Experimental osteoarthritis in rabbits: lesion progression

The aim of this study was to evaluate the progression of lesions in different stages of osteoarthritis (OA) experimental by radiography (RX), computed tomography (CT), macroscopic and histopathology, linking these different diagnostic methods, helped to provide information that helps the best time for the therapeutic approach. Four experimental periods were delineated at 3, 6, 9 and 12 weeks after induction of OA, known as PI, PII, PIII and PIV, respectively, each with six animals. We evaluated the five compartments of the femorotibial joint: medial femoral condyle (MFC), lateral femoral condyle (LFC), medial tibial plateau (MTP), lateral tibial plateau (LTP) and femoral trochlea (FT). Therefore we established an index by compartment (IC) and by adding such an index was estimated joint femorotibial (IFT). It was observed that the CFM was the compartment with the highest IC also differed significantly (p<0.05) from other compartments. Compartments showed no significant difference (p>0.05) between the PI and PII, however contrary fact occurred between the PII and PIII (p<0.05), PIII and PIV (p<0.01) and between PI and PIV (p<0.001). Similarly the IFT, showed a significant difference in the animals of PIV compared to PI (p<0.001), PII (p<0.001) and PIII (p<0.01), and there was no statistical difference (p> 0.05) between the PI and PII. In the variation of the average interval between periods, there was a higher value between the PIII PIV and for the other intervals of time periods (PI, PII, and PIII-PII). However, these intervals showed no statistically significant difference (p>0.05). Through the RX, CT, macroscopic and histopathological findings, we found similar patterns among individuals within the same period demonstrating a gradual progression of the disease. These results show that between 3 and 6 weeks progression of the lesion is slower and probably also can be reversed in comparison to other ranges where proved further progression between 9 and 12 weeks after induction of trauma OA. These results may provide a better therapeutic approach aimed at reversing the lesions in early stages of OA. We conclude that the interconnection of the four diagnostic methods individually classified into scores, which were unified in both indices in the evaluation by the femorotibial joint compartment and may represent a diagnostic condition closer to the true condition of the injury and its progression.

RADAR Roadmap: The application of EPrints for the continued development of RADAR at The Glasgow School of Art

Presentation at Open Repositories 2014, Helsinki, Finland, June 9-13, 2014

Erythrocytes modulate cell cycle progression but not the baseline frequency of sister chromatid exchanges in pig lymphocytes

The effect of co-culturing varying concentrations of pig and human red blood cells (RBCs) on the baseline frequency of sister chromatid exchanges (SCEs) and cell-cycle progression in pig plasma (PLCs) and whole blood leukocyte cultures (WBCs) was studied. No variation in SCE frequency was observed between pig control WBC and PLC. Addition of pig and human RBCs to pig PLCs did not modify the baseline frequency of SCEs. On the other hand, cell proliferation was slower in PLCs than in WBCs. The addition of pig or human RBCs to PLCs accelerated the cell-cycle progression of pig lymphocytes. When RBCs were added to PLCs the concentration and time sequence of RBC incorporation affected the cell-cycle progression of swine lymphocytes. When doses of pig or human RBCs equivalent to those present in WBCs were added immediately after PLC stimulation, the cell-cycle kinetics were similar to those of WBCs. Shorter co-incubation periods or a reduction in the dose of RBCs made cell-cycle progression intermediate between PLC and WBC values. Thus, pig and human RBCs modulated the in vitro cell-cycle progression of pig lymphocytes in a time- and dose-dependent manner, and the low baseline frequency of SCEs of pig lymphocytes is independent of the presence or absence of erythrocytes in culture

Functions of the extracellular matrix and matrix degrading proteases during tumor progression

Cell interactions with extracellular matrices are important to pathological changes that occur during cell transformation and tumorigenesis. Several extracellular matrix proteins including fibronectin, thrombospondin-1, laminin, SPARC, and osteopontin have been suggested to modulate tumor phenotype by affecting cell migration, survival, or angiogenesis. Likewise, proteases including the matrix metalloproteinases (MMPs) are understood to not only facilitate migration of cells by degradation of matrices, but also to affect tumor formation and growth. We have recently demonstrated an in vivo role for the RGD-containing protein, osteopontin, during tumor progression, and found evidence for distinct functions in the host versus the tumor cells. Because of the compartmentalization and temporal regulation of MMP expression, it is likely that MMPs may also function dually in host stroma and the tumor cell. In addition, an important function of proteases appears to be not only degradation, but also cleavage of matrix proteins to generate functionally distinct fragments based on receptor binding, biological activity, or regulation of growth factors.

alpha-Smooth muscle actin and proliferating cell nuclear antigen expression in focal segmental glomerulosclerosis: functional and structural parameters of renal disease progression

The aim of the present study was to investigate the expression of alpha-smooth muscle actin (alpha-SM-actin) and proliferating cell nuclear antigen (PCNA) in renal cortex from patients with focal segmental glomerulosclerosis (FSGS) and their correlations with parameters of renal disease progression. We analyzed renal biopsies from 41 patients with idiopathic FSGS and from 14 control individuals. The alpha-SM-actin immunoreaction was evaluated using a score that reflected the changes in the extent and intensity of staining in the glomerular or cortical area. The PCNA reaction was quantified by counting the labeled cells of the glomeruli or renal cortex. The results, reported as median ± percentile (25th; 75th), showed that the alpha-SM-actin scores in the glomeruli and tubulointerstitium from the renal cortex were 2.0 (2.0; 4.0) and 3.0 (3.0; 4.0), respectively, in patients with FSGS, and 0.5 (0.0; 1.0) and 0.0 (0.0; 0.5) in the controls. The number of PCNA-positive cells per glomerulus and graded field of tubulointerstitium from the renal cortex was 0.2 (0.0; 0.4) and 1.1 (0.3; 2.2), respectively, for patients with FSGS, and 0.0 (0.0; 0.5) and 0.0 (0.0; 0.0) for controls. The present data showed an increase of alpha-SM-actin and PCNA expression in glomeruli and renal cortex from FSGS patients. The extent of immunoreaction for alpha-SM-actin in the tubulointerstitial area was correlated with the intensity of proteinuria. However, there was no correlation between the kidney expression of these proteins and the reciprocal of plasma creatinine level or renal fibrosis. These findings suggest that the immunohistochemical alterations may be reversible.

Effect of dietary linoleic acid on the progression of chronic renal failure in rats

The role of linoleic acid in chronic renal failure (CRF) is controversial. In the present study 21 male Wistar rats submitted to 5/6 renal mass reduction (R) and 16 normal controls (C) were fed a supplement (S) or normal (N) linoleic acid diet for 60 days starting 10 days after CRF. As expected, serum creatinine, cholesterol and triglycerides (mean ± SEM) were higher in the CRF groups compared to the C groups (P<0.05). The RS group presented lower cholesterol (84 ± 4 vs 126 ± 13 mg%) and triglyceride (88 ± 9 vs 132 ± 19 mg%) levels compared to the RN group. Proteinuria and kidney weight did not differ between CRF groups. Glomerular area increased 78% in RS and 100% in RN compared to control rats. Glomerular sclerosis index tended to be lower in RS (27%) compared to RN (38%), tubulointerstitial damage was similar between CRF groups (RS = 1.91 ± 0.2 and RN = 2.14 ± 0.3), and mesangial fractional volume increased to the same extent in both CRF groups. The data suggest that a linoleic acid-enriched diet did not protect against the progression of CRF after 60 days.

Remodeling in the ischemic heart: the stepwise progression for heart

Abstract Coronary artery disease is the leading cause of death in the developed world and in developing countries. Acute mortality from acute myocardial infarction (MI) has decreased in the last decades. However, the incidence of heart failure (HF) in patients with healed infarcted areas is increasing. Therefore, HF prevention is a major challenge to the health system in order to reduce healthcare costs and to provide a better quality of life. Animal models of ischemia and infarction have been essential in providing precise information regarding cardiac remodeling. Several of these changes are maladaptive, and they progressively lead to ventricular dilatation and predispose to the development of arrhythmias, HF and death. These events depend on cell death due to necrosis and apoptosis and on activation of the inflammatory response soon after MI. Systemic and local neurohumoral activation has also been associated with maladaptive cardiac remodeling, predisposing to HF. In this review, we provide a timely description of the cardiovascular alterations that occur after MI at the cellular, neurohumoral and electrical level and discuss the repercussions of these alterations on electrical, mechanical and structural dysfunction of the heart. We also identify several areas where insufficient knowledge limits the adoption of better strategies to prevent HF development in chronically infarcted individuals.

Late emergence of A594V and L595W mutations related to ganciclovir resistance in a patient with HCMV retinitis and long-term HIV progression

The emergence of ganciclovir (GCV) resistance during the treatment of human cytomegalovirus (HCMV) infection is a serious clinical challenge, and is associated with high morbidity and mortality. In this case report, we describe the emergence of two consecutive mutations (A594V and L595W) related to GCV resistance in a patient with HCMV retinitis and long-term HIV progression after approximately 240 days of GCV use. Following the diagnosis of retinitis, the introduction of GCV did not result in viral load reduction. The detected mutations appeared late in the treatment, and we propose that other factors (high initial HCMV load, previous GCV exposure, low CD4+ cell count), in addition to the presence of resistance mutations, may have contributed to the treatment failure of HCMV infection in this patient.

Roles of novel biomarkers in progression of cutaneous squamous cell carcinoma

Roles of novel biomarkers was studied in progression of cutaneous squamous cell carcinoma (cSCC) as the most common metastatic skin cancer. The incidence of cSCC is increasing worldwide due to lifestyle changes such as recreational exposure to sunlight and the aging of the population. Because of an emerging need for molecular markers for the progression of cSCC, we set our goal to characterize three distinct novel markers overexpressed in cSCC cells. Our results identified overexpression of serpin peptidase inhibitor clade A member 1 (SerpinA1), EphB2 and absent in melanoma 2 (AIM2) in cSCC cell lines compared with normal human epidermal keratinocytes (NHEKs). Immunohistochemical analysis of SerpinA1, EphB2 and AIM2 revealed abundant tumor cell-specific expression of cytoplasmic SerpinA1 and AIM2 and cytoplasmic and membranous EphB2 in cSCC tumors in vivo. The staining intensity of SerpinA1, EphB2 and AIM2 was significantly stronger in cSCC as compared with carcinoma in situ (cSCCIS) and actinic keratosis (AK). Tumor cell-associated SerpinA1 and EphB2 was noted in chemically induced mouse skin SCC, and the staining intensity was stronger in mouse cSCCs than in untreated skin. AIM2 staining intensity was significantly more abundant in cSCC of organ transplant recipients (OTR) than in sporadic cSCC in vivo. EphB2 knockdown resulted in inhibition of migration in cSCC cells. In addition, knockdown of EphB2 and AIM2 was found to inhibit the proliferation and invasion of cSCC cells and to delay the growth and vascularization of cSCC xenografts in vivo. Altogether, these findings identify SerpinA1 as a novel biomarker for cSCC. In addition, characterization of the roles of EphB2 and AIM2 in the progression of cSCC was implicated them as possible therapeutic targets for the treatment of cSCC particularly in unresectable and metastatic tumors.

Urana työllistyminen

Tutkimuksen tarkoituksena on ollut selvittää pitkään työttömänä olleiden ammatinvaihtajien ammatinvaihdon ja työllistymisen etenemistä. Tämän lisäksi tutkimuksessa on tarkasteltu kohderyhmän mielikuvaa ohjaavasta koulutuksesta. Pitkittäistutkimus on toteutettu seurannalla, jonka välietappina on ollut kohderyhmän osallistuminen ohjaavaan koulutukseen. Työvoimapoliittinen ohjaava koulutus edusti erityisesti vaikeasti työllistettäville kohdistettavaa interventiota, jolla pyrittiin puuttumaan työttömyyskierteeseen ja ehkäisemään syrjäytymiskehityksen jatkuminen. Tutkimuksen kohderyhmäksi valitut ihmiset (51) ovat suoranaisessa keskiössä tutkittaessa työelämästä syrjäytymistä. Heikentyneet työelämävalmiudet ja työmarkkinakelpoisuus ovat tehneet heistä vaikeasti työllistettäviä. Heidän valintansa kohderyhmäksi, työhallinnon tekemän kurssiosoituksen kriteereinä olevien pitkäaikaistyöttömyyden sekä epäonnistuneen ammatinvaihdon perusteella, osoittaa heidän olevan erityisen ohjauksen ja tuen tarpeessa. On kuitenkin huomattava, että heidät on valittu kohderyhmäksi paitsi kurssiosoituksen saaneina pitkäaikaistyöttöminä myös ammatinvaihtajina, jotka itse haluavat vaihtaa ammattiaan. Tutkimusaineistona ovat olleet työhallinnon asiakasrekisteritiedot ja seurantatutkimuksen perusteella muodostetuista ryhmistä valittujen neljän tapaushenkilön teemahaastatteluaineistot. Tutkimusaineistoa on käsitelty laadullisesti, koska tutkimus kuuluu laadullisen tutkimuksen piiriin sekä tutkimuksen kohteena olevan ilmiön, tutkimuskysymysten ja -aineistojen että tarkoituksensa perusteella. Tutkimuksessa on kuvattu pitkäaikaistyöttömien henkilöiden ammatinvaihtoa ja työllistymistä. Kuvatuissa tapauksissa ammatinvaihtotarve perustuu suurimmalla osalla terveydellisiin rajoitteisiin, joiden vuoksi aikaisemmassa työssä toimiminen on mahdotonta. Useimmiten vajaakuntoisuus on merkittävästi pitkittänyt heidän työttömyyttään. Tämän vuoksi seurantatutkimuksessa on keskitytty tarkastelemaan ammatinvaihtoprosessin etenemistä. Muun muassa työttömyyttä laajasti tutkineet Aho ja Vähätalo ovat todenneet vajaakuntoisuuden olevan merkittävä työttömyyden pitkittymiseen vaikuttava tekijä. Ahon mukaan vajaakuntoisiksi diagnosoituja on jopa viidennes kroonisesti pitkäaikaistyöttömistä työhallinnon asiakasrekisteriin kirjatuista henkilöistä. Monen tekijän summana pitkään työttömänä olleet henkilöt ovat vaarassa ajautua tilanteeseen, jossa he eivät enää kykene omin avuin löytämään ulospääsyä työttömyydestä Tämän seurantatutkimuksen perusteella vain hyvin harvalla kohderyhmään kuuluvista on ammatinvaihdossa ja työllistymisessä tapahtunut merkittävää edistymistä huolimatta useiden vuosien yrittämisestä. Ammatinvaihdon ja työllistymisen edistymistä on tarkasteltu sen perusteella, miten työelämään ja/tai koulutukseen sijoittumiset tai muut toiminnot ovat edesauttaneet tavoitteen toteutumista. Seurantatutkimuksessa on muodostettu neljä tyyppiryhmää ammatinvaihdon ja työllistymisen etenemisen perusteella. Ryhmät ovat: Ammatinvaihdossa onnistuneet (5), ammatinvaihdossa edistyneet (19), pitkäaikaistyöttömäksi jääneet (12) ja epätarkoituksenmukaisesti sijoittuneet (15). Ammatinvaihdossa onnistuneet ovat toteuttaneet ammatinvaihtonsa siirtymällä suoraan työelämään uudelle alalle, työllistymällä koulutusta vastaavaan työhön uudelleenkoulutuksen jälkeen tai kouluttautumalla uuteen ammattiin työllistymättä. Kuitenkin vain kolme heistä on sijoittunut seurannan päättyessä pysyväisluonteiseen terveydelleen soveltuvaan työhön muiden ollessa edelleen työttömänä. Ammatinvaihdossa edistyneet ovat suurimmaksi osaksi edistyneet ammatinvaihdossaan soveltuvien tukitöiden avulla. Työttömyys on kuitenkin jatkunut valtaosalla ja vain yksi heistä on sijoittuneena työelämään seurannan päättyessä. Tämä sijoittuminen ei ole kuitenkaan edistänyt ammatinvaihtoa. Pitkäaikaistyöttömäksi jääneet ovat olleet yhtäjaksoisesti työttömänä kokoseurantajakson ajan. Epätarkoituksenmukaisesti sijoittuneet ovat enimmäkseen sijoittuneet terveytensä kannalta haitallisiin ja/tai ammatinvaihtosuunnitelmilleen soveltumattomiin sijoitustöihin ja määräaikaisuuksiin. Seurannan päättyessä heovat joko työttömänä tai toimivat ammatinvaihtotavoitteensa kannalta haitallisissa työtehtävissä. Tämä on vahvistanut mielikuvaa, joka usealle heille on muodostunut ohjaavasta koulutuksesta työttömille suunnattuna sanktiona, joka ei edistä työllistymistä. Ohjaavassa koulutuksessa suurin osa heistä on kokenut hyötyneensä työharjoittelujaksosta, joka on antanut käyttökelpoista tietoa ammatinvalintaa varten. Lukuun ottamatta kolmea henkilöä, jotka ovat seurannan päättyessä pysyväisluonteisessa työssä terveydelleen soveltuvassa ammatissa, ovat kaikki muut kohderyhmään kuuluvat edelleen erityisen ohjauksen ja tuen tarpeessa johtuen ammatinvaihdon keskeneräisyydestä ja/tai työttömyyden jatkumisesta. Yhdistävänä tekijänä ammatinvaihdossa onnistuneilla vaikuttaa olleen tulevaisuususkon säilyminen pitkäaikaistyöttömyydessä. Sekä ammatinvaihdossa onnistuneet että edistyneet ovat kokeneet työttömyyteen katkoksia tuoneet työt merkityksellisinä riippumatta siitä, ovatko työtehtävät edistäneet ammatinvaihtoa.

The relationship between body mass index and breast cancer recurrence/progression and breast cancer-specific death

The aim of this study was to describe the nonlinear association between body mass index (BMI) and breast cancer outcomes and to determine whether BMI improves prediction of outcomes. A cohort of906 breast cancer patients diagnosed at Henry Ford Health System, Detroit (1985-1990) were studied. The median follow-up was 10 years. Multivariate logistic regression was used to model breast cancer recurrence/progression and breast cancer-specific death. Restricted cubic splines were used to model nonlinear effects. Receiver operator characteristic areas under the curves (ROC AUC) were used to evaluate prediction. BMI was nonlinearly associated with recurrence/progression and death (p= 0.0230 and 0.0101). Probability of outcomes increased with increase or decrease ofBMI away from 25. BMI splines were suggestive of improved prediction of death. The ROC AUCs for nested models with and without BMI were 0.8424 and 0.8331 (p= 0.08). I f causally associated, modifying patients BMI towards 25 may improve outcomes.

Aboriginal status is a prognostic factor for mortality among antiretroviral naïve HIV-positive individuals first initiating HAART

Affiliation: Mark Daniel: Département de médecine sociale et préventive, Faculté de médecine, Université de Montréal et Centre de recherche du Centre hospitalier de l'Université de Montréal