Cutaneous metastases as the presenting feature of lung cancer.

Lung cancer is the second most common cancer diagnosed in men and women worldwide with the highest mortality. A rare site of metastases for lung cancer is the skin. Typically, the diagnosis is secure prior to developing cutaneous metastases. We present a case of a man in his mid-70s who presented to dermatology with cutaneous metastases. We outline the presentation, diagnostic workup and management of this case. We also review the literature of cutaneous metastases in lung cancer; highlighting the clinical need for a timely accurate diagnosis and the implication in terms of prognosis.

Explaining the variability in cardiovascular risk factors among First Nations communities in Canada: a population-based study.

BACKGROUND: Historical, colonial, and racist policies continue to influence the health of Indigenous people, and they continue to have higher rates of chronic diseases and reduced life expectancy compared with non-Indigenous people. We determined factors accounting for variations in cardiovascular risk factors among First Nations communities in Canada. METHODS: Men and women (n=1302) aged 18 years or older from eight First Nations communities participated in a population-based study. Questionnaires, physical measures, blood samples, MRI of preclinical vascular disease, and community audits were collected. In this cross-sectional analysis, the main outcome was the INTERHEART risk score, a measure of cardiovascular risk factor burden. A multivariable model was developed to explain the variations in INTERHEART risk score among communities. The secondary outcome was MRI-detected carotid wall volume, a measure of subclinical atherosclerosis. FINDINGS: The mean INTERHEART risk score of all communities was 17·2 (SE 0·2), and more than 85% of individuals had a risk score in the moderate to high risk range. Subclinical atherosclerosis increased significantly across risk score categories (p<0·0001). Socioeconomic advantage (-1·4 score, 95% CI -2·5 to -0·3; p=0·01), trust between neighbours (-0·7, -1·2 to -0·3; p=0·003), higher education level (-1·9, -2·9 to -0·8, p<0·001), and higher social support (-1·1, -2·0 to -0·2; p=0·02) were independently associated with a lower INTERHEART risk score; difficulty accessing routine health care (2·2, 0·3 to 4·1, p=0·02), taking prescription medication (3·5, 2·8 to 4·3; p<0·001), and inability to afford prescription medications (1·5, 0·5 to 2·6; p=0·003) were associated with a higher INTERHEART risk score. Collectively, these factors explained 28% variation in the cardiac risk score among communities. Communities with higher socioeconomic advantage and greater trust, and individuals with higher education and social support, had a lower INTERHEART risk score. Communities with difficulty accessing health care, and individuals taking or unable to afford prescription medications, had a higher INTERHEART risk score. INTERPRETATION: Cardiac risk factors are lower in communities with high socioeconomic advantage, greater trust, social support and educational opportunities, and higher where it is difficult to access health care or afford prescription medications. Strategies to optimise the protective factors and reduce barriers to health care in First Nations communities might contribute to improved health and wellbeing. FUNDING: Heart and Stroke Foundation of Canada, Canadian Partnership Against Cancer, Canadian Institutes for Health Research.

Short-term outcomes associated with drain use in shoulder arthroplasties: a prospective, randomized controlled trial.

BACKGROUND: This study examined the immediate outcomes during the perioperative period associated with drains in the setting of total shoulder arthroplasty or reverse shoulder arthroplasty. We hypothesized that drain use would result in lower postoperative hemoglobin and hematocrit levels that would increase transfusion rates and longer hospital stays that would increase hospital costs. METHODS: The study prospectively randomized 100 patients (55% women; average age, 69.3 years) who underwent total shoulder arthroplasty or reverse shoulder arthroplasty to receive a closed-suction drainage device (drain group, n = 50) or not (control group, n = 50) at the time of wound closure. Basic demographic information and intraoperative and postoperative data were collected. RESULTS: The groups were similar with respect to basic patient demographics. Postoperatively, drains had no effect on transfusion rates or any perioperative complication (P > .715). There were also no significant differences in hemoglobin or hematocrit levels immediately after surgery or on postoperative day 1. On average, patients were discharged from the hospital 1.6 days and 2.1 days postoperatively in the control and drain groups, respectively (P = .124). The average cost associated for the control cohort's hospital stay was $35,796 ± $13,078 compared with $43,219 ± $24,679 for the drain cohort (P = .063). DISCUSSION: Drain use after shoulder arthroplasty had no appreciable difference on short-term perioperative outcomes, postoperative anemia, length of hospital stay, or cost. It is possible that the potential negative effects of postoperative drainage are blunted by the routine use of tranexamic acid.

Canadian Alliance for Healthy Hearts and Minds: First Nations Cohort Study Rationale and Design.

BACKGROUND: This is the first national indigenous cohort study in which a common, in-depth protocol with a common set of objectives has been adopted by several indigenous communities across Canada. OBJECTIVES: The overarching objective of the Canadian Alliance for Healthy Hearts and Minds (CAHHM) cohort is to investigate how the community-level environment is associated with individual health behaviors and the presence and progression of chronic disease risk factors and chronic diseases such as cardiovascular disease (CVD) and cancer. METHODS: CAHHM aims to recruit approximately 2,000 First Nations indigenous individuals from up to nine communities across Canada and have participants complete questionnaires, blood collection, physical measurements, cognitive assessments, and magnetic resonance imaging (MRI). RESULTS: Through individual- and community-level data collection, we will develop an understanding of the specific role of the socioenvironmental, biological, and contextual factors have on the development of chronic disease risk factors and chronic diseases. CONCLUSIONS: Information collected in the indigenous cohort will be used to assist communities to develop local management strategies for chronic disease, and can be used collectively to understand the contextual, environmental, socioeconomic, and biological determinants of differences in health status in harmony with First Nations beliefs and reality.

Integrated genome and transcriptome sequencing identifies a noncoding mutation in the genome replication factor DONSON as the cause of microcephaly-micromelia syndrome.

While next-generation sequencing has accelerated the discovery of human disease genes, progress has been largely limited to the "low hanging fruit" of mutations with obvious exonic coding or canonical splice site impact. In contrast, the lack of high-throughput, unbiased approaches for functional assessment of most noncoding variants has bottlenecked gene discovery. We report the integration of transcriptome sequencing (RNA-seq), which surveys all mRNAs to reveal functional impacts of variants at the transcription level, into the gene discovery framework for a unique human disease, microcephaly-micromelia syndrome (MMS). MMS is an autosomal recessive condition described thus far in only a single First Nations population and causes intrauterine growth restriction, severe microcephaly, craniofacial anomalies, skeletal dysplasia, and neonatal lethality. Linkage analysis of affected families, including a very large pedigree, identified a single locus on Chromosome 21 linked to the disease (LOD > 9). Comprehensive genome sequencing did not reveal any pathogenic coding or canonical splicing mutations within the linkage region but identified several nonconserved noncoding variants. RNA-seq analysis detected aberrant splicing in DONSON due to one of these noncoding variants, showing a causative role for DONSON disruption in MMS. We show that DONSON is expressed in progenitor cells of embryonic human brain and other proliferating tissues, is co-expressed with components of the DNA replication machinery, and that Donson is essential for early embryonic development in mice as well, suggesting an essential conserved role for DONSON in the cell cycle. Our results demonstrate the utility of integrating transcriptomics into the study of human genetic disease when DNA sequencing alone is not sufficient to reveal the underlying pathogenic mutation.

The role of PKCζ in cord blood T-cell maturation towards Th1 cytokine profile and its epigenetic regulation by fish oil.

While immunodeficiency of immaturity of the neonate has been considered important as the basis for unusual susceptibility to infection, it has also been recognized that the ability to progress from an immature Th2 cytokine predominance to a Th1 profile has relevance in determining whether children will develop allergy, providing an opportunity for epigenetic regulation through environmental pressures. However, this notion remains relatively unexplored. Here, we present evidence that there are two major control points to explain the immunodeficiency in cord blood (CB) T-cells, a deficiency in interleukin (IL)-12 (IL-12) producing and IL-10 overproducing accessory cells, leading to a decreased interferon γ (IFNγ) synthesis and the other, an intrinsic defect in T-cell protein kinase C (PKC) ζ (PKCζ) expression. An important finding was that human CB T-cells rendered deficient in PKCζ, by shRNA knockdown, develop into low tumour necrosis factor α (TNFα) and IFNγ but increased IL-13 producing cells. Interestingly, we found that the increase in PKCζ levels in CB T-cells caused by prenatal supplementation with fish oil correlated with modifications of histone acetylation at the PKCζ gene (PRKCZ) promoter. The data demonstrate that PKCζ expression regulates the maturation of neonatal T-cells into specific functional phenotypes and that environmental influences may work via PKCζ to regulate these phenotypes and disease susceptibility.

Combined angiogenic and osteogenic factor delivery for bone regenerative engineering.

Both osteogenesis and angiogenesis are integrated parts of bone growth and regeneration. Combined delivery of osteogenic and angiogenic factors is a novel approach in bone regenerative engineering. Exogenous addition of mesenchymal stem cells (MSCs), vascular endothelial growth factor (VEGF) and bone morphogenetic proteins (BMPs) together with an osteoconductive scaffold is a very promising method to enhance bone repair. This concept has been incorporated into the development of new strategies for bone tissue engineering and significant advancements have been made in last 10 years. In contrary to previous belief that VEGF modulates bone repair only by enhancing angiogenesis in the proximity of bone injury, recent evidence also suggests that cross-talk between VEGF and BMP signaling pathways in MSCs promotes osteoblastic differentiation of MSCs which aids in fracture repair. Future studies should focus on cross-talk between angiogenesis and osteogenesis, optimization of VEGF/BMP ratios, selection of the most potent BMPs, and optimization of delivery methods for VEGF and BMP. Recent discoveries from basic research including effective delivery of growth factors and cells to the area of interest will help bring VEGF plus BMP for bone healing from the bench to the patient's bedside.

Osteogenic response of human adipose-derived stem cells to BMP-6, VEGF, and combined VEGF plus BMP-6 in vitro.

Exogenous addition of three factors-mesenchymal stem cells (MSCs), vascular endothelial growth factor (VEGF), and bone morphogenetic proteins (BMPs)-has proven to be more beneficial than delivery of any single factor for fracture repair in animal models. We studied the osteogenic differentiation of human adipose-derived stem cells (hADSCs) in the presence of VEGF, BMP-6, or VEGF plus BMP-6 to better understand their enhancement of osteoblastic differentiation of MSCs. The VEGF plus BMP-6 group demonstrated an additive effect on the enhancement of mineralization and expression of ALP and Msx2 genes. Unlike VEGF or BMP-6 alone, the combination of VEGF and BMP-6 significantly enhanced the expression of COL1A1, osterix, and Dlx5 genes. The data indicate that a cross-talk between VEGF and BMP-6 signaling pathways enhances osteogenic differentiation of hADSCs.

Hybrid repair of aortic arch aneurysm.

Hybrid repair of thoracic aortic aneurysm has been used with increasing frequency over the past decade, as indications for endovascular therapy have continued to expand. Hybrid techniques may avoid and limit the morbidity and mortality associated with sternotomy or thoracotomy, mechanical circulatory support, and hypothermic arrest. We present the case of a patient with extensive aortic aneurysmal disease initially needing open ascending aortic and subsequent thoracoabdominal repair. However, owing to continued enlargement of the aortic arch, hybrid extrathoracic, extra-anatomic complete aortic arch debranching and transcatheter endografting was ultimately pursued with favorable midterm results.

Bone marrow-derived MCP1 required for experimental aortic aneurysm formation and smooth muscle phenotypic modulation.

OBJECTIVES: This study tested the hypothesis that monocyte chemotactic protein 1 (MCP1) is required for abdominal aortic aneurysm (AAA) and smooth muscle phenotypic modulation in a mouse elastase perfusion model. METHODS: Infrarenal aortas of C57BL/6 (wild type [WT]) and MCP1 knockout (KO) mice were analyzed at 14 days after perfusion. Key cellular sources of MCP1 were identified using bone marrow transplantation. Cultured aortic smooth muscle cells (SMCs) were treated with MCP1 to assess its potential to directly regulate SMC contractile protein expression and matrix metalloproteinases (MMPs). RESULTS: Elastase perfused WT aortas had a mean dilation of 102% (n = 9) versus 53.7% for MCP1KO aortas (n = 9, P < .0001) and 56.3% for WT saline-perfused controls (n = 8). Cells positive for MMP9 and Mac-2 were nearly absent in the KO aortas. Complimentarily, the media of the KO vessels had abundant differentiated smooth muscle and intact elastic fibers and markedly less MMP2. Experiments in cultured SMCs showed MCP1 can directly repress smooth muscle markers and induce MMP2 and MMP9. Bone marrow transplantation studies showed that KO of MCP1 in bone marrow-derived cells protects from AAA formation. Moreover, KO in the bone was significantly more protective than global KO, suggesting an unexpected benefit to selectively depleting MCP1 in bone marrow-derived cells. CONCLUSIONS: These results have shown that MCP1 derived from bone marrow cells is required for experimental AAA formation and that retention of nonbone marrow MCP1 limits AAA compared with global depletion. This protein contributes to macrophage infiltration into the AAA and can act directly on SMCs to reduce contractile proteins and induce MMPs.

The impact of coronary artery endarterectomy on outcomes during coronary artery bypass grafting.

BACKGROUND: The impact of coronary artery endarterectomy during coronary artery bypass grafting (CABG) has been debated. We examined the early and late outcomes of CABG with endarterectomy (CE) compared to CABG alone. METHODS: Patients undergoing isolated CABG operations from 2003 to 2008 were retrospectively reviewed. We identified 99 patients who underwent CE and 3:1 propensity matched them to 297 CABG-alone patients based upon clinical factors: Society of Thoracic Surgeons (STS) predicted risk of mortality, age, gender, year of surgery, and ejection fraction. Patient risk factors as well as short- and long-term outcomes were compared by univariate and Kaplan-Meier analysis. RESULTS: Preoperative risk factors were similar between patients undergoing CE or CABG alone. Cross-clamp times (95.6 vs. 71.8 minutes, p = 0.0001) and perfusion times (121.8 vs. 92.7 minutes, p = 0.0001) were longer in patients undergoing CE. Operative mortality (4.0% vs. 1.3%, p = 0.112) and postoperative complications were not significantly different between groups. Patients undergoing coronary endarterectomy incurred longer ICU (75.06 vs. 48.64 hours, p = 0.001) and hospital stays (9.01 vs. 7.7 days, p = 0.034). Long-term mortality (mean follow-up = 27.7 ± 17.7 months) was equivalent despite revascularization technique (p = 0.13); however, patients undergoing CE encountered worse overall freedom from myocardial infarction (MI) (p = 0.03). CONCLUSION: Patients undergoing CABG with coronary CE required longer ventilatory support and ICU stay yet have comparable operative mortality, major complication rates, and long-term survival to isolated CABG. Coronary endarterectomy should be considered an acceptable adjunct to CABG for patients with extensive coronary artery disease to achieve complete revascularization.

Preoperative computed tomography is associated with lower risk of perioperative stroke in reoperative cardiac surgery.

Preoperative computed tomography (CT) use appears to be increasing among patients undergoing cardiac reoperations. We hypothesized that preoperative CT imaging reduces adverse outcomes and operative mortality for these patients. From July 2002 to February 2009, 373 patients underwent cardiac reoperations. Patients were stratified according to those with preoperative CT imaging (CT, n=140) and to those without preoperative CT imaging (NCT) (NCT, n=233). Preoperative risk, operative features, and postoperative outcomes were evaluated. Operative mortality for all cardiac reoperations was 7.5%. Patient risk factors were similar between CT and NCT groups. Preoperative imaging was more commonly performed for reoperative isolated valve operations (CT=70% vs. NCT=55.8%, P=0.01) but less commonly performed for reoperative isolated coronary artery bypass grafting (CABG) operations (14.3% vs. 22.7%, P=0.05). Postoperative renal failure, prolonged ventilation and operative mortality were similar between groups. Importantly, perioperative stroke occurred only within the NCT group (5.6% vs. 0.0%, P=0.003), and emergent operative status [odds ratio (OR): 6.45, confidence interval (CI): 1.15-36.10, P=0.03] as an independent multivariate predictor of perioperative stroke. Thus, preoperative CT imaging is associated with lower rates of perioperative stroke in patients undergoing cardiac reoperations by optimizing cannulation and aortic clamping strategies. Routine use of preoperative CT should be considered for patients undergoing cardiac operations following prior sternotomy.

Treatment of a malpositioned transcutaneous ventricular pacing lead in the left ventricle via direct aortic puncture.

An 81-year-old woman with progressive cough was hospitalized 2 weeks following transcutaneous pacemaker implantation. Imaging revealed an absent brachiocephalic vein and aberrant course of a ventricular lead into the aorta with implantation into the left ventricle. We describe the unusual anatomic course, diagnosis, and surgical extraction of a malpositioned pacer lead.

Novel action of n-3 polyunsaturated fatty acids: inhibition of arachidonic acid-induced increase in tumor necrosis factor receptor expression on neutrophils and a role for proteases.

OBJECTIVE: Neutrophils and tumor necrosis factor (TNF) play important roles in the pathogenesis of rheumatoid arthritis (RA). Modulation of TNF receptors (TNFRs) may contribute to the regulation of tissue damage, and n-6 polyunsaturated fatty acids (PUFAs) such as arachidonic acid (AA) can increase the expression of TNFRI and TNFRII on neutrophils. Because the n-3 PUFAs are antiinflammatory in RA, we examined whether, as a novel mechanism of action, n-3 PUFAs can antagonize the AA-induced increase in TNFR expression. METHODS: Human neutrophils were treated with PUFAs and examined for changes in surface expression of TNFRs by flow cytometry. Translocation of protein kinase C (PKC) and activation of ERK-1/2 MAPK were determined by Western blotting. Intracellular calcium mobilization was measured in Fura 2-loaded cells by luminescence spectrometry. RESULTS: Pretreatment of neutrophils with nanomolar levels of n-3 PUFAs, eicosapentaenoic acid, or docosahexaenoic acid led to a marked inhibition of the AA-induced up-regulation of TNFRs I and II. Such pretreatment, however, did not prevent AA from stimulating the activities of PKC and ERK-1/2, which is required for the actions of AA or its ability to mobilize Ca(2+). Nevertheless, treatment with n-3 PUFAs caused the stimulation of serine proteases that could cleave the TNFRs. CONCLUSION: These findings suggest a mechanism by which the n-3 PUFAs inhibit the inflammatory response in RA, by regulating the ability of AA to increase TNFR expression. These results help fill the gaps in our knowledge regarding the mechanisms of action of n-3 PUFAs, thus allowing us to make specific recommendations for the use of n-3 PUFAs in the regulation of inflammatory diseases.

Radionuclides and trace metals in Canadian moose near uranium mines: comparison of radiation doses and food chain transfer with cattle and caribou.

Tissues from 45 moose and 4 cattle were collected to assess the health of country foods near uranium mines in northern Saskatchewan. Bone, liver, kidney, muscle and rumen contents were analyzed for uranium, radium-226 (226Ra), lead-210 (210Pb), and polonium-210 (210Po). Cesium-137 (137Cs), potassium-40 (40K), and 27 trace metals were also measured in some tissues. Within the most active mining area, Po in liver and muscle declined significantly with distance from tailings, possibly influenced by nearby natural uranium outcrops. Moose from this area had significantly higher 226Ra, 210Pb, 210Po, and 137Cs in some edible soft tissues vs. one control area. However, soil type and diet may influence concentrations as much as uranium mining activities, given that a) liver levels of uranium, 226Ra, and 210Po were similar to a second positive control area with mineral-rich shale hills and b) 210Po was higher in cattle kidneys than in all moose. Enhanced food chain transfer from rumen contents to liver was found for selenium in the main mining area and for copper, molybdenum and cadmium in moose vs. cattle. Although radiological doses to moose in the main mining area were 2.6 times higher than doses to control moose or cattle, low moose intakes yielded low human doses (0.0068 mSv y(-1)), a mere 0.3% of the dose from intake of caribou (2.4 mSv y(-1)), the dietary staple in the area.

Comparative analysis of QTLs affecting plant height and flowering among closely-related diploid and polyploid genomes.

Quantitative trait loci (QTLs) affecting plant height and flowering were studied in the two Saccharum species from which modern sugarcane cultivars are derived. Two segregating populations derived from interspecific crosses between Saccharum officinarum and Saccharum spontaneum were genotyped with 735 DNA markers. Among the 65 significant associations found between these two traits and DNA markers, 35 of the loci were linked to sugarcane genetic maps and 30 were unlinked DNA markers. Twenty-one of the 35 mapped QTLs were clustered in eight genomic regions of six sugarcane homologous groups. Some of these could be divergent alleles at homologous loci, making the actual number of genes implicated in these traits much less than 35. Four QTL clusters controlling plant height in sugarcane corresponded closely to four of the six plant-height QTLs previously mapped in sorghum. One QTL controlling flowering in sugarcane corresponded to one of three flowering QTLs mapped in sorghum. The correspondence in locations of QTLs affecting plant height and flowering in sugarcane and sorghum reinforce the notion that the simple sorghum genome is a valuable "template" for molecular dissection of the much more complex sugarcane genome.