bluuebunny/crossref_metadata_2025 huggingface dataset:
Predictors of the highest long-term care expenditures in Japan
Authors: Olivares-Tirado Pedro , Tamiya Nanako , Kashiwagi Masayo , Kashiwagi Kimikazu
Published: May 2011

Background

In Japan, as the number of elderly covered by the Long-term Care Insurance (LTCI) system has increased, demand for long-term care services has increased substantially and consequently growing expenditures are threatening the sustainability of the system. Understanding the predictive factors associated with long-term care expenditures among the elderly would be useful in developing future strategies to ensure the sustainability of the system. We report a set of predictors of the highest long-term care expenditures in a cohort of elderly persons who received consecutive long-term care services during a year in a Japanese city.

Methods

Data were obtained from databases of the LTC insurer of City A in Japan. Binary logistic regression was used to examine the predictors of the highest long-term care expenditures. We used a simplified model that focused on the effects of disability status and type of services used, while controlling for several relevant factors. Goodness of fit, a multicollinearity test, and logistic regression diagnostics were carried out for the final model.

Results

The study cohort consisted of 862 current users of LTCI system in city A. After controlling for gender and income, age, increased utilization rate of benefits, decline in functional status, higher care needs level and institutional care were found to be associated with the highest LTCI expenditures. An increased utilization rate of benefits (OR = 24.2) was a strong main effect predictors of the high LTC expenditures. However, a significant interaction between institutional care and high care need level was found, providing evidence of the combined effect of the two covariates.

Conclusions

Beyond to confirm that disability status of elderly persons is the main factor driving the demand of LTC services and consequently the expenditures, we showed that changes in utilization rate of benefits -a specific insurance factor- and the use of institutional care conditional on the high care level, were strongest predictors of the highest LTC expenditures. These findings could become crucial for tracking policies aimed at ensuring financial sustainability of LTCI from a public insurer perspective in Japan.
IκB kinases increase Myc protein stability and enhance progression of breast cancer cells
Authors: Yeh Pei-Yen , Lu Yen-Shen , Ou Da-Liang , Cheng Ann-Lii
Published: May 2011

Background

Both IκB kinase (IKK) complex and oncgenic protein Myc play important roles in cancer progression, including cancer cell invasiveness and metastasis. The levels of Myc is regulated by the phosphorylation of Myc at Thr58 and Ser62.

Results

In this study, we show that the expression of Myc is associated with IKKα and IKKβ in breast cancers and that Myc is an IKKs substrate. Suppression of IKK activity by either chemical inhibitor or transfection of kinase-dead mutants decreases the phosphorylation of Myc at Ser62 and enhances the degradation of Myc. Consequently, these treatments decrease the tumorigenic and invasive ability of breast cancer cells. Furthermore, doxorubicin, a frequently used anticancer drug in breast cancer, activates IKKs and Myc, thereby increasing invasiveness and tumorigenesis of breast carcinoma MCF7 cells. Inhibition of IKKs prevents these doxorubicin-induced effects.

Conclusions

Our study indicates that IKKs tightly regulate Myc expression through prolonging protein stability, and suggests that IKKs are potentially therapeutic targets and that suppression of IKKs may be used following chemotherapy to reduce the risk of treatment-induced tumor progression.
Human umbilical cord blood-derived mononuclear cell transplantation: case series of 30 subjects with Hereditary Ataxia
Authors: Yang Wan-Zhang , Zhang Yun , Wu Fang , Zhang Min , Cho SC , Li Chun-Zhen , Li Shao-Hui , Shu Guo-Jian , Sheng You-Xiang , Zhao Ning , Tang Ying , Jiang Shu , Jiang Shan , Gandjian Matthew , Ichim Thomas E , Hu Xiang
Published: May 2011

Background

The differential diagnosis for hereditary ataxia encompasses a variety of diseases characterized by both autosomal dominant and recessive inheritance. There are no curative treatments available for these neurodegenerative conditions. This open label treatment study used human umbilical cord blood-derived mononuclear cells (CBMC) combined with rehabilitation training as potential disease modulators.

Methods

30 patients suffering from hereditary ataxia were treated with CBMCs administered systemically by intravenous infusion and intrathecally by either cervical or lumbar puncture. Primary endpoint measures were the Berg Balance Scale (BBS), serum markers of immunoglobulin and T-cell subsets, measured at baseline and pre-determined times post-treatment.

Results

A reduction of pathological symptoms and signs was shown following treatment. The BBS scores, IgG, IgA, total T cells and CD3+CD4 T cells all improved significantly compared to pre-treatment values (P < 0.01~0.001). There were no adverse events.

Conclusion

The combination of CBMC infusion and rehabilitation training may be a safe and effective treatment for ataxia, which dramatically improves patients' functional symptoms. These data support expanded double blind, placebo-controlled studies for these treatment modalities.
The influence of colloidal parameters on the specific power absorption of PAA-coated magnetite nanoparticles
Authors: Piñeiro-Redondo Yolanda , Bañobre-López Manuel , Pardiñas-Blanco Iván , Goya Gerardo , López-Quintela M Arturo , Rivas José
Published: May 2011

The suitability of magnetic nanoparticles (MNPs) to act as heat nano-sources by application of an alternating magnetic field has recently been studied due to their promising applications in biomedicine. The understanding of the magnetic relaxation mechanism in biocompatible nanoparticle systems is crucial in order to optimize the magnetic properties and maximize the specific absorption rate (SAR). With this aim, the SAR of magnetic dispersions containing superparamagnetic magnetite nanoparticles bio-coated with polyacrylic acid of an average particle size of ≈10 nm has been evaluated separately by changing colloidal parameters such as the MNP concentration and the viscosity of the solvent. A remarkable decrease of the SAR values with increasing particle concentration and solvent viscosity was found. These behaviours have been discussed on the basis of the magnetic relaxation mechanisms involved.

PACS: 80; 87; 87.85jf
Experimental infection of a newly emerging Korean type I porcine reproductive and respiratory syndrome virus isolate in colostrum-deprived pigs
Authors: Kim Hye Kwon , Lee Chul Seung , Kang Bo Kyu , Yeom Min Ju , Moon Hyoung Joon , Park Seong Jun , Nguyen Van Giap , Song Dae Sub , Park Bong Kyun
Published: May 2011

Background

Recently, new emergence of type I PRRSV has been reported in Korea by several research groups. Although specific subgroups of type I PRRSVs in Korea were observed in the previous phylogenetic analysis, there is a lack of information about the virulence of type I PRRSV recently isolated in Korea.

Methods

One type I PRRSV isolate (G2446, 3 times passaged in primarily cultured pulmonary macrophages) in Korea was experimentally infected in colostrum-deprived pigs. The pathological and serological evaluations were performed and compared to type II PRRSV strain (CP07-401-9, 5 times passaged in MARC-145 cell lines)-infected pigs, for 21 days post challenge (dpc).

Results

The pneumonia found in gross examination was more severe in type I PRRSV-infected pigs than type II PRRSV-infected pigs. Both groups showed bronchointerstitial pneumonia, mild multifocal perivascular lymphohistiocytic myocarditis and lymphadenopathy at 14 dpc. However, the unique histopathologic lesions were not found in the pigs experimentally infected with a Korean type I PRRSV isolate, when compared to previous data about classical pathology of PRRSV. The PRRS-specific antibodies were detected in the first week after challenge and viremia continued at least until 21 dpc in both groups.

Conclusion

The gross and histopathologic lesion in this study indicated that Korean type I PRRSV strain (G2446) caused classical PRRSV-specific lesions. Although this study evaluated one representative strain of Korean type I PRRSV, the results may provide information regarding the pathogenicity of type I PRRSV recently emerged in Korea.
Latent tuberculosis in nursing professionals of a Brazilian hospital
Authors: Severo Karen Gisele Person , Oliveira Julia da Silva , Carneiro Marcelo , Valim Andréia Rosane de Moura , Krummenauer Eliane Carlosso , Possuelo Lia Gonçalves
Published: May 2011

Tuberculosis (TB) is considered an occupational disease among health-care workers (HCWs). Direct contact with TB patients leads to an increased risk to become latently infected by Mycobacterium tuberculosis. The objective of this study is to estimate the prevalence of latent M. tuberculosis minfection among nursing professionals of a hospital in Rio Grande do Sul, Brazil, assessed by tuberculin skin test (TST). From November 2009 to May 2010, latent M. tuberculosis infection was assessed by TST in 55 nursing professionals. Epidemiological information was collected using a standardized questionnaire. A positive TST result (> or = 10 mm) was observed in 47.3% of the HCWs tested. There was no significant difference in TST positivity when duration of employment or professional category (technician or nurse) was evaluated. The results of this work reinforce the need for control measures to prevent latent M. tuberculosis infection among nursing professionals at the hospital where the study was conducted.
Comprehensive expressional analyses of antisense transcripts in colon cancer tissues using artificial antisense probes
Authors: Saito Rintaro , Kohno Keisuke , Okada Yuki , Osada Yuko , Numata Koji , Kohama Chihiro , Watanabe Kazufumi , Nakaoka Hajime , Yamamoto Naoyuki , Kanai Akio , Yasue Hiroshi , Murata Soichiro , Abe Kuniya , Tomita Masaru , Ohkohchi Nobuhiro , Kiyosawa Hidenori
Published: May 2011

Background

Recent studies have identified thousands of sense-antisense gene pairs across different genomes by computational mapping of cDNA sequences. These studies have shown that approximately 25% of all transcriptional units in the human and mouse genomes are involved in cis-sense-antisense pairs. However, the number of known sense-antisense pairs remains limited because currently available cDNA sequences represent only a fraction of the total number of transcripts comprising the transcriptome of each cell type.

Methods

To discover novel antisense transcripts encoded in the antisense strand of important genes, such as cancer-related genes, we conducted expression analyses of antisense transcripts using our custom microarray platform along with 2376 probes designed specifically to detect the potential antisense transcripts of 501 well-known genes suitable for cancer research.

Results

Using colon cancer tissue and normal tissue surrounding the cancer tissue obtained from 6 patients, we found that antisense transcripts without poly(A) tails are expressed from approximately 80% of these well-known genes. This observation is consistent with our previous finding that many antisense transcripts expressed in a cell are poly(A)-. We also identified 101 and 71 antisense probes displaying a high level of expression specifically in normal and cancer tissues respectively.

Conclusion

Our microarray analysis identified novel antisense transcripts with expression profiles specific to cancer tissue, some of which might play a role in the regulatory networks underlying oncogenesis and thus are potential targets for further experimental validation. Our microarray data are available at http://www.brc.riken.go.jp/ncrna2007/viewer-Saito-01/index.html.
Prognostic significance of STAT3 and phosphorylated STAT3 in human soft tissue tumors - a clinicopathological analysis
Authors: David Diana , Rajappan Lakshmy M , Balachandran Krishna , Thulaseedharan Jissa V , Nair Asha S , Pillai Radhakrishna M
Published: May 2011

Background

Signal transducer and activator of transcription 3 (STAT3) is a key signaling molecule and a central cytoplasmic transcription factor, implicated in the regulation of growth. Its aberrant activation has been demonstrated to correlate with many types of human malignancy. However, whether constitutive STAT3 signaling plays a key role in the survival and growth of soft-tissue tumors is still unclear and hence needs to be elucidated further. In our study we examined the expression levels of STAT3 and pSTAT3 in different grades of soft tissue tumors and correlated with its clinicopathological characteristics.

Methods

Expression levels of STAT3 and pSTAT3 in soft tissue tumors were studied using Immunohistochemistry, Western blotting and Reverse transcriptase- PCR and correlated with its clinicopathological characteristics using Chi squared or Fisher's exact test and by logistic regression analysis. Statistical analysis was done using Intercooled Stata software (Intercooled Stata 8.2 version).

Results

Of the 82 soft tissue tumor samples, fifty four (65.8%) showed immunoreactivity for STAT3 and twenty eight (34.1%) for pSTAT3. Expression of STAT3 and pSTAT3 was significantly associated with tumor grade (P < 0.001; P < 0.001), tumor location (P = 0.025; P = 0.027), plane of tumor (P = 0.011; P = 0.006), and tumor necrosis (P = 0.001; P = 0.002). Western blotting and RT-PCR analysis showed increased expression of STAT3 and p-STAT3 as grade of malignancy increased.

Conclusion

These findings suggest that constitutive activation of STAT3 is an important factor related to carcinogenesis of human soft tissue tumors and is significantly associated with its clinicopathological parameters which may possibly have potential diagnostic implications.
Pyrosequencing, a method approved to detect the two major EGFR mutations for anti EGFR therapy in NSCLC
Authors: Dufort Sandrine , Richard Marie-Jeanne , Lantuejoul Sylvie , de Fraipont Florence
Published: May 2011

Background

Epidermal Growth Factor Receptor (EGFR) mutations, especially in-frame deletions in exon 19 (ΔLRE) and a point mutation in exon 21 (L858R) predict gefitinib sensitivity in patients with non-small cell lung cancer. Several methods are currently described for their detection but the gold standard for tissue samples remains direct DNA sequencing, which requires samples containing at least 50% of tumor cells.

Methods

We designed a pyrosequencing assay based on nested PCR for the characterization of theses mutations on formalin-fixed and paraffin-embedded tumor tissue.

Results

This method is highly specific and permits precise characterization of all the exon 19 deletions. Its sensitivity is higher than that of "BigDye terminator" sequencing and enabled detection of 3 additional mutations in the 58 NSCLC tested. The concordance between the two methods was very good (97.4%). In the prospective analysis of 213 samples, 7 (3.3%) samples were not analyzed and EGFR mutations were detected in 18 (8.7%) patients. However, we observed a deficit of mutation detection when the samples were very poor in tumor cells.

Conclusions

pyrosequencing is then a highly accurate method for detecting ΔLRE and L858R EGFR mutations in patients with NSCLC when the samples contain at least 20% of tumor cells.
Facilitators and obstacles in pre-hospital medical response to earthquakes: a qualitative study
Authors: Djalali Ahmadreza , Khankeh Hamidreza , Öhlén Gunnar , Castrén Maaret , Kurland Lisa
Published: May 2011

Background

Earthquakes are renowned as being amongst the most dangerous and destructive types of natural disasters. Iran, a developing country in Asia, is prone to earthquakes and is ranked as one of the most vulnerable countries in the world in this respect. The medical response in disasters is accompanied by managerial, logistic, technical, and medical challenges being also the case in the Bam earthquake in Iran. Our objective was to explore the medical response to the Bam earthquake with specific emphasis on pre-hospital medical management during the first days.

Methods

The study was performed in 2008; an interview based qualitative study using content analysis. We conducted nineteen interviews with experts and managers responsible for responding to the Bam earthquake, including pre-hospital emergency medical services, the Red Crescent, and Universities of Medical Sciences. The selection of participants was determined by using a purposeful sampling method. Sample size was given by data saturation.

Results

The pre-hospital medical service was divided into three categories; triage, emergency medical care and transportation, each category in turn was identified into facilitators and obstacles. The obstacles identified were absence of a structured disaster plan, absence of standardized medical teams, and shortage of resources. The army and skilled medical volunteers were identified as facilitators.

Conclusions

The most compelling, and at the same time amenable obstacle, was the lack of a disaster management plan. It was evident that implementing a comprehensive plan would not only save lives but decrease suffering and enable an effective praxis of the available resources at pre-hospital and hospital levels.
Prone position and recruitment manoeuvre: the combined effect improves oxygenation
Authors: Rival Gilles , Patry Cyrille , Floret Nathalie , Navellou Jean Christophe , Belle Evelyne , Capellier Gilles
Published: May 2011

Introduction

Among the various methods for improving oxygenation while decreasing the risk of ventilation-induced lung injury in patients with acute respiratory distress syndrome (ARDS), a ventilation strategy combining prone position (PP) and recruitment manoeuvres (RMs) can be practiced. We studied the effects on oxygenation of both RM and PP applied in early ARDS patients.

Methods

We conducted a prospective study. Sixteen consecutive patients with early ARDS fulfilling our criteria (ratio of arterial oxygen partial pressure to fraction of inspired oxygen (PaO2/FiO2) 98.3 ± 28 mmHg; positive end expiratory pressure, 10.7 ± 2.8 cmH2O) were analysed. Each patient was ventilated in both the supine position (SP) and the PP (six hours in each position). A 45 cmH2O extended sigh in pressure control mode was performed at the beginning of SP (RM1), one hour after turning to the PP (RM2) and at the end of the six-hour PP period (RM3).

Results

The mean arterial oxygen partial pressure (PaO2) changes after RM1, RM2 and RM3 were 9.6%, 15% and 19%, respectively. The PaO2 improvement after a single RM was significant after RM3 only (P < 0.05). Improvements in PaO2 level and PaO2/FiO2 ratio were transient in SP but durable during PP. PaO2/FiO2 ratio peaked at 218 mmHg after RM3. PaO2/FiO2 changes were significant only after RM3 and in the pulmonary ARDS group (P = 0.008). This global strategy had a benefit with regard to oxygenation: PaO2/FiO2 ratio increased from 98.3 mmHg to 165.6 mmHg 13 hours later at the end of the study (P < 0.05). Plateau airway pressures decreased after each RM and over the entire PP period and significantly after RM3 (P = 0.02). Some reversible side effects such as significant blood arterial pressure variations were found when extended sighs were performed.

Conclusions

In our study, interventions such as a 45 cmH2O extended sigh during PP resulted in marked oxygenation improvement. Combined RM and PP led to the highest increase in PaO2/FiO2 ratio without major clinical side effects.
EBV LMP1, a viral mimic of CD40, activates dendritic cells and functions as a molecular adjuvant when incorporated into an HIV vaccine
Authors: Gupta Sachin , Termini James M , Niu Liguo , Kanagavelu Saravana K , Schmidtmayerova Helena , Snarsky Victoria , Kornbluth Richard S , Stone Geoffrey W
Published: May 2011

HIV-1 does not significantly activate cellular immunity, which has made it difficult to use attenuated forms of HIV-1 as a vaccine. In contrast, EBV induces robust T cell responses in most infected individuals, perhaps as this virus contains LMP1, a viral mimic of CD40, which is a key activating molecule for DCs and macrophages. Consequently, studies were conducted using LMP1 and LMP1-CD40, a related construct formed by replacing the intracellular signaling domain of LMP1 with that of CD40. Upon electroporation into DCs, LMP1 and LMP1-CD40 mRNAs were sufficient to up-regulate costimulatory molecules and proinflammatory cytokines, indicating that these molecules can function in isolation as adjuvant-like molecules. As a first step toward an improved HIV vaccine, LMP1 and LMP1-CD40 were introduced into a HIV-1 construct to produce virions encoding these proteins. Transduction of DCs and macrophages with these viruses induced morphological changes and up-regulated costimulatory molecules and cytokine production by these cells. HIV-LMP1 enhanced the antigen-presenting function of DCs, as measured in an in vitro immunization assay. Taken together, these data show that LMP1 and LMP1-CD40 are portable gene cassettes with strong adjuvant properties that can be introduced into viruses such as HIV, which by themselves, are insufficient to induce protective cellular immunity.
Inhibitory effect of prostaglandin I2 on bone marrow kinetics of eosinophils in the guinea pig
Authors: Sturm Eva M , Schuligoi Rufina , Konya Viktoria , Sturm Gunter J , Heinemann Akos
Published: May 2011

Enhanced eosinophil trafficking from bone marrow to the tissue is a hallmark of allergic diseases. We have shown previously that PGI2 markedly attenuates the locomotion of human eosinophils in vitro. Here, we set out to determine the effect of PGI2 on the trafficking of bone marrow eosinophils in the guinea pig. Shape change of bone marrow eosinophils was determined by flow cytometry, and chemotaxis assays were performed using a transwell migration system. Eosinophil release from bone marrow of guinea pigs was investigated in the isolated, perfused hind-limb preparation. We found that PGI2 prevented the mobilization of eosinophils from bone marrow and attenuated the shape change and chemotactic responses of bone marrow eosinophils. These effects were mimicked by iloprost and were prevented by the IP antagonist CAY10441 and the adenylyl cyclase inhibitor SQ22536. Immunohistochemical staining of bone marrow confirmed the expression of IPs by bone marrow eosinophils. The rate-limiting enzyme of PGI2 formation, PGIS, was found in large mononuclear cells. These data show that IP activation negatively modulates the mobilization and locomotion of bone marrow eosinophils and might therefore also protect against exaggerated recruitment of eosinophils to inflammatory sites.
Arginine transport in human monocytic leukemia THP-1 cells during macrophage differentiation
Authors: Barilli Amelia , Rotoli Bianca Maria , Visigalli Rossana , Bussolati Ovidio , Gazzola Gian C , Dall'Asta Valeria
Published: May 2011

l-arginine metabolism in myeloid cells plays a central role in the processes of macrophage activation and in the regulation of immune responses. In this study, we investigated arginine transport activity and the expression of the related transporter genes during the differentiation of monocytes to macrophages. We show here that the induction of THP-1 monocyte differentiation by PMA markedly increases the expression of SLC7A7 mRNA and of y+LAT1 protein and consequently, the activity of system y+L-mediated arginine transport. Conversely, the activity of system y+ decreases during macrophage differentiation as a result of a reduction in CAT1 protein expression. The PMA-induced, macrophage-differentiated phenotype and the increased activity of system y+L through the induction of SLC7A7 gene are mediated by the specific activation of PKCβ. SLC7A7 gene silencing causes a significant reduction of system y+L activity and a subsequent, marked increase of arginine and lysine cell content, thus suggesting that in macrophagic cells, system y+L activity is mainly directed outwardly. Differentiating agents other than PMA, i.e., VD3 and ATRA, are equally effective in the stimulation of system y+L transport activity through the increased expression of SLC7A7 mRNA and y+LAT1 protein. Moreover, we found that also during differentiation of human monocytes from peripheral blood SLC7A7 mRNA and system y+L activity are increased. These findings point to SLC7A7 gene as a marker of macrophage differentiation.
Partners and Partnerships: Trends in Private Oncology Practice
Authors: Paivanas Thomas A.
Published: May 2011

There are approximately 6,500 medical oncologists in private practice in the United States. Regional vacancy rates can range from 30% to 50%, putting enormous stress on existing providers. Regulatory, financial and emotional burdens continue to restructure the medical marketplace.
Characteristics and Outcomes of Patients With Advanced Gastric Cancer Who Declined to Participate in a Randomized Clinical Chemotherapy Trial
Authors: Tanai Chiharu , Nakajima Takako Eguchi , Nagashima Kengo , Kato Ken , Hamaguchi Tetsuya , Yamada Yasuhide , Muro Kei , Shirao Kuniaki , Kunitoh Hideo , Matsumura Yasuhiro , Yamamoto Seiichiro , Shimada Yasuhiro
Published: May 2011

The authors found no evidence to suggest any significant differences in the characteristics or clinical outcomes between clinical trials participants and nonparticipants.
A Model for Rural Oncology
Authors: Heifetz Laurence J. , Christensen Scott D. , deVere-White Ralph W. , Meyers Fredrick J.
Published: May 2011

The authors describe the development and implementation of a collaborative cancer center serving rural patients.
Racial Variation in the Cost-Effectiveness of Chemotherapy for Prostate Cancer
Authors: Grabner Michael , Onukwugha Eberechukwu , Jain Rahul , Mullins C. Daniel
Published: May 2011

The likelihood of chemotherapy being cost-effective for patients with metastatic prostate cancer differs across racial subgroups. This uncertainty presents challenges for managed-care decision makers.
Genomic Testing and Therapies for Breast Cancer in Clinical Practice
Authors: Haas Jennifer S. , Phillips Kathryn A. , Liang Su-Ying , Hassett Michael J. , Keohane Carol , Elkin Elena B. , Armstrong Joanne , Toscano Michele
Published: May 2011

Despite almost universal testing for HER2, many women with HER2-positive cancer may not receive trastuzumab. Fewer women received newer gene expression profile testing.
Impact of Clinical Oral Chemotherapy Program on Wastage and Hospitalizations
Authors: Khandelwal Nikhil , Duncan Ian , Ahmed Tamim , Rubinstein Elan , Pegus Cheryl
Published: May 2011

An oral chemotherapy cycle management program offers clinical support, reduces medication wastage, and provides management of adverse effects to realize cost savings for payers and patients.
Impact of New Drugs and Biologics on Colorectal Cancer Treatment and Costs
Authors: Karaca-Mandic Pinar , McCullough Jeffrey S. , Siddiqui Mustaqeem A. , Van Houten Holly , Shah Nilay D.
Published: May 2011

We measured the financial consequences of new CRC treatment regimens. New regimens have increased cost directly through price and indirectly through nonstandard and second-line regimen use.
US Insurance Program's Experience With a Multigene Assay for Early-Stage Breast Cancer
Authors: Hornberger John , Chien Rebecca , Krebs Katie , Hochheiser Louis
Published: May 2011

This study presents Humana's experience with a multigene breast cancer assay and provides an analysis of the clinical utility and economics of this technology.
Do Economic Evaluations of Targeted Therapy Provide Support for Decision Makers?
Authors: Ferrusi Ilia L. , Leighl Natasha B. , Kulin Nathalie A. , Marshall Deborah A.
Published: May 2011

Economic evaluations of adjuvant trastuzumab were reviewed. Three primary shortcomings were identified including incorporation of local data and estimation and representation (visual) of decision uncertainty.
Patient and Plan Characteristics Affecting Abandonment of Oral Oncolytic Prescriptions
Authors: Streeter Sonya Blesser , Schwartzberg Lee , Husain Nadia , Johnsrud Michael
Published: May 2011

Ten percent of patients abandon newly initiated oral oncolytics at the pharmacy. Patients facing higher cost sharing or increased concurrent prescription activity have a higher abandonment rate.
Phospholipase Cβ3 Mediates LH-Induced Granulosa Cell Differentiation
Authors: Donadeu Francesc X. , Esteves Cristina L. , Doyle Lynsey K. , Walker Catherine A. , Schauer Stephanie N. , Diaz Catalina A.
Published: May 2011

Previous studies showed that under certain conditions LH can stimulate not only adenylate cyclase (AC) but also phospholipase Cβ (PLCβ) signaling in target cells; however, the physiological involvement of PLCβ in LH-induced ovarian follicular cell differentiation has not been determined. To address this, ex vivo expression analyses and specific PLCβ targeting were performed in primary bovine granulosa cells. Expression analyses in cells from small (2.0–5.9 mm), medium (6.0–9.9 mm), and ovulatory-size (10.0–13.9 mm) follicles revealed an increase in mRNA and protein levels of heterotrimeric G protein subunits-αs, -αq, -α11, and -αi2 in ovulatory-size follicles, simultaneous with a substantial increase in LH receptor expression. Among the four known PLCβ isoforms, PLCβ3 (PLCB3) was specifically up-regulated in cells from ovulatory-size follicles, in association with a predominantly cytoplasmic location of PLCB3 in these cells and a significant inositol phosphate response to LH stimulation. Furthermore, RNA interference-mediated PLCB3 down-regulation reduced the ability of LH to induce hallmark differentiation responses of granulosa cells, namely transcriptional up-regulation of prostaglandin-endoperoxide synthase 2 and down-regulation of both aromatase expression and estradiol production. Responses to the AC agonist, forskolin, however, were not affected. In addition, PLCB3 down-regulation did not alter cAMP responses to LH in granulosa cells, ruling out a primary involvement of AC in mediating the effects of PLCB3. In summary, we provide evidence of a physiological involvement of PLCβ signaling in ovulatory-size follicles and specifically identify PLCB3 as a mediator of LH-induced differentiation responses of granulosa cells.
Voluntary Exercise Improves High-Fat Diet-Induced Leptin Resistance Independent of Adiposity
Authors: Carhuatanta Kimberly A. Krawczewski , Demuro Giovanna , Tschöp Matthias H. , Pfluger Paul T. , Benoit Stephen C. , Obici Silvana
Published: May 2011

The efficacy of exercise as primary prevention of obesity is the subject of intense investigation. Here, we show that voluntary exercise in a mouse strain susceptible to diet-induced obesity (C57B6J) decreases fat mass and increases energy expenditure. In addition, exercise attenuates obesity in mice fed a high-fat diet (HFD). Using FosB immunoreactivity as a marker of chronic neuronal activation, we found that exercise activates leptin receptor-positive neurons in the ventromedial hypothalamic nucleus, involved in homeostatic control of energy balance. FosB immunoreactivity in the ventromedial hypothalamic nucleus is decreased in sedentary mice exposed to HFD but is increased in exercised mice independent of adiposity. To determine whether the antiobesity effects of voluntary exercise improve central nervous system (CNS) leptin action, we measured the anorectic and weight reducing effects of intracerebroventricular (ICV) leptin in sedentary and exercised mice exposed to HFD (EH), as well as in sedentary mice that have been calorie restricted (SR) to match the fat mass of EH mice. ICV leptin was ineffective in lowering food intake and body weight (BW) in sedentary mice exposed to HFD mice. The anorectic potency of leptin was partially restored in EH and SR groups. However, ICV leptin significantly lowered BW in EH but not SR mice. Thus, exercise leads to the maintenance of a lower BW and leaner composition, as well as to improved CNS leptin action, independent of fat mass. These results support the notion that physical exercise directly influences the responsiveness of the CNS circuits involved in energy homeostasis by allowing the defense of a lowered BW.
Effects of Peripherally Administered Neuromedin U on Energy and Glucose Homeostasis
Authors: Peier Andrea M. , Desai Kunal , Hubert James , Du Xiaobing , Yang Liming , Qian Ying , Kosinski Jennifer R. , Metzger Joseph M. , Pocai Alessandro , Nawrocki Andrea R. , Langdon Ronald B. , Marsh Donald J.
Published: May 2011

Neuromedin U (NMU) is a highly conserved peptide reported to modulate energy homeostasis. Pharmacological studies have shown that centrally administered NMU inhibits food intake, reduces body weight, and increases energy expenditure. NMU-deficient mice develop obesity, whereas transgenic mice overexpressing NMU become lean and hypophagic. Two high-affinity NMU receptors, NMUR1 and NMUR2, have been identified. NMUR1 is found primarily in the periphery and NMUR2 primarily in the brain, where it mediates the anorectic effects of centrally administered NMU. Given the broad expression pattern of NMU, we evaluated whether peripheral administration of NMU has effects on energy homeostasis. We observed that acute and chronic peripheral administration of NMU in rodents dose-dependently reduced food intake and body weight and that these effects required NMUR1. The anorectic effects of NMU appeared to be partly mediated by vagal afferents. NMU treatment also increased core body temperature and metabolic rate in mice, suggesting that peripheral NMU modulates energy expenditure. Additionally, peripheral administration of NMU significantly improved glucose excursion. Collectively, these data suggest that NMU functions as a peripheral regulator of energy and glucose homeostasis and the development of NMUR1 agonists may be an effective treatment for diabetes and obesity.
Centrally Administered Resistin Enhances Sympathetic Nerve Activity to the Hindlimb but Attenuates the Activity to Brown Adipose Tissue
Authors: Kosari S. , Rathner J. A. , Chen F. , Kosari S. , Badoer E.
Published: May 2011

Resistin, an adipokine, is believed to act in the brain to influence energy homeostasis. Plasma resistin levels are elevated in obesity and are associated with metabolic and cardiovascular disease. Increased muscle sympathetic nerve activity (SNA) is a characteristic of obesity, a risk factor for diabetes and cardiovascular disease. We hypothesized that resistin affects SNA, which contributes to metabolic and cardiovascular dysfunction. Here we investigated the effects of centrally administered resistin on SNA to muscle (lumbar) and brown adipose tissue (BAT), outputs that influence cardiovascular and energy homeostasis. Overnight-fasted rats were anesthetized, and resistin (7 μg) was administered into the lateral cerebral ventricle (intracerebroventricular). The lumbar sympathetic nerve trunk or sympathetic nerves supplying BAT were dissected free, and nerve activity was recorded. Arterial blood pressure, heart rate, body core temperature, and BAT temperature were also recorded. Responses to resistin or vehicle were monitored for 4 h after intracerebroventricular administration. Acutely administered resistin increased lumbar SNA but decreased BAT SNA. Mean arterial pressure and heart rate, however, were not significantly affected by resistin. BAT temperature was significantly reduced by resistin, and there was a concomitant fall in body temperature. The findings indicate that resistin has differential effects on SNA to tissues involved in metabolic and cardiovascular regulation. The decreased BAT SNA and the increased lumbar SNA elicited by resistin suggest that it may contribute to the increased muscle SNA and reduced energy expenditure observed in obesity and diabetes.
Effects of Farnesyl Pyrophosphate Accumulation on Calvarial Osteoblast Differentiation
Authors: Weivoda Megan M. , Hohl Raymond J.
Published: May 2011

Statins, drugs commonly used to lower serum cholesterol, have been shown to stimulate osteoblast differentiation and bone formation. Statins inhibit 3-hydroxy-3-methylglutaryl (HMG)-coenzyme A reductase (HMGCR), the first step of the isoprenoid biosynthetic pathway, leading to the depletion of the isoprenoids farnesyl pyrophosphate (FPP) and geranylgeranyl pyrophosphate (GGPP). The effects of statins on bone have previously been attributed to the depletion of GGPP, because the addition of exogenous GGPP prevented statin-stimulated osteoblast differentiation in vitro. However, in a recent report, we demonstrated that the specific depletion of GGPP did not stimulate but, in fact, inhibited osteoblast differentiation. This led us to hypothesize that isoprenoids upstream of GGPP play a role in the regulation of osteoblast differentiation. We demonstrate here that the expression of HMGCR and FPP synthase decreased during primary calvarial osteoblast differentiation, correlating with decreased FPP and GGPP levels during differentiation. Zaragozic acid (ZGA) inhibits the isoprenoid biosynthetic pathway enzyme squalene synthase, leading to an accumulation of the squalene synthase substrate FPP. ZGA treatment of calvarial osteoblasts led to a significant increase in intracellular FPP and resulted in inhibition of osteoblast differentiation as measured by osteoblastic gene expression, alkaline phosphatase activity, and matrix mineralization. Simultaneous HMGCR inhibition prevented the accumulation of FPP and restored osteoblast differentiation. In contrast, specifically inhibiting GGPPS to lower the ZGA-induced increase in GGPP did not restore osteoblast differentiation. The specificity of HMGCR inhibition to restore osteoblast differentiation of ZGA-treated cultures through the reduction in isoprenoid accumulation was confirmed with the addition of exogenous mevalonate. Similar to ZGA treatment, exogenous FPP inhibited the mineralization of primary calvarial osteoblasts. Interestingly, the effects of FPP accumulation on osteoblasts were found to be independent of protein farnesylation. Our findings are the first to demonstrate that the accumulation of FPP impairs osteoblast differentiation and suggests that the depletion of this isoprenoid may be necessary for normal and statin-induced bone formation.
Axonal Protection by 17β-Estradiol through Thioredoxin-1 in Tumor Necrosis Factor-Induced Optic Neuropathy
Authors: Kitaoka Yasushi , Munemasa Yasunari , Hayashi Yasuhiro , Kuribayashi Junko , Koseki Natsuko , Kojima Kaori , Kumai Toshio , Ueno Satoki
Published: May 2011

Axonal degeneration often leads to the death of neuronal cell bodies. Previous studies demonstrated the substantial protective role of 17β-estradiol (E2) in several types of neuron. However, most studies examined cell body protection, and the role of 17β-E2 in axonal degeneration of retinal ganglion cells (RGC) remains unclear. In this study, we showed the presence of thioredoxin-1 (Trx1) in the optic nerve axons and found that the levels of Trx1 protein were significantly decreased in isolated RGC and the optic nerve after intravitreal injection of TNF, which was shown previously to induce optic nerve degeneration and subsequent loss of RGC. These changes were concomitant with disorganization of the microtubules with neurofilament accumulation, which were blocked by 17β-E2 implantation. 17β-E2 treatment also totally abolished TNF-induced decreases in Trx1 protein levels in isolated RGC and the optic nerve. The induction of Trx1 by 17β-E2 in the optic nerve was significantly inhibited by simultaneous injection of Trx1 small interfering RNA (siRNA) with TNF. Up-regulation of Trx1 by 17β-E2 in RGC-5 cells was prevented by Trx1 siRNA treatment. 17β-E2 significantly prevented TNF-induced axonal loss, and this axonal-protective effect was inhibited by intravitreal injection of Trx1 siRNA. This finding was also supported by the quantification of microtubules and neurofilaments. These results suggest that a Trx1 decrease in RGC bodies and their axons may be associated with TNF-induced optic nerve axonal degeneration. Axonal protection by 17β-E2 may be related to its regulatory effect on Trx1 induction.
Development and validation of a timed urinary collection system for use in the cat
Authors: Pelligand Ludovic , Lees Peter , Elliott Jonathan
Published: May 2011

The aim of the study was to develop and validate a feline urinary collection system for accurate 24 h urine output measurement and glomerular filtration rate (GFR) evaluation. We hypothesized that precise identification of urination time improves the accuracy of the collection system. In a group of nine cats, urinary volume and micturition times were repeatedly recorded for up to 48 h using purpose-built collection trays containing a temperature data logger. Collection time was determined both with and without using the data loggers on 22 occasions and agreement between estimated 24 h urine outputs obtained with the two calculation methods was evaluated. GFR was repeatedly measured by endogenous urinary creatinine clearance on three occasions. Twenty-four-hour urine output was measured in 98.5% of the attempted collections (300 cat-sampling days). Sensitivity and specificity of the detection system were 97.8% and 100%, respectively. Mean 24 h urine output was 12.4 ± 4.94 mL/kg/day and mean intra-cat between-days coefficient of variation (CV) was 16.6 ± 5.6% when data loggers were used. The absolute relative volume error between the two calculation methods ranged from 0% to 131%. Median absolute relative [interquartile range] error was 9.1% [3.25–19.8]. Bias was −1.3% and lower and upper limits of agreement were −39.7% and 35.2%, respectively. Mean estimated GFR was lower than previously reported with comparable urinary clearance methods (1.92 ± 0.37 mL/min/kg) and mean within-cat CV was 12 ± 6.9%. The system was simple in design, readily affordable, allowed normal micturition behaviour and reduced intra-animal variability in 24 h feline urine collection.
Elective preterm delivery as a management option in cryptogenic organizing pneumonia
Authors: Holder Kelly L , Scardo James A , Laye M Ryan
Published: May 2011

Bronchiolitis obliterans organizing pneumonia, now termed as cryptogenic organizing pneumonia (COP), is a fibrotic lung disease of the small airways with the potential to progress to end-stage lung disease. COP in pregnancy carries a high risk of maternal and neonatal complications and only two prior cases have been reported. This is the first case of pre-existing COP in pregnancy. We report a 16-year-old primigravid with COP who elected inpatient management and preterm delivery as a successful management option.
Nephrotic syndrome due to focal segmental glomerulosclerosis occurring in early pregnancy
Authors: Smyth A , Wall C A
Published: May 2011

Physiological proteinuria is common during pregnancy, but pathological proteinuria may also occur. Nephrotic range proteinuria most commonly occurs due to preeclampsia, but primary renal disease may also occur. We present a case of a woman who presented with nephrotic range proteinuria and nephrotic syndrome at an early stage of her second pregnancy. Due to proteinuria, haematuria, progressive symptoms and high need for medical treatment, renal biopsy was performed and she was noted to have focal segmental glomerulosclerosis (FSGS). She commenced immunosuppression but remained nephrotic during pregnancy. She delivered a healthy baby boy at 35 weeks gestation. Postpartum she remained nephrotic, and developed further complications requiring renal replacement therapy. Despite a successful pregnancy, this case of FSGS highlights that despite aggressive treatment FSGS in pregnancy is often associated with adverse renal outcome. We discuss investigations, including renal biopsy and empiric treatment options in this report.
How often do we ask about pregnancy in the diabetes review clinic?
Authors: Grant Paul , Lipscomb David
Published: May 2011

Background

Sub-optimal control of diabetes is a significant cause of complications during pregnancy. One of the aims of diabetes management should be to ensure that all women of child-bearing age with diabetes should be regularly screened with regard to their plans for pregnancy to ensure that their overall diabetic control and fitness for pregnancy can be maximized.

Methods

We analysed the electronic patient records of a target population of young women of child-bearing age (16–45) with both type 1 and type 2 diabetes who were attending the diabetes review clinic over a period of three years from 2007 to 2010. The Diabeta 3 software program which is commonly used has a query builder function which allows immediate recall and analysis of data.

Results

Of 1808 patients within the fertile range, only a small number appeared to have had information accurately documented with regard to any of the following: pregnancy plans, preconception counselling, contraception and also the recording of whether patients with diabetes were pregnant or not and enrolled in the ante-natal diabetes clinic.

Conclusions

The main inference from the data is its paucity and inaccuracy. It would appear that we are failing to enquire and/or record the fertility intentions of young female patients with diabetes. This is important because it means that we subsequently then miss those patients who need to be targeted for preconception counselling/optimization, which has implications for the morbidity and mortality associated with diabetes in pregnancy.
Evaluation of lymph drainage using bioelectrical impedance of the body
Authors: de Godoy J M P , Valente F M , Azoubel L M , Godoy M F G
Published: May 2011

Aim

The aim of this study was to investigate the effects of manual and mechanical lymph drainage on the bioelectrical composition of body tissues of patients with lymphoedema of the lower limbs.

Method

Twenty-one patients with lymphoedema of one leg were evaluated using single frequency bioelectrical impedance with four electrodes (SF-BIA4) immediately before and after a combination of manual and mechanical lymph drainage. Statistical analysis used the two-tailed paired t-test with an alpha error of 5% being considered acceptable.

Results

On comparing the results before and after lymph drainage, statistically significant differences were identified for both lymphoedematous and apparently healthy legs, but there were no significant differences in the alterations caused by the treatment between the healthy and lymphoedematous limbs of the same patient.

Conclusion

It was concluded that the association of manual and mechanical lymph drainage both modified the body composition as identified by bioelectrical impedance, and reduced the oedema.
Changes in popliteal vein diameter and flow velocity with knee flexion and hyperextension
Authors: Levine A , Huber J , Huber D
Published: May 2011

Objective

To compare popliteal vein (PV) diameter and peak flow velocity generated by a calf compressor, when the knee is either flexed or hyperextended.

Method

Subjects lay supine on a couch with a calf compressor on each leg. Peak flow velocities in the PV were measured by duplex ultrasound during activation of the compressor, when the knee was either flexed or hyperextended. Hyperextension of the knee is seen when the heel is elevated to prevent heel pressure ulcers.

Results

The results were analysed using the Wilcoxon signed rank test. This showed a significant increase in peak flow measurements related to narrowing of the PV when the knee was hyperextended.

Conclusion

There is a functional narrowing of the PV during hyperextension of the knee. We developed a model, which postulates an increase in the risk of deep vein thrombosis in patients whose knee is hyperextended. Based on this model, we suggest that the knee should be flexed slightly when patients are supine and anaesthetized.