bluuebunny/crossref_metadata_2025 huggingface dataset:
Design and evaluation of a treatment programme for Spanish adolescents with overweight and obesity. The EVASYON Study
Authors: Martinez-Gomez David , Gomez-Martinez Sonia , Puertollano M Angeles , Nova Esther , Wärnberg Julia , Veiga Oscar L , Martí Amelia , Campoy Cristina , Garagorri Jesus M , Azcona Cristina , Vaquero M Pilar , Redondo-Figuero Carlos , Delgado Manuel , Martínez J Alfredo , Garcia-Fuentes Miguel , Moreno Luis A , Marcos Ascension ,   EVASYON Study Group
Published: November 2009

Background

The prevalence of overweight and obesity (OW/OB) among adolescents worldwide has increased since the 60 s. Spain has reached one of the highest OW/OB prevalence rates among adolescents from European countries. The aim of this methodological paper is to describe the design and evaluation in the EVASYON study (Development, implementation and evaluation of the efficacy of a therapeutic programme for adolescents with OW/OB: integral education on nutrition and physical activity).

Methods/Design

The EVASYON was planned by a multidisciplinary team to treat OW/OB in Spanish adolescents. The EVASYON is a multi-centre study conducted in 5 hospitals in 5 Spanish cities (Granada, Madrid, Pamplona, Santander and Zaragoza) and two hundred and four OW/OB Spanish adolescents were recruited for this intervention. The treatment was implemented for approximately one-year follow-up. The adolescents were treated in groups of a maximum of 10 subjects; each group had 20 visits during the treatment period in two phases: intensive during the first 2 months (1stto 9thvisits), and extensive during the last 11 months (10thto 20thvisits). In order to assess the efficacy of the treatment, 8 dimensions were measured: diet; physical activity and fitness; eating behaviour; body composition; haematological profile; metabolic profile; minerals and vitamins; immuno-inflammatory markers. Moreover, genetic polymorphisms were also determined.

Discussion

The treatment programme developed in the EVASYON study was designed as a national pilot study to be implemented as an effective treatment for adolescents with OW/OB into the Spanish Health Care Service.
Interleukin-6 and Cyclooxygenase-2 downregulation by fatty-acid fractions of Ranunculus constantinopolitanus
Authors: Fostok Sabreen F , Ezzeddine Rima A , Homaidan Fadia R , Al-Saghir Jamal A , Salloum Ralph G , Saliba Najat A , Talhouk Rabih S
Published: November 2009

Background

Medicinal plants represent alternative means for the treatment of several chronic diseases, including inflammation. The genus Ranunculus, a representative of the Ranunculaceae family, has been reported to possess anti-inflammatory, analgesic, antiviral, antibacterial, antiparasitic and antifungal activities, possibly due to the presence of anemonin and other. Different studies have shown the occurrence of unusual fatty acids (FAs) in Ranunculaceae; however, their therapeutic role has not been investigated. The purpose of this study is to characterize potential anti-inflammatory bioactivities in Ranunculus constantinopolitanus D'Urv., traditionally used in Eastern Mediterranean folk medicine.

Methods

The aerial part of R. constantinopolitanus was subjected to methanol (MeOH) extraction and solvent fractionation. The bioactive fraction (I.2) was further fractionated using column chromatography, and the biologically active subfraction (Y2+3) was identified using infrared (IR) spectroscopy, nuclear magnetic resonance (NMR) and gas chromatography-mass spectrometry (GC-MS). The effects of I.2 and Y2+3 on cell viability were studied in mouse mammary epithelial SCp2 cells using trypan blue exclusion method. To study the anti-inflammatory activities of I.2 and Y2+3, their ability to reduce interleukin (IL)-6 levels was assessed in endotoxin (ET)-stimulated SCp2 cells using enzyme-linked immunosorbent assay (ELISA). In addition, the ability of Y2+3 to reduce cyclooxygenase (COX)-2 expression was studied in IL-1-treated mouse intestinal epithelial Mode-K cells via western blotting. Data were analyzed by one-way analysis of variance (ANOVA), Student-Newman-Keuls (SNK), Tukey HSD, two-sample t-test and Dunnett t-tests for multiple comparisons.

Results

The chloroform fraction (I.2) derived from crude MeOH extract of the plant, in addition to Y2+3, a FA mix isolated from this fraction and containing palmitic acid, C18:2 and C18:1 isomers and stearic acid (1:5:8:1 ratio), reduced ET-induced IL-6 levels in SCp2 cells without affecting cell viability or morphology. When compared to fish oil, conjugated linoleic acid (CLA) and to individual FAs as palmitic, linoleic, oleic and stearic acid or to a mix of these FAs (1:5:8:1 ratio), Y2+3 exhibited higher potency in reducing ET-induced IL-6 levels within a shorter period of time. Y2+3 also reduced COX-2 expression in IL-1-treated Mode-K cells.

Conclusion

Our studies demonstrate the existence of potential anti-inflammatory bioactivities in R. constantinopolitanus and attribute them to a FA mix in this plant.
In vivo administration of BL-3050: highly stable engineered PON1-HDL complexes
Authors: Gaidukov Leonid , Bar Dganit , Yacobson Shiri , Naftali Esmira , Kaufman Olga , Tabakman Rinat , Tawfik Dan S , Levy-Nissenbaum Etgar
Published: November 2009

Background

Serum paraoxonase (PON1) is a high density lipoprotein (HDL)-associated enzyme involved in organophosphate (OP) degradation and prevention of atherosclerosis. PON1 comprises a potential candidate forin vivotherapeutics, as an anti-atherogenic agent, and for detoxification of pesticides and nerve agents. Because human PON1 exhibits limited stability, engineered, recombinant PON1 (rePON1) variants that were designed for higher reactivity, solubility, stability, and bacterial expression, are candidates for treatment. This work addresses the feasibility ofin vivoadministration of rePON1, and its HDL complex, as a potentially therapeutic agent dubbed BL-3050.

Methods

For stability studies we applied different challenges related to thein vivodisfunctionalization of HDL and PON1 and tested for inactivation of PON1's activity. We applied acute, repetitive administrations of BL-3050 in mice to assess its toxicity and adverse immune responses. Thein vivoefficacy of recombinant PON1 and BL-3050 were tested with an animal model of chlorpyrifos-oxon poisoning.

Results

Inactivation studies show significantly improvedin vitrolifespan of the engineered rePON1 relative to human PON1. Significant sequence changes relative to human PON1 might hamper thein vivoapplicability of BL-3050 due to adverse immune responses. However, we observed no toxic effects in mice subjected to repetitive administration of BL-3050, suggesting that BL-3050 could be safely used. To further evaluate the activity of BL-3050in vivo, we applied an animal model that mimics human organophosphate poisoning. In these studies, a significant advantages of rePON1 and BL-3050 (>87.5% survival versus <37.5% in the control groups) was observed. Furthermore, BL-3050 and rePON1 were superior to the conventional treatment of atropine-2-PAM as a prophylactic treatment for OP poisoning.

Conclusion

In vitroandin vivodata described here demonstrate the potential advantages of rePON1 and BL-3050 for treatment of OP toxicity and chronic cardiovascular diseases like atherosclerosis. Thein vivodata also suggest that rePON1 and BL-3050 are stable and safe, and could be used for acute, and possibly repeated treatments, with no adverse effects.
Age, chronic non-communicable disease and choice of traditional Chinese and western medicine outpatient services in a Chinese population
Authors: Chung Vincent CH , Lau Chun Hong , Yeoh Eng Kiong , Griffiths Sian Meryl
Published: November 2009

Background

In 1997 Hong Kong reunified with China and the development of traditional Chinese medicine (TCM) started with this change in national identity. However, the two latest discussion papers on Hong Kong's healthcare reform have failed to mention the role of TCM in primary healthcare, despite TCM's public popularity and its potential in tackling the chronic non-communicable disease (NCD) challenge in the ageing population. This study aims to describe the interrelationship between age, non-communicable disease (NCD) status, and the choice of TCM and western medicine (WM) services in the Hong Kong population.

Methods

This study is a secondary analysis of the Thematic Household Survey (THS) 2005 dataset. The THS is a Hong Kong population representative face to face survey was conducted by the Hong Kong Administrative Region Government of China. A random sample of respondents aged >15 years were invited to report their use of TCM and WM in the past year, together with other health and demographic information. A total of 33,263 persons were interviewed (response rate 79.2%).

Results

Amongst those who received outpatient services in the past year (n = 18,087), 80.23% only visited WM doctors, 3.17% consulted TCM practitioners solely, and 16.60% used both type of services (double consulters). Compared to those who only consulted WM doctor, multinomial logistic regression showed that double consulters were more likely to be older, female, NCD patients, and have higher socioeconomic backgrounds. Further analysis showed that the association between age and double consulting was curvilinear (inverted U shaped) regardless of NCD status. Middle aged (45-60 years) NCD patients, and the NCD free "young old" group (60-75 years) were most likely to double consult. On the other hand, the relationship between age and use of TCM as an alternative to WM was linear regardless of NCD status. The NCD free segment of the population was more inclined to use TCM alone as they become older.

Conclusion

In Hong Kong, most patients have chosen WM provided in the public sector as their sole outpatient service provider for NCD. Amongst TCM service users, middle aged NCD patients are more likely to choose both TCM and WM outpatient services. Meanwhile, older people without NCD are more likely to use TCM as their main form of care, but the size of this population group is small. These utilization patterns show that patients choose both modalities to manage their NCD and TCM should be considered within policies for supporting patients with NCD under the wider primary health and social care system that supports patient choice.
Sex separation strategies: past experience and new approaches
Authors: Papathanos Philippos A , Bossin Hervé C , Benedict Mark Q , Catteruccia Flaminia , Malcolm Colin A , Alphey Luke , Crisanti Andrea
Published: November 2009

The success of the sterile insect technique (SIT) and other genetic strategies designed to eliminate large populations of insects relies on the efficient inundative releases of competitive, sterile males into the natural habitat of the target species. As released sterile females do not contribute to the sterility in the field population, systems for the efficient mass production and separation of males from females are needed. For vector species like mosquitoes, in which only females bite and transmit diseases, the thorough removal of females before release while leaving males competent to mate is a stringent prerequisite. Biological, genetic and transgenic approaches have been developed that permit efficient male-female separation for some species considered for SIT. However, most sex separation methods have drawbacks and many of these methods are not directly transferable to mosquitoes. Unlike genetic and transgenic systems, biological methods that rely on sexually dimorphic characters, such as size or development rate, are subject to natural variation, requiring regular adjustment and re-calibration of the sorting systems used. The yield can be improved with the optimization of rearing, but the scale of mass production places practical limits on what is achievable, resulting in a poor rearing to output ratio. High throughput separation is best achieved with scalable genetic or transgenic approaches.
Expression and function of hypoxia inducible factor-1 alpha in human melanoma under non-hypoxic conditions
Authors: Mills Caroline N , Joshi Sandeep S , Niles Richard M
Published: November 2009

Background

Hypoxia inducible factor-1 alpha (HIF-1α) protein is rapidly degraded under normoxic conditions. When oxygen tensions fall HIF-1α protein stabilizes and transactivates genes involved in adaptation to hypoxic conditions. We have examined the normoxic expression of HIF-1α RNA and protein in normal human melanocytes and a series of human melanoma cell lines isolated from radial growth phase (RGP), vertical growth phase (VGP) and metastatic (MET) melanomas.

Results

HIF-1α mRNA and protein was increased in RGP vs melanocytes, VGP vs RGP and MET vs VGP melanoma cell lines. We also detected expression of a HIF-1α mRNA splice variant that lacks part of the oxygen-dependent regulation domain in WM1366 and WM9 melanoma cells. Over-expression of HIF-1α and its splice variant in the RGP cell line SbCl2 resulted in a small increase in soft agar colony formation and a large increase in matrigel invasion relative to control transfected cells. Knockdown of HIF-1α expression by siRNA in the MET WM9 melanoma cell line resulted in a large decrease in both soft agar colony formation and matrigel invasion relative to cells treated with non-specific siRNA. There is a high level of ERK1/2 phosphorylation in WM9 cells, indicating an activated Ras-Raf-MEK-ERK1/2 MAPK pathway. Treatment of WM9 cells with 30 μM U0126 MEK inhibitor, decreased ERK1/2 phosphorylation and resulted in a decrease in HIF-1α expression. However, a 24 h treatment with 10 μM U0126 totally eliminated Erk1/2 phosphorylation, but did not change HIF-1alpha levels. Furthermore, siRNA knockdown of MEK siRNA did not change HIF-1alpha levels.

Conclusion

We speculate that metabolic products of U0126 decrease HIF-1alpha expression through "off target" effects. Overall our data suggest that increased HIF-1α expression under normoxic conditions contributes to some of the malignant phenotypes exhibited by human melanoma cells. The expanded role of HIF-1α in melanoma biology increases its importance as a therapeutic target.
Up-regulation of CatSper genes family by selenium
Authors: Mohammadi Shabnam , Movahedin Mansoureh , Mowla Seyed Javad
Published: November 2009

Background

CatSper1-4 are a unique family of sperm cation channels, which are exclusively expressed in the testis and play an important role in sperm motility and male fertility. Despite their vital role in male fertility, almost nothing is known about the factors regulating their expression. Here, we investigated the effects of selenium (Se) on the expression of CatSper genes and sperm parameters in aging versus young male mice.

Methods

Forty 11-13 months aging male mice and forty 2-3 months young adult male mice were used. The animals were divided in two experimental groups: first group including aging males and second group comprising of young adult males, both treated with Se. The experimental groups were injected intra-peritoneally with Se (0.2 mg/kg) daily, for up to 5 weeks. Two other groups, aging and young adult mice without Se treatment were used as controls. All the animals were rapidly sacrificed by cervical dislocation on the days 21, 28, 35 and 42 after Se treatment. Subsequently, the morphology of the collected sperms was analyzed, and one of the testes from each mouse used for semi-quantitative RT-PCR. The significancy of the data was analyzed using ANOVA.

Results and Discussion

Our data revealed that there was a significant up-regulation of CatSper genes in the experimental groups compared to the control ones. Furthermore, the results of sperm analysis showed that the sperm parameters were improved in the aging as well as young adult male mice following Se treatment.

Conclusion

Se treatment in the aging subjects could up-regulate the expression of CatSper genes, and therefore results in elevation of sperm motility. Furthermore, Se treatment improved sperm parameters, especially morphology and viability rates.
Sustainable scaling up of good quality health worker education for tuberculosis control in Indonesia: a case study
Authors: Basri Carmelia , Bergström Karin , Walton Wanda , Surya Asik , Voskens Jan , Metha Firdosi
Published: November 2009

Background

In 2000, an external review mission of the National Tuberculosis Control Programme of Indonesia identified suboptimal results of TB control activities. This led to a prioritization on human resource capacity building representing a major shift in the approach following the recommendations of the external review team.

Case description

The National Tuberculosis Control Programme (NTP) used a systematic process to develop and implement two strategic action plans focussing on competence development based on specific job descriptions. The approach was a change from only focussing on training, to a broader, long term approach to human resource development for comprehensive TB control.

A structured plan for capacity building, including standardized competency based training modules and curricula, was developed in the first phase. This was supported by an organisational system comprised of a training focal point, master trainers, and regional training centres in which nationwide training of supervisors was implemented. Training was expanded to the health service delivery level in the second phase, as well as broadened in the scope of activities beyond training to also include other aspects of human resource development.

Discussion and evaluation

The result was improved technical and managerial capacity of health workers for TB control at all levels. The impact on case detection and treatment outcome was spectacular, with major improvements in quality of all aspects of service delivery.

Conclusion

The strategic decision by the NTP in 2000 to put the highest priority on capacity building has resulted in impressive progress towards TB control targets, a progress that despite many challenges has been sustained.
Factors necessary to produce basoapical polarity in human glandular epithelium formed in conventional and high-throughput three-dimensional culture: example of the breast epithelium
Authors: Plachot Cedric , Chaboub Lesley S , Adissu Hibret A , Wang Lei , Urazaev Albert , Sturgis Jennifer , Asem Elikplimi K , Lelièvre Sophie A
Published: November 2009

Background

Basoapical polarity in epithelia is critical for proper tissue function, and control of proliferation and survival. Cell culture models that recapitulate epithelial tissue architecture are invaluable to unravel developmental and disease mechanisms. Although factors important for the establishment of basal polarity have been identified, requirements for the formation of apical polarity in three-dimensional tissue structures have not been thoroughly investigated.

Results

We demonstrate that the human mammary epithelial cell line-3522 S1, provides a resilient model for studying the formation of basoapical polarity in glandular structures. Testing three-dimensional culture systems that differ in composition and origin of substrata reveals that apical polarity is more sensitive to culture conditions than basal polarity. Using a new high-throughput culture method that produces basoapical polarity in glandular structures without a gel coat, we show that basal polarity-mediated signaling and collagen IV are both necessary for the development of apical polarity.

Conclusion

These results provide new insights into the role of the basement membrane, and especially collagen IV, in the development of the apical pole, a critical element of the architecture of glandular epithelia. Also, the high-throughput culture method developed in this study should open new avenues for high-content screening of agents that act on mammary tissue homeostasis and thus, on architectural changes involved in cancer development.
Expression of complement system components during aging and amyloid deposition in APP transgenic mice
Authors: Reichwald Julia , Danner Simone , Wiederhold Karl-Heinz , Staufenbiel Matthias
Published: November 2009

Background

A causal role of the complement system in Alzheimer's disease pathogenesis has been postulated based on the identification of different activated components up to the membrane attack complex at amyloid plaques in brain. However, histological studies of amyloid plaque bearing APP transgenic mice provided only evidence for an activation of the early parts of the complement cascade. To better understand the contribution of normal aging and amyloid deposition to the increase in complement activation we performed a detailed characterization of the expression of the major mouse complement components.

Methods

APP23 mice expressing human APP751 with the Swedish double mutation as well as C57BL/6 mice were used at different ages. mRNA was quantified by Realtime PCR and the age- as well as amyloid induced changes determined. The protein levels of complement C1q and C3 were analysed by Western blotting. Histology was done to test for amyloid plaque association and activation of the complement cascade.

Results

High mRNA levels were detected for C1q and some inhibitory complement components. The expression of most activating components starting at C3 was low. Expression of C1q, C3, C4, C5 and factor B mRNA increased with age in control C57BL/6 mice. C1q and C3 mRNA showed a substantial additional elevation during amyloid formation in APP23 mice. This increase was confirmed on the protein level using Western blotting, whereas immunohistology indicated a recruitment of complement to amyloid plaques up to the C3 convertase.

Conclusion

Early but not late components of the mouse complement system show an age-dependent increase in expression. The response to amyloid deposition is comparatively smaller. The low expression of C3 and C5 and failure to upregulate C5 and downstream components differs from human AD brain and likely contributes to the lack of full complement activation in APP transgenic mice.
Preliminary study on temporal variations in biting activity of Simulium damnosum s.l. in Abeokuta North LGA, Ogun State Nigeria
Authors: Oluwole Akinola S , Ekpo Uwem F , Mafiana Chiedu F , Adeofun Clement O , Idowu Olufunmilayo A
Published: November 2009

Background

Simulum damnosum Theobald sensu lato (s.l.) is the vector of the parasitic filarial worm Onchocerca volvulus Leuckart which causes onchocerciasis. In order to understand the vector population dynamics, a preliminary 12 months entomological evaluation was carried out at Abeokuta, the Southwest Zone of Nigeria, an onchocerciasis endemic area, where vector control has not been previously initiated. S.damnosum s.l. flies were caught on human attractants between 700 to1800 hours each day, for 4 days each month, from August 2007 to July 2008. The flies caught were classified as either forest-dwelling or savanna-dwelling groups based on the colour of certain morphological characters. Climatic data such as rainfall, humidity and temperature were also collected monthly during the period of survey.

Results

A total of 1,139 flies were caught, 596 (52.33%) were forest-dwelling group while 543 (47.67%) were savanna-dwelling group of S. damnosum s.l. The highest percentage of forest-dwelling group was caught in the month of August 2007 (78.06%) and the least percentage of forest-dwelling groups was caught in November 2007 (8.14%). The highest percentage of savannah-dwelling group was caught in the month of November 2007 (91.86%) and the least percentage of savannah-dwelling group was caught in August 2007 (21.94%). There was no significant difference between the population of forest and savannah-dwelling groups of the fly when the means of the fly population were compared (P = 0.830). Spearman correlation analysis showed a significant relationship between monthly fly population with monthly average rainfall (r = 0.550, n = 12, P = 0.033), but no significant relationship with monthly average temperature (r = 0.291, n = 12, P = 0.179). There was also a significant relationship between monthly fly population and monthly average relative humidity (r = 0.783, n = 12 P = 0.001). There was no significant correlation between the population of forest-dwelling group of S. damnosum s.l. and monthly average rainfall (r = 0.466, n = 12, P = 0.064) and monthly average temperature (r = 0.375, n = 12, P = 0.115) but there was significant correlation with monthly average relative humidity (r = 0.69, n = 12, P = 0.006). There was significant correlation between savannah-dwelling group and monthly average rainfall (r = 0.547, n = 12, P = 0.033), and monthly average relative humidity (r = 0.504, n = 12, P = 0.047) but there was no significant correlation with monthly average temperature (r = 0.142, n = 12, P = 0.329)

Conclusion

The results from this study showed that both the forest and the savannah dwelling groups of S. damnosum s.l. were caught biting in the study area. This could have implications on the transmission and epidemiology of human onchocerciasis if not monitored.
Distribution of Brugia malayi larvae and DNA in vector and non-vector mosquitoes: implications for molecular diagnostics
Authors: Erickson Sara M , Fischer Kerstin , Weil Gary J , Christensen Bruce M , Fischer Peter U
Published: November 2009

Background

The purpose of this study was to extend prior studies of molecular detection ofBrugia malayiDNA in vector (Aedes aegypti-Liverpool) and non-vector (Culex pipiens) mosquitoes at different times after ingestion of infected blood.

Results

Parasite DNA was detected over a two week time course in 96% of pooled thoraces of vector mosquitoes. In contrast, parasite DNA was detected in only 24% of thorax pools from non-vectors; parasite DNA was detected in 56% of midgut pools and 47% of abdomen pools from non-vectors. Parasite DNA was detected in vectors in the head immediately after the blood meal and after 14 days. Parasite DNA was also detected in feces and excreta of the vector and non-vector mosquitoes which could potentially confound results obtained with field samples. However, co-housing experiments failed to demonstrate transfer of parasite DNA from infected to non-infected mosquitoes. Parasites were also visualized in mosquito tissues by immunohistololgy using an antibody to the recombinant filarial antigen Bm14. Parasite larvae were detected consistently after mf ingestion inAe. aegypti-Liverpool. Infectious L3s were seen in the head, thorax and abdomen of vector mosquitoes 14 days after Mf ingestion. In contrast, parasites were only detected by histology shortly after the blood meal inCx. pipiens, and these were not labeled by the antibody.

Conclusion

This study provides new information on the distribution of filarial parasites and parasite DNA in vector and non-vector mosquitoes. This information should be useful for those involved in designing and interpreting molecular xenomonitoring studies.
Luteinizing hormone-induced Akt phosphorylation and androgen production are modulated by MAP Kinase in bovine theca cells
Authors: Fukuda Shin , Orisaka Makoto , Tajima Kimihisa , Hattori Katsushige , Kotsuji Fumikazu
Published: November 2009

Background

Theca cells play an important role in controlling ovarian steroidogenesis by providing aromatizable androgens for granulosa cell estrogen biosynthesis. Although it is well established that the steroidogenic activity of theca cells is mainly regulated by LH, the intracellular signal transduction mechanisms that regulate thecal proliferation and/or steroidogenesis remain obscure. In this study, we examined whether and how LH controls the PI3K/Akt signaling pathway and androgen production in bovine theca cells. We also explored whether this LH-induced PI3K/Akt activation is modulated with other signaling pathways (i.e. PKA and MAPK).

Methods

Ovarian theca cells were isolated from bovine small antral follicles and were incubated with LH for various durations. Phospho-Akt and total-Akt content in the cultured theca cells were examined using Western blotting. Androstenedione levels in the spent media were determined using EIA. Semi-quantitative RT-PCR analyses were conducted to analyze the mRNA levels of CYP17A1 and StAR in the theca cells. To examine whether Akt activity is involved in theca cell androgen production, the PI3K inhibitors wortmannin and LY294002 were also added to the cells.

Results

Akt is constitutively expressed, but is gradually phosphorylated in cultured bovine theca cells through exposure to LH. LH significantly increased androstenedione production in bovine theca cells, whereas addition of the wortmannin and LY294002 significantly decreased LH-induced androstenedione production. LH significantly increased CYP17A1 mRNA level in theca cells, whereas addition of LY294002 significantly decreased LH-induced CYP17A1 expression. Neither LH nor PI3K inhibitors alter the mRNA levels of StAR in theca cells. Although H89 (a selective inhibitor of PKA) does not affect LH-mediated changes in Akt, U0126 (a potent MEK inhibitor) suppressed LH-induced Akt phosphorylation, CYP17A1 expression, and androgen production in theca cells.

Conclusion

These results indicate that LH stimulates CYP17 mRNA expression and androgen production in theca cells via activation of the PI3K/Akt pathway. The LH-induced Akt phosphorylation and androgen production are modulated by the MAPK signaling in bovine theca cells.
Association of arterial blood pressure and vasopressor load with septic shock mortality: a post hoc analysis of a multicenter trial
Authors: Dünser Martin W , Ruokonen Esko , Pettilä Ville , Ulmer Hanno , Torgersen Christian , Schmittinger Christian A , Jakob Stephan , Takala Jukka
Published: November 2009

Introduction

It is unclear to which level mean arterial blood pressure (MAP) should be increased during septic shock in order to improve outcome. In this study we investigated the association between MAP values of 70 mmHg or higher, vasopressor load, 28-day mortality and disease-related events in septic shock.

Methods

This is a post hoc analysis of data of the control group of a multicenter trial and includes 290 septic shock patients in whom a mean MAP ≥ 70 mmHg could be maintained during shock. Demographic and clinical data, MAP, vasopressor requirements during the shock period, disease-related events and 28-day mortality were documented. Logistic regression models adjusted for the geographic region of the study center, age, presence of chronic arterial hypertension, simplified acute physiology score (SAPS) II and the mean vasopressor load during the shock period was calculated to investigate the association between MAP or MAP quartiles ≥ 70 mmHg and mortality or the frequency and occurrence of disease-related events.

Results

There was no association between MAP or MAP quartiles and mortality or the occurrence of disease-related events. These associations were not influenced by age or pre-existent arterial hypertension (all P > 0.05). The mean vasopressor load was associated with mortality (relative risk (RR), 1.83; confidence interval (CI) 95%, 1.4-2.38; P < 0.001), the number of disease-related events (P < 0.001) and the occurrence of acute circulatory failure (RR, 1.64; CI 95%, 1.28-2.11; P < 0.001), metabolic acidosis (RR, 1.79; CI 95%, 1.38-2.32; P < 0.001), renal failure (RR, 1.49; CI 95%, 1.17-1.89; P = 0.001) and thrombocytopenia (RR, 1.33; CI 95%, 1.06-1.68; P = 0.01).

Conclusions

MAP levels of 70 mmHg or higher do not appear to be associated with improved survival in septic shock. Elevating MAP >70 mmHg by augmenting vasopressor dosages may increase mortality. Future trials are needed to identify the lowest acceptable MAP level to ensure tissue perfusion and avoid unnecessary high catecholamine infusions.
Differential binding and co-binding pattern of FOXA1 and FOXA3 and their relation to H3K4me3 in HepG2 cells revealed by ChIP-seq
Authors: Motallebipour Mehdi , Ameur Adam , Reddy Bysani Madhu Sudhan , Patra Kalicharan , Wallerman Ola , Mangion Jonathan , Barker Melissa A , McKernan Kevin J , Komorowski Jan , Wadelius Claes
Published: November 2009

Background

The forkhead box/winged helix family members FOXA1, FOXA2, and FOXA3 are of high importance in development and specification of the hepatic linage and the continued expression of liver-specific genes.

Results

Here, we present a genome-wide location analysis of FOXA1 and FOXA3 binding sites in HepG2 cells through chromatin immunoprecipitation with detection by sequencing (ChIP-seq) studies and compare these with our previous results on FOXA2. We found that these factors often bind close to each other in different combinations and consecutive immunoprecipitation of chromatin for one and then a second factor (ChIP-reChIP) shows that this occurs in the same cell and on the same DNA molecule, suggestive of molecular interactions. Using co-immunoprecipitation, we further show that FOXA2 interacts with both FOXA1 and FOXA3 in vivo, while FOXA1 and FOXA3 do not appear to interact. Additionally, we detected diverse patterns of trimethylation of lysine 4 on histone H3 (H3K4me3) at transcriptional start sites and directionality of this modification at FOXA binding sites. Using the sequence reads at polymorphic positions, we were able to predict allele specific binding for FOXA1, FOXA3, and H3K4me3. Finally, several SNPs associated with diseases and quantitative traits were located in the enriched regions.

Conclusions

We find that ChIP-seq can be used not only to create gene regulatory maps but also to predict molecular interactions and to inform on the mechanisms for common quantitative variation.
Discovery of microvascular miRNAs using public gene expression data: miR-145 is expressed in pericytes and is a regulator of Fli1
Authors: Larsson Erik , Fredlund Fuchs Peder , Heldin Johan , Barkefors Irmeli , Bondjers Cecilia , Genové Guillem , Arrondel Christelle , Gerwins Pär , Kurschat Christine , Schermer Bernhard , Benzing Thomas , Harvey Scott J , Kreuger Johan , Lindahl Per
Published: November 2009

Background

A function for the microRNA (miRNA) pathway in vascular development and angiogenesis has been firmly established. miRNAs with selective expression in the vasculature are attractive as possible targets in miRNA-based therapies. However, little is known about the expression of miRNAs in microvessels in vivo. Here, we identified candidate microvascular-selective miRNAs by screening public miRNA expression datasets.

Methods

Bioinformatics predictions of microvascular-selective expression were validated with real-time quantitative reverse transcription PCR on purified microvascular fragments from mouse. Pericyte expression was shown with in situ hybridization on tissue sections. Target sites were identified with 3' UTR luciferase assays, and migration was tested in a microfluid chemotaxis chamber.

Results

miR-145, miR-126, miR-24, and miR-23a were selectively expressed in microvascular fragments isolated from a range of tissues. In situ hybridization and analysis of Pdgfb retention motif mutant mice demonstrated predominant expression of miR-145 in pericytes. We identified the Ets transcription factor Friend leukemia virus integration 1 (Fli1) as a miR-145 target, and showed that elevated levels of miR-145 reduced migration of microvascular cells in response to growth factor gradients in vitro.

Conclusions

miR-126, miR-24 and miR-23a are selectively expressed in microvascular endothelial cells in vivo, whereas miR-145 is expressed in pericytes. miR-145 targets the hematopoietic transcription factor Fli1 and blocks migration in response to growth factor gradients. Our findings have implications for vascular disease and provide necessary information for future drug design against miRNAs with selective expression in the microvasculature.
Effectiveness of a Home Care Nursing Program in the Symptom Management of Patients With Colorectal and Breast Cancer Receiving Oral Chemotherapy: A Randomized, Controlled Trial
Authors: Molassiotis Alex , Brearley Sarah , Saunders Mark , Craven Olive , Wardley Andrew , Farrell Carole , Swindell Ric , Todd Chris , Luker Karen
Published: November 2009

Purpose

To assess the effectiveness of a symptom-focused home care program in patients with cancer who were receiving oral chemotherapy in relation to toxicity levels, anxiety, depression, quality of life, and service utilization.

Patients and Methods

A randomized, controlled trial was carried out with 164 patients with a diagnosis of colorectal (n = 110) and breast (n = 54) cancers who were receiving oral capecitabine. Patients were randomly assigned to receive either a home care program by a nurse or standard care for 18 weeks (ie, six cycles of chemotherapy). Toxicity assessments were carried out weekly for the duration of the patients' participation in the trial, and validated self-report tools assessed anxiety, depression, and quality of life.

Results

Significant improvements were observed in the home care group in relation to the symptoms of oral mucositis, diarrhea, constipation, nausea, pain, fatigue (first four cycles), and insomnia (all P < .05). This improvement was most significant during the initial two cycles. Unplanned service utilization, particularly the number of inpatient days (57 v 167 days; P = .02), also was lower in the home care group.

Conclusion

A symptom-focused home care program was able to assist patients to manage their treatment adverse effects more effectively than standard care. It is imperative that patients receiving oral chemotherapy are supported with such programs, particularly during initial treatment cycles, to improve their treatment and symptom experiences.
Defining the Optimal Treatment for Clinical Stage I Nonseminomatous Germ Cell Testicular Cancer Using Decision Analysis
Authors: Nguyen Carvell T. , Fu Alex Z. , Gilligan Timothy D. , Wells Brian J. , Klein Eric A. , Kattan Michael W. , Stephenson Andrew J.
Published: November 2009

Purpose

There is equipoise regarding the optimal treatment of clinical stage (CS) I nonseminomatous germ cell testicular cancer (NSGCT). Formal mechanisms that enable patients to consider cancer outcomes, treatment-related morbidity, and personal preferences are needed to facilitate decision making between retroperitoneal lymph node dissection (RPLND), primary chemotherapy, and surveillance.

Methods

Decision analysis was performed using a Markov model that incorporated likelihoods of survival, treatment-related morbidity, and utilities for seven undesired post-treatment health states to estimate the quality-adjusted survival (QAS) for each treatment option. Utilities were obtained from 24 hypothetical NSGCT patients using a visual analog (rating) scale and standard gamble.

Results

Overall, QAS associated with each treatment was high and differences in QAS were small. Surveillance was the preferred intervention for patients with a risk of relapse less than 33% and 37% using the rating scale and standard-gamble method of utility assessment, respectively. Active treatment was favored over surveillance for patients with relapse risk on surveillance greater than 33% and 37% by the rating scale (RPLND preferred) and standard-gamble methods (primary chemotherapy preferred), respectively. Substantial differences in average utilities were seen depending on the method used. By the rating scale, patients substantially devalued life in six of seven undesired health states but they were surprisingly tolerant of treatment-related morbidity using standard gamble.

Conclusion

A decision model has been developed for CS I NSGCT that estimates QAS for RPLND, primary chemotherapy, and surveillance by considering cancer outcomes, morbidity, and patient preferences. Surveillance was the preferred intervention for all except those patients at high risk for relapse.
Immunochemotherapy and Autologous Stem-Cell Transplantation for Untreated Patients With Mantle-Cell Lymphoma: CALGB 59909
Authors: Damon Lloyd E. , Johnson Jeffrey L. , Niedzwiecki Donna , Cheson Bruce D. , Hurd David D. , Bartlett Nancy L. , LaCasce Ann S. , Blum Kristie A. , Byrd John C. , Kelly Michael , Stock Wendy , Linker Charles A. , Canellos George P.
Published: November 2009

Purpose

Mantle-cell lymphoma (MCL) is an aggressive B-cell non-Hodgkin's lymphoma with a poor prognosis. We explored the feasibility, safety, and effectiveness of an aggressive immunochemotherapy treatment program that included autologous stem-cell transplantation (ASCT) for patients up to age 69 years with newly diagnosed MCL.

Patients and Methods

The primary end point was 2-year progression-free survival (PFS). A successful trial would yield a 2-year PFS of at least 50% and an event rate (early progression plus nonrelapse mortality) less than 20% at day +100 following ASCT. Seventy-eight patients were treated with two or three cycles of rituximab combined with methotrexate and augmented CHOP (cyclophosphamide, doxorubicin, vincristine, and prednisone). This treatment was followed by intensification with high doses of cytarabine and etoposide combined with rituximab and filgrastim to mobilize autologous peripheral-blood stem cells. Patients then received high doses of carmustine, etoposide, and cyclophosphamide followed by ASCT and two doses of rituximab.

Results

There were two nonrelapse mortalities, neither during ASCT. With a median follow-up of 4.7 years, the 2-year PFS was 76% (95% CI, 64% to 85%), and the 5-year PFS was 56% (95% CI, 43% to 68%). The 5-year overall survival was 64% (95% CI, 50% to 75%). The event rate by day +100 of ASCT was 5.1%.

Conclusion

The Cancer and Leukemia Group B 59909 regimen is feasible, safe, and effective in patients with newly diagnosed MCL. The incorporation of rituximab with aggressive chemotherapy and ASCT may be responsible for the encouraging outcomes demonstrated in this study, which produced results comparable to similar treatment regimens.
Late-Occurring Neurologic Sequelae in Adult Survivors of Childhood Acute Lymphoblastic Leukemia: A Report From the Childhood Cancer Survivor Study
Authors: Goldsby Robert E. , Liu Qi , Nathan Paul C. , Bowers Daniel C. , Yeaton-Massey Amanda , Raber Shannon H. , Hill Daniel , Armstrong Gregory T. , Yasui Yutaka , Zeltzer Lonnie , Robison Leslie L. , Packer Roger J.
Published: November 2009

Purpose

Children with acute lymphoblastic leukemia (ALL) are often cured, but the therapies they receive may be neurotoxic. Little is known about the incidence and severity of late-occurring neurologic sequelae in ALL survivors. Data were analyzed to determine the incidence of adverse long-term neurologic outcomes and treatment-related risk factors.

Patients and Methods

We analyzed adverse neurologic outcomes that occurred after diagnosis in 4,151 adult survivors of childhood ALL who participated in the Childhood Cancer Survivor Study (CCSS), a retrospective cohort of 5-year survivors of childhood cancer diagnosed between 1970 and 1986. A randomly selected cohort of the survivors' siblings served as a comparison group. Self-reported auditory-vestibular-visual sensory deficits, focal neurologic dysfunction, seizures, and serious headaches were assessed.

Results

The median age at outcome assessment was 20.2 years for survivors. The median follow-up time to death or last survey since ALL diagnosis was 14.1 years. Of the survivors, 64.5% received cranial radiation and 94% received intrathecal chemotherapy. Compared with the sibling cohort, survivors were at elevated risk for late-onset auditory-vestibular-visual sensory deficits (rate ratio [RR], 1.8; 95% CI, 1.5 to 2.2), coordination problems (RR, 4.1; 95% CI, 3.1 to 5.3), motor problems (RR, 5.0; 95% CI, 3.8 to 6.7), seizures (RR, 4.6; 95% CI, 3.4 to 6.2), and headaches (RR, 1.6; 95% CI, 1.4 to 1.7). In multivariable analysis, relapse was the most influential factor that increased risk of late neurologic complications.

Conclusion

Children treated with regimens that include cranial radiation for ALL and those who suffer a relapse are at increased risk for late-onset neurologic sequelae.
Trastuzumab for Patients With Axillary-Node–Positive Breast Cancer: Results of the FNCLCC-PACS 04 Trial
Authors: Spielmann Marc , Roché Henri , Delozier Thierry , Canon Jean-Luc , Romieu Gilles , Bourgeois Hugues , Extra Jean-Marc , Serin Daniel , Kerbrat Pierre , Machiels Jean-Pascal , Lortholary Alain , Orfeuvre Hubert , Campone Mario , Hardy-Bessard Anne-Claire , Coudert Bruno , Maerevoet Marie , Piot Gilles , Kramar Andrew , Martin Anne-Laure , Penault-Llorca Frédérique
Published: November 2009

Purpose

To evaluate the efficacy of trastuzumab in patients with node-positive breast cancer treated with surgery, adjuvant chemotherapy, radiotherapy, and hormone therapy if applicable.

Patients and Methods

Three thousand ten patients with operable node-positive breast cancer were randomly assigned to receive adjuvant anthracycline-based chemotherapy with or without docetaxel. Patients who presented human epidermal growth factor receptor 2 (HER2) -overexpressing tumors were secondary randomly assigned to either a sequential regimen of trastuzumab (6 mg/kg every 3 weeks) for 1 year or observation. The primary end point was disease-free survival (DFS).

Results

Overall 528 patients were randomly assigned between trastuzumab (n = 260) and observation (n = 268) arm. Of the 234 patients (90%) who received at least one administration of trastuzumab, 196 (84%) received at least 6 months of treatment, and 41 (18%) discontinued treatment due to cardiac events (any grade). At the date of analysis (October 2007), 129 DFS events were recorded. Random assignment to the trastuzumab arm was associated with a nonsignificant 14% reduction in the risk of relapse (hazard ratio, 0.86; 95% CI, 0.61 to 1.22; P = .41, log-rank stratified on pathologic node involvement). Three-year DFS rates were 78% (95% CI, 72.3 to 82.5) and 81% (95% CI, 75.3 to 85.4) in the observation and trastuzumab arms, respectively.

Conclusion

After a 47-month median follow-up, 1 year of trastuzumab given sequentially after adjuvant chemotherapy was not associated with a statistically significant decrease in the risk of relapse.
Tubular Carcinoma of the Breast: Further Evidence to Support Its Excellent Prognosis
Authors: Rakha Emad A. , Lee Andrew H.S. , Evans Andrew J. , Menon Sindhu , Assad Nancy Y. , Hodi Zsolt , Macmillan Douglas , Blamey Roger W. , Ellis Ian O.
Published: November 2009

Purpose

Although tubular carcinoma (TC) is known to have a favorable prognosis, it is still unknown whether this subtype represents a distinct type of breast carcinoma or whether it behaves like other low-grade luminal A–type breast carcinomas.

Methods

In this study, we performed a retrospective analysis of a large well-characterized series of breast cancers (2,608 carcinomas) to assess the clinicopathologic and molecular features and prognostic value of TC compared with grade 1 ductal carcinomas of the breast.

Results

When compared with grade 1 ductal carcinoma (n = 212), TC (n = 102) was more likely to be detected on mammographic screening, had smaller median size, and less frequently showed lymphovascular invasion. Compared with grade 1 ductal carcinoma, TC was associated with longer disease-free survival (χ2= 13.25, P < .001) and breast cancer–specific survival (χ2= 8.8, P = .003). In this study, none of the patients with TC developed distant metastasis or died from the disease without an intervening recurrence as invasive carcinoma of different histologic type.

Conclusion

We conclude that the biologic behavior of TC is excellent and is more favorable than that of grade 1 ductal carcinoma. Patients with TC may be at risk of developing second primary carcinomas in the contralateral breast, which may be of higher grade and poorer potential prognostic outcome. In addition, patients with TC seem to have a close to normal life expectancy, and as a consequence, adjuvant systemic therapy may not be justified in their routine management.