bluuebunny/crossref_metadata_2025 huggingface dataset:
Large-Sample Bayesian Posterior Distributions for Probabilistic Sensitivity Analysis
Authors: Hazen Gordon B. , Huang Min
Published: September 2006

In probabilistic sensitivity analyses, analysts assign probability distributions to uncertain model parameters and use Monte Carlo simulation to estimate the sensitivity of model results to parameter uncertainty. The authors present Bayesian methods for constructing large-sample approximate posterior distributions for probabilities, rates, and relative effect parameters, for both controlled and uncontrolled studies, and discuss how to use these posterior distributions in a probabilistic sensitivity analysis. These results draw on and extend procedures from the literature on large-sample Bayesian posterior distributions and Bayesian random effects meta-analysis. They improve on standard approaches to probabilistic sensitivity analysis by allowing a proper accounting for heterogeneity across studies as well as dependence between control and treatment parameters, while still being simple enough to be carried out on a spreadsheet. The authors apply these methods to conduct a probabilistic sensitivity analysis for a recently published analysis of zidovudine prophylaxis following rapid HIV testing in labor to prevent vertical HIV transmission in pregnant women.
The Impact of Unmeasured Clinical Variables on the Accuracy of Hospital Report Cards: A Monte Carlo Study
Authors: Austin Peter C.
Published: September 2006

Purpose. Hospital report cards are commonly produced using administrative data. The objective of this study was to determine the impact of unmeasured clinical data on the accuracy of hospitals’ report cards.

Methods. Monte Carlo simulations were based on both administrative and detailed clinical data for patients hospitalized with an acute myocardial infarction in Ontario, Canada. Data were simulated such that the true performance of each hospital was known. Both clinical and administrative risk scores were randomly generated for each patient. The ability of hospital report cards to correctly identify hospitals that truly had higher than acceptable mortality was compared when both clinical and administrative data were used and when only administrative data were used. By using Monte Carlo simulations, we were able to incrementally increase the divergence between the 2 risk scores.

Results. In a wide range of settings, sensitivity and specificity of hospital report cards was only negligibly greater when both administrative and clinical data were used compared to when only administrative data were used.

Conclusions. Unmeasured clinical data have at most a minor impact on the accuracy of cardiac hospital report cards.
Estimation of Mortality Rates for Disease Simulation Models Using Bayesian Evidence Synthesis
Authors: McMahon Pamela M. , Zaslavsky Alan M. , Weinstein Milton C. , Kuntz Karen M. , Weeks Jane C. , Gazelle G. Scott
Published: September 2006

Purpose. The authors propose a Bayesian approach for estimating competing risks for inputs to disease simulation models. This approach is suggested when modeling a disease that causes a large proportion of all-cause mortality, particularly when mortality from the disease of interest and other-cause mortality are both affected by the same risk factor.

Methods. The authors demonstrate a Bayesian evidence synthesis by estimating other-cause mortality, stratified by smoking status, for use in a simulation model of lung cancer. National (US) survey data linked to death registries (National Health Interview Survey [NHIS]—Multiple Cause of Death files) were used to fit cause-specific hazard models for 3 causes of death (lung cancer, heart disease, and all other causes), controlling for age, sex, race, and smoking status. Synthesis of NHIS data with national vital statistics data on numbers and causes of deaths was performed in WinBUGS (version 1.4.1, MRC Biostatistics Unit, UK). Correction for inconsistencies between the NHIS and vital statistics data is described. A published cohort study was a source of prior information for smoking-related mortality.

Results. Marginal posterior densities of annual mortality rates for lung cancer and other-cause death (further divided into heart disease and all other causes), stratified by 5-year age interval, race (white and black), gender, and smoking status (current, former, never), were estimated, specific to a time period (1987-1995). Overall, black current smokers experienced the highest mortality rates.

Conclusions. Bayesian evidence synthesis is an effective method for estimation of cause-specific mortality rates, stratified by demographic factors.
Predicting Regulation of the Phosphorylation Cycle of KaiC Clock Protein Using Mathematical Analysis
Authors: Takigawa-Imamura Hisako , Mochizuki Atsushi
Published: September 2006

Abstract The cyanobacterial clock protein KaiC regulates the circadian cycle by exhibiting rhythms in transcription, translation, and phosphorylation. KaiC phosphorylation persists in circadian cycling even under transcription-less conditions and was reconstituted in vitro by incubating KaiC, KaiA, and KaiB. This presents a novel perspective for circadian oscillation occurring due to interactions between clock proteins. Using mathematical models, the authors investigated the mechanism for the transcription-less KaiC phosphorylation cycle. They developed a simple model based on the possible KaiC behavior, which is experimentally suggested by Kitayama et al. (2003, EMBO J, 22:2127–2134). They hypothesized that the KaiC-KaiA complex formation, followed by a decrease in free KaiA molecules, may attenuate the KaiC phosphorylation rate, and it acts as negative feedback in the system. However, this model was shown not to be adequate to generate the KaiC phosphorylation cycle. The authors developed the general version of the model and determined the necessary condition to generate the KaiC phosphorylation cycle. Linear stability analysis revealed that oscillations can occur when the distance of feedback between the recipient reaction and the effector is far enough. Furthermore, they classified negative feedback regulations in the closed system into 2 types: destabilizing inhibition and stabilizing inhibition. Based on this result, the authors predicted that, in addition to the identified states of KaiC, another unknown state must be present between KaiC phosphorylation and the complex formation. By incorporating the unknown state into the previous model, they realized the periodic pattern reminiscent of the KaiC phosphorylation cycle in computer simulation. This result implies that the KaiC-KaiA complex formation requires more than 1 step of posttranslational modification, including phosphorylation or conformational change of KaiC.
Dim Light Adaptation Attenuates Acute Melatonin Suppression in Humans
Authors: Jasser Samar A. , Hanifin John P. , Rollag Mark D. , Brainard George C.
Published: September 2006

Abstract Studies in rodents with retinal degeneration indicated that neither the rod nor the cone photoreceptors obligatorily participate in circadian responses to light, including melatonin suppression and photoperiodic response. Yet there is a residual phase-shifting response in melanopsin knockout mice, which suggests an alternate or redundant means for light input to the SCN of the hypothalamus. The findings of Aggelopoulos and Meissl suggest a complex, dynamic interrelationship between the classic visual photoreceptors and SCN cell sensitivity to light stimuli, relative to various adaptive lighting conditions. These studies raised the possibility that the phototransductive physiology of the retinohypothalamic tract in humans might be modulated by the visual rod and cone photoreceptors. The aim of the following two-part study was to test the hypothesis that dim light adaptation will dampen the subsequent suppression of melatonin by monochromatic light in healthy human subjects. Each experiment included 5 female and 3 male human subjects between the ages of 18 and 30 years, with normal color vision. Dim white light and darkness adaptation exposures occurred between midnight and 0200 h, and a full-field 460-nm light exposure subsequently occurred between 0200 and 0330-h for each adaptation condition, at 2 different intensities. Plasma samples were drawn following the 2-h adaptation, as well as after the 460-nm monochromatic light exposure, and melatonin was measured by radioimmunoassay. Comparison of melatonin suppression responses to monochromatic light in both studies revealed a loss of significant suppression after dim white light adaptation compared with dark adaptation ( p < 0.04 and p < 0.01). These findings indicate that the activity of the novel circadian photoreceptive system in humans is subject to subthreshold modulation of its sensitivity to subsequent monochromatic light exposure, varying with the conditions of light adaptation prior to exposure.
Phase and Period Responses of the Circadian System of Mice (Mus musculus) to Light Stimuli of Different Duration
Authors: Comas M. , Beersma D. G. M. , Spoelstra K. , Daan S.
Published: September 2006

To understand entrainment of circadian systems to different photoperiods in nature, it is important to know the effects of single light pulses of different durations on the free-running system. The authors studied the phase and period responses of laboratory mice (C57BL6J//OlaHsd) to single light pulses of 7 different durations (1, 3, 4, 6, 9, 12, and 18 h) given once per 11 days in otherwise constant darkness. Light-pulse duration affected both amplitude and shape of the phase response curve. Nine-hour light pulses yielded the maximal amplitude PRC. As in other systems, the circadian period slightly lengthened following delays and shortened following advances. The authors aimed to understand how different parts of the light signal contribute to the eventual phase shift. When PRCs were plotted using the onset, midpoint, and end of the pulse as a phase reference, they corresponded best with each other when using the mid-pulse. Using a simple phase-only model, the authors explored the possibility that light affects oscillator velocity strongly in the 1st hour and at reduced strength in later hours of the pulse due to photoreceptor adaptation. They fitted models based on the 1-h PRC to the data for all light pulses. The best overall correspondence between PRCs was obtained when the effect of light during all hours after the first was reduced by a factor of 0.22 relative to the 1st hour. For the predicted PRCs, the light action centered on average at 38% of the light pulse. This is close to the reference phase yielding best correspondence at 36% of the pulses. The result is thus compatible with an initial major contribution of the onset of the light pulse followed by a reduced effect of light responsible for the differences between PRCs for different duration pulses. The authors suggest that the mid-pulse is a better phase reference than lights-on to plot and compare PRCs of different light-pulse durations.
Early acquisition of cytolytic function and transcriptional changes in a primary CD8+ T-cell response in vivo
Authors: Chiu Christopher , Heaps Adrian G. , Cerundolo Vincenzo , McMichael Andrew J. , Bangham Charles R. , Callan Margaret F. C.
Published: September 2006

Functional studies show that programming of CD8+ T cells occurs early after initial antigen encounter within as little as 2 hours. To define the molecular basis of these events, we transferred TCR transgenic T cells from F5 Rag−/− mice into naive recipients and stimulated them with recombinant vaccinia expressing the immunodominant influenza epitope NP366-374. Transcription in epitope-specific cytotoxic T lymphocytes (CTLs) was analyzed using Affymetrix 430 2.0 GeneChips and quantitative polymerase chain reaction (PCR). We demonstrated an early transcriptional burst with the greatest number of genes reaching peak expression 12 hours after stimulation. Using in vivo cytotoxicity assays we demonstrated that early up-regulation of cytolytic genes was accompanied by acquisition of killing capacity within 24 hours of stimulation. However, T-cell proliferation was not observed until 48 hours. We therefore conclude that clonal expansion rather than acquisition of effector function is the rate-limiting step in the development of a primary CTL response.
MK-0457, a novel kinase inhibitor, is active in patients with chronic myeloid leukemia or acute lymphocytic leukemia with the T315I BCR-ABL mutation
Authors: Giles Francis J. , Cortes Jorge , Jones Dan , Bergstrom Donald , Kantarjian Hagop , Freedman Steven J.
Published: September 2006

MK-0457 (VX-680) is a small-molecule aurora kinase (AK) inhibitor with preclinical antileukemia activity. The T315I BCR-ABL mutation mediates resistance to imatinib, nilotinib, and dasatinib. MK-0457 has in vitro activity against cells expressing wild-type or mutated BCR-ABL, including the T315I BCR-ABL mutation. Three patients with T315I abl-mutated chronic myeloid leukemia (CML) or Philadelphia chromosome (Ph)–positive acute lymphocytic leukemia (ALL) have achieved clinical responses to doses of MK-04547 that are not associated with adverse events. Higher MK-0457 dose levels were associated with clinical responses and down-regulation of CrkL phosphorylation in leukemia cells. The possible role of AK inhibition in these clinical responses requires further investigation. The currently reported cases are the first observed clinical activity of a kinase inhibitor against the T315I phenotype. The observation of responses in 3 patients with T315I phenotype–refractory CML or Ph-positive ALL, at doses of MK-0457 associated with no significant extramedullary toxicity, is very encouraging.
Identification of a 2-stage platelet aggregation process mediating shear-dependent thrombus formation
Authors: Maxwell Mhairi J. , Westein Erik , Nesbitt Warwick S. , Giuliano Simon , Dopheide Sacha M. , Jackson Shaun P.
Published: September 2006

Disturbances of blood flow at sites of atherosclerotic plaque rupture are one of the key pathogenic events promoting platelet activation and arterial thrombus formation. Shear effects of platelets have been extensively investigated in vitro; however, the mechanisms by which shear promotes platelet aggregation in vivo remain incompletely understood. By employing high-resolution imaging techniques to in vitro and in vivo thrombosis models, we demonstrate a unique mechanism initiating shear-dependent platelet aggregation involving aggregate formation between discoid platelets. These discoid platelet aggregates are initially unstable and result from the development of membrane tethers between coadhering platelets. Tether formation involves the adhesive function of GPIb/V/IX and integrin αIIbβ3, and conversion of discoid platelet aggregates into stable aggregates requires released ADP. The efficiency of this process is regulated by 3 independent variables, including the reactivity of the adhesive substrate, the level of shear flow, and the platelet density at the adhesive surface. These studies identify a new mechanism initiating platelet aggregation that is critically influenced by shear, physical proximity between translocating platelets, and membrane tether formation. Moreover, they provide a model to explain how the discoid morphology of platelets facilitates the maintenance of adhesive interactions with thrombogenic surfaces under high shear stress conditions.
Vascular endothelial growth factor-A induces plaque expansion in ApoE knock-out mice by promoting de novo leukocyte recruitment
Authors: Lucerna Markus , Zernecke Alma , de Nooijer Ramon , de Jager Saskia C. , Bot Ilze , van der Lans Christian , Kholova Ivana , Liehn Elisa A. , van Berkel Theo J. C. , Yla-Herttuala Seppo , Weber Christian , Biessen Eric A. L.
Published: September 2006

Vascular endothelial growth factor-A is widely used in clinical trials for the treatment of cardiac ischemia. VEGF-A was recently suggested to act in a proinflammatory manner, which could aggravate adjacent atherogenesis in VEGF-A–based therapy. To assess potential bystander effects, VEGF-A was focally overexpressed in advanced atherosclerotic plaques in ApoE−/− mice. Sheer-induced carotid artery plaques were transluminally incubated with Ad.hVEGF-A leading to neointimal overexpression of VEGF-A. Ad.hVEGF-A treatment of pre-existing lesions was seen to promote plaque expansion, with a concomitant increase in macrophage and lipid content, whereas it lowered collagen content. In general, Ad.hVEGF-A–treated plaques displayed a more vulnerable phenotype. VEGF-A overexpression was not accompanied by increased microvessel development in the neointima, suggesting that VEGF-A destabilizes atherosclerotic plaques through an angiogenesis-independent mechanism. Intravital microscopy confirmed that treatment with Ad.hVEGF-A led to an increased monocyte adhesion, which was mediated by a VCAM-1/PECAM-1–dependent pathway. VEGF-A indeed induced a differential expression of VCAM-1 and PECAM-1 in endothelial cells. Our data underline the importance of regular monitoring of stenotic vessels adjacent to the site of VEGF-A application. We propose that VCAM-1/PECAM-1–directed cotherapy may be an efficient strategy to prevent bystander effects of focal VEGF-A therapy in patients suffering from cardiovascular disease.
Safety and efficacy of risk-adapted cyclophosphamide, thalidomide, and dexamethasone in systemic AL amyloidosis
Authors: Wechalekar Ashutosh D. , Goodman Hugh J. B. , Lachmann Helen J. , Offer Mark , Hawkins Philip N. , Gillmore Julian D.
Published: September 2006

High-dose melphalan with stem-cell transplantation is believed to be the most effective treatment for systemic light-chain (AL) amyloidosis, but many patients are ineligible because of the extent of their disease, and treatment-related mortality (TRM) remains substantial. We report the use of a risk-adapted oral regimen of cyclophosphamide, thalidomide, and dexamethasone (CTD) or attenuated CTD (CTDa) in 75 patients with advanced AL amyloidosis, including 44 patients with clonal relapse after prior therapy. Fifty-one (68%) patients received CTD and 24 (32%) received CTDa. A hematologic response occurred in 48 (74%) of 65 evaluable patients, including complete responses in 14 (21%) and partial responses in 34 (53%) cases. Median estimated overall survival (OS) from commencement of treatment was 41 months, and from diagnosis median was not reached with a median follow-up of 22 months. Three-year estimated OS was 100% and 82% among complete and partial hematologic responders, respectively. Toxicity necessitating cessation of therapy occurred in 8% and was at least grade 2 in 52% of patients. TRM was 4%. The clonal response rates to CTD reported here are higher than any previously reported nontransplantation regimen in AL amyloidosis, and risk adaptation allows its use in poorer risk patients. CTD merits prospective randomized study.
Dasatinib (BMS-354825) is active in Philadelphia chromosome–positive chronic myelogenous leukemia after imatinib and nilotinib (AMN107) therapy failure
Authors: Quintas-Cardama Alfonso , Kantarjian Hagop , Jones Dan , Nicaise Claude , O'Brien Susan , Giles Francis , Talpaz Moshe , Cortes Jorge
Published: September 2006

Developing strategies to counteract imatinib resistance constitutes a challenge in chronic myelogenous leukemia (CML). Therapy with the tyrosine kinase inhibitors nilotinib (AMN107) and dasatinib (BMS-354825) has produced high rates of hematologic and cytogenetic response. Src kinase activation has been linked to Bcr-Abl–mediated leukemogenesis and CML progression. In addition to binding Abl kinase with less stringent conformational requirements than imatinib, dasatinib is a potent Src kinase inhibitor. In the current study, we report on 23 patients with CML (19 of them in accelerated or blastic phases) treated with dasatinib after treatment failure with both imatinib and nilotinib. More than half (13; 57%) of 23 patients responded to dasatinib: 10 (43%) had a complete hematologic response (CHR), including 7 (30%) who had a cytogenetic response (2 complete, 4 partial, and 1 minor). These results suggest that dasatinib may be active in some patients after failure with both imatinib and nilotinib.
CROPPER: a metagene creator resource for cross-platform and cross-species compendium studies
Authors: Paananen Jussi , Storvik Markus , Wong Garry
Published: September 2006

Background

Current genomic research methods provide researchers with enormous amounts of data. Combining data from different high-throughput research technologies commonly available in biological databases can lead to novel findings and increase research efficiency. However, combining data from different heterogeneous sources is often a very arduous task. These sources can be different microarray technology platforms, genomic databases, or experiments performed on various species. Our aim was to develop a software program that could facilitate the combining of data from heterogeneous sources, and thus allow researchers to perform genomic cross-platform/cross-species studies and to use existing experimental data for compendium studies.

Results

We have developed a web-based software resource, called CROPPER that uses the latest genomic information concerning different data identifiers and orthologous genes from the Ensembl database. CROPPER can be used to combine genomic data from different heterogeneous sources, allowing researchers to perform cross-platform/cross-species compendium studies without the need for complex computational tools or the requirement of setting up one's own in-house database. We also present an example of a simple cross-platform/cross-species compendium study based on publicly available Parkinson's disease data derived from different sources.

Conclusion

CROPPER is a user-friendly and freely available web-based software resource that can be successfully used for cross-species/cross-platform compendium studies.
An ABRE-binding factor, OSBZ8, is highly expressed in salt tolerant cultivars than in salt sensitive cultivars of indica rice
Authors: Mukherjee Kakali , Choudhury Aryadeep Roy , Gupta Bhaskar , Gupta Sudhiranjan , Sengupta Dibyendu N
Published: September 2006

Background

The bZIP class Abscisic acid Responsive Element (ABRE)-binding factor, OSBZ8 (38.5 kD) has been considered to regulate ABA-mediated transcription in the suspension cultured cells of japonica rice. Still, nothing is known about the expression of OSBZ8 at protein level in vegetative tissue of salt sensitive and salt tolerant rice plants. In our previous study, Electrophoretic Mobility Shift Assay (EMSA) of [32P]ABRE-DNA and nuclear extracts prepared from the lamina of Pokkali rice plants has detected the presence of an ABRE-binding factor. Northern analysis has also detected salinity stress induced accumulation of transcripts for bZIP class of factor. Therefore, OSBZ8 was considered to play an important role in the regulation of transcription in the vegetative tissue of rice. The aim of this study is to find out whether OSBZ8 has any role in regulating the NaCl-stress induced gene expression in vegetative tissue and whether the expression of OSBZ8 factor directly correlates with the stress tolerance of different varieties of indica type rice.

Results

Northern analysis of total RNA from roots and lamina of salt-sensitive M-I-48 and salt-tolerant Nonabokra, when probed with the N-terminal unique region of OSBZ8 (OSBZ8p, without the highly conserved basic region), a transcript of 1.3 kb hybridized and its level was much higher in tolerant cultivar. EMSA with Em1a, the strongest ABA Responsive Element till reported from the upstream of EmBP1, and the nuclear extracts from laminar tissue of untreated and salt-treated seedlings of three salt sensitive, one moderately sensitive and two salt tolerant indica rice cultivars showed specific binding of nuclear factor to ABRE element. Intensity of binding was low and inducible in salt sensitive rice cultivars while high and constitutive in salt tolerant cultivars. EMSA with 300 bp 5'upstream region of Rab16A gene, a well known salt stress and ABA-inducible gene of rice, showed formation of two complexes, again very weak in salt sensitive and strong in salt tolerant rice cultivar.

Conclusion

The bZIP factor OSBZ8 was found to be present in the ABRE-DNA: protein complex as shown by the supershift of the complex by the purified antiserum raised against OSBZ8p. Treatment of the seedlings with NaCl was found to enhance the complex formation, suggesting the regulation of OSBZ8 gene at both transcriptional and post-translational steps. Comparative EMSA with different varieties of rice suggests a positive correlation with the expression pattern of OSBZ8 and salt tolerance in rice cultivars.
Molecular and immunological characterization of allergens from the entomopathogenic fungus Beauveria bassiana
Authors: Westwood Greg S , Huang Shih-Wen , Keyhani Nemat O
Published: September 2006

Background

Entomopathogenic fungi such asBeauveria bassianaare considered promising biological control agents for a variety of arthropod pests.Beauveriaspecies, however, have the potential to elicit allergenic reactions in humans, although no specific allergens have been characterized to date.

Methods

Four putative allergens were identified withinB. bassianaexpressed sequence tag (EST) datasets. IgE-reactivity studies were performed using sera from patients displaying mold allergies against recombinantB. bassianaproteins expressed inE. coli.

Results

Full length cDNA and genomic nucleotide sequences of four potentialB. bassianaallergens were isolated. BLASTX search results led to their putative designation as follows; Bb-Eno1, with similarity to fungal enolases; Bb-f2, similar to theAspergillus fumigatusmajor allergen, Asp f2 and to a fibrinogen binding mannoprotein; Bb-Ald, similar to aldehyde dehydrogenases; and Bb-Hex, similar to N-acetyl-hexosaminadases. All four genes were cloned intoE. coliexpression systems and recombinant proteins were produced. Immunoblots ofE. coliextracts probed with pooled as well as individual human sera from patients displaying mould allergies demonstrated IgE reactivity versus recombinant Bb-Eno1 and Bb-Ald.

Conclusion

Four putativeBeauveria bassianaallergens were identified. Recombinant proteins corresponding to two of the four, Bb-Eno1 and Bb-Ald were bound by sera IgEs derived from patients with fungal allergies. These data confirm the potential allergenicity ofB. bassianaby identification of specific human IgE reactive epitopes.
Differences in fruit and vegetable intake and determinants of intakes between children of Dutch origin and non-Western ethnic minority children in the Netherlands – a cross sectional study
Authors: te Velde Saskia J , Wind Marianne , van Lenthe Frank J , Klepp Knut-Inge , Brug Johannes
Published: September 2006

Background

Fruit and vegetable consumption is low in the Netherlands and a key target in healthy diet promotion. However, hardly any information is available on differences in fruit and vegetable consumption between Dutch children and ethnic minority children. Therefore, the aim of present study was to determine differences in usual fruit and vegetable intake between native Dutch and non-Western ethnic minority children and to study differences in and mediating effects of potential psychosocial and environmental determinants.

Methods

Ethnicity, usual fruit and vegetable consumption, psychosocial and environmental determinants and mothers' educational level were measured with a self-administered questionnaire during school hours in primary schools in Rotterdam, the Netherlands. Complete data was available for 521 10–11 year-old-children, of which 50.5% of non-Western origin. Differences between the groups regarding potential determinants and fruit and vegetable intake were assessed with Mann Whitney tests or multiple regression analyses. Multiple regression analyses were also conducted to assess mediating effects.

Results

Ethnic minority girls ate fruit more frequently (1.41 ± 1.0 times/day) than Dutch girls (1.03 ± 0.82 times/day); no differences in frequency of intake were found for vegetables or among boys. Ethnic differences were found for almost all potential determinants. The Dutch children reported lower scores on these determinants than the ethnic minority children, except for perceived self-efficacy and barriers to eat fruit and vegetables. Knowledge of recommendations and facilitating behaviors of the parents mediated the association between ethnicity and fruit consumption among girls.

Conclusion

Ethnic minority girls in the Netherlands appear to have more favorable fruit intakes than Dutch girls, and ethnic minority children in general show more positive prerequisites for fruit and vegetable consumption. Interventions addressing multi-ethnic populations of children must take such differences into account.
Canine faecal contamination and parasitic risk in the city of Naples (southern Italy)
Authors: Rinaldi Laura , Biggeri Annibale , Carbone Sabrina , Musella Vincenzo , Catelan Dolores , Veneziano Vincenzo , Cringoli Giuseppe
Published: September 2006

Background

Dogs are associated with more than 60 zoonotic diseases among which, parasitosis and, in particular, helminthosis, can pose serious public-health concerns worldwide. Many canine gastrointestinal parasites eliminate their dispersion elements (eggs, larvae, oocysts) by the faecal route. The quantity of canine faeces deposited on public and private property in cities worldwide is both a perennial nuisance and an important health issue. Public sites such as playgrounds, parks, gardens, public squares and sandpits may be an important source of human infection. The aim of this study was to evaluate the extent of both canine faecal contamination in the city of Naples (southern Italy), and presence of canine parasitic elements, with particular regard to those which are potential agents of zoonosis. A regular grid of sub-areas (1 km × 700 m) was overlaid on the city map using a Geographical Information System (GIS). In each sub-area the straightest 1 km transect was drawn and digitalized on-screen in the GIS. Between February and May 2005 canine faeces were counted along the 1 km transects in 143 sub-areas, and 415 canine faecal samples were collected and submitted to coprological examinations. Negative binomial regression models and Gaussian random effects models were used to analyze the association between faeces count and human population density taking into account for extraPoisson variability. Logistic regression model was used to evaluate the association between positivity to parasitic elements and number of canine faeces.

Results

Out of the 143 studied sub-areas, 141 (98.6%) contained canine faeces. There was a strong spatial gradient with 48% of the total variability accounted by between neighbourhood variability; a positive association between the number of faeces and the human population density was found. Seventy (over 415, 16.9%) canine faecal samples were positive for parasitic elements. There was no association between positivity to parasitic elements and the number of canine faeces. Eggs of Toxocara canis, Toxascaris leonina, Ancylostoma caninum and Trichuris vulpis were found, as well as oocysts of Isospora canis.

Conclusion

In conclusion, the results of the present study, conducted using GIS both for planning and sampling and for evaluation and presentation of findings, showed the presence of canine faecal contamination in the city of Naples, and the presence of canine parasitic elements, some of which are potential agents of zoonosis.
The Role of the Glucocorticoid Receptor in Mineralocorticoid/Salt-Mediated Cardiac Fibrosis
Authors: Rickard Amanda J. , Funder John W. , Fuller Peter J. , Young Morag J.
Published: September 2006

The pathophysiological consequences of excess mineralocorticoid for salt status include hypertension, vascular inflammation, and cardiac fibrosis. Mineralocorticoid receptor (MR) blockade can both prevent and reverse established inflammation and fibrosis due to exogenous mineralocorticoids or endogenous glucocorticoid activation of the MR. Glucocorticoids also exert potent antiinflammatory effects via glucocorticoid receptors (GR) in the vascular wall. We propose that GR signaling may ameliorate mineralocorticoid/salt-induced vascular inflammation and fibrosis in the mineralocorticoid/salt model. In the present study, the role of GR in the mineralocorticoid/salt model was explored in uninephrectomized rats that were maintained on 0.9% saline solution to drink and treated as follows: control (CON), no further treatment; deoxycorticosterone (DOC; 20 mg/wk) for 4 wk (DOC4); DOC for 8 wk (DOC8); DOC for 8 wk plus the GR antagonist RU486 (2 mg/d) wk 5–8 (DOC8/RU486); and DOC for 8 wk plus RU486 and the MR antagonist eplerenone (EPL; 50 mg/kg·d) for wk 5–8 (DOC8/RU486+EPL). DOC treatment significantly increased systolic blood pressure, cardiac fibrosis, inflammation (ED-1-positive macrophages and osteopontin), and mRNA for markers of oxidative stress (p22phox, gp91phox, and NAD(P)H-4). GR blockade reduced the DOC-mediated increase in systolic blood pressure and the number of infiltrating ED-1-positive macrophages but had no effect on fibrosis, oxidative stress, or osteopontin mRNA levels. EPL reversed DOC-induced pathology in the absence or presence of GR blockade. Thus, blocking agonist activity at the GR neither enhances nor attenuates the fibrotic response, although it may modulate systolic blood pressure and macrophage recruitment in the mineralocorticoid/salt model.
Bone Material Properties in Trabecular Bone From Human Iliac Crest Biopsies After 3- and 5-Year Treatment With Risedronate
Authors: Durchschlag Erich , Paschalis Eleftherios P , Zoehrer Ruth , Roschger Paul , Fratzl Peter , Recker Robert , Phipps Roger , Klaushofer Klaus
Published: September 2006

Long-term effects of risedronate on bone mineral maturity/crystallinity and collagen cross-link ratio in triple iliac crest biopsies of osteoporotic women were evaluated. In this double-blinded study, 3- and 5-year treatment with risedronate arrested the tissue aging encountered in untreated osteoporosis and in osteoporosis treated with other antiresorptives. This effect may be contributing to risedronate's antifracture efficacy.

Introduction: Risedronate is widely used in the treatment of osteoporosis. It reduces bone turnover, increases BMD, and decreases fracture risk. To date, there are no data available on the long-term effects of risedronate on bone material properties in humans.

Materials and Methods: Osteoporotic women enrolled in the VERT-NA trial received either risedronate (5 mg/day, orally) or placebo for up to 5 years. All subjects received calcium. They also received vitamin D supplementation if deficient at baseline. Triple iliac crest biopsies were collected from a subset of these subjects at baseline, 3 years, and 5 years. Mineral maturity/crystallinity and collagen cross-link ratio was measured in these biopsies using Fourier transform infrared imaging.

Results: Patients that received placebo exhibited increased mineral maturity/crystallinity and collagen cross-link ratio after 3 and 5 years compared with baseline values. On the contrary, patients that received risedronate retained baseline values in both bone material indices throughout. A more spatially detailed analysis revealed that this was achieved mainly through beneficial effects on active bone-forming areas. Surprisingly, patients that received risedronate achieved premenopausal values at bone-forming areas in both indices after 5 years of treatment.

Conclusion: Long-term treatment with risedronate affects bone material properties (mineral maturity/crystallinity and collagen cross-link ratio) and arrests the tissue aging apparent in untreated osteoporosis. These changes at the material level of the bone matrix may contribute to risedronate's rapid and sustained antifracture efficacy in osteoporotic patients.
Rickets in the 17th Century
Authors: O'Riordan Jeffrey LH
Published: September 2006

Rickets was first documented as a cause of death in the Bills of Mortality for The City of London in 1634, but detailed descriptions were only published between 1645 and 1668. It was thought at the time that this was a new disease in England, but there was no indication as to the cause of the condition. However, air pollution from smoke produced by burning coal caused serious problems at that time, and so it can be suggested that vitamin D deficiency was responsible.
Epidemiology of Paget's Disease in Europe: The Prevalence Is Decreasing
Authors: Poór Gyula , Donáth Judit , Fornet Béla , Cooper Cyrus
Published: September 2006

This study estimated changes in the age- and sex-specific prevalence of Paget's disease of bone in six European towns over a 20-year period. Declines in prevalence were observed in this disorder, occurring among both men and women.

Introduction: To estimate secular changes in the age-and sex-specific prevalence of Paget's disease of bone in Europe, we conducted a second radiographic survey using identical sampling and methods in six European towns where a baseline study was performed in 1978–1979. In addition to these towns, the survey was carried out in two Hungarian centers not included in the initial study.

Materials and Methods: In each center, a sample of abdominal radiographs of people ≥55 years of age was taken from stored films within the radiology department of the principal general hospital. Radiographs showing the entire pelvis, sacrum, femoral heads, and lumbar vertebrae were studied for the period of 2000–2001. The films were evaluated by a trained observer and a consultant radiologist.

Results: A total of 6935 radiographs (3512 women and 3423 men) were assessed in the eight towns. The overall age- and sex-standardized prevalence rate of Paget's disease was 0.3% with a male/female ratio of 1.5. Prevalence increased with age among men and women rising to 0.8% of men and 0.9% of women ≥85 years of age. The differences in prevalence rate among the European centers were relatively small, especially in women. There was a decline in rates between 1978/79 and 2000/01.

Conclusions: These European data confirm the decrease in frequency of Paget's disease observed in Britain. These declines favor an environmental contribution to the causation of the disease that requires further research.
Hypothalamic Regulation of Cortical Bone Mass: Opposing Activity of Y2 Receptor and Leptin Pathways
Authors: Baldock Paul A , Allison Susan , McDonald Michelle M , Sainsbury Amanda , Enriquez Ronaldo F , Little David G , Eisman John A , Gardiner Edith M , Herzog Herbert
Published: September 2006

NeuropeptideY–, Y2 receptor (Y2)-, and leptin-deficient mice show similar anabolic action in cancellous bone but have not been assessed in cortical bone. Cortical bone mass is elevated in Y2−/− mice through greater osteoblast activity. In contrast, leptin deficiency results in reduced bone mass. We show opposing central regulation of cortical bone.

Introduction: Treatment of osteoporosis is confounded by a lack of agents capable of stimulating the formation of bone by osteoblasts. Recently, the brain has been identified as a potent anabolic regulator of bone formation. Hypothalamic leptin or Y2 receptor signaling are known to regulate osteoblast activity in cancellous bone. However, assessment of these pathways in the structural cortical bone is critical to understanding their role in skeletal health and their potential clinical relevance to osteoporosis and its treatment.

Materials and Methods: Long bones of 16-week male ob/ob and germline and hypothalamic Y2−/− mice were assessed by QCT. Cortical osteoblast activity was assessed histologically.

Results: The femora of skeletally mature Y2−/− mice and of leptin-deficient ob/ob and Y2−/−ob/ob mice were assessed for changes in cortical osteoblast activity and bone mass. Ablation of Y2 receptors increased osteoblast activity on both endosteal and periosteal surfaces, independent of leptin, resulting in increased cortical bone mass and density in Y2−/− mice along the entire femur. Importantly, these changes were evident after deletion of hypothalamic Y2 receptors in adult mice, with a 5-fold elevation in periosteal bone formation. This is in marked contrast to leptin-deficient models that displayed reduced cortical mass and density. These changes were associated with substantial differences in calculated strength between the Y2−/− and leptin-deficient mice.

Conclusions: These results indicate that the Y2-mediated anabolic pathway stimulates cortical and cancellous bone formation, whereas the leptin-mediated pathway has opposing effects in cortical and cancellous bone, diminishing the production of cortical bone. The findings from conditional hypothalamic Y2 knockout show a novel, inducible control mechanism for cortical bone formation and a potential new pathway for anabolic treatment of osteoporosis.
Mixed Metastatic Lung Cancer Lesions in Bone Are Inhibited by Noggin Overexpression and Rank:Fc Administration
Authors: Feeley Brian T , Liu Nancy Q , Conduah Augustine H , Krenek Lucie , Roth Kevin , Dougall William C , Huard Johnny , Dubinett Steve , Lieberman Jay R
Published: September 2006

Lung cancer metastases to bone produce a primarily mixed osteolytic/osteoblastic lesion. The purpose of this study was to determine if blockade of both pathways would inhibit the formation these lesions in bone. Inhibition of the osteoblastic lesion with noggin and the osteolytic lesion with RANK:Fc was a successful treatment strategy to inhibit progression of mixed lung cancer lesions in bone.

Introduction: Approximately 9–30% of patients with lung cancer develop bone metastases, leading to significant morbidity and mortality. A549 is a non–small-cell lung cancer (NSCLC) line that produces a mixed metastatic lesion in bone. We sought to determine if blockade of key components in both osteolytic and osteoblastic pathways would result in a reduction of a NSCLC tumor progression in a murine model of bony metastasis.

Materials and Methods: The study used a retroviral vector overexpressing noggin (RN), a specific inhibitor of BMP, and RANK:Fc, a chimeric protein that inhibits the RANK–RANKL interaction. A549 cells were transduced with RN before implantation in SCID mice. Cells were implanted in a subcutaneous model and tibial injection model. RANK:Fc was administered twice weekly at 15 mg/kg. There were five treatment groups: A549; A549 + RN; A549 + RANK:Fc; A549 + empty vector; and A549 + RN + RANK:Fc (n = 10/group).

Results: In SCID mice who underwent subcutaneous A549 tumor cell injection, animals treated with A549 + RN had significantly smaller subcutaneous tumor size at 8 weeks. In an intratibial model of bony metastasis, animals injected with A549 cells developed a mixed lytic/blastic lesion with cortical destruction at 8 weeks. Treatment with RANK:Fc inhibited the formation of osteoclasts, led to a smaller tumor volume in bone, and inhibited the lytic component of the mixed lesion. Animals treated with A549 + RN had a decreased number of osteoblasts in bone lesions, smaller tumor volume, and inhibition of the blastic component of the mixed lesions. Combination treatment inhibited both the lytic and blastic components of the lesion.

Conclusions: The NSCLC cell line A549 forms a mixed osteolytic/osteoblastic lesion in vivo. Noggin overexpression inhibited the formation of the osteoblastic aspect of the lesion in bone and the tumor growth in vivo. Treatment with RANK:Fc limited the formation of the lytic aspect of the mixed lesion and also inhibited the rate of in vivo tumor growth. Inhibition of both pathways is necessary to effectively inhibit the progression of mixed metastatic lesions in bone.
Association Between Prior Non-Spine Non-Hip Fractures or Prevalent Radiographic Vertebral Deformities Known to be at Least 10 Years Old and Incident Hip Fracture
Authors: Schousboe John T , Fink Howard A , Lui Li-Yung , Taylor Brent C , Ensrud Kristine E
Published: September 2006

In this large cohort of elderly women, prior non-spine non-hip fractures and radiographic vertebral deformities >10 years old were modestly associated with incident hip fracture, but the excess risks of hip fracture attributable to those prior fractures and deformities seem to wane over time.

Introduction: Whereas prior clinical fractures and prevalent radiographic vertebral deformities are well-documented predictors of incident hip fracture, the excess risks of incident fractures attributable to those prior fractures and deformities may decrease over time. Current guidelines regarding the assessment of fracture risk do not consider elapsed time since prior fracture or ascertainment of radiographic vertebral deformity.

Materials and Methods: We ascertained self-reported history of prior clinical fractures and calcaneal and total hip bone BMD and performed lateral spine radiographs in a cohort of 9516 community-dwelling elderly women who had not had a prior hip fracture. We prospectively followed them to assess incident hip fracture. Prevalent radiographic vertebral deformities were identified at baseline using morphometry, and incident hip fractures were confirmed by review of radiographic reports during three follow-up periods (0–5, >5–10, and >10 years after baseline exam).

Results: Among women who survived for 10 or more years after the baseline exam without having had a hip fracture, a history of non-spine non-hip fracture since age 50 reported at the baseline study examination was associated with a 21% age- and calcaneal BMD–adjusted excess risk (hazard ratio [HR], 1.21; 95% CI, 1.01–1.45) for subsequent incident hip fracture. Baseline radiographic vertebral deformity was associated with a 41% age- and BMD-adjusted excess risk (HR, 1.41; 95% CI, 1.15–1.73) of hip fracture after 10 years of follow-up. In comparison, the age- and BMD-adjusted HRs of incident hip fracture during the first 5 years of follow-up associated with prior non-spine non-hip fractures reported at the baseline study exam and prevalent radiographic vertebral deformities were 1.70 (95% CI, 1.30–2.22) and 2.10 (95% CI, 1.58–2.78), respectively.

Conclusions: Self-reported prior non-spine non-hip fractures and prevalent radiographic vertebral deformities known to be at least 10 years old are modestly associated with incident hip fracture. The association between these predictor fractures and subsequent hip fractures seems to wane with increased time after ascertainment of the predictor fracture. Hip fracture risk assessment strategies incorporating prior fracture history should also consider elapsed time since those prior fractures.