bluuebunny/crossref_metadata_2025 huggingface dataset:
Cinacalcet lowering of serum fibroblast growth factor-23 concentration may be independent from serum Ca, P, PTH and dose of active vitamin D in peritoneal dialysis patients: a randomized controlled study
Authors: Kim Hyo Jin , Kim Hyunsuk , Shin Nara , Na Ki Young , Kim Yong Lim , Kim Daejung , Chang Jae Hyun , Song Young Rim , Hwang Young-Hwan , Kim Yon Su , Ahn Curie , Lee Joongyub , Oh Kook-Hwan ,   Representing the Cinacalcet stUdy for Peritoneal Dialysis Patients In Double Arm on the Lowering Effect Of iPTH Level (CUPID) Study Group
Published: May 2013

Background

Elevated serum level of fibroblast growth factor-23 (FGF23) is associated with adverse outcomes in dialyzed patients.

Objectives

The CUPID study compared the efficacy of a cinacalcet-based regimen with conventional care (vitamin D and P binders) for achieving the stringent NKF-K/DOQI targets for peritoneal dialysis (PD) patients. Additionally, we analyzed change in FGF23 levels between two treatments to explore the cinacalcet effect in lowering FGF23.

Design

Multicenter, open-labeled, randomized controlled study.

Setting

Seven university-affiliated hospitals in Korea.

Participants

Overall, 66 peritoneal dialysis patients were enrolled.

Intervention

Sixty six patients were randomly assigned to treatment with either cinacalcet + oral vitamin D (cinacalcet group, n = 33) or oral vitamin D alone (control group, n = 33) to achieve K/DOQI targets. CUPID included a 4-week screening for vitamin D washout, a 12-week dose-titration, and a 4-week assessment phases. We calculated mean values of iPTH, Ca, P, Ca x P, during assessment phase and final FGF23 to assess the outcome.

Main outcome measures

Achievement of >30% reduction of iPTH from baseline (primary) and FGF23 reduction (secondary).

Results

72.7% (n = 24) of the cinacalcet group and 93.9% (n = 31) of the control group completed the study. Cinacalcet group received 30.2 ± 18.0 mg/day of cinacalcet and 0.13 ± 0.32 μg/d oral vitamin D (P < 0.001 vs. control with 0.27 ± 0.18 μg/d vitamin D). The proportion of patients who reached the primary endpoint was not statistically different (48.5% vs. 51.5%, cinacalcet vs. control, P = 1.000). After treatment, cinacalcet group experienced a significant reduction in FGF23 levels (median value from 3,960 to 2,325 RU/ml, P = 0.002), while an insignificant change was shown for control group (from 2,085 to 2,415 RU/ml). The percent change of FGF23 after treatment was also significantly different between the two groups (− 42.54% vs. 15.83%, P = 0.008). After adjustment, cinacalcet treatment was independently associated with the serum FGF23 reduction.

Conclusion

Cinacalcet treatment was independently associated with the reduction of FGF23 in our PD patients.

Trial registration

Controlled trials NCT01101113
OSU-03012 sensitizes breast cancers to lapatinib-induced cell killing: a role for Nck1 but not Nck2
Authors: West N Winston , Garcia-Vargas Aileen , Chalfant Charles E , Park Margaret A
Published: May 2013

Background

Lapatinib is characterized as an ErbB1/ErbB2 dual inhibitor and has recently been approved for the treatment of metastatic breast cancer. In this study, we examined mechanisms associated with enhancing the activity of lapatinib via combination with other therapies.

Methods

In the present studies, estrogen receptor (ER) positive and ER negative breast cancer cells were genetically manipulated to up- or downregulate eIF2-alpha, its phospho-mutant, Nck1, or Nck2, then treated with OSU-03012, lapatinib or the combination and assayed for cytotoxicity/cytostaticity using clonogenic assays.

Results

Treatment of breast cancer cell lines with lapatinib and OSU-03012 (a small molecule derivative of the Cox-2 inhibitor celecoxib) induced synergistic cytotoxic/cytostatic effects. This combination therapy corresponded to an increase in the phosphorylation of eIF2-α at serine51 and a decrease in Nck1 expression. Ectopic expression of phospho-mutant eIF2-α (Ser51Ala) or downregulation of eIF2-α in addition to downregulation of the eIF2-α kinase PERK inhibited the synergistic and cytotoxic effects. Furthermore, ectopic expression of Nck1, but not Nck2 abolished the decrease in cell viability observed in combination-treated cells. Downregulation of Nck1 failed to “rescue” the ablation of the cytotoxic/cytostatic effects by the phospho-mutant of eIF2-α (Ser51Ala) demonstrating that Nck1 downregulation is upstream of eIF2-α phosphorylation in the anti-survival pathway activated by lapatinib and OSU-03012 treatment. Finally, co-immunoprecipitation assays indicated that eIF2-α dissociates from the Nck1/PP1 complex after OSU-03012 and lapatinib co-treatment.

Conclusions

These data indicate that OSU-03012 and lapatinib co-treatment is an effective combination therapy, which functions to enhance cell killing through the Nck1/eIF2 complex. Hence, this complex is a novel target for the treatment of metastatic breast cancer.
Inorganic phosphate and the risk of cancer in the Swedish AMORIS study
Authors: Wulaningsih Wahyu , Michaelsson Karl , Garmo Hans , Hammar Niklas , Jungner Ingmar , Walldius Göran , Holmberg Lars , Van Hemelrijck Mieke
Published: May 2013

Background

Both dietary and serum levels of inorganic phosphate (Pi) have been linked to development of cancer in experimental studies. This is the first population-based study investigating the relation between serum Pi and risk of cancer in humans.

Methods

From the Swedish Apolipoprotein Mortality Risk (AMORIS) study, we selected all participants (> 20 years old) with baseline measurements of serum Pi, calcium, alkaline phosphatase, glucose, and creatinine (n = 397,292). Multivariable Cox proportional hazards regression analyses were used to assess serum Pi in relation to overall cancer risk. Similar analyses were performed for specific cancer sites.

Results

We found a higher overall cancer risk with increasing Pi levels in men ( HR: 1.02 (95% CI: 1.00-1.04) for every SD increase in Pi), and a negative association in women (HR: 0.97 (95% CI: 0.96-0.99) for every SD increase in Pi). Further analyses for specific cancer sites showed a positive link between Pi quartiles and the risk of cancer of the pancreas, lung, thyroid gland and bone in men, and cancer of the oesophagus, lung, and nonmelanoma skin cancer in women. Conversely, the risks for developing breast and endometrial cancer as well as other endocrine cancer in both men and women were lower in those with higher Pi levels.

Conclusions

Abnormal Pi levels are related to development of cancer. Furthermore, the in verse association between Pi levels and risk of breast, endometrial and other endocrine cancers may indicate the role of hormonal factors in the relation between Pi metabolism and cancer.
Morphometry of the suprascapular notch: correlation with scapular dimensions and clinical relevance
Authors: Albino Paolo , Carbone Stefano , Candela Vittorio , Arceri Valerio , Vestri Anna Rita , Gumina Stefano
Published: May 2013

Background

Better knowledge of the suprascapular notch anatomy may help to prevent and to assess more accurately suprascapular nerve entrapment syndrome. Our purposes were to verify the reliability of the existing data, to assess the differences between the two genders, to verify the correlation between the dimensions of the scapula and the suprascapular notch, and to investigate the relationship between the suprascapular notch and the postero-superior limit of the safe zone for the suprascapular nerve.

Methods

We examined 500 dried scapulae, measuring seven distances related to the scapular body and suprascapular notch; they were also catalogued according to gender, age and side. Suprascapular notch was classified in accordance with Rengachary’s method. For each class, we also took into consideration the width/depth ratio. Furthermore, Pearson's correlation was calculated.

Results

The frequencies were: Type I 12.4%, Type II 19.8%, Type III 22.8%, Type IV 31.1%, Type V 10.2%, Type VI 3.6%. Width and depth did not demonstrate a statistical significant difference when analyzed according to gender and side; however, a significant difference was found between the depth means elaborated according to median age (73 y.o.). Correlation indexes were weak or not statistically significant. The differences among the postero-superior limits of the safe zone in the six types of notches was not statistically significant.

Conclusions

Patient’s characteristics (gender, age and scapular dimensions) are not related to the characteristics of the suprascapular notch (dimensions and Type); our data suggest that the entrapment syndrome is more likely to be associated with a Type III notch because of its specific features.
Raman imaging at biological interfaces: applications in breast cancer diagnosis
Authors: Surmacki Jakub , Musial Jacek , Kordek Radzislaw , Abramczyk Halina
Published: May 2013

Background

One of the most important areas of Raman medical diagnostics is identification and characterization of cancerous and noncancerous tissues. The methods based on Raman scattering has shown significant potential for probing human breast tissue to provide valuable information for early diagnosis of breast cancer. A vibrational fingerprint from the biological tissue provides information which can be used to identify, characterize and discriminate structures in breast tissue, both in the normal and cancerous environment.

Results

The paper reviews recent progress in understanding structure and interactions at biological interfaces of the human tissue by using confocal Raman imaging and IR spectroscopy. The important differences between the noncancerous and cancerous human breast tissues were found in regions characteristic for vibrations of carotenoids, fatty acids, proteins, and interfacial water. Particular attention was paid to the role played by unsaturated fatty acids and their derivatives as well as carotenoids and interfacial water.

Conclusions

We demonstrate that Raman imaging has reached a clinically relevant level in regard to breast cancer diagnosis applications. The results presented in the paper may have serious implications on understanding mechanisms of interactions in living cells under realistically crowded conditions of biological tissue.
Gene expression profiling reveals distinct features of various porcine adipose tissues
Authors: Zhou Chaowei , Zhang Jie , Ma Jideng , Jiang Anan , Tang Guoqing , Mai Miaomiao , Zhu Li , Bai Lin , Li Mingzhou , Li Xuewei
Published: May 2013

Background

The excessive accumulation of body fat is a major risk factor to develop a variety of metabolic diseases. To investigate the systematic association between the differences in gene expression profiling and adipose deposition, we used pig as a model, and measured the gene expression profiling of six variant adipose tissues in male and females from three pig breeds which display distinct fat level.

Results

We identified various differential expressed genes among breeds, tissues and between sexes, and further used a clustering method to identify sets of functionally co-expression genes linked to different obesity-related phenotypes. Our results reveal that the subcutaneous adipose tissues mainly modulate metabolic indicators, nonetheless, the visceral adipose tissues as well as the intermuscular adipose tissue were mainly associated with the impaired inflammatory and immune response.

Conclusions

The present study provided the evidence of gene expression profiling that the subcutaneous adipose tissues are mainly affected the metabolism process, whereas the visceral and intermuscular adipose tissues should been term as the metabolic risk factors of obesity.
Blood neutrophil-lymphocyte ratio predicts survival for stages III-IV gastric cancer treated with neoadjuvant chemotherapy
Authors: Jin Hailong , Zhang Geer , Liu Xiaosun , Liu Xiaokun , Chen Chao , Yu Hang , Huang Xiaomei , Zhang Qing , Yu Jiren
Published: May 2013

Background

Accurate predictors of survival for patients with advanced gastric cancer treated with neoadjuvant chemotherapy are currently lacking. In this study, we aimed to evaluate the prognostic significance of the neutrophil-lymphocyte ratio (NLR) in patients with stage III-IV gastric cancer who received neoadjuvant chemotherapy.

Methods

We enrolled 46 patients in this study. The NLR was divided into two groups: high (>2.5) and low (≤2.5). Univariate analysis on progression-free survival (PFS) and overall survival(OS) was performed using the Kaplan-Meier and log-rank tests, and multivariate analysis was conducted using the Cox proportional hazards regression model. We analyzed whether chemotherapy normalized high NLR or not, and evaluated the prognostic significance of normalization on survival.

Results

The univariate analysis showed that PFS and OS were both worse for patients with high NLR than for those with low NLR before chemotherapy (median PFS 16 and 49 months, respectively,P= 0.012; median OS 21 and 52 months,P= 0.113). PFS and OS were also worse for patients with high NLR than for those with low NLR before surgery (median PFS 12 and 35 months,P= 0.019; median OS 21 and 52 months,P= 0.082). Multivariate analysis showed that both NLR before chemotherapy and surgery were independent prognostic factors of PFS. Neoadjuvant chemotherapy normalized high NLR in 11 of 24 patients, and these 11 patients had better median PFS and OS than the 13 patients who had high NLR both before chemotherapy and before surgery (PFS: 35.0 and 10.0 months,P= 0.003; OS: 60 and 16 months,P= 0.042).

Conclusions

NLR may serve as a potential biomarker for survival prognosis in patients with stage III-IV gastric cancer receiving neoadjuvant chemotherapy.
A short protocol using dexamethasone and monophosphoryl lipid A generates tolerogenic dendritic cells that display a potent migratory capacity to lymphoid chemokines
Authors: García-González Paulina , Morales Rodrigo , Hoyos Lorena , Maggi Jaxaira , Campos Javier , Pesce Bárbara , Gárate David , Larrondo Milton , González Rodrigo , Soto Lilian , Ramos Verónica , Tobar Pía , Molina María Carmen , Pino-Lagos Karina , Catalán Diego , Aguillón Juan Carlos
Published: May 2013

Background

Generation of tolerogenic dendritic cells (TolDCs) for therapy is challenging due to its implications for the design of protocols suitable for clinical applications, which means not only using safe products, but also working at defining specific biomarkers for TolDCs identification, developing shorter DCs differentiation methods and obtaining TolDCs with a stable phenotype. We describe here, a short-term protocol for TolDCs generation, which are characterized in terms of phenotypic markers, cytokines secretion profile, CD4+ T cell-stimulatory ability and migratory capacity.

Methods

TolDCs from healthy donors were generated by modulation with dexamethasone plus monophosphoryl lipid A (MPLA-tDCs). We performed an analysis of MPLA-tDCs in terms of yield, viability, morphology, phenotypic markers, cytokines secretion profile, stability, allogeneic and antigen-specific CD4+ T-cell stimulatory ability and migration capacity.

Results

After a 5-day culture, MPLA-tDCs displayed reduced expression of costimulatory and maturation molecules together to an anti-inflammatory cytokines secretion profile, being able to maintain these tolerogenic features even after the engagement of CD40 by its cognate ligand. In addition, MPLA-tDCs exhibited reduced capabilities to stimulate allogeneic and antigen-specific CD4+ T cell proliferation, and induced an anti-inflammatory cytokine secretion pattern. Among potential tolerogenic markers studied, only TLR-2 was highly expressed in MPLA-tDCs when compared to mature and immature DCs. Remarkable, like mature DCs, MPLA-tDCs displayed a high CCR7 and CXCR4 expression, both chemokine receptors involved in migration to secondary lymphoid organs, and even more, in an in vitro assay they exhibited a high migration response towards CCL19 and CXCL12.

Conclusion

We describe a short-term protocol for TolDC generation, which confers them a stable phenotype and migratory capacity to lymphoid chemokines, essential features for TolDCs to be used as therapeutics for autoimmunity and prevention of graft rejection.
A proteomic view of isoproterenol induced cardiac hypertrophy: Prohibitin identified as a potential biomarker in rats
Authors: Chowdhury Debabrata , Tangutur Anjana Devi , Khatua Tarak Nath , Saxena Priyanka , Banerjee Sanjay K , Bhadra Manika Pal
Published: May 2013

Background

The present study aimed at using a proteomics based approach to: a) analyze and contrast the proteome of the healthy and isoproterenol induced hypertrophied hearts and b) identify potential biomarkers for diagnosis of cardiac hypertrophy.

Methods

Male Sprague Dawley (SD) rats were administered isoproterenol (ISO, 5 mg/kg, sc, once daily) for 14 days to induce cardiac hypertrophy. There was a significant (p<0.05) increase (~ 55%) in the heart weight to tail length ratio after 14 days of treatment and cardiac hypertrophy was evidenced by significant increase of β-MHC and ANP, two indicative markers of cardiac hypertrophy, in the treated heart compared to that of control. Following confirmation of hypertrophy, 2DE of the tissue samples was done followed by MS/MS analysis of the protein spots to obtain a proteomic view for identification of novel biomarkers.

Results

Several important proteins were identified by proteomics analysis. They belong to the major functional categories such as cholesterol and protein metabolism, muscle contraction and development, transport, TCAcycle, ATP-biosynthesis, chaperone, signal transduction, DNA synthesis and ubiquitinisation. Careful examination of these protein spots by image analysis led to the successful identification of 7 differentially expressed proteins in the diseased sample. Further extension of this work for validation of differential expression of these proteins was also achieved by RTPCR and western blotting.

Conclusions

Our results demonstrate characteristic protein expression profile in control and hypertrophy condition in SD rats and also expand the existing knowledge on differentially expressed proteins in hypertrophy. The study signifies the importance of reduced expression of a novel protein such as Prohibitin (PHB) which may be associated with the cardiomyocytes growth and cardiac hypertrophy. However, further work is necessary to confirm the role of PHB in human heart and its potential role in diagnostic and therapeutic intervention in the clinic.
Gadd45a levels in human breast cancer are hormone receptor dependent
Authors: Tront Jennifer S , Willis Alliric , Huang Yajue , Hoffman Barbara , Liebermann Dan A
Published: May 2013

Background

Gadd45a is a member of the Gadd45 family of genes that are known stress sensors. Gadd45a has been shown to serve as an effector in oncogenic stress in breast carcinogenesis in murine models. The present study was aimed at clarifying the expression of Gadd45a in human breast cancer and its correlation with clinicopathologic features.

Methods

The expression levels of Gadd45a in breast tissue samples of female breast surgery cases were examined by immunohistochemistry (IHC) using a Gadd45a antibody. Percent staining was determined and statistical analyses were applied to determine prognostic correlations.

Results

56 female breast surgery cases were studied: Normal (11), Luminal A (9), Luminal B (11), HER2+ (10), Triple Negative (15). There was a highly significant difference in percent Gadd45a staining between groups [Mean]: Normal 16.3%; Luminal A 65.3%; Luminal B 80.7%; HER2+ 40.5%; TN 32%, P < 0.001, ANOVA. Gadd45a IHC levels for Normal cases found 82% negative/low. Luminal A breast cancer cases were found to be 67% high. Luminal B breast cancers were 100% high. Her2+ cases were 50% negative/low. Triple Negative cases were 67% negative/low. This difference in distribution of Gadd45a levels across breast cancer receptor subtypes was significant, P = 0.0009.

Conclusions

Gadd45a levels are significantly associated with hormone receptor status in human breast cancer. Normal breast tissue displays low Gadd45a levels. High Gadd45a levels are associated with Luminal A and Luminal B subtypes. Absence of hormone receptors in Triple Negative subtype is associated with Negative/Low levels of Gadd45a. Further studies are indicated to elucidate the role of Gadd45a in breast cancer as a potential prognosticator or target for treatment.
The neonatal CNS is not conducive for encephalitogenic Th1 T cells and B cells during experimental autoimmune encephalomyelitis
Authors: Cravens Petra D , Kieseier Bernd C , Hussain Rehana , Herndon Emily , Arellano Benjamine , Ben Li-Hong , Timmons Brenda C , Castro-Rojas Cyd , Hartung Hans-Peter , Hemmer Bernhard , Weber Martin S , Zamvil Scott S , Stüve Olaf
Published: May 2013

Multiple sclerosis (MS) is thought to be a CD4+T cell mediated autoimmune demyelinating disease of the central nervous system (CNS) that is rarely diagnosed during infancy. Cellular and molecular mechanisms that confer disease resistance in this age group are unknown. We tested the hypothesis that a differential composition of immune cells within the CNS modulates age-associated susceptibility to CNS autoimmune disease. C57BL/6 mice younger than eight weeks were resistant to experimental autoimmune encephalomyelitis (EAE) following active immunization with myelin oligodendrocyte glycoprotein (MOG) peptide (p) 35–55. Neonates also developed milder EAE after transfer of adult encephalitogenic T cells primed by adult or neonate antigen presenting cells (APC). There was a significant increase in CD45+hematopoietic immune cells and CD45+high side scatter granulocytes in the CNS of adults, but not in neonates. Within the CD45+immune cell compartment of adults, the accumulation of CD4+T cells, Gr-1+and Gr-1-monocytes and CD11c+dendritic cells (DC) was identified. A significantly greater percentage of CD19+B cells in the adult CNS expressed MHC II than neonate CNS B cells. Only in the adult CNS could IFNγ transcripts be detected 10 days post immunization for EAE. IFNγ is highly expressed by adult donor CD4+T cells that are adoptively transferred but not by transferred neonate donor cells. In contrast, IL-17 transcripts could not be detected in adult or neonate CNS in this EAE model, and neither adult nor neonate donor CD4+T cells expressed IL-17 at the time of adoptive transfer.
The design of a new truncated and engineered alpha1-antitrypsin based on theoretical studies: an antiprotease therapeutics for pulmonary diseases
Authors: Pirooznia Nazanin , Hasannia Sadegh , Arab Seyed Shahriar , Lotfi Abbas Sahebghadam , Ghanei Mostafa , Shali Abbas
Published: May 2013

Alpha 1- antitrypsin (α1AT) a 54 kDa glycoprotein is a protease inhibitor. In the absence of α1AT, elastase released by lung macrophages, was not inhibited and lead to elastin breakdown and pulmonary problems such as emphysema or COPD. α1AT has three site of N-glycosylation and a characteristic reactive central loop (RCL). As small-scale medicines are preferred for pulmonary drug delivery, in this study α1ATs (1, 2, 3, 4 and 5) were engineered and shortened from the N-terminal region. In order to investigate the effect of different mutations and the deletion of 46 amino acids theoretical studies were performed. Homology modeling was performed to generate the 3D structure of α1ATs. The 10 ns Molecular Dynamic (MD) simulations were carried out to refine the models. Results from MD and protein docking showed that α1AT2 has the highest binding affinity for neutrophil elastase, provided the basis for the experimental phase in which sequences from the five α1AT constructs were inserted into the expression vector pGAPZα and expressed in the yeast Pichia pastoris. Although, the α1AT2 construct has the highest inhibitory activity even more that the native construct (α1AT5), results indicated the presence of protease inhibitory function of all the proteins' construct against elastase.
Postoperative radiotherapy improves local control and survival in patients with uterine leiomyosarcoma
Authors: Wong Philip , Han Kathy , Sykes Jenna , Catton Charles , Laframboise Stephane , Fyles Anthony , Manchul Lee , Levin Wilfred , Milosevic Michael
Published: May 2013

Background

To examine the role of radiotherapy (RT) in uterine leiomyosarcomas (LMS) and to determine the patient population who may benefit from RT.

Methods

From 1998–2008, 69 patients with primary uterine LMS underwent hysterectomy with or without pelvic radiotherapy to a median dose of 45 Gy. Univariate analysis was performed using the Kaplan-Meier method and cumulative-incidence function, and multivariate analyses using Fine and Gray or Cox proportional hazard models.

Results

Following surgery, 32 out of 69 patients received RT. There was no evidence of any correlation between patient, disease and treatment characteristics and the use of RT. Median follow-up was 57 months. RT was associated with reduced local recurrence (3y LR 19% vs. 39%; Gray’s p = 0.019) and improved overall survival (3y OS 69% vs. 35%; log-rank p = 0.025) on univariate analysis. Multivariate analysis demonstrated that RT reduced LR (HR: 0.28, CI: 0.11-0.69, p = 0.006) and increased OS (HR: 0.44, CI: 0.23-0.85, p = 0.014) independent of other clinical and pathologic factors. Positive surgical margins increased the odds of LR (HR: 5.6, CI: 2.3-13.4, p = 0.00012). Large tumor size and advanced stage (II-IV) were associated with the development of distant metastases and inferior OS.

Conclusions

Postoperative pelvic RT reduces LR and improves OS of patients with uterine LMS.
Identification of novel arthropod vector G protein-coupled receptors
Authors: Nowling Ronald J , Abrudan Jenica L , Shoue Douglas A , Abdul-Wahid Badi’ , Wadsworth Mariha , Stayback Gwen , Collins Frank H , McDowell Mary Ann , Izaguirre Jesús A
Published: May 2013

Background

The control of vector-borne diseases, such as malaria, dengue fever, and typhus fever is often achieved with the use of insecticides. Unfortunately, insecticide resistance is becoming common among different vector species. There are currently no chemical alternatives to these insecticides because new human-safe classes of molecules have yet to be brought to the vector-control market. The identification of novel targets offer opportunities for rational design of new chemistries to control vector populations. One target family, G protein-coupled receptors (GPCRs), has remained relatively under explored in terms of insecticide development.

Methods

A novel classifier, Ensemble*, for vector GPCRs was developed. Ensemble* was validated and compared to existing classifiers using a set of all known GPCRs from Aedes aegypti, Anopheles gambiae, Apis Mellifera, Drosophila melanogaster, Homo sapiens, and Pediculus humanus. Predictions for unidentified sequences from Ae. aegypti, An. gambiae, and Pe. humanus were validated. Quantitative RT-PCR expression analysis was performed on previously-known and newly discovered Ae. aegypti GPCR genes.

Results

We present a new analysis of GPCRs in the genomes of Ae, aegypti, a vector of dengue fever, An. gambiae, a primary vector of Plasmodium falciparum that causes malaria, and Pe. humanus, a vector of epidemic typhus fever, using a novel GPCR classifier, Ensemble*, designed for insect vector species. We identified 30 additional putative GPCRs, 19 of which we validated. Expression of the newly discovered Ae. aegypti GPCR genes was confirmed via quantitative RT-PCR.

Conclusion

A novel GPCR classifier for insect vectors, Ensemble*, was developed and GPCR predictions were validated. Ensemble* and the validation pipeline were applied to the genomes of three insect vectors (Ae. aegypti, An. gambiae, and Pe. humanus), resulting in the identification of 52 GPCRs not previously identified, of which 11 are predicted GPCRs, and 19 are predicted and confirmed GPCRs.
Modelling the geographical distribution of soil-transmitted helminth infections in Bolivia
Authors: Chammartin Frédérique , Scholte Ronaldo GC , Malone John B , Bavia Mara E , Nieto Prixia , Utzinger Jürg , Vounatsou Penelope
Published: May 2013

Background

The prevalence of infection with the three common soil-transmitted helminths (i.e. Ascaris lumbricoides, Trichuris trichiura, and hookworm) in Bolivia is among the highest in Latin America. However, the spatial distribution and burden of soil-transmitted helminthiasis are poorly documented.

Methods

We analysed historical survey data using Bayesian geostatistical models to identify determinants of the distribution of soil-transmitted helminth infections, predict the geographical distribution of infection risk, and assess treatment needs and costs in the frame of preventive chemotherapy. Rigorous geostatistical variable selection identified the most important predictors of A. lumbricoides, T. trichiura, and hookworm transmission.

Results

Results show that precipitation during the wettest quarter above 400 mm favours the distribution of A. lumbricoides. Altitude has a negative effect on T. trichiura. Hookworm is sensitive to temperature during the coldest month. We estimate that 38.0%, 19.3%, and 11.4% of the Bolivian population is infected with A. lumbricoides, T. trichiura, and hookworm, respectively. Assuming independence of the three infections, 48.4% of the population is infected with any soil-transmitted helminth. Empirical-based estimates, according to treatment recommendations by the World Health Organization, suggest a total of 2.9 million annualised treatments for the control of soil-transmitted helminthiasis in Bolivia.

Conclusions

We provide estimates of soil-transmitted helminth infections in Bolivia based on high-resolution spatial prediction and an innovative variable selection approach. However, the scarcity of the data suggests that a national survey is required for more accurate mapping that will govern spatial targeting of soil-transmitted helminthiasis control.
Quantitative medical cost-effectiveness analysis of molecular-targeting cancer drugs in Japan
Authors: Ebara Takeshi , Ohno Tatsuya , Nakano Takashi
Published: May 2013

Background

In Japan, both incidence and mortality rates of cancers have continuously increased and medical costs are growing more rapidly than the overall economy of Japan. However, there is no consensus threshold for cost-effectiveness in medical care, and few studies have investigated cost-effectiveness of medical care in Japan. The present study was to determine the direct costs of molecular-targeting drugs that were recently approved in Japan through simple and quantitative calculations. Thus, we calculated an incremental cost-effectiveness ratio (ICER) and the cost per life-year gained (LYG) by using reported data from randomized clinical trials for various cancers.

Methods

Between 2008 and 2011, we reviewed seven molecular-targeting drugs that were approved for treatment of five cancers in Japan. These drugs included Bevacizumab, sorafenib, sunitinib, temsirolimus, Lapatinib, and panitumumab. Direct cost, ICER, and LYG of the drugs were estimated from the randomized phase III clinical trial data referred to in package leaflets. Effectiveness was defined as the prolongation of both median overall survival (OS) and progression-free survival (PFS). Costs were calculated as those of molecular-targeting drugs. Subsequently, ICER was based on 1-month increases in both OS and PFS periods and 1% increases in OS, and LYG was determined.

Results

Direct costs ranged from ¥724,804 ($9,060) to ¥1,506,628 ($18,833). ICERs of the drugs ranged from ¥724,804 ($9,060) to ¥1,506,628 ($18,833) for a 1-month increase in OS. For each month of PFS, ICERs ranged from ¥372,243 ($4,653) to ¥7,399,877 ($92,498). The costs of Bevacizumab and sorafenib for treatment of HCC per 1% increase in OS were ¥376,657 ($4,708) and ¥313,733 ($3,922), respectively. LYG ranged from ¥8,697,650 ($108,721) to ¥18,079,530 ($225,994).

Conclusions

Some molecular-targeting drugs are not cost-effective. Considering ethical and moral issues, we should establish economic endpoints to approve new drugs in Japan.
Converting non-metallic printed circuit boards waste into a value added product
Authors: Muniyandi Shantha Kumari , Sohaili Johan , Hassan Azman , Mohamad Siti Suhaila
Published: May 2013

The aim of this study was to investigate the feasibility of using nonmetallic printed circuit board (PCB) waste as filler in recycled HDPE (rHDPE) in production of rHDPE/PCB composites. Maleic anhydride modified linear low-density polyethylene (MAPE) was used as compatibilizer. In particular, the effects of nonmetallic PCB and MAPE on mechanical properties of the composites were assessed through tensile, flexural and impact testing. Scanning electron microscope (SEM) was used to study the dispersion of nonmetallic PCB and MAPE in the matrix. Nonmetallic PCB was blended with rHDPE from 0–30 wt% and prepared by counter-rotating twin screw extruder followed by molding into test samples via hot press for analysis. A good balance between stiffness, strength and toughness was achieved for the system containing 30 wt% PCB. Thus, this system was chosen in order to investigate the effect of the compatibilizer on the mechanical properties of the composites. The results indicate that MAPE as a compatiblizer can effectively promote the interfacial adhesion between nonmetallic PCB and rHDPE. The addition of 6 phr MAPE increased the flexural strength, tensile strength and impact strength by 71%, 98% and 44% respectively compared to the uncompatibilized composites.
Biological degradation of catechol in wastewater using the sequencing continuous-inflow reactor (SCR)
Authors: Aghapour Ali Ahmad , Moussavi Gholamreza , Yaghmaeian Kamyar
Published: May 2013

Catechol is used in many industries. It can be removed from wastewater by various methods but biological processes are the most superior and commonly used technology. The SCR is a modified form of SBR used to degrade catechol. The objective of this study was to investigate the performance of SCR for biodegradation and mineralization of catechol under various inlet concentrations (630–1500 mg/L) and hydraulic retention times (HRT) (18–9 h). This study used a bench scale SCR setup to test catechol degradation. The acclimation time of biomass for catechol at degradation at 630 mg/L was 41 d. The SCR operating cycle time was 6 h and the consecutive times taken for aerating, settling and decanting were 4, 1.5 and 0.5 h, respectively. This study investigated the effects of inlet catechol concentration (630–1560 mg/L) and HRT (18–9 h). The average catechol removal efficiencies in steady-state conditions of 630, 930, 12954 and 1559 mg/L of catechol were 98.5%, 98.5%, 98.2% and 96.9% in terms catechol and 97.8%, 97.7%, 96.4% and 94.3% for COD, respectively. SCR with acclimated biomasses could effectively remove the catechol and the corresponding COD from wastewater with concentrations of up to 1560, at the loading rate of 5.38 kg COD/m3.d and at a HRT of up to 13 h. The HRT was determined as an important variable affecting catechol removal from wastewater. Reducing the HRT to below 13 h led to reduced removal of catechol and COD.
Growth differentiation factor-15 and prognosis in acute respiratory distress syndrome: a retrospective cohort study
Authors: Clark Brendan J , Bull Todd M , Benson Alexander B , Stream Amanda R , Macht Madison , Gaydos Jeanette , Meadows Christina , Burnham Ellen L , Moss Marc ,   the ARDS Network Investigators
Published: May 2013

Introduction

We sought to determine whether higher levels of the novel biomarker growth differentiation factor-15 (GDF-15) are associated with poor outcomes and the presence of pulmonary vascular dysfunction (PVD) in patients with acute respiratory distress syndrome (ARDS).

Methods

We conducted a retrospective cohort study in patients enrolled in the Acute Respiratory Distress Syndrome Network Fluid and Catheter Treatment (FACT) Trial. Patients enrolled in the FACT Trial who received a pulmonary artery catheter (PAC), had plasma available from the same study day and sufficient hemodynamic data to determine the presence of PVD were included. Logistic regression was used to determine the association between GDF-15 level and 60-day mortality.

Results

Of the 513 patients enrolled in the FACT Trial assigned to receive a PAC, 400 were included in this analysis. Mortality at 60 days was significantly higher in patients whose GDF-15 levels were in the third (28%) or fourth (49%) quartile when compared to patients with GDF-15 levels in the first quartile (12%) (P <0.001). Adjusting for severity of illness measured by APACHE III score, the odds of death for patients with GDF-15 levels in the fourth quartile when compared to the first quartile was 4.26 (95% CI 2.18, 10.92, P <0.001). When added to APACHE III alone for prediction of 60-day mortality, GDF-15 levels increased the area under the receiver operating characteristic curve from 0.72 to 0.77. At an optimal cutoff of 8,103 pg/mL, the sensitivity and specificity of GDF-15 for predicting 60-day mortality were 62% (95% CI 53%, 71%) and 76% (95% CI 71%, 81%), respectively. Levels of GDF-15 were not useful in identifying the presence of PVD, as defined by hemodynamic measurements obtained by a PAC.

Conclusions

In patients with ARDS, higher levels of GDF-15 are significantly associated with poor outcome but not PVD.
The 372 T/C genetic polymorphism of TIMP-1 is associated with serum levels of TIMP-1 and survival in patients with severe sepsis
Authors: Lorente Leonardo , Martín Mar , Plasencia Fátima , Solé-Violán Jordi , Blanquer José , Labarta Lorenzo , Díaz César , Borreguero-León Juan María , Jiménez Alejandro , Páramo José Antonio , Orbe Josune , Rodríguez José A , Salido Eduardo
Published: May 2013

Introduction

Previous studies have found higher circulating levels of tissue inhibitor of matrix metalloproteinase (TIMP)-1 in nonsurviving septic patients than in surviving septic patients, and an association between the 372 T/C genetic polymorphism of TIMP-1 and the risk of developing certain diseases. However, the relationship between genetic polymorphisms of TIMP-1, circulating TIMP-1 levels and survival in patients with severe sepsis has not been examined, and this was the objective of the study.

Methods

This multicentre, prospective, observational study was carried out in six Spanish ICUs. We determined the 372 T/C genetic polymorphism of TIMP-1 (rs4898), serum levels of TIMP-1, matrix metalloproteinase (MMP)-9, MMP-10, TNFα, IL-10 and plasma plasminogen activator inhibitor-1 (PAI-1). Survival at 30 days from ICU admission was the endpoint assessed. The association between continuous variables was carried out using Spearman's rank correlation coefficient or Spearman's rho coefficient. Multivariate logistic regression analysis was applied to determine the association between the 372 T/C genetic polymorphism and survival 30 days from ICU admission.

Results

Of 275 patients with severe sepsis, 80 had genotype CC, 55 had genotype CT and 140 had genotype TT of the 372 T/C genetic polymorphism of TIMP-1. Patients with the T allele showed higher serum levels of TIMP-1 than patients without the T allele (P = 0.004). Multiple logistic regression analysis showed that the T allele was associated with higher mortality at 30 days (odds ratio = 2.08; 95% confidence interval = 1.06 to 4.09; P = 0.03). Survival analysis showed that patients with the T allele presented lower 30-day survival than patients without the T allele (χ2 = 5.77; P = 0.016). We found an association between TIMP-1 levels and levels of MMP-9 (ρ = -0.19; P = 0.002), MMP-10 (ρ = 0.55; P <0.001), TNFα (ρ = 0.56; P <0.001), IL-10 (ρ = 0.48; P <0.001) and PAI-1 (ρ = 0.49; P <0.001).

Conclusion

The novel findings of our study are that septic patients with the T allele in the 372 T/C genetic polymorphism of TIMP-1 showed higher serum TIMP-1 levels and lower survival rate. The determination of the 372 T/C genetic polymorphism of TIMP-1 thus has prognostic implications and could help in the selection of patients who may benefit from modulation of the MMP/TIMP balance.
Transdimensional uncertainty estimation for dispersive seabed sediments
Authors: Dettmer Jan , Holland Charles W. , Dosso Stan E.
Published: May 2013

We have applied probabilistic inversion using a transdimensional hierarchical model to ocean-acoustic reflection measurements to recover shallow sediment structure including sound-velocity dispersion, frequency-dependent attenuation, and their uncertainties. Parameter and uncertainty inferences were obtained from Markov-chain simulations using the Metropolis-Hastings algorithm for transdimensional models where the number of sediment layers is unknown. Transdimensional algorithms often exhibit slow convergence that is greatly exacerbated by computationally intensive data predictions. Advances were made to improve the performance of Markov-chain simulation and data prediction. Chain-mixing across dimensions was addressed using a tempered sequence of interacting Markov chains, which substantially improves convergence rates. The acoustic recordings were processed to give seabed reflection coefficients as a function of frequency, grazing angle, and integration time (penetration depth). Such reflection-coefficient data cannot be generally described by plane-wave theory. Therefore, data were predicted using plane-wave decomposition and solving the Sommerfeld integral to compute spherical-wave reflection coefficients. This computationally intensive forward model was implemented massively in parallel using the compute unified device architecture on an inexpensive graphics processing unit, which substantially increases performance and allows transdimensional uncertainty estimation for complex layered seabeds. Velocity- and attenuation-frequency dependence were modeled using Buckingham’s viscous grain-shearing theory, which predicts frequency dependence similar to that of Biot’s theory at low frequencies but due to different physical causes. The algorithm was applied at two experiment sites off the coast of Sicily that exhibit different degrees of sediment complexity. The rigorous uncertainty estimation allows inferences that can distinguish between friction- and viscous-loss mechanisms in complex layered media. Results at both sites indicated dispersive sediments at some depths where the variability of velocity and attenuation as a function of frequency clearly exceeds the estimated uncertainties.
Transdimensional change-point modeling as a tool to investigate uncertainty in applied geophysical inference: An example using borehole geophysical logs
Authors: Reading Anya M. , Gallagher Kerry
Published: May 2013

Recently developed methods for inferring abrupt changes in data series enable such change points in time or space to be identified, and also allow us to estimate noise levels of the observed data. The inferred probability distributions of these parameters provide insights into the capacity of the observed data to constrain the geophysical analysis and hence the magnitudes, and likely sources, of uncertainty. We carry out a change-point analysis of sections of four borehole geophysical logs (density, neutron absorption, sonic interval time, and electrical resistivity) using transdimensional Bayesian Markov chain Monte Carlo to sample a model parameter space. The output is an ensemble of values which approximate the posterior distribution of model parameters. We compare the modeled change points, borehole log parameters, and the variance of the noise distribution of each log with the observed lithology classes down the borehole to make an appraisal of the uncertainty characteristics inherent in the data. Our two examples, one with well-defined lithology changes and one with more subtle contrasts, show quantitatively the nature of the lithology contrasts for which the geophysical borehole log data will produce a detectable response in terms of inferred change points. We highlight the different components of variation in the observed data: due to the geologic process (dominant lithology changes) that we hope to be able to infer, geologic noise due to variability within each lithology, and analytical noise due to the measurement process. This inference process will be a practical addition to the analytical tool box for borehole and other geophysical data series. It reveals the level of uncertainties in the relationships between the data and the observed lithologies and would be of great use in planning and interpreting the results of subsequent routine processing.
Quantification of uncertainty in a multistage/multiparameter modeling workflow: Pore pressure from geophysical well logs
Authors: Wessling Stefan , Bartetzko Anne , Tesch Philipp
Published: May 2013

Calculating subsurface pressures and predicting overpressured zones, in particular for safe drilling operations, is an integrated approach based on data and assumptions from various sources. Uncertainties arise from the input data and assumptions, but also from the pore-pressure modeling workflow including shale discrimination and the definition of a normal compaction trend line. These stages are usually performed manually by an expert and are prone to subjective, human interpretation. The quantification of pore-pressure uncertainty associated with the manual modeling stages is, therefore, challenging. Algorithms were developed to account for and quantify the resulting uncertainty and enable automated user support of at least parts of the workflow, thus introducing more objectivity into the modeling steps. The first algorithm performs a statistical analysis on gamma ray logs to discriminate between shale and nonshale formations. The second algorithm calculates a series of normal compaction trend lines from porosity-indicating logs from which average pore-pressure models and uncertainty envelopes can be determined. Furthermore, the behavior of trend-line envelopes from the series of trend lines was quantified by a parameter [Formula: see text], which turned out to become constant in the overpressure region. The algorithms were applied to 23 data sets from different regions worldwide. Pore-pressure uncertainty was identified to be in the range of up to 8% for shale discrimination and less than 20% for normal compaction trend-line setting. In addition, pore-pressure uncertainty in the overpressure zone correlated with the [Formula: see text]-factor, which can be used to estimate pore-pressure uncertainty at greater depth from while-drilling measurements in the normal compaction zone. The results also exemplify regional uncertainty variations, which imply that modeling parameters need to be adjusted for specific regions. Moreover, the examples demonstrate that automated algorithms are beneficial methods to add objectivity and reproducibility to the modeling procedure.
Cognitive dysfunctions in recreational and dependent cocaine users: role of attention-deficit hyperactivity disorder, craving and early age at onset
Authors: Vonmoos Matthias , Hulka Lea M. , Preller Katrin H. , Jenni Daniela , Baumgartner Markus R. , Stohler Rudolf , Bolla Karen I. , Quednow Boris B.
Published: May 2013

Background

Dependent cocaine users consistently display cognitive deficits but cognitive performance of recreational cocaine users has rarely been investigated.

Aims

To examine whether cognitive performance is impaired in relatively pure recreational and dependent cocaine users.

Method

The cognitive performance of recreational (n = 68) and dependent cocaine users (n = 30) was compared with the performance of stimulant-naive controls (n = 68) employing an extensive neuropsychological test battery. Moreover, the impact of attention-deficit hyperactivity disorder (ADHD) symptoms, craving and early age at onset was analysed.

Results

Dependent cocaine users display broad cognitive impairments in the domains of attention, working memory, declarative memory and executive functions. The performance of recreational cocaine users in all four domains was intermediate between that of controls and dependent users and they displayed significant deficits foremost in the domains of attention and working memory. In addition, ADHD symptoms, craving and age at onset were important modulators of cognitive function in cocaine users.

Conclusions

Cognitive deficits occur at a recreational and non-dependent level of cocaine use. Cocaine use and ADHD seem to have mutually aggravating effects on cognitive impairment.