bluuebunny/crossref_metadata_2025 huggingface dataset:
Sister chromatid cohesion defects are associated with chromosome instability in Hodgkin lymphoma cells
Authors: Sajesh Babu V , Lichtensztejn Zelda , McManus Kirk J
Published: August 2013

Background

Chromosome instability manifests as an abnormal chromosome complement and is a pathogenic event in cancer. Although a correlation between abnormal chromosome numbers and cancer exist, the underlying mechanisms that cause chromosome instability are poorly understood. Recent data suggests that aberrant sister chromatid cohesion causes chromosome instability and thus contributes to the development of cancer. Cohesion normally functions by tethering nascently synthesized chromatids together to prevent premature segregation and thus chromosome instability. Although the prevalence of aberrant cohesion has been reported for some solid tumors, its prevalence within liquid tumors is unknown. Consequently, the current study was undertaken to evaluate aberrant cohesion within Hodgkin lymphoma, a lymphoid malignancy that frequently exhibits chromosome instability.

Methods

Using established cytogenetic techniques, the prevalence of chromosome instability and aberrant cohesion was examined within mitotic spreads generated from five commonly employed Hodgkin lymphoma cell lines (L-1236, KM-H2, L-428, L-540 and HDLM-2) and a lymphocyte control. Indirect immunofluorescence and Western blot analyses were performed to evaluate the localization and expression of six critical proteins involved in the regulation of sister chromatid cohesion.

Results

We first confirmed that all five Hodgkin lymphoma cell lines exhibited chromosome instability relative to the lymphocyte control. We then determined that each Hodgkin lymphoma cell line exhibited cohesion defects that were subsequently classified into mild, moderate or severe categories. Surprisingly, ~50% of the mitotic spreads generated from L-540 and HDLM-2 harbored cohesion defects. To gain mechanistic insight into the underlying cause of the aberrant cohesion we examined the localization and expression of six critical proteins involved in cohesion. Although all proteins produced the expected nuclear localization pattern, striking differences in RAD21 expression was observed: RAD21 expression was lowest in L-540 and highest within HDLM-2.

Conclusion

We conclude that aberrant cohesion is a common feature of all five Hodgkin lymphoma cell lines evaluated. We further conclude that aberrant RAD21 expression is a strong candidate to underlie aberrant cohesion, chromosome instability and contribute to the development of the disease. Our findings support a growing body of evidence suggesting that cohesion defects and aberrant RAD21 expression are pathogenic events that contribute to tumor development.
IGF-1 receptor and IGF binding protein-3 might predict prognosis of patients with resectable pancreatic cancer
Authors: Hirakawa Toshiki , Yashiro Masakazu , Murata Akihiro , Hirata Keiichiro , Kimura Kenjiro , Amano Ryosuke , Yamada Nobuya , Nakata Bunzo , Hirakawa Kosei
Published: August 2013

Background

The present study aimed to elucidate the clinicopathologic role of insulin-like growth factor-1 receptor (IGF1R) and IGF binding protein-3 (IGFBP3) in patients with pancreatic cancer. The function of IGFBP3 is controversial, because both inhibition and facilitation of the action of IGF as well as IGF-independent effects have been reported. In this study, IGF1R and IGFBP3 expression was examined, and their potential roles as prognostic markers in patients with pancreatic cancer were evaluated.

Methods

Clinicopathological features of 122 patients with curatively resected pancreatic cancer were retrospectively reviewed, and expression of IGF1R and IGFBP3 was immunohistochemically analyzed.

Results

Expression of IGF1R and IGFBP3 was observed in 50 (41.0%) and 37 (30.3%) patients, respectively. IGF1R expression was significantly associated with histological grade (p = 0.037). IGFBP3 expression had a significant association with tumor location (p = 0.023), and a significant inverse association with venous invasion (p = 0.037). Tumors with IGF1R-positive and IGFBP3-negative expression (n = 32) were significantly frequently Stage II and III (p = 0.011). The prognosis for IGF1R positive patients was significantly poorer than that for IGF1R negative patients (p = 0.0181). IGFBP3 protein expression did not correlate significantly with patient survival. The subset of patients with both positive IGF1R and negative IGFBP3 had worse overall survival (8.8 months versus 12.6 months, respectively, p < 0.001).

Conclusion

IGF1R signaling might be associated with tumor aggressiveness, and IGFBP3 might show antiproliferative effects in pancreatic cancer. Both high IGF1R expression and low IGFBP3 expression represent useful prognostic markers for patients with curatively resected pancreatic cancer.
Effect of glycemic control on soluble RAGE and oxidative stress in type 2 diabetic patients
Authors: Motawi Tarek MK , Abou-Seif Mohamed A , Bader Ahmed MA , Mahmoud Mohamed O
Published: August 2013

Background

The interaction of advanced glycation end products (AGEs) and its receptor (RAGE) has played an important role in the pathogenesis of diabetes and its complications. A soluble form of RAGE (sRAGE) has been reported as a decoy receptor for AGEs. Oxidative stress is demonstrated in pathological condition such as atherosclerosis and diabetes mellitus. It has been suggested to be involved in the pathogenesis of both macro- and microvascular complications. This study was designed to evaluate the effect of glycemic control on sRAGE and oxidative stress markers in type 2 diabetic patients.

Methods

Seventy patients with type 2 diabetes and 20 healthy subjects were recruited into the study. Blood glutathione (GSH) and plasma total nitric oxide (NOx) levels were measured using commercially available colorimetric kits, blood superoxide dismutase (SOD) activity was measured by the method of Marklund and Marklund, and plasma C-peptide, oxidized LDL (ox-LDL), sRAGE, and VCAM-1 levels were measured using competitive ELISA kits.

Results

Plasma sRAGE levels were significantly lower (p < 0.05) while VCAM-1 levels were significantly higher (p < 0.05) in poorly controlled diabetic patients compared with healthy control. Blood GSH levels were significantly lower in diabetic patients compared with healthy control (p < 0.05). Plasma C-peptide, NOx, ox-LDL levels, and SOD activity were not significantly different in diabetic patients compared with healthy control. Plasma levels of sRAGE were negatively associated with circulating VCAM-1 levels in diabetic patients.

Conclusion

Poor glycemic control decreases plasma sRAGE and increases VCAM-1 levels while good glycemic control improves these abnormalities which provides benefit to diabetic patients.
Disrupting the CXCL12/CXCR4 axis disturbs the characteristics of glioblastoma stem-like cells of rat RG2 glioblastoma
Authors: Lee Chin-Cheng , Lai Jin-Huei , Hueng Dueng-Yang , Ma Hsin-I , Chung Yuan- Chiang , Sun Ya-yun , Tsai Yih-Ju , Wu Wen-Ben , Chen Chih-Li
Published: August 2013

Background

Glioblastoma stem-like cells (GSC) have been shown to promote tumor growth, tumor-associated neovascularization, therapeutic resistance, and metastasis. CXCR4 receptors have been found involved in the proliferation, metastasis, angiogenesis, and drug-resistant characteristics of glioblastoma. However, the role of CXCR4 in modulating the stem-like cell properties of rat glioblastoma remains ambiguous.

Methods

To explore the role of the CXCL12/CXCR4 axis in maintaining rat GSC properties, we disrupted the CXCR4 signaling by using small hairpin interfering RNA (shRNA). To investigate the role of the CXCL12/CXCR4 axis in maintaining rat GSC properties, we used a spheroid formation assay to assess the stem cell self-renewal properties. A western blot analysis and PCR arrays were used to examine the genes involved in proliferation, self-renewal, and cancer drug resistance. Finally, DNA content and flow cytometry, an immunohistochemical analysis, and methylcellulose colony formation, in vitro invasive and intracranial injection xenograft assays were employed to examine the disruptive effect of CXCR4 on the characteristics of GSCs of the RG2 cell line.

Results

Disrupting CXCR4 inhibited the proliferation of RG2 cells both in vitro and in vivo. The spheroid formation assay indicated that CXCR4 was vital for the self-renewal of RG2 GSCs. Disrupting the CXCL12/CXCR4 pathway also reduced the expression of GSC cell markers, including Nestin, ABCG2, and musashi (Msi), and the expression of genes involved in regulating stem cell properties, including Oct4, Nanog, maternal embryonic leucine zipper kinase (MELK), MGMT, VEGF, MMP2, and MMP9.

Conclusion

The chemokine receptor CXCR4 is crucial for maintaining the self-renewal, proliferation, therapeutic resistance, and angiogenesis of GSCs of rat RG2 glioblastoma.
Fate of TLR-1/TLR-2 agonist functionalised pDNA nanoparticles upon deposition at the human bronchial epithelium in vitro
Authors: Heuking Simon , Rothen-Rutishauser Barbara , Raemy David Olivier , Gehr Peter , Borchard Gerrit
Published: August 2013

Background

Plasmid DNA vaccination is a promising approach, but studies in non-human primates and humans failed to achieve protective immunity. To optimise this technology further with focus on pulmonary administration, we developed and evaluated an adjuvant-equipped DNA carrier system based on the biopolymer chitosan. In more detail, the uptake and accompanying immune response of adjuvantPam3Cys(Toll-like receptor-1/2 agonist) decorated chitosan DNA nanoparticles (NP) were explored by using a three-dimensional (3D) cell culture model of the human epithelial barrier.Pam3Cysfunctionalised and non-functionalised chitosan DNA NP were sprayed by a microsprayer onto the surface of 3D cell cultures and uptake of NP by epithelial and immune cells (blood monocyte-derived dendritic cells (MDDC) and macrophages (MDM)) was visualised by confocal laser scanning microscopy. In addition, immune activation by TLR pathway was monitored by analysis of interleukin-8 and tumor necrosis factor-α secretions (ELISA).

Results

At first, a high uptake rate into antigen-presenting cells (MDDC: 16-17%; MDM: 68–75%) was obtained. Although no significant difference in uptake patterns was observed forPam3Cysadjuvant functionalised and non-functionalised DNA NP, ELISA of interleukin-8 and tumor necrosis factor-α demonstrated clearly thatPam3Cysfunctionalisation elicited an overall higher immune response with the ranking ofPam3Cyschitosan DNA NP > chitosan DNA NP = DNA unloaded chitosan NP > control (culture medium).

Conclusions

Chitosan-based DNA delivery enables uptake into abluminal MDDC, which are the most immune competent cells in the human lung for the induction of antigen-specific immunity. In addition,Pam3Cysadjuvant functionalisation of chitosan DNA NP enhances significantly an environment favoring recruitment of immune cells together with a Th1 associated (cellular) immune response due to elevated IL-8 and TNF-α levels. The latter renders this DNA delivery approach attractive for potential DNA vaccination against intracellular pathogens in the lung (e.g.,Mycobacterium tuberculosisor influenza virus).
Fc-gamma receptor polymorphisms as predictive and prognostic factors in patients receiving oncolytic adenovirus treatment
Authors: Hirvinen Mari , Heiskanen Raita , Oksanen Minna , Pesonen Saila , Liikanen Ilkka , Joensuu Timo , Kanerva Anna , Cerullo Vincenzo , Hemminki Akseli
Published: August 2013

Background

Oncolytic viruses have shown potential as cancer therapeutics, but not all patients seem to benefit from therapy. Polymorphisms in Fc gamma receptors (FcgRs) lead to altered binding affinity of IgG between the receptor allotypes and therefore contribute to differences in immune defense mechanisms. Associations have been identified between FcgR polymorphisms and responsiveness to different immunotherapies. Taken together with the increasing understanding that immunological factors might determine the efficacy of oncolytic virotherapy we studied whether FcgR polymorphisms would have prognostic and/or predictive significance in the context of oncolytic adenovirus treatments.

Methods

235 patients with advanced solid tumors were genotyped for two FcgR polymorphisms, FcgRIIa-H131R (rs1801274) and FcgRIIIa-V158F (rs396991), using TaqMan based qPCR. The genotypes were correlated with patient survival and tumor imaging data.

Results

In patients treated with oncolytic adenoviruses, overall survival was significantly shorter if the patient had an FcgRIIIa-VV/ FcgRIIa-HR (VVHR) genotype combination (P = 0,032). In contrast, patients with FFHR and FFRR genotypes had significantly longer overall survival (P = 0,004 and P = 0,006, respectively) if they were treated with GM-CSF-armed adenovirus in comparison to other viruses. Treatment of these patients with unarmed virus correlated with shorter survival (P < 0,0005 and P = 0,016, respectively). Treating FFHH individuals with CD40L-armed virus resulted in longer survival than treatment with other viruses (P = 0,047).

Conclusions

Our data are compatible with the hypothesis that individual differences in effector cell functions, such as NK cell-mediated antibody-dependent cellular cytotoxicity (ADCC) and tumor antigen presentation by APCs caused by polymorphisms in FcgRs could play role in the effectiveness of oncolytic virotherapies. If confirmed in larger populations, FcgR polymorphisms could have potential as prognostic and predictive biomarkers for oncolytic adenovirus therapies to enable better selection of patients for clinical trials. Also, putative associations between genotypes, different viruses and survival implicate potentially important mechanistic issues.
Fluorescence-based in situ assay to probe the viability and growth kinetics of surface-adhering and suspended recombinant bacteria
Authors: Avalos Vizcarra Ima , Emge Philippe , Miermeister Philipp , Chabria Mamta , Konradi Rupert , Vogel Viola , Möller Jens
Published: August 2013

Bacterial adhesion and biofilm growth can cause severe biomaterial-related infections and failure of medical implants. To assess the antifouling properties of engineered coatings, advanced approaches are needed for in situ monitoring of bacterial viability and growth kinetics as the bacteria colonize a surface. Here, we present an optimized protocol for optical real-time quantification of bacterial viability. To stain living bacteria, we replaced the commonly used fluorescent dye SYTO® 9 with endogenously expressed eGFP, as SYTO® 9 inhibited bacterial growth. With the addition of nontoxic concentrations of propidium iodide (PI) to the culture medium, the fraction of live and dead bacteria could be continuously monitored by fluorescence microscopy as demonstrated here using GFP expressing Escherichia coli as model organism. The viability of bacteria was thereby monitored on untreated and bioactive dimethyloctadecyl[3-(trimethoxysilyl)propyl]ammonium chloride (DMOAC)-coated glass substrates over several hours. Pre-adsorption of the antimicrobial surfaces with serum proteins, which mimics typical protein adsorption to biomaterial surfaces upon contact with host body fluids, completely blocked the antimicrobial activity of the DMOAC surfaces as we observed the recovery of bacterial growth. Hence, this optimized eGFP/PI viability assay provides a protocol for unperturbed in situ monitoring of bacterial viability and colonization on engineered biomaterial surfaces with single-bacteria sensitivity under physiologically relevant conditions.
Rule–based regulatory and metabolic model for Quorum sensing in P. aeruginosa
Authors: Schaadt Nadine S , Steinbach Anke , Hartmann Rolf W , Helms Volkhard
Published: August 2013

Background

In the pathogenP. aeruginosa, the formation of virulence factors is regulated via Quorum sensing signaling pathways. Due to the increasing number of strains that are resistant to antibiotics, there is a high interest to develop novel antiinfectives. In the combat of resistant bacteria, selective blockade of the bacterial cell–to–cell communication (Quorum sensing) has gained special interest as anti–virulence strategy. Here, we modeled thelas,rhl, andpqsQuorum sensing systems by a multi–level logical approach to analyze how enzyme inhibitors and receptor antagonists effect the formation of autoinducers and virulence factors.

Results

Our rule–based simulations fulfill the behavior expected from literature considering the external level of autoinducers. In the presence of PqsBCD inhibitors, the external HHQ and PQS levels are indeed clearly reduced. The magnitude of this effect strongly depends on the inhibition level. However, it seems that the pyocyanin pathway is incomplete.

Conclusions

To match experimental observations we suggest a modified network topology in which PqsE and PqsR acts as receptors and an autoinducer as ligand that up–regulate pyocyanin in a concerted manner. While the PQS biosynthesis is more appropriate as target to inhibit the HHQ and PQS formation, blocking the receptor PqsR that regulates the biosynthesis reduces the pyocyanin level stronger.
External Quality Assessment (EQA) program for the preanalytical and analytical immunohistochemical determination of HER2 in breast cancer: an experience on a regional scale
Authors: Terrenato Irene , Arena Vincenzo , Pizzamiglio Sara , Pennacchia Ilaria , Perracchio Letizia , Buglioni Simonetta , Ercolani Cristiana , Sperati Francesca , Costarelli Leopoldo , Bonanno Elena , Baldini Daniela , Candia Silvia , Crescenzi Anna , Dal Mas Antonella , Di Cristofano Claudio , Gomes Vito , Grillo Lucia Rosalba , Pasquini Paola , Pericoli Maria Nicoletta , Ramieri Maria Teresa , Di Stefano Domenica , Ruco Luigi , Scarpino Stefania , Vitolo Domenico , d’Amati Giulia , Paradiso Angelo , Verderio Paolo , Mottolese Marcella
Published: August 2013

Background

An External Quality Assessment (EQA) program was developed to investigate the state of the art of HER2 immunohistochemical determination in breast cancer (BC) in 16 Pathology Departments in the Lazio Region (Italy). This program was implemented through two specific steps to evaluate HER2 staining (step 1) and interpretation (step 2) reproducibility among participants.

Methods

The management activities of this EQA program were assigned to the Coordinating Center (CC), the Revising Centers (RCs) and the Participating Centers (PCs). In step 1, 4 BC sections, selected by RCs, were stained by each PC using their own procedures. In step 2, each PC interpreted HER2 score in 10 BC sections stained by the CC. The concordance pattern was evaluated by using the kappa category-specific statistic and/or the weighted kappa statistic with the corresponding 95% Jackknife confidence interval.

Results

In step 1, a substantial/almost perfect agreement was reached between the PCs for scores 0 and 3+ whereas a moderate and fair agreement was observed for scores 1+ and 2+, respectively.

In step 2, a fully satisfactory agreement was observed for 6 out of the 16 PCs and a quite satisfactory agreement was obtained for the remaining 10 PCs.

Conclusions

Our findings highlight that in the whole HER2 evaluation process the two intermediate categories, scores 1+ and 2+, are less reproducible than scores 0 and 3+. These findings are relevant in clinical practice where the choice of treatment is based on HER2 positivity, suggesting the need to share evaluation procedures within laboratories and implement educational programs.
Impact of diabetes mellitus on arterial stiffness in a representative sample of an urban Brazilian population
Authors: de Oliveira Alvim Rafael , Santos Paulo Caleb Junior Lima , Musso Mariane Manso , de Sá Cunha Roberto , Krieger José Eduardo , Mill José Geraldo , Pereira Alexandre Costa
Published: August 2013

Background

Independent of other cardiovascular (CV) risk factors, increased arterial stiffness has been established as a predictor of morbidity and mortality. The main aim of this study was to investigate the impact of diabetes on arterial stiffness in a representative sample of an urban Brazilian population plus Amerindians.

Methods

A total of 1,415 individuals from the general population were randomly selected plus 588 Amerindians from a native community in Brazil. In addition, a sub-sample of 380 individuals from the general population had 5-year follow-up data. Pulse wave velocity (PWV) was measured with a non-invasive automatic device (Complior, Colson; Garges les Gonesses, France) and increased arterial stiffness was defined as PWV ≥ 12 m/s.

Results

In the overall group, diabetic individuals had higher frequencies of increased arterial stiffness and hypertension. They also had higher values of PWV, body mass index, total cholesterol, triglycerides, systolic and diastolic blood pressures compared to non-diabetic individuals (p < 0.01). In an analysis stratified by hypertension, PWV values and increased arterial stiffness frequency were higher in diabetic individuals in both groups (hypertensive and non-hypertensive) (p < 0.05). Furthermore, higher risk for increased arterial stiffness was observed in the diabetic individuals from the overall group (OR = 2.27; CI = 1.47-3.52,p < 0.001) and from the hypertensive group (OR = 2.70; CI = 1.58-4.75,p < 0.001), adjusted for covariates. Regarding the ethnic stratification, diabetic individuals from Amerindian, White, and Mulatto (mixed-race) groups had higher PWV values and a greater frequency of increased arterial stiffness compared to non-diabetic individuals. Both diabetic and non-diabetic individuals had higher PWV values after 5 years. There was no significant difference in the 5-year PWV progression in diabetic compared to non-diabetic individuals.

Conclusions

These results confirm, in a sample of Brazilian population, that the presence of diabetes is associated with increased arterial stiffness and it may contribute in part to increased cardiovascular risk in diabetic patients.
Extensive deamidation at asparagine residue 279 accounts for weak immunoreactivity of tau with RD4 antibody in Alzheimer’s disease brain
Authors: Dan Ayaho , Takahashi Muneaki , Masuda-Suzukake Masami , Kametani Fuyuki , Nonaka Takashi , Kondo Hiromi , Akiyama Haruhiko , Arai Takao , Mann David MA , Saito Yuko , Hatsuta Hiroyuki , Murayama Shigeo , Hasegawa Masato
Published: August 2013

Background

Intracytoplasmic inclusions composed of filamentous tau proteins are defining characteristics of neurodegenerative tauopathies, but it remains unclear why different tau isoforms accumulate in different diseases and how they induce abnormal filamentous structures and pathologies. Two tau isoform-specific antibodies, RD3 and RD4, are widely used for immunohistochemical and biochemical studies of tau species in diseased brains.

Results

Here, we show that extensive irreversible post-translational deamidation takes place at asparagine residue 279 ( N279) in the RD4 epitope of tau in Alzheimer’s disease (AD), but not corticobasal degeneration (CBD) or progressive supranuclear palsy (PSP), and this modification abrogates the immunoreactivity to RD4. An antiserum raised against deamidated RD4 peptide specifically recognized 4R tau isoforms, regardless of deamidation, and strongly stained tau in AD brain. We also found that mutant tau with N279D substitution showed reduced ability to bind to microtubules and to promote microtubule assembly.

Conclusion

The biochemical and structural differences of tau in AD from that in 4R tauopathies found in this study may therefore have implications for prion-like propagation of tau.
Trade-offs in quality of life and survival with chemotherapy for advanced breast cancer: mature results of a randomized trial comparing single-agent mitoxantrone with combination cyclophosphamide, methotrexate, 5-fluorouracil and prednisone
Authors: Lee Chee Khoon , Gebski Val J , Coates Alan S , Veillard Anne-Sophie , Harvey Vernon , Tattersall Martin HN , Byrne Michael J , Brigham Brian , Forbes John , Simes R John
Published: August 2013

Background

We evaluate trade-offs between quality of life (QoL) and survival improvement for two chemotherapy regimens in advanced breast cancer. We also report on the long-term survival of patients in the ANZ 8614 clinical trial.

Methods

A total of 391 patients were randomized to mitoxantrone (14 mg/m2 intravenously every 21 days) or a combination of cyclophosphamide 100 mg/m2 and prednisone 40 mg/m2 orally days 1 to 14 plus methotrexate 40 mg/m2 and 5-fluorouracil 600 mg/m2 intravenously days 1 and 8 every 28 days (CMFP). QoL was self-assessed on 14 linear analog scales. We computed the mean differences between the two treatments as products of the mean differences in global QoL, progression-free survival and overall survival.

Results

CMFP led to a higher overall tumor response (39% vs. 25%, P=0.004) and longer progression-free survival (PFS) (median 5.6 vs 3.9 months, P=0.02) but with significantly more toxicity from alopecia, mucositis, diarrhea, anemia and lethargy. Overall survival (OS) was similar in the two groups (median 10.1 vs 11.6 months, P=0.81). QoL over the first 12 weeks was rated better by patients on CMFP for mood (P=0.04), nausea and vomiting (P=0.01), and feeling sick (P=0.02) but worse for hair loss (P<0.0001). A weighted combination of individual QoL items favoured CMFP (subset score mean difference 2.4, P=0.03). A global QoL score tended to favour CMFP (global score mean difference 1.7, P=0.18). Quality-adjusted PFS was significantly longer with CMFP (mean 7.208 vs 5.965 months, P=0.04), but quality-adjusted OS was not significantly different (mean 11.832 vs 11.315 months, P=0.57).

Conclusion

Despite the greater toxicity, the superior antitumor activity of CMFP led to an overall improvement in quality-adjusted PFS. In advanced breast cancer, in clinical decision making about treatment for palliative intent, the principle used to assess trade-offs between antitumor efficacy and toxicity remains relevant and applicable to all modern therapeutic agents.
SCORE and REGICOR function charts underestimate the cardiovascular risk in Spanish patients with rheumatoid arthritis
Authors: Gómez-Vaquero Carmen , Corrales Alfonso , Zacarías Andrea , Rueda-Gotor Javier , Blanco Ricardo , González-Juanatey Carlos , Llorca Javier , González-Gay Miguel A
Published: August 2013

Introduction

Our objective was to determine which one of the two function charts available in Spain to calculate cardiovascular (CV) risk, Systematic COronary Risk Evaluation (SCORE) or Framingham-REgistre GIroní del COR (REGICOR), should be used in patients with rheumatoid arthritis (RA).

Methods

A series of RA patients seen over a one-year period without history of CV events were assessed. SCORE, REGICOR, modified (m)SCORE and mREGICOR according to the European League Against Rheumatism (EULAR) recommendations were applied. Carotid ultrasonography (US) was performed. Carotid intima-media thickness (cIMT) > 0.90 mm and/or carotid plaques were used as the gold standard test for severe subclinical atherosclerosis and high CV risk (US+). The area under the receiver operating curves (AUC) for the predicted risk for mSCORE and mREGICOR were calculated according to the presence of severe carotid US findings (US+).

Results

We included 370 patients (80% women; mean age 58.9 ± 13.7 years); 36% had disease duration of 10 years or more; rheumatoid factor (RF) and/or anticyclic citrullinated peptide (anti-CCP) were positive in 68%; and 17% had extra-articular manifestations. The EULAR multiplier factor was used in 122 (33%) of the patients. The mSCORE was 2.16 ± 2.49% and the mREGICOR 4.36 ± 3.46%. Regarding US results, 196 (53%) patients were US+. The AUC mSCORE was 0.798 (CI 95%: 0.752 to 0.844) and AUC mREGICOR 0.741 (95% CI; 0.691 to 0.792). However, mSCORE and mREGICOR failed to identify 88% and 91% of US+ patients. More than 50% of patients with mSCORE ≥1% or mREGICOR >1% were US+.

Conclusions

Neither of these two function charts was useful in estimating CV risk in Spanish RA patients.
Distinct development and functions of resident and recruited liver Kupffer cells/macrophages
Authors: Ikarashi Masami , Nakashima Hiroyuki , Kinoshita Manabu , Sato Atsushi , Nakashima Masahiro , Miyazaki Hiromi , Nishiyama Kiyoshi , Yamamoto Junji , Seki Shuhji
Published: August 2013

Although mouse liver F4/80+ Kupffer cells consist of cytokine-producing CD11b+ cells and phagocytic CD68+ cells, an undefined CD11b− CD68− subset (30%) also exists. We herein demonstrate a more fundamental classification by adding CD32 (FcγRII), which covers most liver F4/80+ cells and the distinct functions of them. Among the F4/80+ cells, 50%, 40%, and 30% of cells were CD32+, CD68+, and CD11b+, respectively, and one-half of the CD68+ cells coexpressed CD32. CD68+ and CD32+ cells, but not CD11b+ cells, expressed a phagocytosis-related CRIg. Gy (6) irradiation depleted liver CD11b+ cells and those in the spleen, bone marrow, and peripheral blood but not liver CD32/CD68+ cells. Transfer of bone marrow cells into the irradiated mice reconstituted liver CD11b+ cells. Conversely, clodronate pretreatment depleted only liver CD32/CD68+ cells but not liver CD11b+ cells and peripheral blood or spleen CD11b+ monocytes/macrophages. Moreover, the CD32+ cells might be precursors of CD68+ cells, as a large proportion of CD32+ cells expressed the c-kit (CD117), and CD34 and CD32+ cells acquired CD68 immediately after bacteria administration. CD32/CD68+ cells, but not CD11b+ cells, expressed resident macrophage-specific MerTK and CD64 (FcγRI). Challenge with Staphylococcus aureus or liver metastatic EL-4 tumor cells indicated that the CD68+ subset is engaged in systemic bactericidal activity, whereas the CD11b+ subset is pivotal for liver antitumor immunity. Human liver CD14+ Kupffer cells could also be classified into three similar subsets. These results suggest that liver CD68+ Kupffer cells and CD11b+ Kupffer cells/macrophages are developmentally and functionally distinct subsets.
Extrinsic and intrinsic control of macrophage inflammatory responses
Authors: Cohen Heather B , Mosser David M
Published: August 2013

Macrophages make major contributions to inflammatory immunopathology. In this work, we examine three disease scenarios, in which M1s play a major role early in the disease but eventually transitions into a population of cells with immunoregulatory activity. We propose that the transition from an inflammatory to a regulatory phenotype is a natural progression that regularly occurs in stimulated macrophages and that the timing of this transition is critical to maintaining homeostasis. In the first section of this review, we discuss the exogenous microenvironmental cues that may induce macrophages to enter a regulatory state. In the second half of this review, we discuss a novel mechanism, whereby TLR-stimulated macrophages can intrinsically induce their own regulatory activation state. They do so by secreting and synthesizing endogenous “reprogramming” signals that work in an autocrine fashion to promote a regulatory phenotype. We propose that these endogenous regulatory mechanisms exist to prevent macrophage-mediated immunopathology. Thus, macrophages can respond to endogenous and exogenous cues to regulate their activation state, and without these controlled regulatory responses, M1 would persist to the detriment of the host.
Oxygen levels determine the ability of glucocorticoids to influence neutrophil survival in inflammatory environments
Authors: Marwick John A , Dorward David A , Lucas Christopher D , Jones Katie O , Sheldrake Tara A , Fox Sarah , Ward Carol , Murray Joanna , Brittan Mairi , Hirani Nik , Duffin Rodger , Dransfield Ian , Haslett Christopher , Rossi Adriano G
Published: August 2013

GCs are highly effective in treating a wide range of inflammatory diseases but are limited in their ability to control neutrophilic lung inflammation in conditions such as COPD. Neutrophil apoptosis, a central feature of inflammation resolution, is delayed in response to microenvironmental cues, such as hypoxia and inflammatory cytokines, present at inflamed sites. GCs delay neutrophil apoptosis in vitro, and this may therefore limit the ability of GCs to control neutrophilic inflammation. This study assesses the effect GCs have on hypoxia- and inflammatory cytokine-induced neutrophil survival. Human neutrophils were treated with GCs in the presence or absence of GM-CSF or inflammatory macrophage-CM at a range of oxygen concentrations (21–1% oxygen). Neutrophil apoptosis and survival were assessed by flow cytometry and morphological analysis and neutrophil function, by stimulus-induced shape change and respiratory burst. Dexamethasone promoted neutrophil survival at 21%, 10%, and 5% oxygen but not at 1% oxygen. Interestingly, GM-CSF and inflammatory CM increased neutrophil survival significantly, even at 1% oxygen, with cells remaining functionally active at 96 h. Dexamethasone was able to reduce the prosurvival effect of GM-CSF and inflammatory CM in a hypoxic environment. In conclusion, we found that GCs do not augment neutrophil survival in the presence of severe hypoxia or proinflammatory mediators. This suggests that GCs would not promote neutrophil survival at sites of inflammation under these conditions.
Mechanical performance of spider orb webs is tuned for high-speed prey
Authors: Sensenig Andrew T. , Kelly Sean P. , Lorentz Kimberly A. , Lesher Brittany , Blackledge Todd A.
Published: August 2013

Spiders in the Orbiculariae spin orb webs that dissipate the mechanical energy of their flying prey, bringing the insects to rest and retaining them long enough for the spider to attack and subdue their meals. Small prey are easily stopped by webs but provide little energetic gain. While larger prey offer substantial nourishment, they are also challenging to capture and can damage the web if they escape. We therefore hypothesized that spider orb webs exhibit properties that improve their probability of stopping larger insects while minimizing damage when the mechanical energy of those prey exceeds the web's capacity. Large insects are typically both heavier and faster flying than smaller prey, but speed plays a disproportionate role in determining total kinetic energy, so we predicted that orb webs may dissipate energy more effectively under faster impacts, independent of kinetic energy per se. We used high-speed video to visualize the impact of wooden pellets fired into orb webs to simulate prey strikes and tested how capture probability varied as a function of pellet size and speed. Capture probability was virtually nil above speeds of ~3 m s−1. However, successful captures do not directly measure the maximum possible energy dissipation by orb webs because these events include lower-energy impacts that may not significantly challenge orb web performance. Therefore, we also compared the total kinetic energy removed from projectiles that escaped orb webs by breaking through the silk, asking whether more energy was removed at faster speeds. Over a range of speeds relevant to insect flight, the amount of energy absorbed by orb webs increases with the speed of prey (i.e. the rates at which webs are stretched). Orb webs therefore respond to faster – and hence higher kinetic energy – prey with better performance, suggesting adaptation to capture larger and faster flying insect prey. This speed-dependent toughness of a complex structure suggests the utility of the intrinsic toughness of spider silk and/or features of the macro-design of webs for high-velocity industrial or military applications, such as ballistic energy absorption.
Dose and developmental responses of Anopheles merus larvae to salinity
Authors: White Bradley J. , Kundert Peter N. , Turissini David A. , Van Ekeris Leslie , Linser Paul J. , Besansky Nora J.
Published: August 2013

Saltwater tolerance is a trait that carries both ecological and epidemiological significance for Anopheles mosquitoes that transmit human malaria, as it plays a key role in determining their habitat use and ecological distribution, and thus their local contribution to malaria transmission. Here, we lay the groundwork for genetic dissection of this trait by quantifying saltwater tolerance in three closely related cryptic species and malaria vectors from the Afrotropical Anopheles gambiae complex that are known to differ starkly in their tolerance to salinity: the obligate freshwater species A. gambiae and A. coluzzii, and the saltwater-tolerant species A. merus. We performed detailed comparisons of survivorship under varying salinities, using multiple strains of A. gambiae, A. coluzzii and A. merus, as well as F1 progeny from reciprocal crosses of A. merus and A. coluzzii. Additionally, using immunohistochemistry, we compared the location of three ion regulatory proteins (Na+/K+-ATPase, carbonic anhydrase and Na+/H+-antiporter) in the recta of A. coluzzii and A. merus reared in freshwater or saline water. As expected, we found that A. merus survives exposure to high salinities better than A. gambiae and A. coluzzii. Further, we found that exposure to a salinity level of 15.85 g NaCl l−1 is a discriminating dose that kills all A. gambiae, A. coluzzii and A. coluzzii–A. merus F1 larvae, but does not negatively impact the survival of A. merus. Importantly, phenotypic expression of saltwater tolerance by A. merus is highly dependent upon the developmental time of exposure, and based on immunohistochemistry, salt tolerance appears to involve a major shift in Na+/K+-ATPase localization in the rectum, as observed previously for the distantly related saline-tolerant species A. albimanus.
Medicus Petrus Hispanus (cl205-77 Peter of Spain): a XIII century Pope and Author of a Medieval Sex Guide
Authors: Ambrose Charles T
Published: August 2013

Petrus Hispanus was the only practicing physician ever to become Pope (1276-77). By all accounts he was an interim choice when rival French and Italian Cardinals could not elect one of their own nationality. Although not clearly responsible for any major political actions by the Church, Petrus was famous for several centuries after his death because of his secular writings - a text on logic (Summulae logicales) and a handbook on medicine (Thesaurus pauperum). The latter is noteworthy because it contains two sections on coitus - how to enhance the sexual act and how to subdue sexual urges. Promoting coitus seems an odd topic for a medieval Catholic cleric-writer and raises the question as to whether the first section may have been added by a later copyist or editor, but an examination of a very early manuscript of the Thesaurus gives assurance that the two sexual sections were written by Petrus, probably around 1270.
Dr Thomas Aitchison Latta (cl796-1833): pioneer of intravenous fluid replacement in the treatment of cholera
Authors: Janakan Gnananandan , Ellis Harold
Published: August 2013

In 1832 pandemic cholera travelled across Europe with devastating mortality. Before this, doctors had speculated on the benefits of intravenous therapy but none had tried. Only in 1832 did Thomas Latta perform intravenous infusions. This treatment disappeared after Latta's death. This was mainly due to general medical scepticism, lack of biochemical and physiological knowledge and poor patient selection. Finally, there were no further pandemics comparable with that of 1832 to provide the catalyst to accelerate medical development in this field.
William Sampson Handley (1872-1962): champion of the permeation theory of dissemination of breast cancer
Authors: Abdalla Sala , Ellis Harold
Published: August 2013

The Halsted radical mastectomy that prevailed in the first half of the 20th century derived its scientific basis from the ‘lymphatic permeation theory’ of William Sampson Handley an Honorary Senior Consulting Surgeon and former Vice President of the Royal College of Surgeons. Through his pioneering work in the cancer research laboratories at the Middlesex Hospital in London, Handley propounded the theory of centrifugal lymphatic permeation as the leading mechanism for the spread of cancer. This work won him worldwide renown and celebrated recognition in 1911 from the Royal College of Surgeons of England for the best work in the pathology and therapeutics in cancer. During his active life he was one of the great names and influences in the world of surgery. He held many roles at the Royal College of Surgeons and was involved with the international surgical fraternity. His philosophy of the uniqueness of the individual and his kind and courteous disposition won him praise from juniors, colleagues and patients alike. Although much of his work was rejected later, much still remains noteworthy in the history of surgery and cancer research.
Pathology in four epochs: Max Borst (1869-1946), Chairman of Pathology at Munich University from 1910-46
Authors: Babaryka Gregor
Published: August 2013

Max Borst was the pre-eminent tumour pathologist among Rudolf Virchow's (1821-1902) heirs. In his magnum opus of 1902 Borst established the first complete system of tumours based upon histogenetic and biological criteria. Borst was the Chairman of Pathology at Munich University from 1910-46, over a unique period in German history. In the 1930s he was the leading figure in German cancer research. Borst was no Nazi but neither did he join the Resistance. He came to an arrangement with the National Socialist regime, living with it in a relationship of mutual utilitarianism. He never belonged to a political party and he cultivated an image of an apolitical professor except for his engagement against the Räterepublik (Bavarian Soviet Republic) in 1918/19. During World War I, Borst was the first German pathologist to establish systematic ‘war pathology’ and he served in the Army again in World War II as a septuagenarian. Art played an important part in his life. As a gifted musician he performed publicly and he published songs. Borst was an Idealist and Neo-Vitalist who always felt more obliged to authenticity and truthfulness than to truth. He died in a car crash in the Bavarian uplands in October 1946.
Electrical treatment of spinal cord injuries in the 18th and 19th centuries
Authors: Silver John R , Weiner M-F
Published: August 2013

Two centuries ago, electricity was being used for the treatment of paraplegia and trials were taking place in France. This study aims to identify cases of traumatic paraplegia treated with electricity in the 19th century in order to assess the therapeutic benefit. Only four such cases were identified, none with a complete transection of the spinal cord since these patients would have died from pressure sores and urinary tract infections. The personalities involved, William Gull, William Erb, Guillaume Duchenne and Cyril Henry Golding Bird are portrayed and contemporaneous views on electrotherapy analysed. While the four patients apparently benefited from the treatment, the lack of follow-up and the incomplete data prevented a definitive conclusion on the therapeutic value of electrical treatment in traumatic paraplegia.
Comparison of EJC-enhanced and EJC-independent NMD in human cells reveals two partially redundant degradation pathways
Authors: Metze Stefanie , Herzog Veronika A. , Ruepp Marc-David , Mühlemann Oliver
Published: August 2013

Nonsense-mediated mRNA decay (NMD) is a eukaryotic post-transcriptional gene regulation mechanism that eliminates mRNAs with the termination codon (TC) located in an unfavorable environment for efficient translation termination. The best-studied NMD-targeted mRNAs contain premature termination codons (PTCs); however, NMD regulates even many physiological mRNAs. An exon-junction complex (EJC) located downstream from a TC acts as an NMD-enhancing signal, but is not generally required for NMD. Here, we compared these “EJC-enhanced” and “EJC-independent” modes of NMD with regard to their requirement for seven known NMD factors in human cells using two well-characterized NMD reporter genes (immunoglobulin μ and β-Globin) with or without an intron downstream from the PTC. We show that both NMD modes depend on UPF1 and SMG1, but detected transcript-specific differences with respect to the requirement for UPF2 and UPF3b, consistent with previously reported UPF2- and UPF3-independent branches of NMD. In addition and contrary to expectation, a higher sensitivity of EJC-independent NMD to reduced UPF2 and UPF3b concentrations was observed. Our data further revealed a redundancy of the endo- and exonucleolytic mRNA degradation pathways in both modes of NMD. Moreover, the relative contributions of both decay pathways differed between the reporters, with PTC-containing immunoglobulin μ transcripts being preferentially subjected to SMG6-mediated endonucleolytic cleavage, whereas β-Globin transcripts were predominantly degraded by the SMG5/SMG7-dependent pathway. Overall, the surprising heterogeneity observed with only two NMD reporter pairs suggests the existence of several mechanistically distinct branches of NMD in human cells.
Temporal variation of the algae-associated molluscan assemblage of artificial substrata in Bay of Tunis (Tunisia)
Authors: ANTIT M. , DAOULATLI A. , RUEDA J.L. , SALAS C.
Published: August 2013

The molluscan assemblage inhabiting the photophilous algae from artificial rocky shores in theBay of Tunis) was studied from February 2009 to February 2010. Five monthly replicates were taken with a quadrat of 25 × 25 cm .. A total of 16105 individuals of molluscs, belonging to 93 species, were collected. Gastropods were the most species-rich group, with 66 species (70.96%), followed by bivalves with 26 species (27.95%). Gastropods were also the most abundant with 11529 individuals (71.60%), followed by bivalves with 4575 individuals (28.41%). Nevertheless,Mytilaster minimus was the dominant species overall during the studied period (15.6% of total abundance), followed by Tricolia miniata (11.6%), Bittium reticulatum (11.5%), Gibbula racketti (10.4%) and Rissoa similis (9.8%). The high abundance of juveniles of soft (e.g. Venerupis aurea, Nassarius corniculum) and hard bottom species (e.g. M. minimus, Fissurella nubecula) point out the important role   of this habitat as nursery for species from nearby located habitats. The presence of the alien molluscs Mitrella psilla (2.5% dominance) and Arcuatula senhousia highlights the importance of algae as vehicle and/or receptor habitat for alien species. Species richness and abundance displayed significant seasonal changes, with maxima in winter 2009, but the Shannon-Wiener diversity index showed similar values throughout the year. Multivariate analyses also indicated the presence of significant seasonal differences of this molluscan assemblage.
Phytoplankton composition and abundance in the coastal waters of the Datça and Bozburun Peninsulas, south-eastern Aegean Sea (Turkey)
Authors: TAS S.
Published: August 2013

A study of the abundance and composition of microphytoplankton was carried out in marine areas of the Datça and Bozburun Peninsulas between the years 2002 and 2004. Simultaneously measured physical (salinity, temperature, secchi disc) and chemical parameters (nutrients, chl-a, dissolved oxygen) were assessed together with microphytoplankton data. Seawater and plankton net samples were taken from 63 stations during 6 sampling periods. A total of 132 taxa belonging to 3 taxonomic classes was reported and a checklist of microphytoplankton was prepared for this study area. Average nutrient values in surface water ranged from 0.01 to 1.19 µM for NO3+NO2–N, from 0.01 to 0.69 µM for PO4–P and from 0.50 to 5.31 µM for SiO2–Si and chl–a values were between 0.19 and 0.68 µg l–1 throughout the study area. The highest number of microphytoplankton cells reached 5400 cells l–1 and dinoflagellate Prorocentrum micans reached 1500 cells l–1 while diatom Thalassionema nitzschioides reached 700 cells l–1. Dinoflagellates showed a more homogeneous distribution in a wider area than diatoms. The dinoflagellate abundance increased in areas close to the fish farms due to the amount of nutrients originating there. Spatial changes in phytoplankton composition observed in this marine area revealed that phytoplankton are very sensitive to ecosystem changes. The study area could generally be defined as oligotrophic in terms of trophic status depending on the nutrient and chl–a concentrations. Moreover, very low cell abundance and high species richness observed in this area also reflect typical characteristics of oligotrophic waters.