Risk factors for renal allograft loss in patients with systemic lupus erythematosus

Risk factors for renal allograft loss in patients with systemic lupus erythematosus. Controversy exists regarding the risk factors for renal allograft loss in patients with systemic lupus erythematosus (SLE). This study is a retrospective evaluation of each of these independent risk factors in 80 renal transplants for ESRD secondary to SLE done at our institution between 1971 and 1994. Our entire non-diabetic cohort of 1,966 renal transplants is used as a comparison group. Our results showed equivalent graft survival rates between lupus patients and the cohort at 1, 5 and 10 years (P = 0.56). However, an analysis of cyclosporine-era cadaver grafts revealed that the lupus group had poorer 5-year graft survival than the cohort (41% vs. 71%, P = 0.02). Evaluation of cyclosporine-era lupus graft survival showed significantly improved out-come in living-related lupus recipients over cadaver grafts at five years (89% vs. 41%, P = 0.003). The majority of grafts lost in the lupus cadaver recipients were due to chronic rejection. Rejection was increased in lupus recipients: 69% of lupus patients experienced rejection in the first year compared to 58% of controls (P = 0.01). Stratified for age, sex, race and cyclosporine use, this difference remained significant (P = 0.003, relative risk 1.7). Nephrectomy, splenectomy and 3 to 6 months of pretransplant dialysis did not improve graft survival. A dialysis duration of greater than 25 months predicted worse graft survival (P = 0.01). Among lupus patients, PRA did not correlate with graft outcome (P = 0.5), and HLA-identical cadaver grafts had improved outcomes compared to cadaver grafts. We conclude that acute and chronic rejection are the major risk factors for graft loss in lupus patients. The superior outcome of living-related over cadaver grafts in lupus patients suggests an increased role for living-related grafts. Pretransplant dialysis, nephrectomy and splenectomy are not indicated

Report of the Pathogenesis and Pathophysiology of Lyme Disease Subcommittee of the HHS Tick Borne Disease Working Group

An understanding of the pathogenesis and pathophysiology of Lyme disease is key to the ultimate care of patients with Lyme disease. To better understand the various mechanisms underlying the infection caused by Borrelia burgdorferi, the Pathogenesis and Pathophysiology of Lyme Disease Subcommittee was formed to review what is currently known about the pathogenesis and pathophysiology of Lyme disease, from its inception, but also especially about its ability to persist in the host. To that end, the authors of this report were assembled to update our knowledge about the infectious process, identify the gaps that exist in our understanding of the process, and provide recommendations as to how to best approach solutions that could lead to a better means to manage patients with persistent Lyme disease

Using digital and hand printing techniques to compensate for loss: re-establishing colour and texture in historic textiles

Conservators use a range of 'gap filling' techniques to improve the structural stability and presentation of objects. Textile conservators often use fabric supports to provide reinforcement for weak areas of a textile and to provide a visual infill in missing areas. The most common technique is to use dyed fabrics of a single colour but while a plain dyed support provides good reinforcement, it can be visually obtrusive when used with patterned or textured textiles. Two recent postgraduate dissertation projects at the Textile Conservation Centre (TCC) have experimented with hand printing and digital imaging techniques to alter the appearance of support fabrics so that they are less visually obtrusive and blend well with the colour and texture of the textile being supported. Case studies demonstrate the successful use of these techniques on a painted hessian rocking horse and a knitted glove from an archaeological context

High frequency poroelastic waves in hydrogels

In this work a continuum model for high frequency poroelastic longitudinal waves in hydrogels is presented. A viscoelastic force describing the interaction between the polymer network and the bounded water present in such materials is introduced. The model is tested by means of ultrasound wave speed and attenuation measurements in polyvinylalcohol hydrogel samples. The theory and experiments show that ultrasound attenuation decreases linearly with the increase of the water volume fraction "{\beta}" of the hydrogel. The introduction of the viscoelastic force between the bounded water and the polymer network leads to a bi-phasic theory showing an ultrasonic fast wave attenuation that can vary as a function of the frequency with a non-integer exponent in agreement with the experimental data in literature. When {\beta} tends to 1 (100% of interstitial water) due to the presence of bounded water in the hydrogel, the ultrasound phase velocity acquires higher value than that of pure water. The ultrasound speed gap at {\beta} = 1 is confirmed by the experimental results that show that it increases in less cross-linked gel samples that own a higher concentration of bounded water

Paradoxical activation of the protein kinase-transcription factor ERK5 by ERK5 kinase inhibitors.

The dual protein kinase-transcription factor, ERK5, is an emerging drug target in cancer and inflammation, and small-molecule ERK5 kinase inhibitors have been developed. However, selective ERK5 kinase inhibitors fail to recapitulate ERK5 genetic ablation phenotypes, suggesting kinase-independent functions for ERK5. Here we show that ERK5 kinase inhibitors cause paradoxical activation of ERK5 transcriptional activity mediated through its unique C-terminal transcriptional activation domain (TAD). Using the ERK5 kinase inhibitor, Compound 26 (ERK5-IN-1), as a paradigm, we have developed kinase-active, drug-resistant mutants of ERK5. With these mutants, we show that induction of ERK5 transcriptional activity requires direct binding of the inhibitor to the kinase domain. This in turn promotes conformational changes in the kinase domain that result in nuclear translocation of ERK5 and stimulation of gene transcription. This shows that both the ERK5 kinase and TAD must be considered when assessing the role of ERK5 and the effectiveness of anti-ERK5 therapeutics

Analyses of clinicopathological, molecular, and prognostic associations of KRAS codon 61 and codon 146 mutations in colorectal cancer: cohort study and literature review

Background: KRAS mutations in codons 12 and 13 are established predictive biomarkers for anti-EGFR therapy in colorectal cancer. Previous studies suggest that KRAS codon 61 and 146 mutations may also predict resistance to anti-EGFR therapy in colorectal cancer. However, clinicopathological, molecular, and prognostic features of colorectal carcinoma with KRAS codon 61 or 146 mutation remain unclear. Methods: We utilized a molecular pathological epidemiology database of 1267 colon and rectal cancers in the Nurse’s Health Study and the Health Professionals Follow-up Study. We examined KRAS mutations in codons 12, 13, 61 and 146 (assessed by pyrosequencing), in relation to clinicopathological features, and tumor molecular markers, including BRAF and PIK3CA mutations, CpG island methylator phenotype (CIMP), LINE-1 methylation, and microsatellite instability (MSI). Survival analyses were performed in 1067 BRAF-wild-type cancers to avoid confounding by BRAF mutation. Cox proportional hazards models were used to compute mortality hazard ratio, adjusting for potential confounders, including disease stage, PIK3CA mutation, CIMP, LINE-1 hypomethylation, and MSI. Results: KRAS codon 61 mutations were detected in 19 cases (1.5%), and codon 146 mutations in 40 cases (3.2%). Overall KRAS mutation prevalence in colorectal cancers was 40% (=505/1267). Of interest, compared to KRAS-wild-type, overall, KRAS-mutated cancers more frequently exhibited cecal location (24% vs. 12% in KRAS-wild-type; P < 0.0001), CIMP-low (49% vs. 32% in KRAS-wild-type; P < 0.0001), and PIK3CA mutations (24% vs. 11% in KRAS-wild-type; P < 0.0001). These trends were evident irrespective of mutated codon, though statistical power was limited for codon 61 mutants. Neither KRAS codon 61 nor codon 146 mutation was significantly associated with clinical outcome or prognosis in univariate or multivariate analysis [colorectal cancer-specific mortality hazard ratio (HR) = 0.81, 95% confidence interval (CI) = 0.29-2.26 for codon 61 mutation; colorectal cancer-specific mortality HR = 0.86, 95% CI = 0.42-1.78 for codon 146 mutation]. Conclusions: Tumors with KRAS mutations in codons 61 and 146 account for an appreciable proportion (approximately 5%) of colorectal cancers, and their clinicopathological and molecular features appear generally similar to KRAS codon 12 or 13 mutated cancers. To further assess clinical utility of KRAS codon 61 and 146 testing, large-scale trials are warranted

Genetic variation in C20orf54, PLCE1 and MUC1 and the risk of upper gastrointestinal cancers in Caucasian populations

Recently, two large genome wide association studies, conducted in Chinese populations, reported associations between upper gastrointestinal (GI) cancer and the rs2274223, rs13042395 and rs4072037 polymorphisms in PLCE1, C20orf54 and MUC1 respectively. We set out to determine whether similar associations existed for Caucasian populations

Gene-Expression Signatures Can Distinguish Gastric Cancer Grades and Stages

Microarray gene-expression data of 54 paired gastric cancer and adjacent noncancerous gastric tissues were analyzed, with the aim to establish gene signatures for cancer grades (well-, moderately-, poorly- or un-differentiated) and stages (I, II, III and IV), which have been determined by pathologists. Our statistical analysis led to the identification of a number of gene combinations whose expression patterns serve well as signatures of different grades and different stages of gastric cancer. A 19-gene signature was found to have discerning power between high- and low-grade gastric cancers in general, with overall classification accuracy at 79.6%. An expanded 198-gene panel allows the stratification of cancers into four grades and control, giving rise to an overall classification agreement of 74.2% between each grade designated by the pathologists and our prediction. Two signatures for cancer staging, consisting of 10 genes and 9 genes, respectively, provide high classification accuracies at 90.0% and 84.0%, among early-, advanced-stage cancer and control. Functional and pathway analyses on these signature genes reveal the significant relevance of the derived signatures to cancer grades and progression. To the best of our knowledge, this represents the first study on identification of genes whose expression patterns can serve as markers for cancer grades and stages

Changes in the distribution of red foxes (Vulpes vulpes) in urban areas in Great Britain: findings and limitations of a media-driven nationwide survey

Urbanization is one of the major forms of habitat alteration occurring at the present time. Although this is typically deleterious to biodiversity, some species flourish within these human-modified landscapes, potentially leading to negative and/or positive interactions between people and wildlife. Hence, up-to-date assessment of urban wildlife populations is important for developing appropriate management strategies. Surveying urban wildlife is limited by land partition and private ownership, rendering many common survey techniques difficult. Garnering public involvement is one solution, but this method is constrained by the inherent biases of non-standardised survey effort associated with voluntary participation. We used a television-led media approach to solicit national participation in an online sightings survey to investigate changes in the distribution of urban foxes in Great Britain and to explore relationships between urban features and fox occurrence and sightings density. Our results show that media-based approaches can generate a large national database on the current distribution of a recognisable species. Fox distribution in England and Wales has changed markedly within the last 25 years, with sightings submitted from 91% of urban areas previously predicted to support few or no foxes. Data were highly skewed with 90% of urban areas having &lt;30 fox sightings per 1000 people km-2. The extent of total urban area was the only variable with a significant impact on both fox occurrence and sightings density in urban areas; longitude and percentage of public green urban space were respectively, significantly positively and negatively associated with sightings density only. Latitude, and distance to nearest neighbouring conurbation had no impact on either occurrence or sightings density. Given the limitations associated with this method, further investigations are needed to determine the association between sightings density and actual fox density, and variability of fox density within and between urban areas in Britain