Vascular grading of angiogenesis: prognostic significance in breast cancer

The study aimed to evaluate the prognostic value of angiogenesis by vascular grading of primary breast tumours, and to evaluate the prognostic impact of adding the vascular grade to the Nottingham Prognostic Index (NPI). The investigation included 836 patients. The median follow-up time was 11 years and 4 months. The microvessels were immunohistochemically stained by antibodies against CD34. Angiogenesis was graded semiquantitatively by subjective scoring into three groups according to the expected number of microvessels in the most vascular tumour area. The vascular grading between observers was moderately reproduced (κ = 0.59). Vascular grade was significantly associated with axillary node involvement, tumour size, malignancy grade, oestrogen receptor status and histological type. In univariate analyses vascular grade significantly predicted recurrence free survival and overall survival for all patients (P< 0.0001), node-negative patients (P< 0.0001) and node-positive patients (P< 0.0001). Cox multivariate regression analysis showed that vascular grading contributed with independent prognostic value in all patients (P< 0.0001). A prognostic index including the vascular grade had clinical impact for 24% of the patients, who had a shift in prognostic group, as compared to NPI, and implied a better prognostic dissemination. We concluded that the angiogenesis determined by vascular grading has independent prognostic value of clinical relevance for patients with breast cancer. © 2000 Cancer Research Campaig

Primary vs. Secondary Antibody Deficiency: Clinical Features and Infection Outcomes of Immunoglobulin Replacement

<div><p>Secondary antibody deficiency can occur as a result of haematological malignancies or certain medications, but not much is known about the clinical and immunological features of this group of patients as a whole. Here we describe a cohort of 167 patients with primary or secondary antibody deficiencies on immunoglobulin (Ig)-replacement treatment. The demographics, causes of immunodeficiency, diagnostic delay, clinical and laboratory features, and infection frequency were analysed retrospectively. Chemotherapy for B cell lymphoma and the use of Rituximab, corticosteroids or immunosuppressive medications were the most common causes of secondary antibody deficiency in this cohort. There was no difference in diagnostic delay or bronchiectasis between primary and secondary antibody deficiency patients, and both groups experienced disorders associated with immune dysregulation. Secondary antibody deficiency patients had similar baseline levels of serum IgG, but higher IgM and IgA, and a higher frequency of switched memory B cells than primary antibody deficiency patients. Serious and non-serious infections before and after Ig-replacement were also compared in both groups. Although secondary antibody deficiency patients had more serious infections before initiation of Ig-replacement, treatment resulted in a significant reduction of serious and non-serious infections in both primary and secondary antibody deficiency patients. Patients with secondary antibody deficiency experience similar delays in diagnosis as primary antibody deficiency patients and can also benefit from immunoglobulin-replacement treatment.</p></div

A randomised controlled trial investigating motor skill training as a function of attentional focus in old age

BACKGROUND: Motor learning research has had little impact on clinical applications and rarely extended to research about how older adults learn motor skills. There is consistent evidence that motor skill performance and learning can be enhanced by giving learners instructions that direct their attention. The aim of this study was to test whether elderly individuals that receive an external focus instruction during training of dynamic balance skills would learn in a different manner compared to individuals that received an internal focus instruction. METHODS: This randomised trial included 26 older persons (81 +/- 6 years) that were training functional balance twice a week for the duration of 5 weeks. Learning outcomes were recorded after every training session. Weight shifting score and dynamic balance parameters (Biodex Balance System), components of the Extended Timed-Get-Up-and-Go test, five chair rises, and falls efficacy (FES-I) was assessed at baseline and post-intervention. RESULTS: Participation for training sessions was 94%. No differences between groups were found following 5 weeks of training for weight shifting score, dynamic balance index and dynamic balance time (p < 0.95, p = 0.16, p < 0.50), implying no learning differences between training groups. Extended Timed-Get-Up-and-Go components Sit-to-stand, p = .036; Gait initiation, p = .039; Slow down, stop, turnaround, and sit down, p = 0.011 and the Fes-I (p = 0.014) showed improvements for the total group, indicating that function improved compared to baseline. CONCLUSION: A 5-week balance training improved weight shifting scores and dynamic balance parameters as well as functional abilities. The observed improvements were independent from the type of attentional focus instructions. The findings provide support for the proposition of different motor learning principles in older adults compared to younger adults

Domesticating the ‘troubled family’: Racialised sexuality and the postcolonial governance of family life in the UK

This article examines how the UK’s Troubled Families Programme (TFP) works as a strategy of domestication which produces and delimits certain forms of ‘family life’. Drawing upon critical geographies of home and empire, the article explores how the TFP works to manage the troubled family as part of a longer history of regulating unruly households in the name of national health and civilisation. Viewing the TFP as part of the production of heteronormative order, highlights how the policy remobilises and reconfigures older forms of colonial rule which work to demarcate between civility/savagery, the developable/undevelopable. In examining the postcolonial dimension of neoliberal social policy, the article stresses how the TFP relies on racializing and sexualised logics of socio-biological control borrowed from imperial eugenics. Reading the TFP in this way contributes to our understanding of neoliberal rule. That the troubled family can be either domesticated or destroyed (through benefit sanctions and eviction) equally reveals the extent to which domesticity works as a key site for the production of both ‘worthy’ and ‘surplus’ life

Systematic review and meta-analysis of the diagnostic accuracy of ultrasonography for deep vein thrombosis

Background Ultrasound (US) has largely replaced contrast venography as the definitive diagnostic test for deep vein thrombosis (DVT). We aimed to derive a definitive estimate of the diagnostic accuracy of US for clinically suspected DVT and identify study-level factors that might predict accuracy. Methods We undertook a systematic review, meta-analysis and meta-regression of diagnostic cohort studies that compared US to contrast venography in patients with suspected DVT. We searched Medline, EMBASE, CINAHL, Web of Science, Cochrane Database of Systematic Reviews, Cochrane Controlled Trials Register, Database of Reviews of Effectiveness, the ACP Journal Club, and citation lists (1966 to April 2004). Random effects meta-analysis was used to derive pooled estimates of sensitivity and specificity. Random effects meta-regression was used to identify study-level covariates that predicted diagnostic performance. Results We identified 100 cohorts comparing US to venography in patients with suspected DVT. Overall sensitivity for proximal DVT (95% confidence interval) was 94.2% (93.2 to 95.0), for distal DVT was 63.5% (59.8 to 67.0), and specificity was 93.8% (93.1 to 94.4). Duplex US had pooled sensitivity of 96.5% (95.1 to 97.6) for proximal DVT, 71.2% (64.6 to 77.2) for distal DVT and specificity of 94.0% (92.8 to 95.1). Triplex US had pooled sensitivity of 96.4% (94.4 to 97.1%) for proximal DVT, 75.2% (67.7 to 81.6) for distal DVT and specificity of 94.3% (92.5 to 95.8). Compression US alone had pooled sensitivity of 93.8 % (92.0 to 95.3%) for proximal DVT, 56.8% (49.0 to 66.4) for distal DVT and specificity of 97.8% (97.0 to 98.4). Sensitivity was higher in more recently published studies and in cohorts with higher prevalence of DVT and more proximal DVT, and was lower in cohorts that reported interpretation by a radiologist. Specificity was higher in cohorts that excluded patients with previous DVT. No studies were identified that compared repeat US to venography in all patients. Repeat US appears to have a positive yield of 1.3%, with 89% of these being confirmed by venography. Conclusion Combined colour-doppler US techniques have optimal sensitivity, while compression US has optimal specificity for DVT. However, all estimates are subject to substantial unexplained heterogeneity. The role of repeat scanning is very uncertain and based upon limited data

Augmented Cardiac Hypertrophy in Response to Pressure Overload in Mice Lacking ELTD1

BACKGROUND: Epidermal growth factor (EGF), latrophilin and seven transmembrane domain-containing protein 1 (ELTD1) is developmentally upregulated in the heart. Little is known about the relationship between ELTD1 and cardiac diseases. Therefore, we aimed to clarify the role of ELTD1 in pressure overload-induced cardiac hypertrophy. METHODS AND RESULTS: C57BL/6J wild-type (WT) mice and ELTD1-knockout (KO) mice were subjected to left ventricular pressure overload by descending aortic banding (AB). KO mice exhibited more unfavorable cardiac remodeling than WT mice 28 days post AB; this remodeling was characterized by aggravated cardiomyocyte hypertrophy, thickening of the ventricular walls, dilated chambers, increased fibrosis, and blunted systolic and diastolic cardiac function. Analysis of signaling pathways revealed enhanced extracellular signal-regulated kinase (ERK) and the c-Jun amino-terminal kinase (JNK) phosphorylation in response to ELTD1 deletion. CONCLUSIONS: ELTD1 deficiency exacerbates cardiac hypertrophy and cardiac function induced by AB-induced pressure overload by promoting both cardiomyocyte hypertrophy and cardiac fibrosis. These effects are suggested to originate from the activation of the ERK and JNK pathways, suggesting that ELTD1 is a potential target for therapies that prevent the development of cardiac disease

A comprehensive 1000 Genomes-based genome-wide association meta-analysis of coronary artery disease

Existing knowledge of genetic variants affecting risk of coronary artery disease (CAD) is largely based on genome-wide association studies (GWAS) analysis of common SNPs. Leveraging phased haplotypes from the 1000 Genomes Project, we report a GWAS meta-analysis of 185 thousand CAD cases and controls, interrogating 6.7 million common (MAF>0.05) as well as 2.7 million low frequency (0.005<MAF<0.05) variants. In addition to confirmation of most known CAD loci, we identified 10 novel loci, eight additive and two recessive, that contain candidate genes that newly implicate biological processes in vessel walls. We observed intra-locus allelic heterogeneity but little evidence of low frequency variants with larger effects and no evidence of synthetic association. Our analysis provides a comprehensive survey of the fine genetic architecture of CAD showing that genetic susceptibility to this common disease is largely determined by common SNPs of small effect siz

Experimental mutation-accumulation on the X chromosome of Drosophila melanogaster reveals stronger selection on males than females

<p>Abstract</p> <p>Background</p> <p>Sex differences in the magnitude or direction of mutational effect may be important to a variety of population processes, shaping the mutation load and affecting the cost of sex itself. These differences are expected to be greatest after sexual maturity. Mutation-accumulation (MA) experiments provide the most direct way to examine the consequences of new mutations, but most studies have focused on juvenile viability without regard to sex, and on autosomes rather than sex chromosomes; both adult fitness and X-linkage have been little studied. We therefore investigated the effects of 50 generations of X-chromosome mutation accumulation on the fitness of males and females derived from an outbred population of <it>Drosophila melanogaster</it>.</p> <p>Results</p> <p>Fitness declined rapidly in both sexes as a result of MA, but adult males showed markedly greater fitness loss relative to their controls compared to females expressing identical genotypes, even when females were made homozygous for the X. We estimate that these mutations are partially additive (h ~ 0.3) in females. In addition, the majority of new mutations appear to harm both males and females.</p> <p>Conclusions</p> <p>Our data helps fill a gap in our understanding of the consequences of sexual selection for genetic load, and suggests that stronger selection on males may indeed purge deleterious mutations affecting female fitness.</p

A mouse model for Luminal epithelial like ER positive subtype of human breast cancer

<p>Abstract</p> <p>Background</p> <p>Generation of novel spontaneous ER positive mammary tumor animal model from heterozygous NIH nude mice.</p> <p>Methods</p> <p>Using brother-sister mating with pedigree expansion system, we derived a colony of heterozygous breeding females showing ER-Positive tumors around the age of 6 months. Complete blood picture, differential leukocyte count, and serum levels of Estrogen, Alanine amino transferase (SGPT), Aspartate amino transferase (SGOT), total protein and albumin were estimated. Aspiration biopsies and microbiology were carried out. Gross pathology of the tumors and their metastatic potential were assessed. The tumors were excised and further characterized using histopathology, cytology, electron microscopy (EM), molecular markers and Mouse mammary Tumor Virus – Long Terminal Repeats (MMTV LTR) specific RT-PCR.</p> <p>Results</p> <p>The tumors originated from 2^ndor 5^thor both the mammary glands and were multi-nodulated with variable central necrosis accompanied with an accumulation of inflammatory exudate. Significant increases in estrogen, SGPT, SGOT and neutrophils levels were noticed. Histopathologically, invasive nodular masses of pleomorphic tubular neoplastic epithelial cells invaded fibro-vascular stroma, adjacent dermis and subcutaneous tissue. Metastatic spread through hematogenous and regional lymph nodes, into liver, lungs, spleen, heart and dermal lymphatics was observed. EM picture revealed no viral particles and MMTV-negativity was confirmed through MMTV LTR-specific RT-PCR. High expression of ER α, moderate to high expression of proliferating cell nuclear antigen (PCNA), moderate expression of vimentin and Cytokeratin 19 (K19) and low expression of p53 were observed in tumor sections, when compared with that of the normal mammary gland.</p> <p>Conclusion</p> <p>Since 75% of human breast cancer were classified ER-positive and as our model mimics (in most of the characteristics, such as histopathology, metastasis, high estrogen levels) the ER-positive luminal epithelial-like human breast cancer, this model will be an attractive tool to understand the biology of estrogen-dependant breast cancer in women. To our knowledge, this is the first report of a spontaneous mammary model displaying regional lymph node involvement with both hematogenous and lymphatic spread to liver, lung, heart, spleen and lymph nodes.</p