bluuebunny/crossref_metadata_2025 huggingface dataset:
In vitro efficacy of forodesine and nelarabine (ara-G) in pediatric leukemia
Authors: Homminga Irene , Zwaan C. Michel , Manz Chantal Y. , Parker Cynthia , Bantia Shanta , Smits Willem Korstiaan , Higginbotham Fiona , Pieters Rob , Meijerink Jules P. P.
Published: July 2011

Forodesine and nelarabine (the pro-drug of ara-G) are 2 nucleoside analogues with promising anti-leukemic activity. To better understand which pediatric patients might benefit from forodesine or nelarabine (ara-G) therapy, we investigated the in vitro sensitivity to these drugs in 96 diagnostic pediatric leukemia patient samples and the mRNA expression levels of different enzymes involved in nucleoside metabolism. Forodesine and ara-G cytotoxicities were higher in T-cell acute lymphoblastic leukemia (T-ALL) samples than in B-cell precursor (BCP)–ALL and acute myeloid leukemia (AML) samples. Resistance to forodesine did not preclude ara-G sensitivity and vice versa, indicating that both drugs rely on different resistance mechanisms. Differences in sensitivity could be partly explained by significantly higher accumulation of intracellular dGTP in forodesine-sensitive samples compared with resistant samples, and higher mRNA levels of dGK but not dCK. The mRNA levels of the transporters ENT1 and ENT2 were higher in ara-G–sensitive than –resistant samples. We conclude that especially T-ALL, but also BCP-ALL, pediatric patients may benefit from forodesine or nelarabine (ara-G) treatment.
Transcriptomic response of the red tide dinoflagellate, Karenia brevis, to nitrogen and phosphorus depletion and addition
Authors: Morey Jeanine S , Monroe Emily A , Kinney Amanda L , Beal Marion , Johnson Jillian G , Hitchcock Gary L , Van Dolah Frances M
Published: July 2011

Background

The role of coastal nutrient sources in the persistence of Karenia brevis red tides in coastal waters of Florida is a contentious issue that warrants investigation into the regulation of nutrient responses in this dinoflagellate. In other phytoplankton studied, nutrient status is reflected by the expression levels of N- and P-responsive gene transcripts. In dinoflagellates, however, many processes are regulated post-transcriptionally. All nuclear encoded gene transcripts studied to date possess a 5' trans-spliced leader (SL) sequence suggestive, based on the trypanosome model, of post-transcriptional regulation. The current study therefore sought to determine if the transcriptome of K. brevis is responsive to nitrogen and phosphorus and is informative of nutrient status.

Results

Microarray analysis of N-depleted K. brevis cultures revealed an increase in the expression of transcripts involved in N-assimilation (nitrate and ammonium transporters, glutamine synthetases) relative to nutrient replete cells. In contrast, a transcriptional signal of P-starvation was not apparent despite evidence of P-starvation based on their rapid growth response to P-addition. To study transcriptome responses to nutrient addition, the limiting nutrient was added to depleted cells and changes in global gene expression were assessed over the first 48 hours following nutrient addition. Both N- and P-addition resulted in significant changes in approximately 4% of genes on the microarray, using a significance cutoff of 1.7-fold and p ≤ 10-4. By far, the earliest responding genes were dominated in both nutrient treatments by pentatricopeptide repeat (PPR) proteins, which increased in expression up to 3-fold by 1 h following nutrient addition. PPR proteins are nuclear encoded proteins involved in chloroplast and mitochondria RNA processing. Correspondingly, other functions enriched in response to both nutrients were photosystem and ribosomal genes.

Conclusions

Microarray analysis provided transcriptomic evidence for N- but not P-limitation in K. brevis. Transcriptomic responses to the addition of either N or P suggest a concerted program leading to the reactivation of chloroplast functions. Even the earliest responding PPR protein transcripts possess a 5' SL sequence that suggests post-transcriptional control. Given the current state of knowledge of dinoflagellate gene regulation, it is currently unclear how these rapid changes in such transcript levels are achieved.
Yersinia enterocolitica palearctica serobiotype O:3/4 - a successful group of emerging zoonotic pathogens
Authors: Batzilla Julia , Antonenka Uladzimir , Höper Dirk , Heesemann Jürgen , Rakin Alexander
Published: July 2011

Background

High-pathogenic Y. enterocolitica ssp. enterocolitica caused several human outbreaks in Northern America. In contrast, low pathogenic Y. enterocolitica ssp. palearctica serobiotype O:3/4 is responsible for sporadic cases worldwide with asymptomatic pigs being the main source of infection. Genomes of three Y. enterocolitica ssp. palearctica serobiotype O:3/4 human isolates (including the completely sequenced Y11 German DSMZ type strain) were compared to the high-pathogenic Y. enterocolitica ssp. enterocolitica 8081 O:8/1B to address the peculiarities of the O:3/4 group.

Results

Most high-pathogenicity-associated determinants of Y. enterocolitica ssp. enterocolitica (like the High-Pathogenicity Island, yts1 type 2 and ysa type 3 secretion systems) are absent in Y. enterocolitica ssp. palearctica serobiotype O:3/4 genomes. On the other hand they possess alternative putative virulence and fitness factors, such as a different ysp type 3 secretion system, an RtxA-like and insecticidal toxins, and a N-acetyl-galactosamine (GalNAc) PTS system (aga-operon). Horizontal acquisition of two prophages and a tRNA-Asn-associated GIYep-01 genomic island might also influence the Y. enterocolitica ssp. palearctica serobiotype O:3/4 pathoadaptation. We demonstrated recombination activity of the PhiYep-3 prophage and the GIYep-01 island and the ability of the aga-operon to support the growth of the Y. enterocolitica ssp. enterocolitica O:8/1B on GalNAc.

Conclusions

Y. enterocolitica ssp. palearctica serobiotype O:3/4 experienced a shift to an alternative patchwork of virulence and fitness determinants that might play a significant role in its host pathoadaptation and successful worldwide dissemination.
A web server for predicting inhibitors against bacterial target GlmU protein
Authors: Singla Deepak , Anurag Meenakshi , Dash Debasis , Raghava Gajendra PS
Published: July 2011

Background

The emergence of drug resistant tuberculosis poses a serious concern globally and researchers are in rigorous search for new drugs to fight against these dreadful bacteria. Recently, the bacterial GlmU protein, involved in peptidoglycan, lipopolysaccharide and techoic acid synthesis, has been identified as an important drug target. A unique C-terminal disordered tail, essential for survival and the absence of gene in host makes GlmU a suitable target for inhibitor design.

Results

This study describes the models developed for predicting inhibitory activity (IC

50
) of chemical compounds against GlmU protein using QSAR and docking techniques. These models were trained on 84 diverse compounds (GlmU inhibitors) taken from PubChem BioAssay (AID 1376). These inhibitors were docked in the active site of the C-terminal domain of GlmU protein (2OI6) using the AutoDock. A QSAR model was developed using docking energies as descriptors and achieved maximum correlation of 0.35/0.12 (r/r2) between actual and predicted pIC

50
. Secondly, QSAR models were developed using molecular descriptors calculated using various software packages and achieved maximum correlation of 0.77/0.60 (r/r2). Finally, hybrid models were developed using various types of descriptors and achieved high correlation of 0.83/0.70 (r/r2) between predicted and actual pIC

50
. It was observed that some molecular descriptors used in this study had high correlation with pIC

50
. We screened chemical libraries using models developed in this study and predicted 40 potential GlmU inhibitors. These inhibitors could be used to develop drugs against Mycobacterium tuberculosis.

Conclusion

These results demonstrate that docking energies can be used as descriptors for developing QSAR models. The current work suggests that docking energies based descriptors could be used along with commonly used molecular descriptors for predicting inhibitory activity (IC

50
) of molecules against GlmU. Based on this study an open source platform, http://crdd.osdd.net/raghava/gdoq, has been developed for predicting inhibitors GlmU.
No evidence for association between SLC11A1and visceral leishmaniasis in India
Authors: Mehrotra Sanjana , Oommen Joyce , Mishra Anshuman , Sudharshan Medhavi , Tiwary Puja , Jamieson Sarra E , Fakiola Michaela , Rani Deepa Selvi , Thangaraj Kumarasamy , Rai Madhukar , Sundar Shyam , Blackwell Jenefer M
Published: July 2011

Background

SLC11A1has pleiotropic effects on macrophage function and remains a strong candidate for infectious disease susceptibility. 5' and/or 3' polymorphisms have been associated with tuberculosis, leprosy, and visceral leishmaniasis (VL). Most studies undertaken to date were under-powered, and none has been replicated within a population. Association with tuberculosis has replicated variably across populations. Here we investigateSLC11A1and VL in India.

Methods

Nine polymorphisms (rs34448891, rs7573065, rs2276631, rs3731865, rs17221959, rs2279015, rs17235409, rs17235416, rs17229009) that tag linkage disequilibrium blocks acrossSLC11A1were genotyped in primary family-based (313 cases; 176 families) and replication (941 cases; 992 controls) samples. Family- and population-based analyses were performed to look for association betweenSLC11A1variants and VL. Quantitative RT/PCR was used to compare SLC11A1 expression in mRNA from paired splenic aspirates taken before and after treatment from 24 VL patients carrying different genotypes at the functional promoter GTnpolymorphism (rs34448891).

Results

No associations were observed between VL and polymorphisms atSLC11A1that were either robust to correction for multiple testing or replicated across primary and replication samples. No differences in expression of SLC11A1 were observed when comparing pre- and post-treatment samples, or between individuals carrying different genotypes at the GTnrepeat.

Conclusions

This is the first well-powered study ofSLC11A1as a candidate for VL, which we conclude does not have a major role in regulating VL susceptibility in India.
The efficacy of hypotonic and near-isotonic saline for parenteral fluid therapy given at low maintenance rate in preventing significant change in plasma sodium in post-operative pediatric patients: protocol for a prospective randomized non-blinded study
Authors: Fläring Urban , Lönnqvist Per-Arne , Frenckner Björn , Svensson Jan F , Ingolfsson Ingimar , Wallensteen Lena , Stigzelius Shayarina , Kowalski Jan , Krmar Rafael T
Published: July 2011

Background

Hyponatremia is the most frequent electrolyte abnormality observed in post-operative pediatric patients receiving intravenous maintenance fluid therapy. If plasma sodium concentration (p-Na+) declines to levels below 125 mmol/L in < 48 h, transient or permanent brain damage may occur. There is an intense debate as to whether the administered volume (full ratevs.restricted rate of infusion) and the composition of solutions used for parenteral maintenance fluid therapy (hypotonicvs.isotonic solutions) contribute to the development of hyponatremia. So far, there is no definitive pediatric data to support a particular choice of parenteral fluid for maintenance therapy in post-surgical patients.

Methods/Design

Our prospective randomized non-blinded study will be conducted in healthy children and adolescents aged 1 to 14 years who have been operated for acute appendicitis. Patients will be randomized either to intravenous hypotonic (0.23% or 0.40% sodium chloride in glucose, respectively) or near-isotonic (0.81% sodium chloride in glucose) solution given at approximately three-fourths of the average maintenance rate. The main outcome of interest from this study is to evaluate 24 h post-operatively whether differences in p-Na+between treatment groups are large enough to be of clinical relevance. In addition, water and electrolyte balance as well as regulatory hormones will be measured.

Discussion

This study will provide valuable information on the efficacy of hypotonic and near-isotonic fluid therapy in preventing a significant decrease in p-Na+. Finally, by means of careful electrolyte and water balance and by measuring regulatory hormones our results will also contribute to a better understanding of the physiopathology of post-operative changes in p-Na+in a population at risk for hyponatremia.

Trial registration

The protocol for this study is registered with the current controlled trials registry; registry number:ISRCTN43896775.
Modification by antioxidant supplementation of changes in human lung function associated with air pollutant exposure: A systematic review
Authors: Tashakkor Amir Y , Chow Katherine S , Carlsten Chris
Published: July 2011

Background

Outdoor air pollution, given its demonstrated negative effects on the respiratory system, is a growing public health concern worldwide, particularly in urban cities. Human exposure to pollutants such as ozone, nitrogen oxides, combustion-related particulate matter and oxides of sulfur is responsible for significant cardiopulmonary morbidity and mortality in both adults and children. Several antioxidants have shown an ability to partially attenuate the negative physiological and functional impacts of air pollutants. This study systematically presents current data on the potential benefits of antioxidant supplementation on lung function outcomes associated with air pollutant exposures in intact humans.

Methods

Electronic databases (MEDLINE, EMBASE, BIOSIS Previews, Web of Sciences, Environmental Sciences & Pollution Management and TOXNET) were systematically searched for all studies published up to April 2009. Search terms relating to the concepts of respiratory tract diseases, respiratory function tests, air pollution, and antioxidants were used. Data was systematically abstracted from original articles that satisfied selection criteria for inclusion. For inclusion, the studies needed to have evaluated human subjects, given supplemental antioxidants, under conditions of known levels of air pollutants with measured lung function before and after antioxidant administration and/or air pollution exposure. Selected studies were summarized and conclusions presented.

Results

Eight studies investigated the role of antioxidant supplementation on measured lung function outcomes after subject exposure to air pollutants under controlled conditions; 5 of these studies concluded that pollutant-induced airway hyper-responsiveness and diminution in lung function measurements were attenuated by antioxidant supplementation. The remaining five studies took place under ambient (uncontrolled) exposures and unanimously concluded that antioxidant supplementations attenuate the negative effects of urban air pollution on lung function.

Conclusions

The data evaluating modification of changes in lung function associated with air pollutant exposure by antioxidant supplementation, in intact humans, is limited. Of 13 studies dedicated to this concern, ten demonstrated an attenuation of pollution-associated decrements. There is growing evidence for the benefit of anti-oxidant supplementation in moderating the effects of air pollution on lung function, but more research on human participants is needed to inform this topic.
Race/Ethnicity and gender differences in health intentions and behaviors regarding exercise and diet for adults with type 2 diabetes: A cross-sectional analysis
Authors: Gavin James R , Fox Kathleen M , Grandy Susan
Published: July 2011

Background

Self-management is the cornerstone of diabetes control and prevention of complications; however, it is undetermined whether differences in intention to adopt healthy lifestyles and actual healthy behavior exist across race/ethnic groups. This study evaluated the differences across racial-ethnic groups in self-reported medical advice received and health intentions and behaviors among adults with type 2 diabetes mellitus.

Methods

A cross-sectional analysis of the 2007 SHIELD US survey ascertained self-reported health intentions and behaviors for regular exercise, diet, and weight management among Non-Hispanic Caucasian (n = 2526), Non-Hispanic African-American (n = 706), and Hispanic (n = 179) respondents with type 2 diabetes.

Results

A similar proportion of respondents from each race-gender group (43%-56%) reported receiving healthcare advice to increase their exercise (P = 0.32). Significantly more minorities reported an intention to follow the exercise recommendation compared with Non-Hispanic Caucasians (P = 0.03). More Non-Hispanic African-American (29%) and Hispanic (27%) men reported exercising regularly compared with other race-gender groups (P = 0.02). Significantly more Non-Hispanic Caucasian women (74%) and Hispanic women (79%) reported trying to lose weight compared with other groups (P < 0.0001).

Conclusions

Differences in health intentions and healthy behaviors were noted across race-gender groups. More Non-Hispanic African-American men reported an intention to follow advice on exercising and self-report of exercising regularly was also higher compared with other race-gender groups. More Hispanic men reported high physical activity levels than other groups. Despite an increased willingness to follow healthcare recommendations for diet, >50% of respondents were obese among all race-gender groups.
Multimodality treatment of brain metastases: an institutional survival analysis of 275 patients
Authors: Elaimy Ameer L , Mackay Alexander R , Lamoreaux Wayne T , Fairbanks Robert K , Demakas John J , Cooke Barton S , Peressini Benjamin J , Holbrook John T , Lee Christopher M
Published: July 2011

Background

Whole brain radiation therapy (WBRT), surgical resection, stereotactic radiosurgery (SRS), and combinations of the three modalities are used in the management of patients with metastatic brain tumors. We present the previously unreported survival outcomes of 275 patients treated for newly diagnosed brain metastases at Cancer Care Northwest and Gamma Knife of Spokane between 1998 and 2008.

Methods

The effects treatment regimen, age, Eastern Cooperative Oncology Group-Performance Status (ECOG-PS), primary tumor histology, number of brain metastases, and total volume of brain metastases have on patient overall survival were analyzed. Statistical analysis was performed using Kaplan-Meier survival curves, Andersen 95% confidence intervals, approximate confidence intervals for log hazard-ratios, and multivariate Cox proportional hazard models.

Results

The median clinical follow up time was 7.2 months. On multivariate analysis, survival statistically favored patients treated with SRS alone when compared to patients treated with WBRT alone (p < 0.001), patients treated with resection with SRS when compared to patients treated with SRS alone (p = 0.020), patients in ECOG-PS class 0 when compared to patients in ECOG-PS classes 2 (p = 0.04), 3 (p < 0.001), and 4 (p < 0.001), patients in the non-small-cell lung cancer group when compared to patients in the combined melanoma and renal-cell carcinoma group (p < 0.001), and patients with breast cancer when compared to patients with non-small-cell lung cancer (p < 0.001).

Conclusions

In our analysis, patients benefited from a combined modality treatment approach and physicians must consider patient age, performance status, and primary tumor histology when recommending specific treatments regimens.
S-Nitrosoglutathione reduces oxidative injury and promotes mechanisms of neurorepair following traumatic brain injury in rats
Authors: Khan Mushfiquddin , Sakakima Harutoshi , Dhammu Tajinder S , Shunmugavel Anandakumar , Im Yeong-Bin , Gilg Anne G , Singh Avtar K , Singh Inderjit
Published: July 2011

Background

Traumatic brain injury (TBI) induces primary and secondary damage in both the endothelium and the brain parenchyma, collectively termed the neurovascular unit. While neurons die quickly by necrosis, a vicious cycle of secondary injury in endothelial cells exacerbates the initial injury in the neurovascular unit following TBI. In activated endothelial cells, excessive superoxide reacts with nitric oxide (NO) to form peroxynitrite. Peroxynitrite has been implicated in blood brain barrier (BBB) leakage, altered metabolic function, and neurobehavioral impairment. S-nitrosoglutathione (GSNO), a nitrosylation-based signaling molecule, was reported not only to reduce brain levels of peroxynitrite and oxidative metabolites but also to improve neurological function in TBI, stroke, and spinal cord injury. Therefore, we investigated whether GSNO promotes the neurorepair process by reducing the levels of peroxynitrite and the degree of oxidative injury.

Methods

TBI was induced by controlled cortical impact (CCI) in adult male rats. GSNO or 3-Morpholino-sydnonimine (SIN-1) (50 μg/kg body weight) was administered orally two hours following CCI. The same dose was repeated daily until endpoints. GSNO-treated (GSNO group) or SIN-1-treated (SIN-1 group) injured animals were compared with vehicle-treated injured animals (TBI group) and vehicle-treated sham-operated animals (Sham group) in terms of peroxynitrite, NO, glutathione (GSH), lipid peroxidation, blood brain barrier (BBB) leakage, edema, inflammation, tissue structure, axon/myelin integrity, and neurotrophic factors.

Results

SIN-1 treatment of TBI increased whereas GSNO treatment decreased peroxynitrite, lipid peroxides/aldehydes, BBB leakage, inflammation and edema in a short-term treatment (4-48 hours). GSNO also reduced brain infarctions and enhanced the levels of NO and GSH. In a long-term treatment (14 days), GSNO protected axonal integrity, maintained myelin levels, promoted synaptic plasticity, and enhanced the expression of neurotrophic factors.

Conclusion

Our findings indicate the participation of peroxynitrite in the pathobiology of TBI. GSNO treatment of TBI not only reduces peroxynitrite but also protects the integrity of the neurovascular unit, indicating that GSNO blunts the deleterious effects of peroxynitrite. A long-term treatment of TBI with the same low dose of GSNO promotes synaptic plasticity and enhances the expression of neurotrophic factors. These results support that GSNO reduces the levels of oxidative metabolites, protects the neurovascular unit, and promotes neurorepair mechanisms in TBI.
Microglial p38α MAPK is a key regulator of proinflammatory cytokine up-regulation induced by toll-like receptor (TLR) ligands or beta-amyloid (Aβ)
Authors: Bachstetter Adam D , Xing Bin , de Almeida Lucia , Dimayuga Edgardo R , Watterson D Martin , Van Eldik Linda J
Published: July 2011

Background

Overproduction of proinflammatory cytokines from activated microglia has been implicated as an important contributor to pathophysiology progression in both acute and chronic neurodegenerative diseases. Therefore, it is critical to elucidate intracellular signaling pathways that are significant contributors to cytokine overproduction in microglia exposed to specific stressors, especially pathways amenable to drug interventions. The serine/threonine protein kinase p38α MAPK is a key enzyme in the parallel and convergent intracellular signaling pathways involved in stressor-induced production of IL-1β and TNFα in peripheral tissues, and is a drug development target for peripheral inflammatory diseases. However, much less is known about the quantitative importance of microglial p38α MAPK in stressor-induced cytokine overproduction, or the potential of microglial p38α MAPK to be a druggable target for CNS disorders. Therefore, we examined the contribution of microglial p38αMAPK to cytokine up-regulation, with a focus on the potential to suppress the cytokine increase by inhibition of the kinase with pharmacological or genetic approaches.

Methods

The microglial cytokine response to TLR ligands 2/3/4/7/8/9 or to Aβ1-42was tested in the presence of a CNS-penetrant p38α MAPK inhibitor, MW01-2-069A-SRM. Primary microglia from mice genetically deficient in p38α MAPK were used to further establish a linkage between microglia p38α MAPK and cytokine overproduction. Thein vivosignificance was determined by p38α MAPK inhibitor treatment in a LPS-induced model of acute neuroinflammation.

Results

Increased IL-1β and TNFα production by the BV-2 microglial cell line and by primary microglia cultures was inhibited in a concentration-dependent manner by the p38α MAPK-targeted inhibitor. Cellular target engagement was demonstrated by the accompanying decrease in the phosphorylation state of two p38α MAPK protein substrates, MK2 and MSK1. Consistent with the pharmacological findings, microglia from p38α-deficient mice showed a diminished cytokine response to LPS. Further, oral administration of the inhibitor blocked the increase of IL-1β in the cerebral cortex of mice stressed by intraperitoneal injection of LPS.

Conclusion

The p38α MAPK pathway is an important contributor to the increased microglial production of proinflammatory cytokines induced by diverse stressors. The results also indicate the feasibility of targeting p38α MAPK to modulate CNS proinflammatory cytokine overproduction.
Increased local concentration of complement C5a contributes to incisional pain in mice
Authors: Jang Jun H , Liang Deyong , Kido Kanta , Sun Yuan , Clark David J , Brennan Timothy J
Published: July 2011

Background

In our previous study, we demonstrated that local injection of complement C5a and C3a produce mechanical and heat hyperalgesia, and that C5a and C3a activate and sensitize cutaneous nociceptors in normal skin, suggesting a contribution of complement fragments to acute pain. Other studies also have shown that the complement system can be activated by surgical incision, and the systemic blockade of C5a receptor (C5aR) reduces incision-induced pain and inflammation. In this study, we further examined the possible contribution of wound area C5a to incisional pain.

Methods

Using of a hind paw incisional model, the effects of a selective C5aR antagonist, PMX53, on nociceptive behaviors were measured after incision in vivo. mRNA levels of C5 and C5aR in skin, dorsal root ganglia (DRG) and spinal cord, and C5a protein levels in the skin were quantified after incision. The responses of nociceptors to C5a were also evaluated using the in vitro skin-nerve preparation.

Results

Local administration of PMX53 suppressed heat hyperalgesia and mechanical allodynia induced by C5a injection or after hind paw incision in vivo. mRNA levels of C5 and C5aR in the skin, but not DRG and spinal cord, were dramatically increased after incision. C5a protein in the skin was also increased after incision. In vitro C5a did not increase the prevalence of fibers with ongoing activity in afferents from incised versus control, unincised skin. C5a sensitized C-fiber afferent responses to heat; however, this was less evident in afferents adjacent to the incision. PMX53 blocked sensitization of C-fiber afferents to heat by C5a but did not by itself influence ongoing activity or heat sensitivity in afferents innervating control or incised skin. The magnitude of mechanical responses was also not affected by C5a in any nociceptive fibers innervating incised or unincised skin.

Conclusions

This study demonstrates that high locally generated C5a levels are present in wounds for at least 72 hours after incision. In skin, C5a contributes to hypersensitivity after incision, but increased responsiveness of cutaneous nociceptors to C5a was not evident in incised skin. Thus, high local concentrations of C5a produced in wounds likely contribute to postoperative pain.
INVESTIGATE-I (INVasive Evaluation before Surgical Treatment of Incontinence Gives Added Therapeutic Effect?): study protocol for a mixed methods study to assess the feasibility of a future randomised controlled trial of the clinical utility of invasive urodynamic testing
Authors: Murdoch Megan , McColl Elaine , Howel Denise , Deverill Mark , Buckley Brian S , Lucas Malcolm , Chapple Christopher R , Tincello Douglas G , Armstrong Natalie , Brennand Cath , Shen Jing , Vale Luke , Hilton Paul
Published: July 2011

Background

Urinary incontinence is an important health problem to the individual sufferer and to health services. Stress and stress predominant mixed urinary incontinence are increasingly managed by surgery due to advances in surgical techniques. Despite the lack of evidence for its clinical utility, most clinicians undertake invasive urodynamic testing (IUT) to confirm a functional diagnosis of urodynamic stress incontinence before offering surgery for this condition. IUT is expensive, embarrassing and uncomfortable for women and carries a small risk. Recent systematic reviews have confirmed the lack of high quality evidence of effectiveness.

The aim of this pilot study is to test the feasibility of a future definitive randomised control trial that would address whether IUT alters treatment decisions and treatment outcome in these women and would test its clinical and cost effectiveness.

Methods/design

This is a mixed methods pragmatic multicentre feasibility pilot study with four components:-

(a) A multicentre, external pilot randomised trial comparing basic clinical assessment with non-invasive tests and IUT. The outcome measures are rates of recruitment, randomisation and data completion. Data will be used to estimate sample size necessary for the definitive trial.

(b) Qualitative interviews of a purposively sampled sub-set of women eligible for the pilot trial will explore willingness to participate, be randomised and their overall trial experience.

(c) A national survey of clinicians to determine their views of IUT in this context, the main outcome being their willingness to randomise patients into the definitive trial.

(d) Qualitative interviews of a purposively sampled group of these clinicians will explore whether and how they use IUT to inform their decisions.

Discussion

The pilot trial will provide evidence of feasibility and acceptability and therefore inform the decision whether to proceed to the definitive trial. Results will inform the design and conduct of the definitive trial and ensure its effectiveness in achieving its research aim.

Trial registration number

Current Controlled Trials ISRCTN71327395 assigned 7th June 2010.
Ectopic cervical thymoma in a patient with Myasthenia gravis
Authors: Wu Ti Hei , Jin Jong Shiaw , Huang Tsai Wang , Chang Hung , Lee Shih Chun
Published: July 2011

Ectopic cervical thymoma is rare and is often misdiagnosed as a thyroid tumor or other malignancy. Ectopic thymic tissue can be found along the entire thymic descent path during embryogenesis. However, a thymoma arising from such ectopic thymic tissue is extremely rare. Herein we report a patient with ectopic cervical thymoma and myasthenia gravis (MG) and discuss the management.
An organogenesis network-based comparative transcriptome analysis for understanding early human development in vivo and in vitro
Authors: Fang Hai , Jin Wen , Yang Ying , Jin Ying , Zhang Ji , Wang Kankan
Published: July 2011

Background

Integrated networks hold great promise in a variety of contexts. In a recent study, we have combined expression and interaction data to identify a putative network underlying early human organogenesis that contains two modules, the stemness-relevant module (hStemModule) and the differentiation-relevant module (hDiffModule). However, owing to its hypothetical nature, it remains unclear whether this network allows for comparative transcriptome analysis to advance our understanding of early human development, both in vivo and in vitro.

Results

Based on this integrated network, we here report comparisons with the context-dependent transcriptome data from a variety of sources. By viewing the network and its two modules as gene sets and conducting gene set enrichment analysis, we demonstrate the network's utility as a quantitative monitor of the stem potential versus the differentiation potential. During early human organogenesis, the hStemModule reflects the generality of a gradual loss of the stem potential. The hDiffModule indicates the stage-specific differentiation potential and is therefore not suitable for depicting an extended developmental window. Processing of cultured cells of different types further revealed that the hStemModule is a general indicator that distinguishes different cell types in terms of their stem potential. In contrast, the hDiffModule cannot distinguish between differentiated cells of different types but is able to predict differences in the differentiation potential of pluripotent cells of different origins. We also observed a significant positive correlation between each of these two modules and early embryoid bodies (EBs), which are used as in vitro differentiation models. Despite this, the network-oriented comparisons showed considerable differences between the developing embryos and the EBs that were cultured in vitro over time to try to mimic in vivo processes.

Conclusions

We strongly recommend the use of these two modules either when pluripotent cell types of different origins are involved or when the comparisons made are constrained to the in vivo embryos during early human organogenesis (and an equivalent in vitro differentiation models). Network-based comparative transcriptome analysis will contribute to an increase in knowledge about human embryogenesis, particularly when only transcriptome data are currently available. These advances will add an extra dimension to network applications.
Spontaneous traumatic macular hole closure in a 50-year-old woman: a case report
Authors: Nasr Mayssa B , Symeonidis Chrysanthos , Tsinopoulos Ioannis , Androudi Sofia , Rotsos Tryfon , Dimitrakos Stavros A
Published: July 2011

Introduction

Traumatic macular holes (TMH) are well-known complications of ocular contusion injury. Spontaneous closure occurs in approximately 50% of cases, but rarely after the age of thirty. We report a case of spontaneous closure of a full thickness macular hole due to a blunt trauma and we suggest possible mechanisms for this closure.

Case presentation

A 50-year-old Greek woman was referred with a history of reduced best-corrected visual acuity after blunt trauma to her right eye. Diagnosis was based on fundoscopic, optical coherence tomography as well as fluorescein angiography findings with follow-up visits at two days, 20 days and five months. Fundoscopy revealed a full-thickness TMH with a minor sub-retinal hemorrhage and posterior vitreous detachment. The presence of a coagulum in the TMH base was observed. Subsequently, TMH closure was observed.

Conclusion

The clot in the TMH base, potentially a hemorrhage by-product containing a significant quantity of platelets, may have simulated the clot observed after autologous serum use, thus facilitating a similar effect. This may have stimulated glial cell migration and proliferation, thus contributing to spontaneous hole closure.
Multiple-center evaluation of mortality associated with acute kidney injury in critically ill patients: a competing risks analysis
Authors: Clec'h Christophe , Gonzalez Frédéric , Lautrette Alexandre , Nguile-Makao Molière , Garrouste-Orgeas Maïté , Jamali Samir , Golgran-Toledano Dany , Descorps-Declere Adrien , Chemouni Frank , Hamidfar-Roy Rebecca , Azoulay Elie , Timsit Jean-François
Published: July 2011

Introduction

In this study, we aimed to assess the association between acute kidney injury (AKI) and mortality in critically ill patients using an original competing risks approach.

Methods

Unselected patients admitted between 1997 and 2009 to 13 French medical or surgical intensive care units were included in this observational cohort study. AKI was defined according to the RIFLE criteria. The following data were recorded: baseline characteristics, daily serum creatinine level, daily Sequential Organ Failure Assessment (SOFA) score, vital status at hospital discharge and length of hospital stay. Patients were classified according to the maximum RIFLE class reached during their ICU stay. The association of AKI with hospital mortality with "discharge alive" considered as a competing event was assessed according to the Fine and Gray model.

Results

Of the 8,639 study patients, 32.9% had AKI, of whom 19.1% received renal replacement therapy. Patients with AKI had higher crude mortality rates and longer lengths of hospital stay than patients without AKI. In the Fine and Gray model, independent risk factors for hospital mortality were the RIFLE classes Risk (sub-hazard ratio (SHR) 1.58 and 95% confidence interval (95% CI) 1.32 to 1.88; P < 0.0001), Injury (SHR 3.99 and 95% CI 3.43 to 4.65; P < 0.0001) and Failure (SHR 4.12 and 95% CI 3.55 to 4.79; P < 0.0001); nonrenal SOFA score (SHR 1.19 per point and 95% CI 1.18 to 1.21; P < 0.0001); McCabe class 3 (SHR 2.71 and 95% CI 2.34 to 3.15; P < 0.0001); and respiratory failure (SHR 3.08 and 95% CI 1.36 to 7.01; P < 0.01).

Conclusions

By using a competing risks approach, we confirm in this study that AKI affecting critically ill patients is associated with increased in-hospital mortality.
Phase I/II Study of Trastuzumab in Combination With Everolimus (RAD001) in Patients With HER2-Overexpressing Metastatic Breast Cancer Who Progressed on Trastuzumab-Based Therapy
Authors: Morrow Phuong K. , Wulf Gerburg M. , Ensor Joe , Booser Daniel J. , Moore Julia A. , Flores Peter R. , Xiong Yan , Zhang Siyuan , Krop Ian E. , Winer Eric P. , Kindelberger David W. , Coviello Jeanna , Sahin Aysegul A. , Nuñez Rodolfo , Hortobagyi Gabriel N. , Yu Dihua , Esteva Francisco J.
Published: July 2011

Purpose

Trastuzumab resistance has been linked to activation of the phosphoinositol 3-kinase (PI3K) pathway. Phosphatase and tensin homolog (PTEN) is a dual phosphatase that counteracts the PI3K function; PTEN loss leads to activation of the Akt cascade and the downstream mammalian target of rapamycin (mTOR). Preclinical studies demonstrated that mTOR inhibition sensitized the response to trastuzumab in mice with HER2 overexpressing and PTEN-deficient breast xenografts. Our trial evaluated the safety and efficacy of the combination of everolimus and trastuzumab in women with HER2-overexpressing metastatic breast cancer (MBC) that progressed on trastuzumab-based therapy.

Patients and Methods

This represents a pooled analysis (n = 47), stemming from two trials that occurred concurrently in The University of Texas MD Anderson Cancer Center, Beth Israel Deaconess Medical Center, and Dana-Farber Cancer Institute. Patients with HER2-overexpressing MBC who had progressed on trastuzumab-based therapy received trastuzumab every 3 weeks in combination with daily everolimus.

Results

Among 47 patients, the combination of everolimus and trastuzumab provided partial responses in seven patients (15%) and persistent stable disease (lasting 6 months or longer) in nine patients (19%), resulting in a clinical benefit rate of 34%. The median progression-free survival (PFS) was 4.1 month. Fatigue, infection, and mucositis were the predominant nonhematologic toxicities. Trastuzumab did not have significant influence on the pharmacokinetic profile of everolimus. Patients with PTEN loss demonstrated decreased overall survival (P = .048). However, PFS was not affected by PTEN loss.

Conclusion

Inhibition of mTOR results in clinical benefit and disease response in patients with trastuzumab-resistant HER2-overexpressing MBC.
Tandem Autologous/Reduced-Intensity Conditioning Allogeneic Stem-Cell Transplantation Versus Autologous Transplantation in Myeloma: Long-Term Follow-Up
Authors: Björkstrand Bo , Iacobelli Simona , Hegenbart Ute , Gruber Astrid , Greinix Hildegard , Volin Liisa , Narni Franco , Musto Pellegrino , Beksac Meral , Bosi Alberto , Milone Giuseppe , Corradini Paolo , Goldschmidt Hartmut , de Witte Theo , Morris Curly , Niederwieser Dietger , Gahrton Gösta
Published: July 2011

Purpose

Results of allogeneic stem-cell transplantation (allo) in myeloma are controversial. In this trial autologous stem-cell transplantation (auto) followed by reduced-intensity conditioning matched sibling donor allo (auto-allo) was compared with auto only in previously untreated multiple myeloma.

Patients and Methods

In all, 357 patients with myeloma up to age 69 years were enrolled from 2001 to 2005. Patients with an HLA-identical sibling donor were allocated to the auto-allo arm (n = 108) and patients without a matched sibling donor were allocated to the auto arm (n = 249). Single (n = 145) or tandem (n = 104) auto was optional. Conditioning for the auto arm was melphalan 200 mg/m2; conditioning for the allo arm was total-body irradiation 2 Gy plus fludarabine 30 mg/m2/d for 3 days. Median follow-up time was 61 months. Primary end point was progression-free survival.

Results

Progression-free survival at 60 months was significantly better with auto-allo than with allo alone (35% v 18%; P = .001), as was the risk of death and of relapse in the long term (P = .047 and P = .003, respectively). Overall survival at 60 months was 65% versus 58%, and relapse incidence was 49% versus 78%. Complete remission rates were 51% and 41%, respectively (P = .020). Nonrelapse mortality at 24 months was 12% after auto-allo compared with 3% in the auto group (P < .001). The incidence of grade 2 to 4 acute graft-versus-host disease (GvHD) was 20%, and the incidence of limited and extensive chronic GvHD was 31% and 23%.

Conclusion

In patients with previously untreated multiple myeloma, long-term outcome with respect to progression-free survival, overall survival, and relapse rate is superior after auto-allo compared with auto only. Nonrelapse mortality is at a reasonable level in both groups.
Variability of Lung Tumor Measurements on Repeat Computed Tomography Scans Taken Within 15 Minutes
Authors: Oxnard Geoffrey R. , Zhao Binsheng , Sima Camelia S. , Ginsberg Michelle S. , James Leonard P. , Lefkowitz Robert A. , Guo Pingzhen , Kris Mark G. , Schwartz Lawrence H. , Riely Gregory J.
Published: July 2011

Purpose

We use changes in tumor measurements to assess response and progression, both in routine care and as the primary objective of clinical trials. However, the variability of computed tomography (CT) –based tumor measurement has not been comprehensively evaluated. In this study, we assess the variability of lung tumor measurement using repeat CT scans performed within 15 minutes of each other and discuss the implications of this variability in a clinical context.

Patients and Methods

Patients with non–small-cell lung cancer and a target lung lesion ≥ 1 cm consented to undergo two CT scans within a period of minutes. Three experienced radiologists measured the diameter of the target lesion on the two scans in a side-by-side fashion, and differences were compared.

Results

Fifty-seven percent of changes exceeded 1 mm in magnitude, and 33% of changes exceeded 2 mm. Median increase and decrease in tumor measurements were +4.3% and −4.2%, respectively, and ranged from 23% shrinkage to 31% growth. Measurement changes were within ± 10% for 84% of measurements, whereas 3% met criteria for progression according to Response Evaluation Criteria in Solid Tumors (RECIST; ≥ 20% increase). Smaller lesions had greater variability of percent measurement change (P = .005).

Conclusion

Apparent changes in tumor diameter exceeding 1 to 2 mm are common on immediate reimaging. Increases and decreases less than 10% can be a result of the inherent variability of reimaging. Caution should be exercised in interpreting the significance of small changes in lesion size in the care of individual patients and in the interpretation of clinical trial results.
Intrahepatic Cholangiocarcinoma: An International Multi-Institutional Analysis of Prognostic Factors and Lymph Node Assessment
Authors: de Jong Mechteld C. , Nathan Hari , Sotiropoulos Georgios C. , Paul Andreas , Alexandrescu Sorin , Marques Hugo , Pulitano Carlo , Barroso Eduardo , Clary Bryan M. , Aldrighetti Luca , Ferrone Cristina R. , Zhu Andrew X. , Bauer Todd W. , Walters Dustin M. , Gamblin T. Clark , Nguyen Kevin T. , Turley Ryan , Popescu Irinel , Hubert Catherine , Meyer Stephanie , Schulick Richard D. , Choti Michael A. , Gigot Jean-Francois , Mentha Gilles , Pawlik Timothy M.
Published: July 2011

Purpose

To identify factors associated with outcome after surgical management of intrahepatic cholangiocarcinoma (ICC) and examine the impact of lymph node (LN) assessment on survival.

Patients and Methods

From an international multi-institutional database, 449 patients who underwent surgery for ICC between 1973 and 2010 were identified. Clinical and pathologic data were evaluated using uni- and multivariate analyses.

Results

Median tumor size was 6.5 cm. Most patients had a solitary tumor (73%) and no vascular invasion (69%). Median survival was 27 months, and 5-year survival was 31%. Factors associated with adverse prognosis included positive margin status (hazard ratio [HR], 2.20; P < .001), multiple lesions (HR, 1.80; P = .001), and vascular invasion (HR, 1.59; P = .015). Tumor size was not a prognostic factor (HR, 1.03; P = .23). Patients were stratified using the American Joint Committee on Cancer/International Union Against Cancer T1, T2a, and T2b categories (seventh edition) in a discrete step-wise fashion (P < .001). Lymphadenectomy was performed in 248 patients (55%); 74 of these (30%) had LN metastasis. LN metastasis was associated with worse outcome (median survival: N0, 30 months v N1, 24 months; P = .03). Although patients with no LN metastasis were able to be stratified by tumor number and vascular invasion (N0; P < .001), among patients with N1 disease, multiple tumors and vascular invasion, either alone or together, failed to discriminate patients into discrete prognostic groups (P = .34).

Conclusion

Although tumor size provides no prognostic information, tumor number, vascular invasion, and LN metastasis were associated with survival. N1 status adversely affected overall survival and also influenced the relative effect of tumor number and vascular invasion on prognosis. Lymphadenectomy should be strongly considered for ICC, because up to 30% of patients will have LN metastasis.
Evidence of Adrenal Failure in Aging Dax1-Deficient Mice
Authors: Scheys Joshua O. , Heaton Joanne H. , Hammer Gary D.
Published: July 2011

Dosage-sensitive sex reversal, adrenal hypoplasia congenita (AHC) critical region on the X chromosome, gene 1 (Dax1) is an orphan nuclear receptor essential for development and function of the mammalian adrenal cortex and gonads. DAX1 was cloned as the gene responsible for X-linked AHC, which is characterized by adrenocortical failure necessitating glucocorticoid replacement. Contrary to these human data, young mice with genetic Dax1 knockout (Dax1−/Y) exhibit adrenocortical hyperfunction, consistent with the historic description of Dax1 as a transcriptional repressor that inhibits steroidogenic factor 1-dependent steroidogenesis. This paradox of molecular function and two apparently opposite phenotypes associated with Dax1 deficiency in mice and humans is compounded by the recent observations that under certain circumstances, Dax1 can serve as a transcriptional activator of steroidogenic factor 1. The recently revealed role of Dax1 in embryonic stem cell pluripotency, together with the observation that its expression in the adult adrenal is restricted to the subcapsular cortex, where presumptive undifferentiated progenitor cells reside, has led us to reexamine the phenotype of Dax1−/Y mice in order to reconcile the conflicting mouse and human data. In this report, we demonstrate that although young Dax1−/Y mice have enhanced steroidogenesis and subcapsular adrenocortical proliferation, as these mice age, they exhibit declining adrenal growth, decreasing adrenal steroidogenic capacity, and a reversal of their initial enhanced hormonal sensitivity. Together with a marked adrenal dysplasia in aging mice, these data reveal that both Dax1−/Y mice and patients with X-linked AHC exhibit adrenal failure that is consistent with adrenocortical subcapsular progenitor cell depletion and argue for a significant role of Dax1 in maintenance of these cells.