bluuebunny/crossref_metadata_2025_split huggingface dataset:
Dose tapering for ciclosporin in cats with nonflea‐induced hypersensitivity dermatitis
Authors: Steffan Jean , Roberts Elizabeth , Cannon Andrea , Prélaud Pascal , Forsythe Peter , Fontaine Jacques , King Stephen , Seewald Wolfgang 
Published: March 2013

BackgroundLittle information is available on the ciclosporin dose‐tapering regimen and clinical response in the treatment of feline hypersensitivity dermatitis.Hypothesis/ObjectivesTo test a dose‐tapering regimen and assess efficacy and clinical safety for up to 18 weeks.AnimalsEighty‐eight client‐owned cats with feline hypersensitivity dermatitis.MethodsCats that received either a placebo or ciclosporin at 2.5 mg/kg or 7 mg/kg daily for 6 weeks were given 7 mg/kg ciclosporin daily for 4 weeks. Depending on the clinical response, the dose was tapered from daily to every other day over the next 4 weeks and further to twice a week for an additional 4 weeks.ResultsAfter all cats received 7 mg/kg for 4 weeks, the dose could be tapered to every other day for the next 4 weeks in 70% of cats remaining in the study. During the next 4 weeks, 57, 15 and 22% of cats remaining in the study could be treated at twice a week, every other day or daily, respectively. After the first 4 weeks, the mean lesion score and owner‐assessed pruritus improved over baseline by 69 and 61%, respectively, and remained stable during the following 8 weeks. Approximately 65% of the cats in the study were reported to have an adverse event (AE), very often mild and resolving spontaneously. The most frequentAEs were gastrointestinal and included primarily vomiting and diarrhoea. Eighty per cent ofAEs occurred when cats were on daily treatment.Conclusions and clinical importanceResults suggest that the induction dose of 7 mg/kg ciclosporin can be tapered as soon as 4 weeks without deterioration of the clinical response. Establishment of the lowest effective dosing regimen of ciclosporin reduced the frequency ofAEs.
Cultivating Our “Frienemies”: Viewing Immunity as Microbiome Management
Authors: Harvill Eric T. 
Published: March 2013

ABSTRACT
Immunology has been studied and understood in the context of the compelling problems of infectious disease. But our rapidly growing knowledge of immune interactions with our healthy microbiota, and the many benefits it confers, suggests there may be value to an alternative view: that mechanisms of defense against pathogens are one aspect of a complex system with the broader purpose of managing our healthy microbiome. From this perspective, adaptive immunity may be viewed as a flexible system for simultaneously recruiting and managing a near limitless number of potential symbionts. This perspective can allow for reinterpretation of many observations and can suggest new experiments to help us better understand our complex interactions with the microbes that surround us.
Overexpression of Specific Cysteine Peptidases Confers Pathogenicity to a Nonpathogenic Entamoeba histolytica Clone
Authors: Matthiesen Jenny , Bär Ann-Katrein , Bartels Anne-Kathrin , Marien Dennis , Ofori Susann , Biller Laura , Tannich Egbert , Lotter Hannelore , Bruchhaus Iris 
Published: March 2013

ABSTRACT

Cysteine peptidases (CPs) of
Entamoeba histolytica
are considered to be important pathogenicity factors. Previous studies have found that under standard axenic culture conditions, only four (
ehcp-a1
,
ehcp-a2
,
ehcp-a5
, and
ehcp-a7
) out of 35 papain-like
ehcp
genes present in the
E. histolytica
genome are expressed at high levels. Little is known about the expression of CPs in
E. histolytica
during amoebic liver abscess (ALA) formation. In the current study, a quantitative real-time PCR assay was developed to determine the expression of the various
ehcp
genes during ALA formation in animal models. Increased expression of four
ehcp
genes (
ehcp-a3
,
-a4
,
-a10
, and
-c13
) was detected in the gerbil and mouse models. Increased expression of another three
ehcp
genes (
ehcp-a5
,
-a6
, and
-a7
) was detected in the mouse model only, and two other
ehcp
genes (
ehcp-b8
and
-b9
) showed increased expression in the gerbil model only. Trophozoites of the nonpathogenic
E. histolytica
HM-1:IMSS clone A1, which was unable to induce ALAs, were transfected with vectors enabling overexpression of those CPs that are expressed at high levels under culture conditions or during ALA formation. Interestingly, overexpression of
ehcp-b8
,
-b9
, and
-c13
restored the pathogenic phenotype of the nonpathogenic clone A1 whereas overexpression of various other peptidase genes had no effect on the pathogenicity of this clone.

IMPORTANCE
Entamoeba histolytica
is a widespread and clinically important protozoan parasite. It normally exists in the human intestine without causing clinical symptoms but can invade the intestinal mucosa, which causes serious intestinal (amoebic colitis) and extraintestinal (amoebic liver abscess [ALA]) diseases. The identification of factors responsible for the invasion of the parasite and disease formation is a major topic in the field. Here, we investigate the roles of different papain-like cysteine peptidases (CPs) as pathogenicity factors. We show that the expression of some of the peptidases that are normally expressed at low levels increases during ALA formation. Furthermore, nonpathogenic amoebae can be transformed to pathogenic amoebae, simply by specific overexpression of some of these CPs. Our findings reinforce the importance of CPs as pathogenicity factors of
E. histolytica
.
The Fungal Pathogen Aspergillus fumigatus Regulates Growth, Metabolism, and Stress Resistance in Response to Light
Authors: Fuller Kevin K. , Ringelberg Carol S. , Loros Jennifer J. , Dunlap Jay C. 
Published: March 2013

ABSTRACTLight is a pervasive environmental factor that regulates development, stress resistance, and even virulence in numerous fungal species. Though much research has focused on signaling pathways inAspergillus fumigatus, an understanding of how this pathogen responds to light is lacking. In this report, we demonstrate that the fungus does indeed respond to both blue and red portions of the visible spectrum. Included in theA. fumigatuslight response is a reduction in conidial germination rates, increased hyphal pigmentation, enhanced resistance to acute ultraviolet and oxidative stresses, and an increased susceptibility to cell wall perturbation. By performing gene deletion analyses, we have found that the predicted blue light receptor LreA and red light receptor FphA play unique and overlapping roles in regulating the described photoresponsive behaviors ofA. fumigatus. However, our data also indicate that the photobiology of this fungus is complex and likely involves input from additional photosensory pathways beyond those analyzed here. Finally, whole-genome microarray analysis has revealed thatA. fumigatusbroadly regulates a variety of metabolic genes in response to light, including those involved in respiration, amino acid metabolism, and metal homeostasis. Together, these data demonstrate the importance of the photic environment on the physiology ofA. fumigatusand provide a basis for future studies into this unexplored area of its biology.IMPORTANCEConsiderable effort has been taken to understand how the mold pathogenAspergillus fumigatussenses its environment to facilitate growth within the immunocompromised host. Interestingly, it was shown that the deletion of a blue light photoreceptor in two divergent fungal pathogens,Cryptococcus neoformansandFusarium oxysporum, leads to an attenuation of virulence in their respective animal infection models. This suggests that light signaling pathways are conservatively involved in the regulation of fungal pathogenesis. However, an understanding of whether and howA. fumigatusresponds to light is lacking. Here we demonstrate that this organism coordinates broad aspects of its physiology with the photic environment, including pathways known to be involved in virulence, such as carbohydrate metabolism and oxidative stress resistance. Moreover, the photoresponse ofA. fumigatusdiffers in notable ways from the well-studied modelAspergillus nidulans. Therefore, this work should represent a general advancement in both photobiology andA. fumigatusresearch communities.
Can a psychosocial intervention programme teaching coping strategies improve the quality of life of Iranian women? A non-randomised quasi-experimental study
Authors: Addelyan Rasi Hamideh , Timpka Toomas , Lindqvist Kent , Moula Alireza 
Published: March 2013

ObjectivesTo assess whether a psychosocial intervention teaching coping strategies to women can improve quality of life (QOL) in groups of Iranian women exposed to social pressures.DesignQuasi-experimental non-randomised group design involving two categories of Iranian women, each category represented by non-equivalent intervention and comparison groups.SettingA large urban area in Iran.Participants44 women; 25 single mothers and 19 newly married women.InterventionsSeventh-month psychosocial intervention aimed at providing coping strategies.Primary outcome measuresEffect sizes in four specific health-related domains and two overall perceptions of QOL and health measured by the WHOQOL-BREF instrument.ResultsLarge effect sizes were observed among the women exposed to the intervention in the WHOQOL-BREF subdomains measuring physical health (r=0.68; p<0.001), psychological health (r=0.72; p<0.001), social relationships (r=0.52; p<0.01), environmental health (r=0.55; p<0.01) and in the overall perception of QOL (r=0.72; p<0.001); the effect size regarding overall perception of health was between small and medium (r=0.20; not significant). Small and not statistically significant effect sizes were observed in the women provided with traditional social welfare services.ConclusionsTeaching coping strategies can improve the QOL of women in societies where gender discrimination is prevalent. The findings require reproduction in studies with a more rigorous design before the intervention model can be recommended for widespread distribution.
Incidence and risk factors for mortality of vertebral osteomyelitis: a retrospective analysis using the Japanese diagnosis procedure combination database
Authors: Akiyama Toru , Chikuda Hirotaka , Yasunaga Hideo , Horiguchi Hiromasa , Fushimi Kiyohide , Saita Kazuo 
Published: March 2013

ObjectiveTo examine the incidence of vertebral osteomyelitis (VO) and the clinical features of VO focusing on risk factors for death using a Japanese nationwide administrative database.DesignRetrospective observational study.SettingHospitals adopting the Diagnosis Procedure Combination system during 2007–2010.ParticipantsWe identified 7118 patients who were diagnosed with VO (International Classification of Diseases, 10th Revision codes: A18.0, M46.4, M46.5, M46.8, M46.9, M48.9 and M49.3, checked with the detailed diagnoses in each case and all other codes indicating the presence of a specific infection) and hospitalised between July and December, 2007–2010, using the Japanese Diagnosis Procedure Combination database.Main outcome measuresThe annual incidence of VO was estimated. Logistic regression analysis was performed to analyse factors affecting in-hospital mortality in the VO patients. Dependent variables included patient characteristics (age, sex and comorbidities), procedures (haemodialysis and surgery) and hospital factors (type of hospital and hospital volume).ResultsOverall, 58.9% of eligible patients were men and the average age was 69.2 years. The estimated incidence of VO increased from 5.3/100 000 population per year in 2007 to 7.4/100 000 population per year in 2010. In-hospital mortality was 6%. There was a linear trend between higher rates of in-hospital mortality and greater age. A higher rate of in-hospital mortality was significantly associated with haemodialysis use (ORs, 10.56 (95% CI 8.12 to 13.74)), diabetes (2.37 (1.89 to 2.98)), liver cirrhosis (2.63 (1.49 to 4.63)), malignancy (2.68, (2.10 to 3.42)) and infective endocarditis (3.19 (1.80 to 5.65)).ConclusionsOur study demonstrates an increasing incidence of VO, and defines risk factors for death with a nationwide database. Several comorbidities were significantly associated with higher rates of in-hospital death in VO patients.
Descriptive study of possible link between cardioankle vascular index and homocysteine in vascular-related diseases
Authors: Wang Hongyu , Liu Jinbo , Wang Qi , Zhao Hongwei , Shi Hongyan , Yu Xiaolan , Fu Xiaobao 
Published: March 2013

ObjectivesCardioankle vascular index (CAVI) is a new index of arterial stiffness independent of immediate blood pressure. Homocysteine (Hcy) is an independent risk factor for vascular diseases. The aim of this study was to investigate the relationship between Hcy and CAVI in the vascular-related diseases.DesignDescriptive research.Participants88 patients (M/F 46/42) with or without hypertension, coronary artery disease or arteriosclerosis obliterans were enrolled to our study. They were divided into two groups according to the level of Hcy.MethodsCAVI, carotid-femoral pulse wave velocity (CF-PWV) and carotid-radial pulse wave velocity (CR-PWV) were measured by VS-1000 and Complior apparatus.ResultsThere was significant correlation between Hcy and CF-PWV, CR-PWV, CAVI in the entire group (r=0.33, p=0.002; r=0.51, p<0.001; r=0.42, p<0.001, respectively). And there was significant correlation between Hcy and CF-PWV, CR-PWV, CAVI in the vascular-related disease group (r=0.23, p=0.048; r=0.51, p<0.001; r=0.392, p=0.001, respectively). The level of Hcy was significantly higher in patients with one or more vascular diseases than in patients without vascular diseases. The levels of CF-PWV, CR-PWV and CAVI were significantly higher in Hcy ≥15 μmol/l group than in Hcy <5 μmol/l group (13.7±3.0 vs 10.8±2.5, p < 0.001; 10.6±2.1 vs 9.2±1.6, p=0.001; 9.30±2.1 vs 7.79±2.1, p=0.001, respectively). Multiple linear regression showed that Hcy, body mass index (BMI) and age were independent associating factors of CAVI in the entire study group (β=0.421, p=0.001; β=−0.309, p=0.006; β=0.297, p=0.012, respectively). And Hcy, BMI and age were independent influencing factors of CAVI in the vascular-related disease group (β=0.434, p=0.001; β=−0.331, p=0.009; β=0.288, p=0.022, respectively).ConclusionsCAVI was positively correlated with Hcy in the vascular-related diseases.
Why residents of Dutch deprived neighbourhoods are less likely to be heavy drinkers: the role of individual and contextual characteristics
Authors: Kuipers Mirte A G , Jongeneel-Grimen Birthe , Droomers Mariël , Wingen Marleen , Stronks Karien , Kunst Anton E 
Published: March 2013

BackgroundEarlier research has shown that residents of Dutch deprived neighbourhoods drink less alcohol than people in other areas. We aimed to assess the role of individual and neighbourhood characteristics in a cross-sectional, nationwide, multilevel study.MethodsIndividual data of 30 117 Dutch adults, living in 1722 neighbourhoods across the Netherlands, were obtained from the 2004 to 2009 national health survey (POLS). Chronic heavy alcohol consumption was measured as ≥14 drinks/week for women and ≥21 for men, and episodic heavy drinking as ≥6 drinks/day at least once a week. Neighbourhood deprivation was dichotomous; deprived districts as selected by the Dutch government versus other areas. Multilevel logistic regression models of the association between deprivation and heavy drinking were corrected for age, gender, household composition, population density and potential predictors ethnicity, socioeconomic status (education, income), neighbourhood-level social cohesion and percentage Muslims.ResultsThe prevalence of heavy drinking was lower in deprived neighbourhoods than in the rest of the Netherlands. This association was found for both chronic and episodic heavy drinking (OR=0.58 (0.47 to 0.72) and OR=0.57 (0.45 to 0.72), respectively). Adding ethnicity to the model reduced these associations by approximately one half. Socioeconomic composition did not contribute to the relationship. The proportion of Muslims explained a small part, while social cohesion explained even less of the association. Stronger associations were observed for women and older adults than for men and younger adults.ConclusionsThe lower prevalence of heavy drinking occurring in deprived areas is largely explained by the ethnicity of neighbourhood residents.
Inhibition of NF-κB–Mediated Signaling by the Cyclin-Dependent Kinase Inhibitor CR8 Overcomes Prosurvival Stimuli to Induce Apoptosis in Chronic Lymphocytic Leukemia Cells
Authors: Cosimo Emilio , McCaig Alison M. , Carter-Brzezinski Luke J.M. , Wheadon Helen , Leach Michael T. , Le Ster Karine , Berthou Christian , Durieu Emilie , Oumata Nassima , Galons Hervé , Meijer Laurent , Michie Alison M. 
Published: March 2013

Abstract
Purpose: Chronic lymphocytic leukemia (CLL) is currently incurable with standard chemotherapeutic agents, highlighting the need for novel therapies. Overcoming proliferative and cytoprotective signals generated within the microenvironment of lymphoid organs is essential for limiting CLL progression and ultimately developing a cure.
Experimental Design: We assessed the potency of cyclin-dependent kinase (CDK) inhibitor CR8, a roscovitine analog, to induce apoptosis in primary CLL from distinct prognostic subsets using flow cytometry–based assays. CLL cells were cultured in in vitro prosurvival and proproliferative conditions to mimic microenvironmental signals in the lymphoid organs, to elucidate the mechanism of action of CR8 in quiescent and proliferating CLL cells using flow cytometry, Western blotting, and quantitative real-time PCR.
Results: CR8 was 100-fold more potent at inducing apoptosis in primary CLL cells than roscovitine, both in isolated culture and stromal-coculture conditions. Importantly, CR8 induced apoptosis in CD40-ligated CLL cells and preferentially targeted actively proliferating cells within these cultures. CR8 treatment induced downregulation of the antiapoptotic proteins Mcl-1 and XIAP, through inhibition of RNA polymerase II, and inhibition of NF-κB signaling at the transcriptional level and through inhibition of the inhibitor of IκB kinase (IKK) complex, resulting in stabilization of IκBα expression.
Conclusions: CR8 is a potent CDK inhibitor that subverts pivotal prosurvival and proproliferative signals present in the tumor microenvironment of CLL patient lymphoid organs. Our data support the clinical development of selective CDK inhibitors as novel therapies for CLL. Clin Cancer Res; 19(9); 2393–405. ©2013 AACR.
Assessment of Audit Methodologies for Bias Evaluation of Tumor Progression in Oncology Clinical Trials
Authors: Zhang Jenny J. , Zhang Lijun , Chen Huanyu , Murgo Anthony J. , Dodd Lori E. , Pazdur Richard , Sridhara Rajeshwari 
Published: March 2013

Abstract
As progression-free survival (PFS) has become increasingly used as the primary endpoint in oncology phase III trials, the U.S. Food and Drug Administration (FDA) has generally required a complete-case blinded independent central review (BICR) of PFS to assess and reduce potential bias in the investigator or local site evaluation. However, recent publications and FDA analyses have shown a high correlation between local site evaluation and BICR assessments of the PFS treatment effect, which questions whether complete-case BICR is necessary. One potential alternative is to use BICR as an audit tool to detect evaluation bias in the local site evaluation. In this article, the performance characteristics of two audit methods proposed in the literature are evaluated on 26 prospective, randomized phase III registration trials in nonhematologic malignancies. The results support that a BICR audit to assess potential bias in the local site evaluation is a feasible approach. However, implementation and logistical challenges need further consideration and discussion. Clin Cancer Res; 19(10); 2637–45. ©2013 AACR.
Effect of Intermittent Dosing Regimens of Erlotinib on Methylnitrosourea-Induced Mammary Carcinogenesis
Authors: Lubet Ronald A. , Szabo Eva , Iwata Kenneth K. , Gill Stanley C. , Tucker Chris , Bode Ann , Steele Vernon E. , Juliana M. Margaret , Nicastro Holly L. , Grubbs Clinton J. 
Published: March 2013

Abstract
EGF receptor (EGFR) inhibitors are used in the therapy of lung and pancreatic cancers and effectively prevent cancers in multiple animal models. Although daily dosing with erlotinib is effective, weekly dosing may reduce toxicity and have advantages, particularly for prevention. We tested alternative dosing regimens for preventive/therapeutic efficacy in a rat mammary cancer model. For prevention, erlotinib was administered by gavage beginning 5 days after methylnitrosourea (MNU). For therapy and biomarker studies, rats with palpable mammary cancers were treated for six weeks or for six days, respectively. Experiment A, erlotinib (6 mg/kg body weight/day, intragastric): daily (7 times/week); one day on/one day off; and two days on/two days off. All regimens decreased tumor incidence, increased tumor latency, and decreased cancer multiplicity versus controls (P &lt; 0.01). However, intermittent dosing was less effective than daily dosing (P &lt; 0.05). Experiment B, erlotinib (6 mg/kg body weight/day) daily or two days on/two days off or one time per week at 42 mg/kg body weight. All regimens reduced cancer incidence and multiplicity versus controls (P &lt; 0.01). Interestingly, daily and weekly dosing were equally effective (P &gt; 0.5). Experiment C, erlotinib administered at 42 or 21 mg/kg body weight 1 time per week, decreased tumor incidence and multiplicity (P &lt; 0.01). Erlotinib had a serum half-life of ≤8 hours and weekly treatment yielded effective serum levels for ≤48 hours. Daily or weekly treatment of cancer bearing rats reduced mammary tumor size 25% to 35%, whereas control cancers increased &gt;250%. Levels of phosphorylated extracellular signal-regulated kinase (ERK) were strongly decreased in rats treated daily/weekly with erlotinib. Thus, altering the dose of erlotinib retained most of its preventive and therapeutic efficacy, and based on prior clinical studies, is likely to reduce its toxicity. Cancer Prev Res; 6(5); 448–54. ©2013 AACR.