Higher Volume at Time of Breast Conserving Surgery Reduces Re-Excision in DCIS

Purpose. The purpose of this study was to compare the surgical and pathological variables which impact rate of re-excision following breast conserving therapy (BCS) with or without concurrent additional margin excision (AM). Methods. The pathology database was queried for all patients with DCIS from January 2004 to September 2008. Pathologic assessment included volume of excision, subtype, size, distance from margin, grade, necrosis, multifocality, calcifications, and ER/PR status. Results. 405 cases were identified and 201 underwent BCS, 151-BCS-AM, and 53-mastectomy. Among the 201 BCS patients, 190 underwent re-excision for close or involved margins. 129 of these were treated with BCS and 61 with BCS-AM (P < .0001). The incidence of residual DCIS in the re-excision specimens was 32% (n = 65) for BCS and 22% (n = 33) for BCS-AM (P < .05). For both the BCS and the BCS-AM cohorts, volume of tissue excised is inversely correlated to the rate of re-excision (P = .0284). Multifocality (P = .0002) and ER status (P = .0382) were also significant predictors for rate of re-excision and variation in surgical technique was insignificant. Conclusions. The rate of positive margins, re-excision, and residual disease was significantly higher in patients with lower volume of excision. The performance of concurrent additional margin excision increases the efficacy of BCS for DCIS

Histiocytoid cardiomyopathy and microphthalmia with linear skin defects syndrome: phenotypes linked by truncating variants in NDUFB11

Variants in NDUFB11, which encodes a structural component of complex I of the mitochondrial respiratory chain (MRC), were recently independently reported to cause histiocytoid cardiomyopathy (histiocytoid CM) and microphthalmia with linear skin defects syndrome (MLS syndrome). Here we report an additional case of histiocytoid CM, which carries a de novo nonsense variant in NDUFB11 (ENST00000276062.8: c.262C > T; p.[Arg88*]) identified using whole-exome sequencing (WES) of a family trio. An identical variant has been previously reported in association with MLS syndrome. The case we describe here lacked the diagnostic features of MLS syndrome, but a detailed clinical comparison of the two cases revealed significant phenotypic overlap. Heterozygous variants in HCCS (which encodes an important mitochondrially targeted protein) and COX7B, which, like NDUFB11, encodes a protein of the MRC, have also previously been identified in MLS syndrome including a case with features of both MLS syndrome and histiocytoid CM. However, a systematic review of WES data from previously published histiocytoid CM cases, alongside four additional cases presented here for the first time, did not identify any variants in these genes. We conclude that NDUFB11 variants play a role in the pathogenesis of both histiocytoid CM and MLS and that these disorders are allelic (genetically related)

Characterization of the Poly-T Variant in the TOMM40 Gene in Diverse Populations

We previously discovered that a polymorphic, deoxythymidine-homopolymer (poly-T, rs10524523) in intron 6 of the TOMM40 gene is associated with age-of-onset of Alzheimer's disease and with cognitive performance in elderly. Three allele groups were defined for rs10524523, hereafter ‘523’, based on the number of ‘T’-residues: ‘Short’ (S, T≤19), ‘Long’ (L, 20≤T≤29) and ‘Very Long’ (VL, T≥30). Homopolymers, particularly long homopolymers like ‘523’, are difficult to genotype because ‘slippage’ occurs during PCR-amplification. We initially genotyped this locus by PCR-amplification followed by Sanger-sequencing. However, we recognized the need to develop a higher-throughput genotyping method that is also accurate and reliable. Here we describe a new ‘523’ genotyping assay that is simple and inexpensive to perform in a standard molecular genetics laboratory. The assay is based on the detection of differences in PCR-fragment length using capillary electrophoresis. We discuss technical problems, solutions, and the steps taken for validation. We employed the novel assay to investigate the ‘523’ allele frequencies in different ethnicities. Whites and Hispanics have similar frequencies of S/L/VL alleles (0.45/0.11/0.44 and 0.43/0.09/0.48, respectively). In African-Americans, the frequency of the L-allele (0.10) is similar to Whites and Hispanics; however, the S-allele is more prevalent (0.65) and the VL-allele is concomitantly less frequent (0.25). The allele frequencies determined using the new methodology are compared to previous reports for Ghanaian, Japanese, Korean and Han Chinese cohorts. Finally, we studied the linkage pattern between TOMM40-‘523’ and APOE alleles. In Whites and Hispanics, consistent with previous reports, the L is primarily linked to ε4, while the majority of the VL and S are linked to ε3. Interestingly, in African-Americans, Ghanaians and Japanese, there is an increased frequency of the ‘523’S-APOEε4 haplotype. These data may be used as references for ‘523’ allele and ‘523’-APOE haplotype frequencies in diverse populations for the design of research studies and clinical trials

Risk in CNS drug discovery: focus on treatment of Alzheimer's Disease

Despite rapid progress in our understanding of disease mechanisms and an exploding list of new targets for therapeutic intervention, drug discovery and development remains a highly risky business. Understanding the risk involved requires appreciation of the differing perspectives of risk held by the various stakeholders involved in drug research. Risk can be reduced by thoughtful management of drug candidate selection, careful planning and program execution by a team of engaged experts, and disciplined decision making. Drug development is particularly challenging for treatments of neurodegenerative diseases such as Alzheimer's disease, in which translation from animal models of efficacy to human success is poor or unknown, the timelines for clinical study are long, and the markers of efficacy are still evolving. Despite this there are several therapies in clinical development that hold the promise of influencing this disease through novel and possibly synergistic mechanisms

The Next WHO Director-General’s Highest Priority: a Global Treaty on the Human Right to Health

Amidst the many challenges facing the next WHO Director-General, the new WHO head should find WHO’s foremost priority in its most important constitutional pillar: the right to health. The centerpiece of this endeavor should be leadership on the Framework Convention on Global Health (FCGH), the proposed global treaty based in the right to health and aimed at national and global health equity. The treaty would reform global governance for health to enhance accountability, transparency, and civil society participation and protect the right to health in trade, investment, climate change, and other international regimes, while catalyzing governments to institutionalize the right to health at community through to national levels. It would usher in a new era of global health with justice – vast improvements in health outcomes, equitably distributed. With the Framework Convention on Tobacco Control having served as a proof of concept, the FCGH would be an innovative treaty finding solutions to overcome global health failings in accountability, equality, financing, and inter-sectoral coherence. It would include a global health accountability framework, encompassing, civil society engagement, independent monitoring, and plans for redress, while catalyzing national health accountability strategies, accountability mechanisms, disaggregated data, and community participation. National health equity strategies, pro-poor pathways to universal health coverage, and robust non-discrimination provisions could elevate the voices, priorities, and ultimately power of marginalized populations. The FCGH would include a national and global health financing framework, while reaching beyond the health sector with right to health assessments, public health participation in developing international agreements, and responsibility for all sectors for improving health outcomes. The FCGH would reinvigorate WHO’s global health leadership, breathing new life into its founding principles. It could become the platform for reforming WHO as a rights-based 21st century institution, with badly-needed reforms, such as community participation, new priorities favouring social determinants of health, and a culture of transparency and accountability. The next Director-General should launch a historic effort to align national and global governance for with human rights through the FCGH, bringing the world closer to global health with justice

The Fukushima nuclear power plant accident. An analysis of the most relevant frames in the Spanish press

The accident at the Fukushima nuclear power plant in Japan on 11 March 2011 unleashed an environmental, economic, political and humanitarian crisis whose effects are still felt today. This study analyses press coverage of the incident by three Spanish daily newspapers, Abc, El País and La Vanguardia, to determine the prevalent frames in the news articles on the disaster. Content analysis based on the stories published between March and May 2011 suggests that the most ubiquitous frames were human interest, economic consequences, political conflict, damage and environmental risks.El accidente de la central nuclear de Fukushima (Japón), producido el 11 de marzo de 2011, desencadenó una crisis medioambiental, económica, política y humanitaria cuyos efectos todavía perduran. En este trabajo se aborda la cobertura del suceso por parte de los diarios españoles Abc, El País y La Vanguardia, con el propósito de determinar los frames predominantes en los textos informativos e interpretativos asociados a él. Del análisis de contenido aplicado a las piezas publicadas por las tres cabeceras entre marzo y mayo de 2011, emergen cinco enfoques: interés humano, consecuencias económicas, conflicto político, daños y riesgos medioambientales

Prevention, control, and elimination of neglected diseases in the Americas: Pathways to integrated, inter-programmatic, inter-sectoral action for health and development

BACKGROUND: In the Latin America and Caribbean region over 210 million people live below the poverty line. These impoverished and marginalized populations are heavily burdened with neglected communicable diseases. These diseases continue to enact a toll, not only on families and communities, but on the economically constrained countries themselves. DISCUSSION: As national public health priorities, neglected communicable diseases typically maintain a low profile and are often left out when public health agendas are formulated. While many of the neglected diseases do not directly cause high rates of mortality, they contribute to an enormous rate of morbidity and a drastic reduction in income for the most poverty-stricken families and communities. The persistence of this "vicious cycle" between poverty and poor health demonstrates the importance of linking the activities of the health sector with those of other sectors such as education, housing, water and sanitation, labor, public works, transportation, agriculture, industry, and economic development. SUMMARY: The purpose of this paper is three fold. First, it focuses on a need for integrated "pro-poor" approaches and policies to be developed in order to more adequately address the multi-faceted nature of neglected diseases. This represents a move away from traditional disease-centered approaches to a holistic approach that looks at the overarching causes and mechanisms that influence the health and well being of communities. The second objective of the paper outlines the need for a specific strategy for addressing these diseases and offers several programmatic entry points in the context of broad public health measures involving multiple sectors. Finally, the paper presents several current Pan American Health Organization and other institutional initiatives that already document the importance of integrated, inter-programmatic, and inter-sectoral approaches. They provide the framework for a renewed effort toward the efficient use of resources and the development of a comprehensive integrated solution to neglected communicable diseases found in the context of poverty, and tailored to the needs of local communities

A Decade of Change: An Institutional Experience with Breast Surgery in 1995 and 2005

Introduction: With the adoption of routine screening mammography, breast cancers are being diagnosed at earlier stages, with DCIS now accouting for 22.5% of all newly diagnosed breast cancers. This has been attributed to both increased breast cancer awareness and improvements in breast imaging techniques. How have these changes, including the increased use of image-guided sampling techniques, influenced the clinical practice of breast surgery?Methods: The institutional pathology database was queried for all breast surgeries, including breast reconstruction, performed in 1995 and 2005. Cosmetic procedures were excluded. The results were analysed utilizing the Chi-square test.Results: Surgical indications changed during 10-year study period, with an increase in preoperatively diagnosed cancers undergoing definitive surgical management. ADH, and to a lesser extent, ALH, became indications for surgical excision. Fewer surgical biopsies were performed for indeterminate abnormalities on breast imaging, due to the introduction of stereotactic large core biopsy. While the rate of benign breast biopsies remained constant, there was a higher percentage of precancerous and DCIS cases in 2005. The overall rate of mastectomy decreased from 36.8% in 1995 to 14.5% in 2005. With the increase in sentinel node procedures, the rate of ALND dropped from 18.3% to 13.7%. Accompanying the increased recognition of early-stage cancers, the rate of positive ALND also decreased, from 43.3% to 25.0%.Conclusions: While the rate of benign breast biopsies has remained constant over a recent 10-year period, fewer diagnostic surgical image-guided biopsies were performed in 2005. A greater percentage of patients with breast cancer or preinvasive disease have these diagnoses determined before surgery. More preinvasive and Stage 0 cancers are undergoing surgical management. Earlier stage invasive cancers are being detected, reflected by the lower incidence of axillary nodal metastases

Disease-modifying effects of an SCAF4 structural variant in a predominantly SOD1 ALS cohort

Objective To test the hypothesis that rs573116164 will have disease-modifying effects in patients with superoxide dismutase 1 (SOD1) familial amyotrophic lateral sclerosis (fALS), we characterized rs573116164 within a cohort of 190 patients with fALS and 560 healthy age-matched controls to assess the variant for association with various measures of disease. Methods Using a previously described bioinformatics evaluation algorithm, a polymorphic short structural variant associated with SOD1 was identified according to its theoretical effect on gene expression. An 12–18 poly-T repeat (rs573116164) within the 3′ untranslated region of serine and arginine rich proteins-related carboxy terminal domain associated factor 4 (SCAF4), a gene that is adjacent to SOD1, was assessed for disease association and influence on survival and age at onset in an fALS cohort using PCR, Sanger sequencing, and capillary separation techniques for allele detection. Results In a North American cohort of predominantly SOD1 fALS patients (n =190) and age-matched healthy controls (n = 560), we showed that carriage of an 18T SCAF4 allele was associated with disease within this cohort (odds ratio [OR] 6.6; 95% confidence interval [CI] 3.9–11.2; p = 4.0e-11), but also within non-SOD1 cases (n = 27; OR 5.3; 95% CI 1.9–14.5; p = 0.0014). This finding suggests genetically SOD1-independent effects of SCAF4 on fALS susceptibility. Furthermore, carriage of an 18T allele was associated with a 26-month reduction in survival time (95% CI 6.6–40.8; p = 0.014), but did not affect age at onset of disease. Conclusions The findings in this fALS cohort suggest that rs573116164 could have SOD1-independent and broader relevance in ALS, warranting further investigation in other fALS and sporadic ALS cohorts, as well as studies of functional effects of the 18T variant on gene expression