bluuebunny/crossref_metadata_2025 huggingface dataset:
Synthetic emmprin peptides with chitobiose substitution stimulate MMP-2 production by fibroblasts
Authors: Kawakami Takehito , Sameshima Tetsuro , Hojo Hironobu , Koga Kaori , Nakahara Yoshiaki , Toole Bryan P , Suzumiya Junji , Okada Yasunori , Iwasaki Akinori , Nabeshima Kazuki
Published: August 2011

Background

Emmprin, a glycoprotein containing two Ig domains, is enriched on tumor cell surfaces and stimulates matrix metalloproteinase (MMP) production by adjacent stromal cells. Its first Ig domain (ECI) contains the biologically active site. The dependence of emmprin activity on N-glycosylation is controversial. We investigated whether synthetic ECI with the shortest sugar is functionally active.

Methods

The whole ECI peptides carrying sugar chains, a chitobiose unit or N-linked core pentasaccharide, were synthesized by the thioester method and added to fibroblasts to examine whether they stimulate MMP-2 production.

Results

ECI carrying a chitobiose unit, ECI-(GlcNAc) 2, but not ECI without a chitobiose unit or the chitobiose unit alone, dose-dependently stimulated MMP-2 production by fibroblasts. ECI with longer chitobiose units, ECI-[(Man)3(GlcNAc)2], also stimulated MMP-2 production, but the extent of its stimulation was lower than that of ECI-(GlcNAc)2.

Conclusions

Our results indicate that ECI can mimic emmprin activity when substituted with chitobiose, the disaccharide with which N-glycosylation starts.
Use of vitamin supplements and risk of total cancer and cardiovascular disease among the Japanese general population: A population-based survey
Authors: Hara Azusa , Sasazuki Shizuka , Inoue Manami , Shimazu Taichi , Iwasaki Motoki , Sawada Norie , Yamaji Taiki , Ishihara Junko , Iso Hiroyasu , Tsugane Shoichiro ,   the Japan Public Health Center-Based Prospective Study Group
Published: August 2011

Background

Despite the popular use of vitamin supplements and several prospective cohort studies investigating their effect on cancer incidence and cardiovascular disease (CVD), scientific data supporting their benefits remain controversial. Inconsistent results may be partly explained by the fact that use of supplements is an inconsistent behavior in individuals. We examined whether vitamin supplement use patterns affect cancer and CVD risk in a population-based cohort study in Japan.

Methods

A total of 28,903 men and 33,726 women in the Japan Public Health Center-based Prospective Study cohort, who answered questions about vitamin supplement use in the first survey from 1990-1994 and the second survey from 1995-1998, were categorized into four groups (never use, past use, recent use, and consistent use) and followed to the end of 2006 for cancer and 2005 for CVD. Sex-specific hazard ratios (HRs) and 95% confidence intervals (95% CIs) were used to describe the relative risks of cancer and CVD associated with vitamin supplement use.

Results

During follow-up, 4501 cancer and 1858 CVD cases were identified. Multivariate adjusted analysis revealed no association of any pattern of vitamin supplement use with the risk of cancer and CVD in men. In women, consistent use was associated with lower risk of CVD (HR 0.60, 95% CI 0.41-0.89), whereas past (HR 1.17, 95% CI 1.02-1.33) and recent use (HR 1.24, 95% CI 1.01-1.52) were associated with higher risk of cancer.

Conclusions

To our knowledge, this is the first prospective cohort study to examine simultaneously the associations between vitamin supplement use patterns and risk of cancer and CVD. This prospective cohort study demonstrated that vitamin supplement use has little effect on the risk of cancer or CVD in men. In women, however, consistent vitamin supplement use might reduce the risk of CVD. Elevated risk of cancer associated with past and recent use of vitamin supplements in women may be partly explained by preexisting diseases or unhealthy background, but we could not totally control for this in our study.
Age-disparity, sexual connectedness and HIV infection in disadvantaged communities around Cape Town, South Africa: a study protocol
Authors: Delva Wim , Beauclair Roxanne , Welte Alex , Vansteelandt Stijn , Hens Niel , Aerts Marc , du Toit Elizabeth , Beyers Nulda , Temmerman Marleen
Published: August 2011

Background

Crucial connections between sexual network structure and the distribution of HIV remain inadequately understood, especially in regard to the role of concurrency and age disparity in relationships, and how these network characteristics correlate with each other and other risk factors. Social desirability bias and inaccurate recall are obstacles to obtaining valid, detailed information about sexual behaviour and relationship histories. Therefore, this study aims to use novel research methods in order to determine whether HIV status is associated with age-disparity and sexual connectedness as well as establish the primary behavioural and socio-demographic predictors of the egocentric and community sexual network structures.

Method/Design

We will conduct a cross-sectional survey that uses a questionnaire exploring one-year sexual histories, with a focus on timing and age disparity of relationships, as well as other risk factors such as unprotected intercourse and the use of alcohol and recreational drugs. The questionnaire will be administered in a safe and confidential mobile interview space, using audio computer-assisted self-interview (ACASI) technology on touch screen computers. The ACASI features a choice of languages and visual feedback of temporal information. The survey will be administered in three peri-urban disadvantaged communities in the greater Cape Town area with a high burden of HIV. The study communities participated in a previous TB/HIV study, from which HIV test results will be anonymously linked to the survey dataset. Statistical analyses of the data will include descriptive statistics, linear mixed-effects models for the inter- and intra-subject variability in the age difference between sexual partners, survival analysis for correlated event times to model concurrency patterns, and logistic regression for association of HIV status with age disparity and sexual connectedness.

Discussion

This study design is intended to facilitate more accurate recall of sensitive sexual history data and has the potential to provide substantial insights into the relationship between key sexual network attributes and additional risk factors for HIV infection. This will help to inform the design of context-specific HIV prevention programmes.
EXACT: EXercise or Advice after ankle fraCTure. Design of a randomised controlled trial
Authors: Beckenkamp Paula R , Lin C Christine , Herbert Robert D , Haas Marion , Khera Kriti , Moseley Anne M ,   the EXACT Team
Published: August 2011

Background

Ankle fractures are common. Management of ankle fractures generally involves a period of immobilisation followed by rehabilitation to reduce pain, stiffness, weakness and swelling. The effects of a rehabilitation program are still unclear. However, it has been shown that important components of rehabilitation programs may not confer additional benefits over exercise alone. The primary aim of this trial is to determine the effectiveness and cost-effectiveness of an exercise-based rehabilitation program after ankle fracture, compared to advice alone.

Methods/Design

A pragmatic randomised trial will be conducted. Participants will be 342 adults with stiff, painful ankles after ankle fracture treated with immobilisation. They will be randomly allocated using a concealed randomisation procedure to either an Advice or Rehabilitation group. Participants in the Advice group will receive verbal and written advice about exercise at the time of removal of immobilisation. Participants in the Rehabilitation group will be provided with a 4-week rehabilitation program that is designed, monitored and progressed by a physiotherapist, in addition to verbal and written advice. Outcomes will be measured by a blinded assessor at 1, 3 and 6 months. The primary outcomes will be activity limitation and quality-adjusted life years.

Discussion

This pragmatic trial will determine if a rehabilitation program reduces activity limitation and improves quality of life, compared to advice alone, after immobilisation for ankle fracture.
Protocol for the Cognitive Interventions and Nutritional Supplements (CINS) trial: A randomized controlled multicenter trial of a brief intervention (BI) versus a BI plus cognitive behavioral treatment (CBT) versus nutritional supplements for patients with long-lasting muscle and back pain
Authors: Reme Silje E , Tveito Torill H , Chalder Trudie , Bjørkkjær Tormod , Indahl Aage , Brox Jens I , Fors Egil , Hagen Eli M , Eriksen Hege R
Published: August 2011

Background

Brief intervention programs are clinically beneficial, and cost efficient treatments for low back pain, when offered at 8-12 weeks, compared with treatment as usual. However, about 30% of the patients do not return to work. The European Guidelines for treatment of chronic low back pain recommends Cognitive Behavioral Therapy (CBT), but conclude that further research is needed to evaluate the effectiveness of CBT for chronic low back pain.

Methods/Design

The aim of the multicenter CINS trial (Cognitive Interventions and Nutritional Supplements) is to compare the effectiveness of 4 different interventions; Brief Intervention, Brief Intervention and CBT, Brief Intervention and nutritional supplements of seal oil, and Brief Intervention and nutritional supplements of soy oil. All participants will be randomly assigned to the interventions. The nutritional supplements will be tested in a double blind design. 400 patients will be recruited from a population of chronic low back pain patients that have been sick listed for 2-10 months. Four outpatient clinics, located in different parts of Norway, will participate in recruitment and treatment of the patients.

The Brief Intervention is a one session cognitive, clinical examination program based on a non-injury model, where return to normal activity and work is the main goal, and is followed by two booster sessions. The CBT is a tailored treatment involving 7 sessions, following a detailed manual. The nutritional supplements consist of a dosage of 10 grams of either soy or seal oil (capsules) per day for 3 months, administered in a double blind design. All patients will be followed up with questionnaires after 3, 6 and 12 months, while sick leave data will be collected up to at least 24 months after randomization. The primary outcome of the study is sick leave and will be based on register data from the National Insurance Administration. Secondary outcomes include self-reported data on disability, pain, and psychological variables.

Conclusions

To our knowledge, the CINS trial will be the largest, randomized trial of psychological and nutritional interventions for chronic low back pain patients to date. It will provide important information regarding the effectiveness of CBT and seal oil for chronic low back pain patients.

Trial Registration

http://www.clinicaltrials.gov, with registration numberNCT00463970.
Spatial epidemiology and spatial ecology study of worldwide drug-resistant tuberculosis
Authors: Liu Yunxia , Jiang Shiwen , Liu Yanxun , Wang Rui , LI Xiao , Yuan Zhongshang , Wang Lixia , Xue Fuzhong
Published: August 2011

Background

Drug-resistant tuberculosis (DR-TB) is a major public health problem caused by various factors. It is essential to systematically investigate the epidemiological and, in particular, the ecological factors of DR-TB for its prevention and control. Studies of the ecological factors can provide information on etiology, and assist in the effective prevention and control of disease. So it is of great significance for public health to explore the ecological factors of DR-TB, which can provide guidance for formulating regional prevention and control strategies.

Methods

Anti-TB drug resistance data were obtained from the World Health Organization/International Union Against Tuberculosis and Lung Disease (WHO/UNION) Global Project on Anti-Tuberculosis Drug Resistance Surveillance, and data on ecological factors were collected to explore the ecological factors for DR-TB. Partial least square path modeling (PLS-PM), in combination with ordinary least squares (OLS) regression, as well as geographically weighted regression (GWR), were used to build a global and local spatial regression model between the latent synthetic DR-TB factor ("DR-TB") and latent synthetic risk factors.

Results

OLS regression and PLS-PM indicated a significant globally linear spatial association between "DR-TB" and its latent synthetic risk factors. However, the GWR model showed marked spatial variability across the study regions. The "TB Epidemic", "Health Service" and "DOTS (directly-observed treatment strategy) Effect" factors were all positively related to "DR-TB" in most regions of the world, while "Health Expenditure" and "Temperature" factors were negatively related in most areas of the world, and the "Humidity" factor had a negative influence on "DR-TB" in all regions of the world.

Conclusions

In summary, the influences of the latent synthetic risk factors on DR-TB presented spatial variability. We should formulate regional DR-TB monitoring planning and prevention and control strategies, based on the spatial characteristics of the latent synthetic risk factors and spatial variability of the local relationship between DR-TB and latent synthetic risk factors.
InN nanorods prepared with CrN nanoislands by plasma-assisted molecular beam epitaxy
Authors: Liu Kuang-Wei , Chang Shoou-Jinn , Young Sheng-Joue , Hsueh Tao-Hung , Hung Hung , Mai Yu-Chun , Wang Shih-Ming , Chen Kuan-Jen , Wu Ya-Ling , Chen Yue-Zhang
Published: August 2011

The authors report the influence of CrN nanoisland inserted on growth of baseball-bat InN nanorods by plasma-assisted molecular beam epitaxy under In-rich conditions. By inserting CrN nanoislands between AlN nucleation layer and the Si (111) substrate, it was found that we could reduce strain form Si by inserting CrN nanoisland, FWHM of the x-ray rocking curve measured from InN nanorods from 3,299 reduced to 2,115 arcsec. It is due to the larger strain from lattice miss-match of the film-like InN structure; however, the strain from lattice miss-match was obvious reduced owing to CrN nanoisland inserted. The TEM images confirmed the CrN structures and In droplets dissociation from InN, by these results, we can speculate the growth mechanism of baseball-bat-like InN nanorods.
Regulation of the arachidonic acid mobilization in macrophages by combustion-derived particles
Authors: Fritsch-Decker Susanne , Both Tanja , Mülhopt Sonja , Paur Hanns-Rudolf , Weiss Carsten , Diabaté Silvia
Published: August 2011

Background

Acute exposure to elevated levels of environmental particulate matter (PM) is associated with increasing morbidity and mortality rates. These adverse health effects, e.g. culminating in respiratory and cardiovascular diseases, have been demonstrated by a multitude of epidemiological studies. However, the underlying mechanisms relevant for toxicity are not completely understood. Especially the role of particle-induced reactive oxygen species (ROS), oxidative stress and inflammatory responses is of particular interest.

In this in vitro study we examined the influence of particle-generated ROS on signalling pathways leading to activation of the arachidonic acid (AA) cascade. Incinerator fly ash particles (MAF02) were used as a model for real-life combustion-derived particulate matter. As macrophages, besides epithelial cells, are the major targets of particle actions in the lung murine RAW264.7 macrophages and primary human macrophages were investigated.

Results

The interaction of fly ash particles with macrophages induced both the generation of ROS and as part of the cellular inflammatory responses a dose- and time-dependent increase of free AA, prostaglandin E2/thromboxane B2 (PGE2/TXB2), and 8-isoprostane, a non-enzymatically formed oxidation product of AA. Additionally, increased phosphorylation of the mitogen-activated protein kinases (MAPK) JNK1/2, p38 and ERK1/2 was observed, the latter of which was shown to be involved in MAF02-generated AA mobilization and phosphorylation of the cytosolic phospolipase A2. Using specific inhibitors for the different phospolipase A2 isoforms the MAF02-induced AA liberation was shown to be dependent on the cytosolic phospholipase A2, but not on the secretory and calcium-independent phospholipase A2. The initiation of the AA pathway due to MAF02 particle exposure was demonstrated to depend on the formation of ROS since the presence of the antioxidant N-acetyl-cysteine (NAC) prevented the MAF02-mediated enhancement of free AA, the subsequent conversion to PGE2/TXB2 via the induction of COX-2 and the ERK1/2 and JNK1/2 phosphorylation. Finally we showed that the particle-induced formation of ROS, liberation of AA and PGE2/TXB2 together with the phosphorylation of ERK1/2 and JNK1/2 proteins was decreased after pre-treatment of macrophages with the metal chelator deferoxamine mesylate (DFO).

Conclusions

These results indicate that one of the primary mechanism initiating inflammatory processes by incinerator fly ash particles seems to be the metal-mediated generation of ROS, which triggers via the MAPK cascade the activation of AA signalling pathway.
Computerized clinical decision support systems for drug prescribing and management: A decision-maker-researcher partnership systematic review
Authors: Hemens Brian J , Holbrook Anne , Tonkin Marita , Mackay Jean A , Weise-Kelly Lorraine , Navarro Tamara , Wilczynski Nancy L , Brian Haynes R ,   the CCDSS Systematic Review Team
Published: August 2011

Background

Computerized clinical decision support systems (CCDSSs) for drug therapy management are designed to promote safe and effective medication use. Evidence documenting the effectiveness of CCDSSs for improving drug therapy is necessary for informed adoption decisions. The objective of this review was to systematically review randomized controlled trials assessing the effects of CCDSSs for drug therapy management on process of care and patient outcomes. We also sought to identify system and study characteristics that predicted benefit.

Methods

We conducted a decision-maker-researcher partnership systematic review. We updated our earlier reviews (1998, 2005) by searching MEDLINE, EMBASE, EBM Reviews, Inspec, and other databases, and consulting reference lists through January 2010. Authors of 82% of included studies confirmed or supplemented extracted data. We included only randomized controlled trials that evaluated the effect on process of care or patient outcomes of a CCDSS for drug therapy management compared to care provided without a CCDSS. A study was considered to have a positive effect (i.e., CCDSS showed improvement) if at least 50% of the relevant study outcomes were statistically significantly positive.

Results

Sixty-five studies met our inclusion criteria, including 41 new studies since our previous review. Methodological quality was generally high and unchanged with time. CCDSSs improved process of care performance in 37 of the 59 studies assessing this type of outcome (64%, 57% of all studies). Twenty-nine trials assessed patient outcomes, of which six trials (21%, 9% of all trials) reported improvements.

Conclusions

CCDSSs inconsistently improved process of care measures and seldomly improved patient outcomes. Lack of clear patient benefit and lack of data on harms and costs preclude a recommendation to adopt CCDSSs for drug therapy management.
Computerized clinical decision support systems for acute care management: A decision-maker-researcher partnership systematic review of effects on process of care and patient outcomes
Authors: Sahota Navdeep , Lloyd Rob , Ramakrishna Anita , Mackay Jean A , Prorok Jeanette C , Weise-Kelly Lorraine , Navarro Tamara , Wilczynski Nancy L , Brian Haynes R ,   the CCDSS Systematic Review Team
Published: August 2011

Background

Acute medical care often demands timely, accurate decisions in complex situations. Computerized clinical decision support systems (CCDSSs) have many features that could help. However, as for any medical intervention, claims that CCDSSs improve care processes and patient outcomes need to be rigorously assessed. The objective of this review was to systematically review the effects of CCDSSs on process of care and patient outcomes for acute medical care.

Methods

We conducted a decision-maker-researcher partnership systematic review. MEDLINE, EMBASE, Evidence-Based Medicine Reviews databases (Cochrane Database of Systematic Reviews, DARE, ACP Journal Club, and others), and the Inspec bibliographic database were searched to January 2010, in all languages, for randomized controlled trials (RCTs) of CCDSSs in all clinical areas. We included RCTs that evaluated the effect on process of care or patient outcomes of a CCDSS used for acute medical care compared with care provided without a CCDSS. A study was considered to have a positive effect (i.e., CCDSS showed improvement) if at least 50% of the relevant study outcomes were statistically significantly positive.

Results

Thirty-six studies met our inclusion criteria for acute medical care. The CCDSS improved process of care in 63% (22/35) of studies, including 64% (9/14) of medication dosing assistants, 82% (9/11) of management assistants using alerts/reminders, 38% (3/8) of management assistants using guidelines/algorithms, and 67% (2/3) of diagnostic assistants. Twenty studies evaluated patient outcomes, of which three (15%) reported improvements, all of which were medication dosing assistants.

Conclusion

The majority of CCDSSs demonstrated improvements in process of care, but patient outcomes were less likely to be evaluated and far less likely to show positive results.
Computerized clinical decision support systems for chronic disease management: A decision-maker-researcher partnership systematic review
Authors: Roshanov Pavel S , Misra Shikha , Gerstein Hertzel C , Garg Amit X , Sebaldt Rolf J , Mackay Jean A , Weise-Kelly Lorraine , Navarro Tamara , Wilczynski Nancy L , Haynes R Brian ,   the CCDSS Systematic Review Team
Published: August 2011

Background

The use of computerized clinical decision support systems (CCDSSs) may improve chronic disease management, which requires recurrent visits to multiple health professionals, ongoing disease and treatment monitoring, and patient behavior modification. The objective of this review was to determine if CCDSSs improve the processes of chronic care (such as diagnosis, treatment, and monitoring of disease) and associated patient outcomes (such as effects on biomarkers and clinical exacerbations).

Methods

We conducted a decision-maker-researcher partnership systematic review. We searched MEDLINE, EMBASE, Ovid's EBM Reviews database, Inspec, and reference lists for potentially eligible articles published up to January 2010. We included randomized controlled trials that compared the use of CCDSSs to usual practice or non-CCDSS controls. Trials were eligible if at least one component of the CCDSS was designed to support chronic disease management. We considered studies 'positive' if they showed a statistically significant improvement in at least 50% of relevant outcomes.

Results

Of 55 included trials, 87% (n = 48) measured system impact on the process of care and 52% (n = 25) of those demonstrated statistically significant improvements. Sixty-five percent (36/55) of trials measured impact on, typically, non-major (surrogate) patient outcomes, and 31% (n = 11) of those demonstrated benefits. Factors of interest to decision makers, such as cost, user satisfaction, system interface and feature sets, unique design and deployment characteristics, and effects on user workflow were rarely investigated or reported.

Conclusions

A small majority (just over half) of CCDSSs improved care processes in chronic disease management and some improved patient health. Policy makers, healthcare administrators, and practitioners should be aware that the evidence of CCDSS effectiveness is limited, especially with respect to the small number and size of studies measuring patient outcomes.
Functional pathway mapping analysis for hypoxia-inducible factors
Authors: Chuang Chia-Sheng , Pai Tun-Wen , Hu Chin-Hua , Tzou Wen-Shyong , Dah-Tsyr Chang Margaret , Chang Hao-Teng , Chen Chih-Chia
Published: August 2011

Background

Hypoxia-inducible factors (HIFs) are transcription factors that play a crucial role in response to hypoxic stress in living organisms. The HIF pathway is activated by changes in cellular oxygen levels and has significant impacts on the regulation of gene expression patterns in cancer cells. Identifying functional conservation across species and discovering conserved regulatory motifs can facilitate the selection of reference species for empirical tests. This paper describes a cross-species functional pathway mapping strategy based on evidence of homologous relationships that employs matrix-based searching techniques for identifying transcription factor-binding sites on all retrieved HIF target genes.

Results

HIF-related orthologous and paralogous genes were mapped onto the conserved pathways to indicate functional conservation across species. Quantitatively measured HIF pathways are depicted in order to illustrate the extent of functional conservation. The results show that in spite of the evolutionary process of speciation, distantly related species may exhibit functional conservation owing to conservative pathways. The novel terms OrthRate and ParaRate are proposed to quantitatively indicate the flexibility of a homologous pathway and reveal the alternative regulation of functional genes.

Conclusion

The developed functional pathway mapping strategy provides a bioinformatics approach for constructing biological pathways by highlighting the homologous relationships between various model species. The mapped HIF pathways were quantitatively illustrated and evaluated by statistically analyzing their conserved transcription factor-binding elements.

Keywords

hypoxia-inducible factor (HIF), hypoxia-response element (HRE), transcription factor (TF), transcription factor binding site (TFBS), KEGG (Kyoto Encyclopedia of Genes and Genomes), cross-species comparison, orthology, paralogy, functional pathway
Increased midgestational IFN-γ, IL-4 and IL-5 in women bearing a child with autism: A case-control study
Authors: Goines Paula E , Croen Lisa A , Braunschweig Daniel , Yoshida Cathleen K , Grether Judith , Hansen Robin , Kharrazi Martin , Ashwood Paul , Van de Water Judy
Published: August 2011

Background

Immune anomalies have been documented in individuals with autism spectrum disorders (ASDs) and their family members. It is unknown whether the maternal immune profile during pregnancy is associated with the risk of bearing a child with ASD or other neurodevelopmental disorders.

Methods

Using Luminex technology, levels of 17 cytokines and chemokines were measured in banked serum collected from women at 15 to 19 weeks of gestation who gave birth to a child ultimately diagnosed with (1) ASD (n = 84), (2) a developmental delay (DD) but not autism (n = 49) or (3) no known developmental disability (general population (GP); n = 159). ASD and DD risk associated with maternal cytokine and chemokine levels was estimated by using multivariable logistic regression analysis.

Results

Elevated concentrations of IFN-γ, IL-4 and IL-5 in midgestation maternal serum were significantly associated with a 50% increased risk of ASD, regardless of ASD onset type and the presence of intellectual disability. By contrast, elevated concentrations of IL-2, IL-4 and IL-6 were significantly associated with an increased risk of DD without autism.

Conclusion

The profile of elevated serum IFN-γ, IL-4 and IL-5 was more common in women who gave birth to a child subsequently diagnosed with ASD. An alternative profile of increased IL-2, IL-4 and IL-6 was more common for women who gave birth to a child subsequently diagnosed with DD without autism. Further investigation is needed to characterize the relationship between these divergent maternal immunological phenotypes and to evaluate their effect on neurodevelopment.
Role of neutrophils in the activation of trypsinogen in severe acute pancreatitis
Authors: Abdulla Aree , Awla Darbaz , Thorlacius Henrik , Regnér Sara
Published: August 2011

The relationship between inflammation and proteolytic activation in pancreatitis is an unresolved issue in pancreatology. The purpose of this study was to define the influence of neutrophils on trypsinogen activation in severe AP. Pancreatitis was induced by infusion of taurocholate into the pancreatic duct in C57BL/6 mice. For neutrophil depletion, an anti-Gr-1 antibody was administered before pancreatitis induction. Administration of the anti-Gr-1 antibody reduced circulating neutrophils by 97%. Pancreatic TAP and serum amylase levels increased 2 h and 24 h after induction of pancreatitis. Neutrophil depletion reduced pancreatic TAP and serum amylase levels at 24 h but not at 2 h after pancreatitis induction. Pancreatic MPO and infiltration of neutrophils, as well as MIP-2 levels, were increased 24 h after taurocholate infusion. Two hours after taurocholate administration, no significant pancreatic infiltration of neutrophils was observed. Injection of the anti-Gr-1 antibody abolished MPO activity, neutrophil accumulation, and MIP-2 levels, as well as acinar cell necrosis, hemorrhage, and edema in the pancreas at 24 h. Moreover, taurocholate-provoked tissue damage and MPO activity in the lung were normalized by neutrophil depletion. Intravital fluorescence microscopy revealed a 97% reduction of leukocytes in the pancreatic microcirculation after administration of the anti-Gr-1 antibody. Our data demonstrate that initial trypsinogen activation is independent of neutrophils, whereas later activation is dependent on neutrophils in the pancreas. Neutrophils are critical in mediating pancreatic and lung tissue damage in severe AP.
Bortezomib, Bendamustine, and Rituximab in Patients With Relapsed or Refractory Follicular Lymphoma: The Phase II VERTICAL Study
Authors: Fowler Nathan , Kahl Brad S. , Lee Peter , Matous Jeffrey V. , Cashen Amanda F. , Jacobs Samuel A. , Letzer Jeffrey , Amin Bipinkumar , Williams Michael E. , Smith Sonali , Saleh Alfred , Rosen Peter , Shi Hongliang , Parasuraman Sudha , Cheson Bruce D.
Published: August 2011

Purpose

The aims of this multicenter study were to evaluate the response rate, progression-free survival, and toxicity of the combination of bortezomib, bendamustine, and rituximab in patients with follicular lymphoma whose disease was relapsed or refractory to prior treatment.

Patients and Methods

Patients received five 35-day cycles of bortezomib, bendamustine, and rituximab: bortezomib administered intravenously (IV) at a dose of 1.6 mg/m2on days 1, 8, 15, and 22, cycles one to five; bendamustine 50, 70, or 90 mg/m2IV over a 60-minute infusion on days 1 and 2, cycles one to five; and rituximab 375 mg/m2on days 1, 8, 15, and 22 of cycle one and day 1 of subsequent cycles. Patients were assessed using the International Workshop Response Criteria, with the primary end point of 60% complete response rate.

Results

Seventy-three patients were enrolled. During the dose-escalation phase, the maximum-tolerated dose for bendamustine was not reached; the 90 mg/m2dose level was expanded for the efficacy assessment, and a total of 63 patients received bendamustine 90 mg/m2. In these 63 patients, the overall response rate was 88% (including 53% complete response). Median duration of response was 11.7 months (95% CI, 9.2 to 13.3). Median progression-free survival was 14.9 months (95% CI, 11.1 to 23.7). Toxicities were manageable; myelosuppression was the main toxicity (25% and 14% of patients experienced grade 3 to 4 neutropenia and grade 3 to 4 thrombocytopenia, respectively). Transient grade 3 to 4 neuropathy occurred in 11% of patients.

Conclusion

The combination of bortezomib, bendamustine, and rituximab is highly active in patients with follicular lymphoma who have received previous treatment.
Incidence and Risk of Congestive Heart Failure in Patients With Renal and Nonrenal Cell Carcinoma Treated With Sunitinib
Authors: Richards Christopher J. , Je Youjin , Schutz Fabio A.B. , Heng Daniel Y.C. , Dallabrida Susan M. , Moslehi Javid J. , Choueiri Toni K.
Published: August 2011

Purpose

Sunitinib is a multitargeted receptor tyrosine kinase inhibitor approved for treatment of renal cell carcinoma (RCC) and GI stromal tumor. Congestive heart failure (CHF) is an important adverse effect that has been reported with sunitinib, but overall incidence and relative risk (RR) remain undefined. We performed an up-to-date meta-analysis to determine the risk of developing CHF in patients with both RCC and non-RCC tumors treated with sunitinib.

Methods

Medline databases were searched for articles published between January 1966 and February 2011. Eligible studies were limited to phase II and III trials of sunitinib with adequate safety reporting in patients with cancer of any tumor type. Summary incidence, RR, and 95% CIs were calculated using random- or fixed-effects models based on the heterogeneity of included studies.

Results

A total of 6,935 patients were included. Overall incidence for all- and high-grade CHF in sunitinib-treated patients was 4.1% (95% CI, 1.5% to 10.6%) and 1.5% (95% CI, 0.8% to 3.0%), respectively. RR of all- and high-grade CHF in sunitinib-treated patients compared with placebo-treated patients was 1.81 (95% CI, 1.30 to 2.50; P < .001) and 3.30 (95% CI, 1.29 to 8.45; P = .01), respectively. On subgroup analysis, there was no difference observed in CHF incidence for patients with RCC versus non-RCC or in trials with or without cardiac monitoring. No evidence of publication bias was observed.

Conclusion

Sunitinib use is associated with increased risk of CHF in patients with cancer.
Physician Characteristics and Variability of Erythropoiesis-Stimulating Agent Use Among Medicare Patients With Cancer
Authors: Wright Jason D. , Neugut Alfred I. , Wilde Elizabeth T. , Buono Donna L. , Malin Jennifer , Tsai Wei Y. , Hershman Dawn L.
Published: August 2011

Purpose

Drugs are usually approved for a specific indication on the basis of randomized trials. However, once approved, these treatments are often used differently than as tested in trials. We performed an analysis to determine the patterns of use of erythropoiesis-stimulating agents (ESAs).

Methods

We used the Surveillance, Epidemiology, and End Results–Medicare database to identify patients age 65 years or older with breast, lung, or colon cancer diagnosed between 1995 and 2005 who had one ESA and chemotherapy claim. Associations of patient, tumor, and physician-related factors with receipt of ESAs were analyzed.

Results

Of 21,091 patients analyzed, 5,099 (24.2%) received ESAs for 1 week or less (misuse), and 1,601 (7.6%) received ESAs for more than 14 weeks (prolonged use). Receipt of ESAs while not actively receiving chemotherapy (off label) occurred in 2,876 patients (13.6%). In a multivariable analysis, ESA misuse was associated with MD degree, female sex of physician, and earlier year of medical school graduation. Private practice physicians (odds ratio [OR], 0.78; 95% CI, 0.72 to 0.84) and high-volume physicians (OR, 0.78; 95% CI, 0.72 to 0.85) were less likely to use 1 week or less of ESA treatment. Treatment by high-volume oncologists (OR, 1.33; 95% CI, 1.14 to 1.55) and by oncologists who graduated from US medical schools (OR, 1.26; 95% CI, 1.12 to 1.42) predicted prolonged-duration ESA use, whereas female oncologists (OR, 0.79; 95% CI, 0.68 to 0.93) were less likely to prescribe prolonged ESA treatment. Private practice physicians (OR, 1.18; 95% CI, 1.02 to 1.38) and high-volume providers (OR, 1.58; 95% CI, 1.33 to 1.87) were more likely to prescribe more than 24 weeks of ESA treatment.

Conclusion

Our study demonstrated widespread variability in the use of ESAs. Physician characteristics exerted substantial influence on ESA use. Policies to discourage inappropriate use of cancer therapies are needed.
Identification of Growth Arrest and DNA-Damage-Inducible Gene β (GADD45β) as a Novel Tumor Suppressor in Pituitary Gonadotrope Tumors
Authors: Michaelis Katherine A. , Knox Aaron J. , Xu Mei , Kiseljak-Vassiliades Katja , Edwards Michael G. , Geraci Mark , Kleinschmidt-DeMasters B. K. , Lillehei Kevin O. , Wierman Margaret E.
Published: August 2011

Gonadotrope and null cell pituitary tumors cause significant morbidity, often presenting with signs of hypogonadism together with visual disturbances due to mass effects. Surgery and radiation are the only therapeutic options to date. To identify dysregulated genes and pathways that may play a role in tumorigenesis and/or progression, molecular profiling was performed on 14 gonadotrope tumors, with nine normal human pituitaries obtained at autopsy serving as controls. Bioinformatic analysis identified putative downstream effectors of tumor protein 53 (p53) that were consistently repressed in gonadotrope pituitary tumors, including RPRM, P21, and PMAIP1, with concomitant inhibition of the upstream p53 regulator, PLAGL1(Zac1). Further analysis of the growth arrest and DNA damage-inducible (GADD45) family revealed no change in the p53 target, GADD45α, but identified repression of GADD45β in pituitary tumors in addition to the previously reported inhibition of GADD45γ. Overexpression of GADD45β in LβT2 mouse gonadotrope cells blocked tumor cell proliferation and increased rates of apoptosis in response to growth factor withdrawal. Stable gonadotrope cell transfectants expressing increased GADD45β showed decreased colony formation in soft agar, confirming its normal role as a tumor suppressor. Unlike previous studies of GADD45γ in pituitary tumors and α and β in other tumors, bisulfite sequencing showed no evidence of hypermethylation of the GADD45β promoter in human pituitary tumor samples to explain the repression of its expression. Thus, GADD45β is a novel pituitary tumor suppressor whose reexpression blocks proliferation, survival, and tumorigenesis. Together these studies identify new targets and mechanisms to explore in pituitary tumor initiation and progression.
CNS Opioid Signaling Separates Cannabinoid Receptor 1-Mediated Effects on Body Weight and Mood-Related Behavior in Mice
Authors: Lockie Sarah Haas , Czyzyk Traci A. , Chaudhary Nilika , Perez-Tilve Diego , Woods Stephen C. , Oldfield Brian J. , Statnick Michael A. , Tschöp Matthias H.
Published: August 2011

Existing monotherapies for the treatment of obesity provide only modest weight loss and/or have adverse side effects, and this is also the case with the cannabinoid receptor 1 (CB1) inverse agonist, rimonabant. We aimed to investigate the possibility of improving efficacy and reducing side effects of rimonabant by cotreatment with opioid system antagonists. Using both genetic and pharmacological removal of opioid signaling in mice, we investigated changes in body weight, food intake, and fat mass as well as behavioral outcomes of interactions between opioid ligands and the CB1 using the inverse agonist, rimonabant. The ability of rimonabant to reduce weight is enhanced by removal of with μ-opioid receptor signaling, while not being greatly affected by κ-opioid receptor blockade. Additionally, lack of opioid signaling, especially κ-opioid receptor, attenuated the ability of rimonabant to decrease immobility time in the Porsolt forced-swim test, a preclinical model of depression. These results indicate that the endogenous opioid system is involved in modulating both the metabolic and mood effects of rimonabant.
The Effect of Vertical Sleeve Gastrectomy on a Rat Model of Polycystic Ovarian Syndrome
Authors: Wilson-Pérez Hilary E. , Seeley Randy J.
Published: August 2011

Polycystic ovarian syndrome (PCOS) is the most common endocrine disorder of women of reproductive age. Although some of the primary symptoms of PCOS are reproductive abnormalities, including hyperandrogenism, menstrual dysfunction, and hirsutism, other metabolic disturbances are also common, including obesity and insulin resistance. Women with PCOS who have undergone weight-loss bariatric surgery have reported surprising postoperative benefits beyond weight loss, including resolution of menstrual dysfunction and improvement of hirsutism. Here, we use a chronic dihydrotestosterone (DHT) exposure model of PCOS in female rats and investigate the efficacy of a specific type of bariatric surgery, namely vertical sleeve gastrectomy (VSG), to resolve the reproductive and metabolic disturbances induced by DHT treatment. We find that VSG causes loss of body weight and body fat in DHT-treated rats but does not improve glucose tolerance or restore estrous cyclicity. Although human PCOS patients have shown decreased androgen levels after bariatric surgery, the chronic nature of DHT administration in this rat model both before and after VSG renders this effect impossible in this case. Therefore, the lack of improvement in glucose tolerance and estrous cyclicity may implicate a direct effect of androgen knockdown as a mechanism for the improvements seen in human PCOS patients after bariatric surgery. In addition, the dissociation of body weight loss without improved glucose tolerance suggests that glucose intolerance may be a body weight-independent phenomenon in women with PCOS.
Competitive Pricing and the Challenge of Cost Control in Medicare
Authors: Coulam Robert F. , Feldman Roger D. , Dowd Bryan E.
Published: August 2011

The Medicare program faces a serious challenge: it must find ways to control costs but must do so through a system of congressional oversight that necessarily limits its choices. We look at one approach to prudent purchasing — competitive pricing — that Medicare has attempted many times and in various ways since the beginning of the program, and in all but one case unsuccessfully due to the politics of provider opposition working through Congress and the courts. We look at some related efforts to change Medicare pricing to explore when the program has been successful in making dramatic changes in how it pays for health care. A set of recommendations emerges for ways to respond to the impediments of law and politics that have obstructed change to more efficient payment methods. Except in unusual cases, competitive pricing threatens too many stakeholders in too many ways for key political actors to support it. But an unusual case may arise in the coming Medicare fiscal crisis, a crisis related in part to the prices Medicare pays. At that point, competitive pricing may look less like a problem and more like a solution coming at a time when the system badly needs one.
LMNA cardiomyopathy: cell biology and genetics meet clinical medicine
Authors: Lu Jonathan T. , Muchir Antoine , Nagy Peter L. , Worman Howard J.
Published: August 2011

Mutations in the LMNA gene, which encodes A-type nuclear lamins (intermediate filament proteins expressed in most differentiated somatic cells), cause a diverse range of diseases, called laminopathies, that selectively affect different tissues and organ systems. The most prevalent laminopathy is cardiomyopathy with or without different types of skeletal muscular dystrophy. LMNA cardiomyopathy has an aggressive clinical course with higher rates of deadly arrhythmias and heart failure than most other heart diseases. As awareness among physicians increases, and advances in DNA sequencing methods make the genetic diagnosis of LMNA cardiomyopathy more common, cardiologists are being faced with difficult questions regarding patient management. These questions concern the optimal use of intracardiac cardioverter defibrillators to prevent sudden death from arrhythmias, and medical interventions to prevent heart damage and ameliorate heart failure symptoms. Data from a mouse model of LMNA cardiomyopathy suggest that inhibitors of mitogen-activated protein kinase (MAPK) signaling pathways are beneficial in preventing and treating cardiac dysfunction; this basic research discovery needs to be translated to human patients.
Tumescent anaesthesia in combination with femoral nerve block for surgery of varicose veins: prilocaine 0.1% versus 0.2%
Authors: Hillermann T , Dullenkopf A , Joechle W , Traber J
Published: August 2011

Objective

Results of a prospective, randomized, double-blinded study about tumescent anaesthesia (TA) in combination with femoral nerve block (FNB) for surgery of varicose veins are reported. The aim is to compare two different concentrations of prilocaine in TA.

Method

With approval of the ethical committee and informed consent, FNB (nerve stimulation, 20 mL prilocaine 0.75%) was performed followed by TA using prilocaine 0.1% versus 0.2% (groups P0.1 and P0.2). Further medication was standardized. Overall amount of prilocaine was recorded, plasma levels of 20 patients measured regularly. Side-effects, patient satisfaction and pain scores were compared ( P < 0.05).

Results

Ninety patients were included. In one patient (P0.1), general anaesthesia was necessary. There was no difference in pain scores, need for rescue medication or patient satisfaction. More prilocaine was administered in P0.2 ( P < 0.0001) with higher but far below toxic plasma levels. In three patients (P0.2) mild met-haemoglobinaemia was confirmed.

Conclusion

TA with prilocaine 0.1% in combination with FNB is sufficient to provide high patient satisfaction during varicosis surgery.
Effect of multilayer high-compression bandaging on ankle range of motion and oxygen cost of walking
Authors: Roaldsen K S , Elfving B , Stanghelle J K , Mattsson E
Published: August 2011

Objective

To evaluate the effects of multilayer high-compression bandaging on ankle range of motion, oxygen consumption and subjective walking ability in healthy subjects.

Method

A volunteer sample of 22 healthy subjects (10 women and 12 men; aged 67 [63–83] years) were studied. The intervention included treadmill-walking at self-selected speed with and without multilayer high-compression bandaging (Proforeº), randomly selected. The primary outcome variables were ankle range of motion, oxygen consumption and subjective walking ability.

Results

Total ankle range of motion decreased 4% with compression. No change in oxygen cost of walking was observed. Less than half the subjects reported that walking-shoe comfort or walking distance was negatively affected.

Conclusion

Ankle range of motion decreased with compression but could probably be counteracted with a regular exercise programme. There were no indications that walking with compression was more exhausting than walking without. Appropriate walking shoes could seem important to secure gait efficiency when using compression garments.
Quality of optometry referrals to neovascular age-related macular degeneration clinic: a prospective study
Authors: Muen Wisam J , Hewick Simon A
Published: August 2011

Objectives

To evaluate the quality of referrals to a neovascular age-related macular degeneration clinic from optometrists using the standard Rapid Access Referral Form (RARF) from the Royal College of Ophthalmologists.

Design

A prospective study. Prospective data were gathered from all optometry referrals using the RARF, between the periods of December 2006 to August 2009. These were assessed for accuracy of history, clinical signs and final diagnosis as compared to a macula expert.

Setting

Highlands NHS Trust.

Participants

All patients referred to the eye department at NHS Highlands Trust using the RARF.

Main outcome measures

The symptoms of neovascular age-related macular degeneration correctly identified by optometrists, and the signs of neovascular age-related macular degeneration correctly identified by optometrists.

Results

Fifty-four RARFs were received during this period, there was an overall agreement with symptomatology in 57.4% of cases. Optometrists scored less well in recognizing the clinical signs of neovascular age-related macular degeneration, with the poorest scores for recognizing macular oedema (44.4%) and drusen (51.9%). Twenty (37%) patients referred had neovascular age-related macular degeneration.

Conclusions

RARFs make up the minority of referrals to the neovascular age-related macular degeneration clinic. Optometrists find it difficult to accurately elicit the signs of macula disease.