent production of nitric oxide (iNOS
−/−
) were infected with the ΔArcA mutant, cutaneous virulence was rescued, demonstrating that the ability of
S. pyogenes
to utilize arginine was dispensable in the absence of nitric oxide-mediated innate immunity. This work demonstrates the importance of arginine and citrulline catabolism and suggests a novel mechanism of virulence by which
S. pyogenes
uses its metabolism to modulate innate immunity through depletion of an essential host nutrient.
Comparative clinical and radiographic study of the lumbar spine between parachute infantry soldiers and non-parachute infantry soldiers in Japanese Ground Self-Defense forces
Authors: Nemoto Osamu , Kitada A , Naitou S , Tsuchihara T , Ito Y , Tachibana A
Published: October 2013

Background

The long-term effect of repetitive trauma by military parachuting on the lumbar spine is not well investigated. Therefore, the purpose of this study was to examine the development of lumbar degenerative changes during a 30-year follow-up in Japanese Ground Self Defense Forces (JGSDF) parachute infantry soldiers with normal lumbar radiographs at entry by comparison with those with non-parachute infantry soldiers.

Methods

79 non-parachutists and 65 parachutists were included for radiological examination and questionnaires for low back pain (LBP). All subjects were non-commissioned officers with similar socioeconomic status and life styles. The number of parachuting descent during the 30-year in the parachute group ranged from 208 to 630, with an average of 322.

Results

The mean age of the subjects was 18.3 ± 0.5 years at entry and 48.5 ± 0.3 years at follow-up. LBP had been experienced by 37% in the non-parachute group and 25% in the parachute group with no significant difference. The nature of their LBP was judged as mild. The prevalence rate of degenerative changes was similar in both groups. Disc space narrowing was detected 37 subjects (47%) in non-parachute group an 23 subjects (35%) in parachute group without significant difference. Vertebral osteophytes were detected in 52 subjects (67%) in non-parachute group and 47 subjects (72%) in parachute group without significant difference.

Conclusions

This study did not identify any significant differences in the development of lumbar degenerative changes between the parachutists and non-parachutists over a 30-year follow-up, suggesting that military parachuting itself does not accelerate the development of intervertebral disc degeneration. Further studies are needed using large cohorts assessed by MRI as well as plain X-ray.
EMISSION SPECTRUM OF A TWO-LEVEL ATOM IN AN OPTOMECHANICAL CAVITY
Authors: TENG JI HUI , WANG HONG FU , YI XUE XI
Published: October 2013

The emission spectrum of a single atom inside an optomechanical cavity is studied in this paper. Our model consists of a single two-level atom coupled to a cavity with a moving end mirror. We numerically calculate the emission spectrum of the atom, taking the effect of the moving mirror into account. The dependence of the spectrum peak on the coupling between the moving mirror and the cavity field is analyzed. For weak cavity-mirror couplings, we expand the spectrum up to the first order of the coupling constant.
Stability of a Functional Equation Deriving from Quadratic and Additive Functions in Non-Archimedean Normed Spaces
Authors: Bodaghi Abasalt , Kim Sang Og
Published: October 2013

We obtain the general solution of the generalized mixed additive and quadratic functional equationfx+my+fx−my=2fx−2m2fy+m2f2y,mis even;fx+y+fx−y−2m2−1fy+m2−1f2y,mis odd, for a positive integerm. We establish the Hyers-Ulam stability for these functional equations in non-Archimedean normed spaces whenmis an even positive integer orm=3.
Mean Platelet Volume in Ocular Behçet’s Disease
Authors: Türkcü Fatih Mehmet , Cingü Abdullah Kürşat , Yüksel Harun , Çınar Yasin , Akkurt Meltem , Şahin Muhammed , Özkurt Zeynep , Şahin Alparslan , Çaça İhsan
Published: October 2013

Objective. To determine whether mean platelet volume (MPV) is an indicator of disease severity in ocular Behçet’s Disease (BD). Materials and Methods. The study population was 30 newly diagnosed ocular BD patients who presented with active uveitis. These patients had no past history of smoking, drug use, or systemic diseases including diabetes mellitus, hypertension, cardiovascular disease, and renal disease. A control group consisting of 34 healthy individuals was included for comparison. MPV measurements were performed serially upon presentation with active uveitis and at one and three month thereafter in BD group whereas only at presentation in the controls. Results. Upon presentation with active uveitis, the mean MPV levels were 7.88 ± 1.14 femtoliters (fL) for BD group. During the posttreatment follow‐up period at first and third months, BD patients demonstrated a mean MPV level of 7.71 ± 1.12 fL and 7.65 ± 1.04 fL, respectively. The mean MPV value of control group, was 8.39 ± 0.66 fL at presentation. Fluctuations in MPV values were not significant in the BD group, while there was a significant difference between the initial measurements of the BD and control groups. Conclusion. MPV measurement in ocular BD is not a predictive laboratory test to determine the clinical improvement in early stages following classical immunosuppressive treatment.
Methanol Extract ofArtemisia apiaceaHance Attenuates the Expression of Inflammatory Mediators via NF-κB Inactivation
Authors: Ryu Ji Choul , Park Sang Mi , Hwangbo Min , Byun Sung Hui , Ku Sae Kwang , Kim Young Woo , Kim Sang Chan , Jee Seon Young , Cho Il Je
Published: October 2013

Artemisia apiaceaHance is one of the most widely used herbs for the treatment of malaria, jaundice, and dyspeptic complaint in oriental medicine. This study investigated the effects of methanol extracts ofA. apiaceaHance (MEAH) on the induction of inducible nitric oxide synthase (iNOS) and proinflammatory mediators by lipopolysaccharide (LPS) in Raw264.7 macrophage cells and also evaluated thein vivoeffect of MEAH on carrageenan-induced paw edema in rats. MEAH treatment in Raw264.7 cells significantly decreased LPS-inducible nitric oxide production and the expression of iNOS in a concentration-dependent manner, while MEAH (up to 100 μg/mL) had no cytotoxic activity. Results from immunoblot analyses and ELISA revealed that MEAH significantly inhibited the expression of cyclooxygenase-2, tumor necrosis factor-α, interleukin-1β, and interleukin-6 in LPS-activated cells. As a plausible molecular mechanism, increased degradation and phosphorylation of inhibitory-κBαand nuclear factor-κB accumulation in the nucleus by LPS were partly blocked by MEAH treatment. Finally, MEAH treatment decreased the carrageenan-induced formation of paw edema and infiltration of inflammatory cells in rats. These results demonstrate that MEAH has an anti-inflammatory therapeutic potential that may result from the inhibition of nuclear factor-κB activation, subsequently decreasing the expression of proinflammatory mediators.
Immunomodulation in Sepsis: The Role of Endotoxin Removal by Polymyxin B-Immobilized Cartridge
Authors: Esteban Elisabeth , Ferrer Ricard , Alsina Laia , Artigas Antonio
Published: October 2013

Severe sepsis results in high morbidity and mortality. Immunomodulation strategies could be an adjunctive therapy to treat sepsis. Endotoxin is a component of gram-negative bacteria and plays an important role in the pathogenesis of septic shock when it is recognized by immune cells. Removal of endotoxin could be an effective adjunctive approach to the management of sepsis. Devices to adsorb endotoxin or inflammatory cytokines have been designed as a strategy to treat severe sepsis, especially sepsis caused by gram-negative bacteria. Polymyxin B-immobilized cartridge has been successfully used to treat patients with sepsis of abdominal origin. Although this cartridge was conceived to adsorb endotoxin, several other immunological mechanisms have been elucidated, and this device has also yielded promising results in patients with nonseptic respiratory failure. In this paper, we summarize the immune modulation actions of Polymyxin B-immobilized cartridge to explore its potential usefulness beyond endotoxin elimination.
Design of Stiffness for Air Spring Based on ABAQUS
Authors: Li Hongguang , Guo Konghui , Chen Shuqi , Wang Wei , Cong Fuzhong
Published: October 2013

In this paper, an axisymmetric finite element (FE) model of an air spring was carried out with the software ABAQUS to design its target vertical stiffness. The bellows was simulated by the reinforced surface element. The compressed gas in the cavity of the air spring was represented by the hydrostatic fluid element. The target stiffness is obtained by modifying the valid area of the cross section. At last, the results of experiment coincided well with the simulation data. The study shows that the static stiffness of air spring is sensitive to the effective area of the cross section. The conclusion has certain practical significance for the design and the optimization of the same kind of air spring.
Evaluation and Optimization of Single Stage Absorption Chiller Using (LiCl + H2O) as the Working Pair
Authors: Parham Kiyan , Atikol Ugur , Yari Mortaza , Agboola O. Phillips
Published: October 2013

The thermodynamic performance of the absorption chiller using (H2O + LiCl) as the working pair was simulated and compared with the absorption chiller using (H2O + LiBr). The effects of evaporation temperature on the performance coefficient, COP, generation temperature, concentration of strong solution, and flow rate ratio were also analyzed. At the same condensing and absorbing temperature, the simulating results indicated that the performance coefficient for (H2O + LiCl) is approximately equal to (H2O + LiBr) and the generation temperature was lower than that for (H2O + LiBr). On the other hand, the exergetic efficiency, ECOP, which is based on the second law of thermodynamics, for the absorption chiller using (H2O + LiCl), was more than the system using (H2O + LiBr) under the same operating conditions. The absorption chiller cycle was then optimized based on the coefficient of performance. The results show that the coefficient of performance of the absorption chiller, using (H2O + LiBr) at the optimum conditions, was around 1.5–2% higher than that of (H2O + LiCl).
Salusins: Potential Use as a Biomarker for Atherosclerotic Cardiovascular Diseases
Authors: Sato Kengo , Watanabe Rena , Itoh Fumiko , Shichiri Masayoshi , Watanabe Takuya
Published: October 2013

Human salusin-αand salusin-βare related peptides produced from prosalusin. Bolus injection of salusin-βinto rats induces more profound hypotension and bradycardia than salusin-α. Central administration of salusin-βincreases blood pressure via release of norepinephrine and arginine-vasopressin. Circulating levels of salusin-αand salusin-βare lower in patients with essential hypertension. Salusin-βexerts more potent mitogenic effects on human vascular smooth muscle cells (VSMCs) and fibroblasts than salusin-α. Salusin-βaccelerates inflammatory responses in human endothelial cells and monocyte-endothelial adhesion. Human macrophage foam cell formation is stimulated by salusin-βbut suppressed by salusin-α. Chronic salusin-βinfusion into apolipoprotein E-deficient mice enhances atherosclerotic lesions; salusin-αinfusion reduces lesions. Salusin-βis expressed in proliferative neointimal lesions of porcine coronary arteries after stenting. Salusin-αand salusin-βimmunoreactivity have been detected in human coronary atherosclerotic plaques, with dominance of salusin-βin macrophage foam cells, VSMCs, and fibroblasts. Circulating salusin-βlevels increase and salusin-αlevels decrease in patients with coronary artery disease. These findings suggest that salusin-βand salusin-αmay contribute to proatherogenesis and antiatherogenesis, respectively. Increased salusin-βand/or decreased salusin-αlevels in circulating blood and vascular tissue are closely linked with atherosclerosis. Salusin-αand salusin-βcould be candidate biomarkers and therapeutic targets for atherosclerotic cardiovascular diseases.
Dysplasia Features of Myelodysplastic Syndrome in Ethnically Chinese People
Authors: Xiong Bei , Tang Ze H. , Zou Ping , Yue Qing F. , Chen Wan X. , Liu Xin Y.
Published: October 2013

Objective: It was our aim to study the diagnostic significances of various dysplasia characteristics in myelodysplastic syndrome (MDS). Methods: We analyzed 160 cases of primary MDS and a control group including 28 cases of paroxysmal nocturnal hemoglobinuria (PNH), 104 cases of idiopathic thrombocytopenic purpura (ITP), 53 cases of non-severe aplastic anemia (NSAA), 40 cases of megaloblastic anemia and 50 cases of infectious and autoimmune diseases. Peripheral blood smears and bone marrow morphology were reviewed. Results: There was no significant difference in the occurrence rates of a variety of dysplasias in three lineages among MDS, megaloblastic anemia and PNH; however, changes in qualities and quantities in three lineages between NSAA and MDS were significantly different. ITP and MDS showed statistical differences in multiple changes in myeloid and erythroid cells. Significant differences also existed in multiple changes in erythroid series and megakaryocytes between infectious and autoimmune diseases and MDS. Morphological abnormalities highly related with MDS included multinucleated erythroblasts, ringed sideroblasts, poikilocytosis and gigantocytes, pseudo-Pelger neutrophils, ring-shaped nucleus, and micromegakaryocytes. Conclusions: It is difficult to discriminate megaloblastic anemia and PNH from MDS by means of cell morphology. Different dysplasias of MDS have specific diagnostic values.
The sexual signals of speciation? A new sexually dimorphic Phymaturus species of the patagonicus clade from Patagonia Argentina
Authors: SCOLARO J. ALEJANDRO , JARA MANUEL , PINCHEIRA-DONOSO DANIEL
Published: October 2013

Evolution is a multivariate process which, therefore, is expected to leave multiple recognizable signals after episodes of speciation. These signals express in the genome regardless of the mechanism driving speciation, and in a few or in multiple phenotypic traits when divergent selection has been implicated. In lineages that have undergone adaptive radiations (i.e. speciation accompanied by ecological diversification), the phenotypic signals of speciation can be substantially pronounced. In contrast, within non-adaptive radiations (i.e. lineage diversification with minimal ecological diversification linked to allopatric or parapatric species distributions), phenotypic signals of speciation can be minimal. The South American lizard genus Phymaturus is regarded as a candidate non-adaptive radiation given the tendency for non-overlapping distributions among its phenotypically and ecologically similar (i.e. niche conservatism) species. Thus, limited phenotypic divergence has evolved among closely related species. Within the patagonicus clade of the genus, sexual monochromatism is highly conserved, while sexual dichromatism is rare, and mostly negligible when observed. In this paper, we provide the description of a new sexually dimorphic and dichromatic species of this clade (Phymaturus camilae sp. nov.). This species is substantially isolated spatially and phylogenetically separated from P. ceii, P. delheyi and P. zapalensis, the most sexually dichromatic members of the clade. In addition, the new taxon was recently identified as a ‘candidate new species’ based on molecular (nuclear) phylogenetic evidence.
Comparison of Dental Health of Patients with Head and Neck Cancer Receiving IMRT vs Conventional Radiation
Authors: Duarte Victor M. , Liu Yuan F. , Rafizadeh Sassan , Tajima Tracey , Nabili Vishad , Wang Marilene B.
Published: October 2013

Objective

To analyze the dental health of patients with head and neck cancer who received comprehensive dental care after intensity‐modulated radiation therapy (IMRT) compared with radiation therapy (RT).

Study Design

Historical cohort study.

Setting

Veteran Affairs (VA) hospital.

Subjects and Methods

In total, 158 patients at a single VA hospital who were treated with RT or IMRT between 2003 and 2011 were identified. A complete dental evaluation was performed prior to radiation treatment, including periodontal probing, tooth profile, cavity check, and mobility. The dental treatment plan was formulated to eliminate current and potential dental disease. The rates of dental extractions, infections, caries, mucositis, xerostomia, and osteoradionecrosis (ORN) were analyzed, and a comparison was made between patients treated with IMRT and those treated with RT.

Results

Of the 158 patients, 99 were treated with RT and 59 were treated with IMRT. Compared with those treated with IMRT, significantly more patients treated with RT exhibited xerostomia (46.5% vs 16.9%; P <. 001; odds ratio [OR], 0.24; 95% confidence interval [CI], 0.11‐0.52), mucositis (46.5% vs 16.9%; P <. 001; OR, 0.24; 95% CI, 0.11‐0.52), and ORN (10.1% vs 0%; P =. 014; OR, 0.07; 95% CI, 0.00‐1.21). However, significantly more patients treated with IMRT were edentulous by the conclusion of radiation treatment (32.2% vs 11.1%; P =. 002; OR, 3.8; 95% CI, 1.65‐8.73).

Conclusion

Patients who were treated with IMRT had fewer instances of dental disease, more salivary flow, and fewer requisite posttreatment extractions compared with those treated with RT. The number of posttreatment extractions has been reduced with the advent of IMRT and more so with a complete dental evaluation prior to treatment.
Parametric sensitivity analysis for biochemical reaction networks based on pathwise information theory
Authors: Pantazis Yannis , Katsoulakis Markos A , Vlachos Dionisios G
Published: October 2013

Background

Stochastic modeling and simulation provide powerful predictive methods for the intrinsic understanding of fundamental mechanisms in complex biochemical networks. Typically, such mathematical models involve networks of coupled jump stochastic processes with a large number of parameters that need to be suitably calibrated against experimental data. In this direction, the parameter sensitivity analysis of reaction networks is an essential mathematical and computational tool, yielding information regarding the robustness and the identifiability of model parameters. However, existing sensitivity analysis approaches such as variants of the finite difference method can have an overwhelming computational cost in models with a high-dimensional parameter space.

Results

We develop a sensitivity analysis methodology suitable for complex stochastic reaction networks with a large number of parameters. The proposed approach is based on Information Theory methods and relies on the quantification of information loss due to parameter perturbations between time-series distributions. For this reason, we need to work on path-space, i.e., the set consisting of all stochastic trajectories, hence the proposed approach is referred to as “pathwise”. The pathwise sensitivity analysis method is realized by employing the rigorously-derived Relative Entropy Rate, which is directly computable from the propensity functions. A key aspect of the method is that an associated pathwise Fisher Information Matrix (FIM) is defined, which in turn constitutes a gradient-free approach to quantifying parameter sensitivities. The structure of the FIM turns out to be block-diagonal, revealing hidden parameter dependencies and sensitivities in reaction networks.

Conclusions

As a gradient-free method, the proposed sensitivity analysis provides a significant advantage when dealing with complex stochastic systems with a large number of parameters. In addition, the knowledge of the structure of the FIM can allow to efficiently address questions on parameter identifiability, estimation and robustness. The proposed method is tested and validated on three biochemical systems, namely: (a) a protein production/degradation model where explicit solutions are available, permitting a careful assessment of the method, (b) the p53 reaction network where quasi-steady stochastic oscillations of the concentrations are observed, and for which continuum approximations (e.g. mean field, stochastic Langevin, etc.) break down due to persistent oscillations between high and low populations, and (c) an Epidermal Growth Factor Receptor model which is an example of a high-dimensional stochastic reaction network with more than 200 reactions and a corresponding number of parameters.
Patterns of genetic differentiation at MHC class I genes and microsatellites identify conservation units in the giant panda
Authors: Zhu Ying , Wan Qiu-Hong , Yu Bin , Ge Yun-Fa , Fang Sheng-Guo
Published: October 2013

Background

Evaluating patterns of genetic variation is important to identify conservation units (i.e., evolutionarily significant units [ESUs], management units [MUs], and adaptive units [AUs]) in endangered species. While neutral markers could be used to infer population history, their application in the estimation of adaptive variation is limited. The capacity to adapt to various environments is vital for the long-term survival of endangered species. Hence, analysis of adaptive loci, such as the major histocompatibility complex (MHC) genes, is critical for conservation genetics studies. Here, we investigated 4 classical MHC class I genes (Aime-C,Aime-F,Aime-I, andAime-L) and 8 microsatellites to infer patterns of genetic variation in the giant panda (Ailuropoda melanoleuca) and to further define conservation units.

Results

Overall, we identified 24 haplotypes (9 forAime-C, 1 forAime-F, 7 forAime-I, and 7 forAime-L) from 218 individuals obtained from 6 populations of giant panda. We found that the Xiaoxiangling population had the highest genetic variation at microsatellites among the 6 giant panda populations and higher genetic variation atAime-MHC class I genes than other larger populations (Qinling, Qionglai, and Minshan populations). Differentiation index (FST)-based phylogenetic and Bayesian clustering analyses forAime-MHC-I and microsatellite loci both supported that most populations were highly differentiated. The Qinling population was the most genetically differentiated.

Conclusions

The giant panda showed a relatively higher level of genetic diversity at MHC class I genes compared with endangered felids. Using all of the loci, we found that the 6 giant panda populations fell into 2 ESUs: Qinling and non-Qinling populations. We defined 3 MUs based on microsatellites: Qinling, Minshan-Qionglai, and Daxiangling-Xiaoxiangling-Liangshan. We also recommended 3 possible AUs based on MHC loci: Qinling, Minshan-Qionglai, and Daxiangling-Xiaoxiangling-Liangshan. Furthermore, we recommend that a captive breeding program be considered for the Qinling panda population.
Genetic control of renal tumorigenesis by the mouse Rtm1 locus
Authors: Jensen José Ricardo , Galvan Antonella , Borrego Andrea , Hanna Koury Cabrera Wafa , Ribeiro Orlando Garcia , Starobinas Nancy , De Franco Marcelo , Colecchia Maurizio , Bertolotti Alessia , Dragani Tommaso Antonio , Martinez Ibañez Olga Célia
Published: October 2013

Background

The genetic basis of susceptibility to renal tumorigenesis has not yet been established in mouse strains. Mouse lines derived by bidirectional phenotypic selection on the basis of their maximal (AIRmax) or minimal (AIRmin) acute inflammatory responsiveness differ widely in susceptibility to spontaneous and urethane-induced renal tumorigenesis. To map the functional loci modulating renal tumor susceptibility in these mice, we carried out a genome-wide genetic linkage study, using SNP arrays, in an (AIRmax x AIRmin)F2 intercross population treated with a single urethane dose at 1 week of age and phenotyped for renal tumors at 35 weeks of age.

Results

AIRmax mice did not develop renal tumors spontaneously nor in response to urethane, whereas in AIRmin mice renal tumors formed spontaneously (in 52% of animals) and after urethane induction (89%). The tumors had a papillary morphology and were positive for alpha-methylacyl-CoA racemase and negative for CD10. By analysis of 879 informative SNPs in 662 mice, we mapped a single quantitative trait locus modulating the incidence of renal tumors in the (AIRmax x AIRmin)F2 intercross population. This locus, which we named Renal tumor modifier QTL 1 (Rtm1), mapped to chromosome 17 at 23.4 Mb (LOD score = 15.8), with SNPs rs3696835 and rs3719497 flanking the LOD score peak. The A allele of rs3719497 from AIRmin mice was associated with a 2.5-fold increased odds ratio for renal tumor development. The LOD score peak included the Tuberous sclerosis 2 (Tsc2) gene which has already been implicated in kidney disease: loss of function by germline retroviral insertion is associated with spontaneous renal tumorigenesis in the Eker rat, and heterozygous-null Tsc2

(+/-)
mice develop renal cystadenomas.

Conclusions

We mapped Rtm1 as a single major locus modulating renal tumorigenesis in a murine intercross population. Thus, the AIR mouse lines can be considered a new genetic model for studying the role of germline and somatic molecular alterations in kidney neoplastic disease.
Comparison of baseline quality of life measures between renal cell carcinoma patients undergoing partial versus radical nephrectomy
Authors: Arnold Michelle L , Thiel David D , Diehl Nancy , Wu Kevin J , Ames Steve , Parker Alexander S
Published: October 2013

Background

To compare demographics, pathologic features, performance scores, comorbidities, symptoms and responses to quality of life (QoL) surveys between nephron-sparing surgery (NSS) and radical nephrectomy (RN) patients prior to surgical intervention. Previous investigators have compared QoL outcomes for patients undergoing RN and NSS; however, there are limited data comparing QoL-related characteristics at baseline between these groups.

Methods

We identified 144 patients with localized RCC who underwent either NSS (n = 71) or RN (n = 73) between May ‘07-November ‘12. We abstracted baseline data on demographic and clinic-pathologic variables as well as responses to the SF-36 and FACT-G surveys from our prospective registry. We amended the FACT-G with 8 additional questions designed to address RCC-specific QoL. For comparisons between the two groups, we employed Wilcoxon rank-sum and Fisher's Exact tests where appropriate.

Results

We observed RN patients to have more aggressive pathology. We noted no difference in performance scores between the two groups; however, RN patients were more likely to have higher Charlson scores (p = 0.022) and various symptoms at presentation (all p <0.001). For the QoL surveys, we did not observe differences on the FACT-G; however, we noted evidence of differential scores between the two groups on specific domains of the SF-36 (e.g. Mental Health; p 0.022) and the RCC-specific QoL questions added to the FACT-G.

Conclusions

We report baseline differences between RN and NSS patients on clinico-pathologic as well as QoL-related metrics. As issues of survivorship become increasingly important, our results underscore the need to consider baseline status in evaluations of QoL-related outcomes for patients undergoing surgery for RCC.
Vacuum Seed Sowing Manifold: a novel device for high-throughput sowing of Arabidopsis seeds
Authors: Barker Richard , Cox Benjamin , Mackie Thomas Rockwell , Masson Patrick
Published: October 2013

The small size of Arabidopsis provides both opportunities and difficulties for laboratory research. Large numbers of plants can be grown in a relatively small area making it easy to observe and investigate interesting phenotypes. Conversely, their small size can also make it difficult to obtain large quantities of tissue for investigation using modern molecular techniques. Sowing large numbers of their seed can overcome this; however, their small seed size makes this difficult. Here we present the Vacuum Seed Sowing Manifold (VSSM), a simple device that can be printed using a 3D printer and provides a new high throughput method to sow large numbers of seeds at a range of densities.
Clinicopathologic features and responses to radiotherapy of myeloid sarcoma
Authors: Chen Wan-Yu , Wang Chun-Wei , Chang Chin-Hao , Liu Heng-Hsiu , Lan Keng-Hsueh , Tang Jih-Luh , Tien Hwei-Fang , Kuo Sung-Hsin , Cheng Ann-Lii
Published: October 2013

Background

To evaluate clinicopathological features, radiotherapeutic parameters, and their associations with responses to radiotherapy (RT) in patients with myeloid sarcoma (MS).

Methods

We reviewed 20 patients receiving RT for MS lesions (in 43 RT courses) and analyzed the patients’ clinicopathologic features and radiotherapeutic parameters, and their associations with complete responses (CR) to RT using Fisher’s exact test and univariate logistic regression analysis. Generalized Estimating Equation was used to analyze all 43 irradiated lesions and account for the correlations in RT responses among lesions from the same patient.

Results

We found that the underlying hematological diseases of the evaluated patients were acute myeloid leukemia (AML) in 14 patients (70%), chronic myeloid leukemia in 4 patients (20%), myelodysplastic syndrome with AML transformation in one patient (5%), and de novo MS in one patient (5%). Most patients (55%) received RT for MS at the time of relapse following bone marrow transplantation (BMT). The most common cytogenetic abnormality was t(8;21)(q22;q22). The median RT dose of 20 Gy (range 6–35 Gy), administered in 1.5-3.5 Gy fractions, provided a 63% CR rate. RT dose, sex, cytogenetics, and bone marrow status at the time of RT had no significant effect on CR. Younger age (<50 y,P = 0.06), BMT prior to RT (P = 0.05), and underlying AML (P = 0.05) were marginally associated with higher CR to RT.

Conclusions

Our results indicate that a modest RT dose (20-30 Gy) achieves good local control of MS. Age, previous BMT, and underlying hematologic disease can affect RT response.
Movilidad social y desigualdad en el Buenos Aires del siglo XIX: el acceso a la propiedad de la tierra entre el rosismo y el orden liberal
Authors: Gelman Jorge , Santilli Daniel
Published: October 2013

Buena parte del discurso historiográfico sobre América Latina señala su fuerte resistencia al cambio económico y la poca movilidad social entre sus habitantes. Sin embargo los estudios sistemáticos para períodos previos al siglo XX son muy escasos. En este trabajo nos proponemos evaluar los procesos de movilidad social intrageneracional en Buenos Aires en las décadas centrales del siglo XIX, a través del acceso a la propiedad de la tierra y las posibilidades de acumulación o pérdida de la misma. Para ello utilizaremos tres bases de datos completas sobre los propietarios de bienes inmuebles de la provincia de Buenos Aires en 1839, 1855 y 1867, momentos en que la región atravesaba por importantes cambios económicos, políticos e institucionales. De esta manera buscamos valorar el impacto de estos cambios en las posibilidades de movilidad social de la población, y propiciar la discusión con las imágenes recibidas sobre el tema.
TAK1 regulates SOX9 expression in chondrocytes and is essential for postnatal development of the growth plate and articular cartilages
Authors: Gao Lin , Sheu Tzong-jen , Dong Yufeng , Hoak Donna M , Zuscik Michael J , Schwarz Edward M , Hilton Matthew J , O'Keefe Regis J , Jonason Jennifer H
Published: October 2013

TAK1 is a MAP3K that mediates non-canonical TGF-β and BMP signaling. During the embryonic period, TAK1 is essential for cartilage and joint development as deletion of Tak1 in chondro-osteo progenitor cells leads to severe chondrodysplasia with defects in both chondrocyte proliferation and maturation. Here, we designed experiments to address the role of TAK1 in committed chondrocytes during early postnatal development. Using the Col2a1-CreERT2; Tak1f/f mouse model, we induced deletion of Tak1 at postnatal day 7 and characterized the skeletal phenotypes of these mice at one and three months of age. Mice with chondrocyte-specific Tak1 deletion exhibited severe growth retardation and reduced proteoglycan and Type II Collagen content in the extracellular matrix of the articular cartilage. We found reduced Col2a1 and Acan expression, but increased Mmp13 and Adamts5 expression, in Tak1-deficient chondrocytes along with reduced expression of the SOX trio of transcription factors, SOX9, SOX5 and SOX6. In vitro, BMP2 stimulated Sox9 gene expression and Sox9 promoter activity, which did not occur after Tak1 deletion or in the presence of a TAK1 kinase inhibitor. TAK1 affects both canonical and non-canonical BMP signal transduction and we found that both of these pathways contributed to BMP2-mediated Sox9 promoter activation. Additionally, we found that ATF2 directly binds the Sox9 promoter in response to BMP signaling and that this effect is dependent upon TAK1 kinase activity. These novel findings establish that TAK1 is essential for BMP2-mediated Sox9 gene expression and the postnatal development of normal growth plate and articular cartilages.
Modulation of integrin activation and signaling by α1/α1′-helix unbending at the junction
Authors: Zhang Chuanmei , Liu Jiafu , Jiang Xiuli , Haydar Nada , Zhang Can , Shan Hu , Zhu Jieqing
Published: October 2013

How conformational signals initiated from one end of the integrin are transmitted to the other end remains elusive. At the ligand-binding βI domain, the α1/α1′-helix changes from a bent to a straightened α-helical conformation upon integrin headpiece opening. We demonstrated that a conserved glycine at the α1/α1′ junction is critical for maintaining the bent conformation of the α1/α1′-helix in the resting state. Mutations that facilitate α1/α1′-helix unbending rendered integrin constitutively active. However, mutations that block the α1/α1′-helix unbending abolished soluble ligand binding upon either outside or inside stimuli. Such mutations also blocked ligand-induced integrin extension from outside the cell, but had no effect on talin-induced integrin extension from inside the cell. In addition, integrin mediated cell spreading, F-actin stress fiber and focal adhesion formation, and focal adhesion kinase activation were also defective in these mutant integrins, although the cells still adhered to immobilized ligands at a reduced level. Our data establish the structural role of the α1/α1′ junction that allows relaxation of the α1/α1′-helix in the resting state and transmission of bidirectional conformational signals by helix unbending upon integrin activation.
An investigation of the effect of AlloMatrix bone graft in distal radial fracture
Authors: D’Agostino P. , Barbier O.
Published: October 2013

The osteoinductive properties of demineralised bone matrix have been demonstrated in animal studies. However, its therapeutic efficacy has yet to be proven in humans. The clinical properties of AlloMatrix, an injectable calcium-based demineralised bone matrix allograft, were studied in a prospective randomised study of 50 patients with an isolated unstable distal radial fracture treated by reduction and Kirschner (K-) wire fixation. A total of 24 patients were randomised to the graft group (13 men and 11 women, mean age 42.3 years (20 to 62)) and 26 to the no graft group (8 men and 18 women, mean age 45.0 years (17 to 69)).

At one, three, six and nine weeks, and six and 12 months post-operatively, patients underwent radiological evaluation, assessments for range of movement, grip and pinch strength, and also completed the Disabilities of Arm, Shoulder and Hand questionnaire. At one and six weeks and one year post-operatively, bone mineral density evaluations of both wrists were performed.

No significant difference in wrist function and speed of recovery, rate of union, complications or bone mineral density was found between the two groups. The operating time was significantly higher in the graft group (p = 0.004). Radiologically, the reduction parameters remained similar in the two groups and all AlloMatrix extraosseous leakages disappeared after nine weeks.

This prospective randomised controlled trial did not demonstrate a beneficial effect of AlloMatrix demineralised bone matrix in the treatment of this category of distal radial fractures treated by K-wire fixation.

Cite this article: Bone Joint J 2013;95-B:1514–20.
Corail uncemented hemiarthroplasty with a Cathcart head for intracapsular hip fractures
Authors: Kendrick B. J. L. , Wilson H. A. , Lippett J. E. , McAndrew A. R. , Andrade A. J. M. D.
Published: October 2013

The National Institute for Health and Clinical Excellence (NICE) guidelines from 2011 recommend the use of cemented hemi-arthroplasty for appropriate patients with an intracapsular hip fracture. In our institution all patients who were admitted with an intracapsular hip fracture and were suitable for a hemi-arthroplasty between April 2010 and July 2012 received an uncemented prosthesis according to our established departmental routine practice. A retrospective analysis of outcome was performed to establish whether the continued use of an uncemented stem was justified. Patient, surgical and outcome data were collected on the National Hip Fracture database. A total of 306 patients received a Cathcart modular head on a Corail uncemented stem as a hemi-arthroplasty. The mean age of the patients was 83.3 years (sd 7.56; 46.6 to 94) and 216 (70.6%) were women. The mortality rate at 30 days was 5.8%. A total of 46.5% of patients returned to their own home by 30 days, which increased to 73.2% by 120 days. The implant used as a hemi-arthroplasty for intracapsular hip fracture provided satisfactory results, with a good rate of return to pre-injury place of residence and an acceptable mortality rate. Surgery should be performed by those who are familiar with the design of the stem and understand what is required for successful implantation.

Cite this article: Bone Joint J 2013;95-B:1538–43.
Intention-to-treat analyses for interventional studies
Authors: Griffin X. L. , Parsons N. , Carey Smith R. , Stengel D. , Costa M. L.
Published: October 2013

The importance for observing the intention-to-treat approach in clinical studies is explained.

Cite this article: Bone Joint J 2013;95-B:1443–4.
Correspondence
Authors: Cook T. M.
Published: October 2013

We welcome letters to the Editor concerning articles that have recently been published. Such letters will be subject to the usual stages of selection and editing; where appropriate the authors of the original article will be offered the opportunity to reply.
MANAGEMENT OF ENDOCRINE DISEASE: GH excess: diagnosis and medical therapy
Authors: Andersen Marianne
Published: October 2013

Acromegaly is predominantly caused by a pituitary adenoma, which secretes an excess of GH resulting in increased IGF1 levels. Most of the GH assays used currently measure only the levels of the 22 kDa form of GH. In theory, the diagnostic sensitivity may be lower compared with the previous assays, which have used polyclonal antibodies. Many GH-secreting adenomas are plurihormonal and may co-secrete prolactin, TSH and α-subunit. Hyperprolactinaemia is found in 30–40% of patients with acromegaly, and hyperprolactinaemia may occasionally be diagnosed before acromegaly is apparent. Although trans-sphenoidal surgery of a GH-secreting adenoma remains the first treatment at most centres, the role of somatostatin analogues, octreotide long-acting repeatable and lanreotide Autogel as primary therapy is still the subject of some debate. Although the normalisation of GH and IGF1 levels is the main objective in all patients with acromegaly, GH and IGF1 levels may be discordant, especially during somatostatin analogue therapy. This discordance usually takes the form of high GH levels and an IGF1 level towards the upper limit of the normal range. Pasireotide, a new somatostatin analogue, may be more efficacious in some patients, but the drug has not yet been registered for acromegaly. Papers published on pasireotide have reported an increased risk of diabetes mellitus due to a reduction in insulin levels. Pegvisomant, the GH receptor antagonist, is indicated – alone or in combination with a somatostatin analogue – in most patients who fail to enter remission on a somatostatin analogue. Dopamine-D2-agonists may be effective as monotherapy in a few patients, but it may prove necessary to apply combination therapy involving a somatostatin analogue and/or pegvisomant.
Thyroid status and functional and cognitive status at baseline and survival after 3 years of follow-up: the OCTABAIX study
Authors: Formiga Francesc , Ferrer Assumpta , Padros Gloria , Contra Anna , Corbella Xavier , Pujol Ramon , _ _
Published: October 2013

Objective

Subclinical thyroid disorders are common in older individuals. Health risks associated with subclinical hypothyroidism in older adults are unclear. The aim of the study is to evaluate whether thyroid status in elderly subjects correlates with physical and cognitive function at baseline and with 3-year mortality.

Design

A population-based, prospective cohort of the OCTABAIX study (307 inhabitants aged 85 years at baseline).

Methods

Chronic drug prescription, functional status (Barthel and Lawton indices) and cognitive status according to the Spanish version of the Mini-Mental State Examination were recorded. Quality of life was assessed using the visual analogue scale of the quality of life test. Concentrations of TSH and thyroxine were measured. Participants were classified in accordance with clinical categories of thyroid function.

Results

Twenty (6.5%) individuals had subclinical hypothyroidism and five (1.6%) had subclinical hyperthyroidism. Compared with euthyroid subjects (n=280; 91.8%), subclinical hypo- and hyperthyroidism subjects were not significantly associated with poor physical or cognitive function at baseline. Fifty-one (15.1%) subjects died during the 36 months of follow-up. TSH values and subclinical hypo- and hyperthyroidism were not associated with an increased overall mortality risk (hazard ratio (HR) 1.086, 95% CI 0.987–1.196 and HR 0.905, 95% CI 0.902–1.053 respectively).

Conclusions

This study does not support the association of TSH or thyroid disorders with physical or cognitive function at baseline or with 3-year mortality in the oldest old subjects.
Új lehetőségek a sebészet gyakorlati oktatásában
Authors: Kormos Katalin , Sándor József , Haidegger Tamás , Ferencz Andrea , Csukás Domokos , Bráth Endre , Szabó Györgyi , Wéber György
Published: October 2013

Absztrakt

A laparoscopos sebészet gyors elterjedése a világon egyúttal az új eljárás oktatásához szükséges módszerek bevezetését is szükségessé tette. Az alkalmazott „gyakorlódobozok” hasznos segítséget jelentettek, majd a „látszólagos valóság” technikája a szimulációs gyakorlás újabb lehetőségét teremtette meg. A sebészet történetében először nyílt rá mód, hogy az orvostanhallgató vagy rezidens kézügyességét mérőszámokkal lehessen jellemezni, a szimulált sebészi beavatkozások mint „komoly játékok” ismerhetők meg. A modern képalkotó eljárások alapján már a műtét előtt megtervezhetők az, egy adott beavatkozás során végzendő mozdulatsorok, melyek ismételhetők, gyakorolhatók, és így a műtét biztonságos kivitelezését is elősegítik. A nyílt műtéteket eljárásspecifikus műanyag táblákon lehet a gyakorlatban elvégezni, illetve interaktív érintőképernyős eszköz használatával és e-learning útján is meg lehet ismerni.