bluuebunny/crossref_metadata_2025 huggingface dataset:
Food Increased the Bioavailability of BMS‐690514, an Orally Active EGFR/HER2/VEGF Receptor Kinase Inhibitor, in Healthy Subjects
Authors: Vakkalagadda Blisse , Park Jong‐Soon , Ahlers Christoph M. , Dorizio Stephanie , Has Teresa , Roongta Vikram , Heller Kevin N. , Derbin George M. , Zhang Steven
Published: October 2011

We studied the effect of food on pharmacokinetics, safety, and tolerability of BMS‐690514. Two open‐label, randomized, single‐dose, 2‐treatment, 2‐period crossover studies were performed in healthy subjects. In study 1 (N = 26), a single oral dose of BMS‐690514, 200 mg, was administered while fasting or after a high‐fat meal, and in study 2 (N = 17), a single oral dose of BMS‐690514, 200 mg, was administered while fasting or after a light meal. Compared with fasting, the adjusted geometric mean maximum observed plasma concentration (Cmax), area under the plasma concentration‐time curve from time zero to time of last quantifiable concentration (AUC0‐T), area under the plasma concentration‐time curve from time zero extrapolated to infinite time (AUCINF) of BMS‐690514 increased by 55%, 33%, and 34%, respectively, following a high‐fat meal (951 kcal, 52% fat) and by 41%, 20%, and 20%, respectively, following a light meal (336 kcal, 75% carbohydrate). BMS‐690514 was well tolerated in both studies. Most frequently occurring adverse events were diarrhea and acne in study 1 and rash, dry skin, and diarrhea in study 2. Systemic exposure of highly soluble BMS‐690514 was increased when given along with a meal, probably through inhibition of intestinal first‐pass metabolism and/or efflux transporters by food. These studies also demonstrated a tolerable safety profile of BMS‐690514 in the absence and presence of food.
The Incidence and Clinical Relevance of Graft Hypertrophy After Matrix-Based Autologous Chondrocyte Implantation
Authors: Pietschmann Matthias F. , Niethammer Thomas R. , Horng Annie , Gülecyüz Mehmet F. , Feist-Pagenstert Isa , Jansson Volkmar , Müller Peter E.
Published: October 2011

Background: Graft hypertrophy is the most common complication of periosteal autologous chondrocyte implantation (p-ACI).

Purpose: The aim of this prospective study was to analyze the development, the incidence rate, and the persistence of graft hypertrophy after matrix-based autologous chondrocyte implantation (mb-ACI) in the knee joint within a 2-year postoperative course.

Study Design: Case series; Level of evidence, 4.

Methods: Between 2004 and 2007, a total of 41 patients with 44 isolated cartilage defects of the knee were treated with the mb-ACI technique. The mean age of the patients was 35.8 years (standard deviation [SD], 11.3 years), and the mean body mass index was 25.9 (SD, 4.2; range, 19-35.3). The cartilage defects were arthroscopically classified as Outerbridge grades III and IV. The mean area of the cartilage defect measured 6.14 cm2 (SD, 2.3 cm2). Postoperative clinical and magnetic resonance imaging (MRI) examinations were conducted at 3, 6, 12, and 24 months to analyze the incidence and course of the graft.

Results: Graft hypertrophy developed in 25% of the patients treated with mb-ACI within a postoperative course of 1 year; 16% of the patients developed hypertrophy grade 2, and 9% developed hypertrophy grade 1. Graft hypertrophy occurred primarily in the first 12 months and regressed in most cases within 2 years. The International Knee Documentation Committee (IKDC) and visual analog scale (VAS) scores improved during the postoperative follow-up time of 2 years. There was no difference between the clinical results regarding the IKDC and VAS pain scores and the presence of graft hypertrophy.

Conclusion: The mb-ACI technique does not lead to graft hypertrophy requiring treatment as opposed to classic p-ACI. The frequency of occurrence of graft hypertrophy after p-ACI and mb-ACI is comparable. Graft hypertrophy can be considered as a temporary excessive growth of regenerative cartilage tissue rather than a true graft hypertrophy. It is therefore usually not a persistent or systematic complication in the treatment of circumscribed cartilage defects with mb-ACI.
Recent developments in the reverse micro-electrical discharge machining in the fabrication of arrayed micro-features
Authors: Mastud S A , Garg M , Singh R , Joshi S S
Published: October 2011

High aspect ratio arrayed micro-structures and textured surfaces are required in diversified applications such as electrical contacts, printing heads, electrodes for micro-batteries, injection nozzles, nano-material delivery systems, biomedical implants, and hydrophobic surfaces. Reverse micro-electrical discharge machining (R-MEDM) process has a capability to fabricate such arrayed features on a variety of workpiece materials irrespective of their mechanical properties. R-MEDM is a variant of micro-electrical discharge machining (MEDM) process, key difference being, extruded arrayed features are fabricated in the R-MEDM process against the micro-cavities that are machined in MEDM. This article highlights the recent advances in process characterization and modelling of mechanics of the R-MEDM process. The focus of discussion is on comparing the process with the other micromachining processes presently available for the fabrication of arrayed micro-features. In addition, R-MEDM process characteristics in the fabrication of arrayed features on ‘easy’ and ‘difficult’ to erode materials are presented. It is understood that R-MEDM has comparable or in some cases better performance in the fabrication of arrayed features than the processes like micro-milling, micro-wire EDM, micro-wire electrical discharge grinding (EDG) and block EDG.
Psychometric Properties of the Lithuanian Adlerian Parental Assessment of Child Behavior Scale (LAPACBS) in Parents of 6- to 12-Year-Olds
Authors: Kern Roy M. , Jonyniene Jolita
Published: October 2011

The structure-related validity and internal consistency reliability of the translated version of the Adlerian Parental Assessment of the Child Behavior Scale (APACBS) which would be referred to as the Lithuanian APACBS (LAPACBS) was the focus of the research study. A factor analysis was performed using a sample of 246 Lithuanian parents. It revealed a four-factor construct related to the parental assessment of child’s behavior: (a) responsible behavior subscale; (b) emotionally charged behavior subscale; (c) school task subscale; and (d) peer relationship subscale. Furthermore, the adequate levels of internal consistency of the LAPACBS subscales as well as the entire instrument were demonstrated. Cronbach’s αs ranged from .62 to .90 and the correlational analysis showed moderate-to-strong relation between the four subscales with absolute values of Pearson correlation coefficient ranging from .26 to .69. However, further research with a more balanced gender and geographical representation is needed on the analysis of the psychometric properties of this research tool.
Approximate solutions of periodic motions in nonlinear systems via a generalized harmonic balance
Authors: Luo Albert CJ , Huang Jianzhe
Published: October 2011

In this paper, the generalized harmonic balance method is presented for approximate, analytical solutions of periodic motions in nonlinear dynamical systems. The nonlinear damping, periodically forced, Duffing oscillator is studied as a sample problem. The approximate, analytical solution of period-1 periodic motion of such an oscillator is obtained by the generalized harmonic balance method. The stability and bifurcation analysis of the HB2 approximate solution of period-1 motions in the forced Duffing oscillator is carried out, and the parameter map for such HB2 solutions is achieved. Numerical illustrations of period-1 motions are presented. Similarly, the same ideas can be extended to period- k motions in such an oscillator. The methodology presented in this paper can be applied to other nonlinear vibration systems, which are independent of small parameters.
Men’s experiences of emotional, physical, and sexual abuse and abuse in health care: A cross-sectional study of a Swedish random male population sample
Authors: Swahnberg Katarina , Davidsson-Simmons Johanna , Hearn Jeff , Wijma Barbro
Published: October 2011

Aims: This article addresses the under-researched area of men’s experiences of abuse. The aims were to estimate prevalence of emotional, physical, and sexual abuse and abuse in health care in a random sample of Swedish adult men, to compare these estimates with previously collected prevalence rates in a male clinical sample to see if prevalence rates were dependant on response rate and sampling method. We also wanted to contribute to a more general analysis of men’s experiences of victimisation. Methods: Cross-sectional study design. The NorVold Abuse Questionnaire that measures the prevalence of four kinds of abuse was sent to 6000 men selected at random from the population of Östergötland, Sweden. Results: The response rate was 50% ( n = 2924). Lifetime experiences of emotional abuse were reported by 16.7%, physical abuse by 48.9%, sexual abuse by 4.5%, and abuse in health care by 7.3%. The proportion of men who currently suffered from abusive experiences was highest for emotional abuse and abuse in health care. No difference in prevalence was seen between the random population sample and the clinical sample despite significant differences regarding response rate and background characteristics. Conclusions: Abuse against men is prevalent and men are victimised as patients in health care. Response rate and sampling method did not influence prevalence rates of abuse. Men’s victimisation from emotional abuse and abuse in health care was associated with low income and being born outside of the Nordic countries and hence needs to be analysed in the intersections of gender, class, and ethnicity.
Treatment Options for Low Back Pain in Athletes
Authors: Petering Ryan C. , Webb Charles
Published: October 2011

Context: Low back pain is one of the most common medical presentations in the general population. It is a common source of pain in athletes, leading to significant time missed and disability. The general categories of treatment for low back pain are medications and therapies.

Evidence acquisition: Relevant studies were identified through a literature search of MEDLINE and the Cochrane Database from 1990 to 2010. A manual review of reference lists of identified sources was also performed.

Results: It is not clear whether athletes experience low back pain more often than the general public. Because of a aucity of trials with athlete-specific populations, recommendations on treatments must be made from reviews of treatments for the general population. Several large systemic reviews and Cochrane reviews have compiled evidence on different modalities for low back pain. Superficial heat, spinal manipulation, nonsteroidal anti-inflammatory medications, and skeletal muscle relaxants have the strongest evidence of benefit.

Conclusions: Despite the high prevalence of low back pain and the significant burden to the athletes, there are few clearly superior treatment modalities. Superficial heat and spinal manipulation therapy are the most strongly supported evidence-based therapies. Nonsteroidal anti-inflammatory medications and skeletal muscle relaxants have benefit in the initial management of low back pain; however, both have considerable side effects that must be considered. Athletes can return to play once they have recovered full range of motion and have the strength to prevent further injury.
Transcript profiling reveals expression differences in wild-type and glabrous soybean lines
Authors: Hunt Matt , Kaur Navneet , Stromvik Martina , Vodkin Lila
Published: October 2011

Background

Trichome hairs affect diverse agronomic characters such as seed weight and yield, prevent insect damage and reduce loss of water but their molecular control has not been extensively studied in soybean. Several detailed models for trichome development have been proposed for Arabidopsis thaliana, but their applicability to important crops such as cotton and soybean is not fully known.

Results

Two high throughput transcript sequencing methods, Digital Gene Expression (DGE) Tag Profiling and RNA-Seq, were used to compare the transcriptional profiles in wild-type (cv. Clark standard, CS) and a mutant (cv. Clark glabrous, i.e., trichomeless or hairless, CG) soybean isoline that carries the dominant P1 allele. DGE data and RNA-Seq data were mapped to the cDNAs (Glyma models) predicted from the reference soybean genome, Williams 82. Extending the model length by 250 bp at both ends resulted in significantly more matches of authentic DGE tags indicating that many of the predicted gene models are prematurely truncated at the 5' and 3' UTRs. The genome-wide comparative study of the transcript profiles of the wild-type versus mutant line revealed a number of differentially expressed genes. One highly-expressed gene, Glyma04g35130, in wild-type soybean was of interest as it has high homology to the cotton gene GhRDL1 gene that has been identified as being involved in cotton fiber initiation and is a member of the BURP protein family. Sequence comparison of Glyma04g35130 among Williams 82 with our sequences derived from CS and CG isolines revealed various SNPs and indels including addition of one nucleotide C in the CG and insertion of ~60 bp in the third exon of CS that causes a frameshift mutation and premature truncation of peptides in both lines as compared to Williams 82.

Conclusion

Although not a candidate for the P1 locus, a BURP family member (Glyma04g35130) from soybean has been shown to be abundantly expressed in the CS line and very weakly expressed in the glabrous CG line. RNA-Seq and DGE data are compared and provide experimental data on the expression of predicted soybean gene models as well as an overview of the genes expressed in young shoot tips of two closely related isolines.
Activation of the human immune system by chemotherapeutic or targeted agents combined with the oncolytic parvovirus H-1
Authors: Moehler Markus , Sieben Maike , Roth Susanne , Springsguth Franziska , Leuchs Barbara , Zeidler Maja , Dinsart Christiane , Rommelaere Jean , Galle Peter R
Published: October 2011

Background

Parvovirus H-1 (H-1PV) infects and lyses human tumor cells including melanoma, hepatoma, gastric, colorectal, cervix and pancreatic cancers. We assessed whether the beneficial effects of chemotherapeutic agents or targeted agents could be combined with the oncolytic and immunostimmulatory properties of H-1PV.

Methods

Using human ex vivo models we evaluated the biological and immunological effects of H-1PV-induced tumor cell lysis alone or in combination with chemotherapeutic or targeted agents in human melanoma cells +/- characterized human cytotoxic T-cells (CTL) and HLA-A2-restricted dendritic cells (DC).

Results

H-1PV-infected MZ7-Mel cells showed a clear reduction in cell viability of >50%, which appeared to occur primarily through apoptosis. This correlated with viral NS1 expression levels and was enhanced by combination with chemotherapeutic agents or sunitinib. Tumor cell preparations were phagocytosed by DC whose maturation was measured according to the treatment administered. Immature DC incubated with H-1PV-induced MZ7-Mel lysates significantly increased DC maturation compared with non-infected or necrotic MZ7-Mel cells. Tumor necrosis factor-α and interleukin-6 release was clearly increased by DC incubated with H-1PV-induced SK29-Mel tumor cell lysates (TCL) and was also high with DC-CTL co-cultures incubated with H-1PV-induced TCL. Similarly, DC co-cultures with TCL incubated with H-1PV combined with cytotoxic agents or sunitinib enhanced DC maturation to a greater extent than cytotoxic agents or sunitinib alone. Again, these combinations increased pro-inflammatory responses in DC-CTL co-cultures compared with chemotherapy or sunitinib alone.

Conclusions

In our human models, chemotherapeutic or targeted agents did not only interfere with the pronounced immunomodulatory properties of H-1PV, but also reinforced drug-induced tumor cell killing. H-1PV combined with cisplatin, vincristine or sunitinib induced effective immunostimulation via a pronounced DC maturation, better cytokine release and cytotoxic T-cell activation compared with agents alone. Thus, the clinical assessment of H-1PV oncolytic tumor therapy not only alone but also in combination strategies is warranted.
Higher incidence of perineal community acquired MRSA infections among toddlers
Authors: McCullough Alexis C , Seifried Melissa , Zhao Xiaochen , Haase Jeffrey , Kabat William J , Yogev Ram , Blumenthal Robert M , Mukundan Deepa
Published: October 2011

Background

A six-fold increase in pediatric MRSA infections, prompted us to examine the clinical profile of children with MRSA infections seen at Mercy Children's Hospital, Toledo, Ohio and to characterize the responsible strains.

Methods

Records were reviewed of pediatric patients who cultured positive for MRSA from June 1 to December 31, 2007. Strain typing by pulsed field gel electrophoresis (PFT) and DiversiLab, SCCmectyping, and PCR-basedlukSF-PVgene (encodes Panton-Valentine leukocidin), arginine catabolic mobile element (ACME) andcap5 gene detection was performed.

Results

Chart review of 63 patients with MRSA infections revealed that 58(92%) were community acquired MRSA (CAMRSA). All CAMRSA were skin and soft tissue infections (SSTI). Twenty five (43%) patients were aged < 3 yrs, 19(33%) aged 4-12 and 14(24%) aged 13-18. Nineteen (76%) of those aged < 3 yrs had higher incidence of perineal infections compared to only 2(11%) of the 4-12 yrs and none of the 13-18 yrs of age. Infections in the extremities were more common in the older youth compared to the youngest children. Overall, there was a significant association between site of the infection and age group (Fisher's Exact p-value < 0.001). All CAMRSA were USA300 PFT, clindamycin susceptible, SCCmectype IVa andlukSF-PV genepositive. Nearly all contained ACME and about 80% werecap5 positive. Of the 58 USA300 strains by PFT, 55(95%) were also identified as USA300 via the automated repetitive sequence-based PCR method from DiversiLab.

Conclusions

CAMRSA SSTI of the perineum was significantly more common among toddlers and that of the extremities in older children. The infecting strains were all USA300 PFT. Further studies are needed to identify the unique virulence and colonization characteristics of USA300 strains in these infections.
Baseline results of the first malaria indicator survey in Iran at the health facility level
Authors: Raiesi Ahmad , Nikpour Fatemeh , Ansari-Moghaddam Alireza , Ranjbar Mansoor , Rakhshani Fatemeh , Mohammadi Mahdi , Haghdost Aliakbar , Taghizadeh-Asl Rahim , Sakeni Mohammad , Safari Reza , Saffari Mehdi
Published: October 2011

Background

Malaria continues to be a global public health challenge, particularly in developing countries. Delivery of prompt and effective diagnosis and treatment of malaria cases, detection of malaria epidemics within one week of onset and control them in less than a month, regular disease monitoring and operational classification of malaria are among the major responsibilities of the national malaria programme. The study was conducted to determine these indicators at the different level of primary health care facilities in malaria-affected provinces of Iran

Methods

In this survey, data was collected from 223 health facilities including health centres, malaria posts, health houses and hospitals as well as the profile of all 5, 836 recorded malaria cases in these facilities during the year preceding the survey. Descriptive statistics (i.e. frequencies, percentages) were used to summarize the results and Chi square test was used to analyse data.

Results

All but one percent of uncomplicated cases took appropriate and correctly-dosed of anti-malarial drugs in accordance to the national treatment guideline. A larger proportion of patients [85.8%; 95% CI: 84.8 - 86.8] were also given complete treatment including anti-relapse course, in line with national guidelines. About one third [35.0%; 95% CI: 33.6 - 36.4] of uncomplicated malaria cases were treated more than 48 hours after first symptoms onset. Correspondingly, half of severe malaria cases took recommended anti-malarial drugs for severe or complicated disease more than 48 hours of onset of first symptoms. The latter cases had given regular anti-malarial drugs promptly.

The majority of malaria epidemics [97%; 95% CI: 90.6 - 100] in study areas were detected within one week of onset, but only half of epidemics were controlled within four weeks of detection. Just half of target districts had at least one health facility/emergency site with adequate supply and equipment stocks. Nevertheless, only one-third of them [33% (95% CI: 0.00 - 67.8)] had updated inventory of malaria foci on quarterly basis.

Conclusion

To sum up, malaria case management still constitutes a public health problem in Iran. Additionally, data suggest scarcity in management and evaluation of malaria foci, detection and control of malaria epidemics as well as assignment of emergency sites across different regions of the country. Consequently, massive and substantial investments need to be made at the Ministry of Health to coordinate national malaria control programmes towards achieving determined goals and targets.
Immune risk phenotype is associated with nosocomial lung infections in elderly in-patients
Authors: Plonquet A , Bastuji-Garin S , Tahmasebi F , Brisacier C , Ledudal K , Farcet JP , Paillaud E
Published: October 2011

Background

Nosocomial infections are extremely common in the elderly and may be related to ageing of the immune system. The Immune Risk Phenotype (IRP), which predicts shorter survival in elderly patients, has not been evaluated as a possible risk factor for nosocomial infection. Our aim was to assess the prevalence of nosocomial infections in elderly in-patients and to investigate potential relationships between nosocomial infections and the immunophenotype, including IRP parameters.

Results

We included 252 consecutive in-patients aged 70 years or over (mean age, 85 ± 6.2 years), between 2006 and 2008. Among them, 97 experienced nosocomial infections, yielding a prevalence rate of 38.5% (95% confidence interval, 32.5-44.5). The main infection sites were the respiratory tract (21%) and urinary tract (17.1%) When we compared immunological parameters including cell counts determined by flow cytometry in the groups with and without nosocomial infections, we found that the group with nosocomial infections had significantly lower values for the CD4/CD8 ratio and naive CD8 and CD4 T-cell counts and higher counts of memory CD8 T-cells with a significant increase in CD28-negative CD8-T cells. Neither cytomegalovirus status (positive in 193/246 patients) nor presence of the IRP was associated with nosocomial infections. However, nosocomial pneumonia was significantly more common among IRP-positive patients than IRP-negative patients (17/60 versus 28/180;p= 0.036).

Conclusion

Immunological parameters that are easy to determine in everyday practice and known to be associated with immune system ageing and shorter survival in the elderly are also associated with an elevated risk of nosocomial pneumonia in the relatively short term.
Identification of gene fusion transcripts by transcriptome sequencing in BRCA1-mutated breast cancers and cell lines
Authors: Ha Kevin CH , Lalonde Emilie , Li Lili , Cavallone Luca , Natrajan Rachael , Lambros Maryou B , Mitsopoulos Costas , Hakas Jarle , Kozarewa Iwanka , Fenwick Kerry , Lord Chris J , Ashworth Alan , Vincent-Salomon Anne , Basik Mark , Reis-Filho Jorge S , Majewski Jacek , Foulkes William D
Published: October 2011

Background

Gene fusions arising from chromosomal translocations have been implicated in cancer. However, the role of gene fusions in BRCA1-related breast cancers is not well understood. Mutations in BRCA1 are associated with an increased risk for breast cancer (up to 80% lifetime risk) and ovarian cancer (up to 50%). We sought to identify putative gene fusions in the transcriptomes of these cancers using high-throughput RNA sequencing (RNA-Seq).

Methods

We used Illumina sequencing technology to sequence the transcriptomes of five BRCA1-mutated breast cancer cell lines, three BRCA1-mutated primary tumors, two secretory breast cancer primary tumors and one non-tumorigenic breast epithelial cell line. Using a bioinformatics approach, our initial attempt at discovering putative gene fusions relied on analyzing single-end reads and identifying reads that aligned across exons of two different genes. Subsequently, latter samples were sequenced with paired-end reads and at longer cycles (producing longer reads). We then refined our approach by identifying misaligned paired reads, which may flank a putative gene fusion junction.

Results

As a proof of concept, we were able to identify two previously characterized gene fusions in our samples using both single-end and paired-end approaches. In addition, we identified three novel in-frame fusions, but none were recurrent. Two of the candidates, WWC1-ADRBK2 in HCC3153 cell line and ADNP-C20orf132 in a primary tumor, were confirmed by Sanger sequencing and RT-PCR. RNA-Seq expression profiling of these two fusions showed a distinct overexpression of the 3' partner genes, suggesting that its expression may be under the control of the 5' partner gene's regulatory elements.

Conclusions

In this study, we used both single-end and paired-end sequencing strategies to discover gene fusions in breast cancer transcriptomes with BRCA1 mutations. We found that the use of paired-end reads is an effective tool for transcriptome profiling of gene fusions. Our findings suggest that while gene fusions are present in some BRCA1-mutated breast cancers, they are infrequent and not recurrent. However, private fusions may still be valuable as potential patient-specific biomarkers for diagnosis and treatment.
Can anti-cyclic citrullinated peptide antibody-negative RA be subdivided into clinical subphenotypes?
Authors: De Rooy Diederik PC , Willemze Annemiek , Mertens Bart , Huizinga Tom WJ , Van der Helm-van Mil Annette HM
Published: October 2011

Introduction

Studies investigating genetic risk factors for susceptibility to rheumatoid arthritis (RA) studied anti-citrullinated peptide antibody (CCP)-positive RA more frequently than anti-CCP-negative RA. One of the reasons for this is the perception that anti-CCP-negative RA may include patients that fulfilled criteria for RA but belong to a wide range of diagnoses. We aimed to evaluate the validity of this notion and explored whether clinical subphenotypes can be discerned within anti-CCP-negative RA.

Methods

The 318 patients with anti-CCP-negative RA (1987 ACR criteria), included in the Leiden Early Arthritis Clinic between 1993 and 2006, were studied for baseline characteristics and radiologic progression data during a mean follow-up of 5 years. Grouping was studied both at variable and patient levels. Principal components analysis and partial least-squares regression were applied to study for clustering of variables. A cluster analysis was performed to look for clustering of patients.

Results

The simultaneous presence of patient characteristics at disease presentation was observed for several groups; however, the three largest groups of patients' characteristics explained only 26.5% of the total variance. Plotting the contribution of each patient to these three groups did not reveal clustering of patients. Comparable observations were made when data on progression of joint destruction were studied in relation to baseline clinical data. A cluster analysis, evaluating whether patients resemble each other, revealed no grouping of patients. Altogether, no clinically distinguishable subphenotypes were observed.

Conclusions

The current data provide evidence that, for risk-factor studies, anti-CCP-negative RA patients can be studied as one group.
MMP-13 stimulates osteoclast differentiation and activation in tumour breast bone metastases
Authors: Pivetta Eliana , Scapolan Martina , Pecolo Marina , Wassermann Bruna , Abu-Rumeileh Imad , Balestreri Luca , Borsatti Eugenio , Tripodo Claudio , Colombatti Alfonso , Spessotto Paola
Published: October 2011

Introduction

The increased bone degradation in osteolytic metastases depends on stimulation of mature osteoclasts and on continuous differentiation of new pre-osteoclasts. Metalloproteinases (MMP)-13 is expressed in a broad range of primary malignant tumours and it is emerging as a novel biomarker. Recent data suggest a direct role of MMP-13 in dissolving bone matrix complementing the activity of MMP-9 and other enzymes. Tumour-microenvironment interactions alter gene expression in malignant breast tumour cells promoting osteolytic bone metastasis. Gene expression profiles revealed that MMP-13 was among the up-regulated genes in tumour-bone interface and its abrogation reduced bone erosion. The precise mechanism remained not fully understood. Our purpose was to further investigate the mechanistic role of MMP-13 in bone osteolytic lesions.

Methods

MDA-MB-231 breast cancer cells that express MMP-13 were used as a model for in vitro and in vivo experiments. Conditioned media from MDA-MB-231 cells were added to peripheral blood mononuclear cultures to monitor pre-osteoclast differentiation and activation. Bone erosion was evaluated after injection of MMP-13-silenced MDA-MB-231 cells into nude mice femurs.

Results

MMP-13 was co-expressed by human breast tumour bone metastases with its activator MT1-MMP. MMP-13 was up-regulated in breast cancer cells after in vitro stimulation with IL-8 and was responsible for increased bone resorption and osteoclastogenesis, both of which were reduced by MMP inhibitors. We hypothesized that MMP-13 might be directly involved in the loop promoting pre-osteoclast differentiation and activity. We obtained further evidence for a direct role of MMP-13 in bone metastasis by a silencing approach: conditioned media from MDA-MB-231 after MMP-13 abrogation or co-cultivation of silenced cells with pre-osteoclast were unable to increase pre-osteoclast differentiation and resorption activity. MMP-13 activated pre-MMP-9 and promoted the cleavage of galectin-3, a suppressor of osteoclastogenesis, thus contributing to pre-osteoclast differentiation. Accordingly, MMP-13 abrogation in tumour cells injected into the femurs of nude mice reduced the differentiation of TRAP positive cells in bone marrow and within the tumour mass as well as bone erosion.

Conclusions

These results indicate that within the inflammatory bone microenvironment MMP-13 production was up-regulated in breast tumour cells leading to increased pre-osteoclast differentiation and their subsequent activation.
Variation in global codon usage bias among prokaryotic organisms is associated with their lifestyles
Authors: Botzman Maya , Margalit Hanah
Published: October 2011

Background

It is widely acknowledged that synonymous codons are used unevenly among genes in a genome. In organisms under translational selection, genes encoding highly expressed proteins are enriched with specific codons. This phenomenon, termed codon usage bias, is common to many organisms and has been recognized as influencing cellular fitness. This suggests that the global extent of codon usage bias of an organism might be associated with its phenotypic traits.

Results

To test this hypothesis we used a simple measure for assessing the extent of codon bias of an organism, and applied it to hundreds of sequenced prokaryotes. Our analysis revealed a large variability in this measure: there are organisms showing very high degrees of codon usage bias and organisms exhibiting almost no differential use of synonymous codons among different genes. Remarkably, we found that the extent of codon usage bias corresponds to the lifestyle of the organism. Especially, organisms able to live in a wide range of habitats exhibit high extents of codon usage bias, consistent with their need to adapt efficiently to different environments. Pathogenic prokaryotes also demonstrate higher extents of codon usage bias than non-pathogenic prokaryotes, in accord with the multiple environments that many pathogens occupy. Our results show that the previously observed correlation between growth rate and metabolic variability is attributed to their individual associations with codon usage bias.

Conclusions

Our results suggest that the extent of codon usage bias of an organism plays a role in the adaptation of prokaryotes to their environments.
Detection of 3-Iodothyronamine in Human Patients: A Preliminary Study
Authors: Galli Elena , Marchini Maja , Saba Alessandro , Berti Sergio , Tonacchera Massimo , Vitti Paolo , Scanlan Thomas S. , Iervasi Giorgio , Zucchi Riccardo
Published: October 2011

Context and Objective:

The primary purpose of this study was to detect and quantify 3-iodothyronamine (T1AM), an endogenous biogenic amine related to thyroid hormone, in human blood.

Design:

T1AM, total T3, and total T4 were assayed in serum by a novel HPLC tandem mass spectrometry assay, which has already been validated in animal investigations, and the results were related to standard clinical and laboratory variables.

Setting and Patients:

The series included one healthy volunteer, 24 patients admitted to a cardiological ward, and 17 ambulatory patients suspected of thyroid disease, who underwent blood sampling at admission for routine diagnostic purposes. Seven patients were affected by type 2 diabetes, and six patients showed echocardiographic evidence of impaired left ventricular function.

Interventions:

No intervention or any patient selection was performed.

Main Outcome Measures:

serum T1AM, total and free T3 and T4, routine chemistry, routine hematology, and echocardiographic parameters were measured.

Results:

T1AM was detected in all samples, and its concentration averaged 0.219 ± 0.012 pmol/ml. The T1AM concentration was significantly correlated to total T4 (r = 0.654, P < 0.001), total T3 (r = 0.705, P < 0.001), glycated hemoglobin (r = 0.508, P = 0.013), brain natriuretic peptide (r = 0.543, P = 0.016), and γ-glutamyl transpeptidase (r = 0.675, P < 0.001). In diabetic vs. nondiabetic patients T1AM concentration was significantly increased (0.232 ± 0.014 vs. 0.203 ± 0.006 pmol/ml, P = 0.044), whereas no significant difference was observed in patients with cardiac dysfunction.

Conclusions:

T1AM is an endogenous messenger that can be assayed in human blood. Our results are consistent with the hypothesis that circulating T1AM is produced from thyroid hormones and encourage further investigations on the potential role of T1AM in insulin resistance and heart failure.
FGF/EGF signaling regulates the renewal of early nephron progenitors during embryonic development
Authors: Brown Aaron C. , Adams Derek , de Caestecker Mark , Yang Xuehui , Friesel Robert , Oxburgh Leif
Published: October 2011

Recent studies indicate that nephron progenitor cells of the embryonic kidney are arranged in a series of compartments of an increasing state of differentiation. The earliest progenitor compartment, distinguished by expression of CITED1, possesses greater capacity for renewal and differentiation than later compartments. Signaling events governing progression of nephron progenitor cells through stages of increasing differentiation are poorly understood, and their elucidation will provide key insights into normal and dysregulated nephrogenesis, as well as into regenerative processes that follow kidney injury. In this study, we found that the mouse CITED1+ progenitor compartment is maintained in response to receptor tyrosine kinase (RTK) ligands that activate both FGF and EGF receptors. This RTK signaling function is dependent on RAS and PI3K signaling but not ERK. In vivo, RAS inactivation by expression of sprouty 1 (Spry1) in CITED1+ nephron progenitors results in loss of characteristic molecular marker expression and in increased death of progenitor cells. Lineage tracing shows that surviving Spry1-expressing progenitor cells are impaired in their subsequent epithelial differentiation, infrequently contributing to epithelial structures. These findings demonstrate that the survival and developmental potential of cells in the earliest embryonic nephron progenitor cell compartment are dependent on FGF/EGF signaling through RAS.
Gene expression profiling of bovine peripartal placentomes: detection of molecular pathways potentially involved in the release of foetal membranes
Authors: Streyl Dominik , Kenngott Rebecca , Herbach Nadja , Wanke Rüdiger , Blum Helmut , Sinowatz Fred , Wolf Eckhard , Zerbe Holm , Bauersachs Stefan
Published: October 2011

The mechanisms underlying detachment of foetal membranes after birth in cows are still unclear. To address this problem in a systematic manner, we performed the first holistic transcriptome study of bovine placentomes antepartum (AP;n=4 cows) and intrapartum (IP;n=4 cows) using Affymetrix GeneChip Bovine Genome Arrays. Three placentomes were extracted from each cow, and tissue samples from the contact zones of the placentomes (foeto-maternal units) were recovered by systematic random sampling and processed for RNA extraction and for stereological quantification of cellular composition. Statistical analysis of microarray data (false discovery rate 1%) revealed 759 mRNAs with at least twofold higher levels in the samples of the AP group, whereas 514 mRNAs showed higher levels in the IP group. The differentially expressed genes were classified according to biological processes and molecular functions using the Functional Annotation Clustering tool of the DAVID Bioinformatics Resources. Genes with higher mRNA levels in the AP group were nearly completely related to mitotic cell cycle and tissue differentiation. During parturition, a complete shift occurred because the genes with higher mRNA levels in IP were nearly all related to three different physiological processes/complexes: i) apoptosis, ii) degradation of extra cellular matrix and iii) innate immune response, which play a fundamental role in placental detachment. These results are an excellent basis for future studies investigating the molecular basis of retained foetal membranes.
Parental Bereavement: A Panoramic View
Authors: Hunt Sonya , Greeff Abraham P.
Published: October 2011

This study is aimed at identifying central themes of bereavement. A qualitative approach was employed in the analyses of interviews with 22 bereaved parents. The analyses yielded four central issues or themes of bereavement, each with its own set of sub-themes or categories, as the narrative demanded. The first of these themes, pertaining to the life of the family before the death of a child had taken place, was named the risk factor. Circumstances leading up to the death, surrounding the death, the cause of death, and the events following the death were coded as bereavement circumstances. The grief reactions codes were divided into categories of emotional, physical, behavioral, relational, spiritual, and cognitive reactions, as described by the participants. Finally, the mourning codes described the mechanisms employed by the participants in their attempts to survive and continue living after the death. These findings can be used in the training of support workers and the development of bereavement interventions.
Barriers to Metabolic Care for Adults with Serious Mental Illness: Provider Perspectives
Authors: McDonell Michael G. , Kaufman Erin A. , Srebnik Debra S. , Ciechanowski Paul S. , Ries Richard K.
Published: October 2011

This study assessed barriers to metabolic care for persons with serious mental illness (SMI) by surveying experienced healthcare providers. Sixty-eight medical, mental health, and other stakeholders who care for patients with SMI attended a CME conference focused on medical management of SMI patients in 2007. They completed a 27-item survey assessing barriers to and systemic responsibility for metabolic care. The top three ranked barriers were: “separate mental health and primary care systems,” “patient's lack of resources,” and “[mental health] providers are not trained to do basic primary care.” Results indicated that ratings of CMHC responsibility for SMI metabolic care (M = 5.2, SD = 1.5) were significantly lower than ratings of public health ( M = 5.7, SD = 1.4), t(66) = 2.3, p = 0.027, and primary care providers ( M = 6.3, SD = 1.1), t(67) = 4.7, p < 0.001. Experienced providers identified a lack of integrated care and patient characteristics as important barriers to metabolic care and concluded that the primary care and public health systems are primarily responsible for metabolic treatment.
Brucellosis: Epizootiologic and diagnostic challenge
Authors: Radojicic Sonja
Published: October 2011

Although it has been known as a separate etiological entity for almost 150 years, brucellosis is, on a global scale, one of the most frequent diseases that is transferred from animals to humans. It is present as an endemic disease in almost all countries of the Mediterranean Sea, which indicates that a large number of aspects in connection with the control and epizootiology of this disease still remain unexplained. Three of the six types of brucella have been officially confirmed in our country as well. They are Brucella melitensis biotip 3, Brucella suis biotip 2 and Brucella canis. Brucellosis is endemically present in Kosovo and Metohija province and in southern Serbia proper; over the past few years, the spread of brucellosis in sheep and goats as primary hosts for B. melitensis to new territories, mostly in Vojvodina province, has shown that risk analysis is one of the main factors in selecting and implementing control programmes. A correctly selected set of diagnostic tests yields reliable data in most cases, but interpretations of results are prone to result in subjective assessments as well. A special problem in the serological diagnosis of brucellosis is the cross reactivity of brucellas and some other bacteria, often a weak immunological response of the animal, or that the type of brucella that causes the infection determines the sensitivity and specificity of the applied tests, most often screenings tests. Due to the big economic losses resulting from disease control and eradication, and the serious risk to human health, brucellosis still poses an epizootiological, and, in particular, a diagnostic challenge.
Diagnostics procedures in rabies
Authors: Malovrh Tadej , Hostnik Peter
Published: October 2011

Rabies is a major zoonosis for which diagnostic techniques can only be performed in the laboratory. Laboratory techniques are preferably oriented on tissue removed from the cranium: hippocampus (Ammon's horn), cerebellum and the medulla oblongata or tissue liquids. Clinical observation may only lead to a suspicion of rabies. The only way to perform a reliable diagnosis of the disease is to identify the virus or some of its specific components using laboratory tests such as histological identification of characteristic cell lesions, immunochemical identification of rabies virus antigen and virus isolation. Serological tests are rarely used in epidemiological surveys but much more frequently in control of the vaccination programs (e.g. oral vaccination). Most commonly used serological tests are the virus neutralization test on cell culture (FAVN), virus neutralization in mice and ELISA.
Risk factors associated with swine dysentery in East-European pig production units
Authors: Mirko C.P. , Bilkei G.
Published: October 2011

The objective of the present study was to determine the risk factors for swine dysentery in East-European middle-size to large farrow to finish units with separate breeding and grower-finisher facilities. Ten breeding animals (3-10% of the female inventory) and 10 grower tinisher pigs (80-140 days-of age) were sampled in each herd for polymerase chain reaction testing (PCR) for Brachyspira hyodysenteriae (B hyo) in their feces. Of 139 farrow to finish units, 51 (36.7%) were positive, 49 (35,3%) were negative, and 39 (28.1%) were inconclusive for B hyo by PCR. In breeding subunits, twelve variables passed the screening criterion for risk factors (P<.2) for B hyo PCR positivity. The odds of the breeding subunits being B hyo PCR positive were 3.5 times greater when the grower-finisher subunit was positive and the fiber content of the diet was >6%. Use of "all in all out" farrowing policy and having >60% multiparous sows, each reduced the odds of being B hyo PCR positive about fourfold. In growing-finishing subunits, fourteen variables passed the screening criterion for risk factors (P<-2) for B hyo PCR positivity. B hyo PCR positive status of the breeding subunits and higher fiber content of the diet were the most influential variable, with the odds of the grower-finisher subunits being B hyo PCR positive almost eight times greater when the breeding subunit was also B hyo PCR positive. Grower-finisher B hyo PCR positivity was also associated with the percentage of pigs housed on concrete slats, with the odds of being positive 7.5 times higher for subunits where more that 70% of the animals were kept on concrete slats compared to all other floor types. There was a strong association between grower-finisher status and whether the animals were in outdoor lots with the odds of being B hyo PCR positive substantially lower for pigs in outdoor lots compared with all other surfaces.
Effects of different commercial solutions in therapy of hypovolemia in dogs
Authors: Stepanovic Predrag
Published: October 2011

Hypovolemia is represented in the clinical pathology of the dog in a high percentage. It mostly presents an accompanying syndrome in many diseased conditions (vomiting, diarrhea, sequestration, burns, cold burns, ascites periocardiac efusions, and others), while they primarily occur following acule hemorrhagia. Having in mind its diverse etiology, hypovolemia, in addition to a lack of fluids, can also be characterized by various other deficiencies (of electrolytes, proteins, albumins, carbohydrates), which presents an important factor for evaluating the condition of the patient and prescribing the adequate therapy.
Investigations of multiresistance to antibiotics and chemotherapeutics and extended spectrum beta: Lactamase effect (ESBL test) in strains E.coli and salmonella originating from domestic animals
Authors: Misic Dusan , Stosic Zorica , Kiskarolj Ferenc , Adamov Vladica , Asanin Ruzica
Published: October 2011

The presence of multiresistance to the effects of antibiotics and chemotherapeutics and extended spectrum beta-lactamase were examined in 45 strains of E. coli and 35 strains of Salmonella. The strains of E. coli originated from several species of domestic animals: dogs, cats, poultry, and cattle, and 30 strains of Salmonella originated from poultry, 4 strains from cattle, and 1 strain from swine. The presence of the following serovarieties was established using serological examinations: Salmonella Enteritidis 17 strains, Salmonella Gallinarum 1 strain, Salmonella Hartford 5 strains, Salmonella Anatum 1 strain, Salmonella Typhimurium 4 strains, Salmonella Agona 1 strain, Salmonella Infantis 1 strain, Salmonella Thompson var. Berlin 1 strain, Salmonella Tennessee 1 strain, Salmonella Senftenberg 1 strain, Salmonella Glostrup 1 strain, and Salmonella Hadar 1 strain. In the examinations of the listed strains we used antibiogram discs of ampicillin, amoxicillin with clavulanic acid, cephalexin, cephtriaxon, cephotaxim, cephtazidime, aztreonam, gentamycin, chloramphenicol, tetracycline, cyprofloxacine, and a combination of sulphamethoxasole and trimethoprim. The lowest prevalence of multiresistance in E. Coli strains to 3 or more antibiotics was established in dogs 20%, and the highest in 60% strains originating from swine. In 62.88% strains of Salmonella we established sensitivity to all applied antibiotics. Resistance was also established in a small number of the examined strains to ampicillin (11 strains), to tetracycline (5 strains), to amoxicillin with clavulanic acid (5 strains), to sulphamethoxasole with trimethoprim (5 strains), to gentamycin (3 strains), and to cloramphenicol (1 strain). Of all the examined strains of Salmonella, 6 strains originating from poultry exhibited multiresistence. The presence of extended spectrum beta-lactamase effects examined using the ESBL test, was not established in strains of E. coli and Salmonella strains.