Lymphatic vessels in bone support regeneration after injury.

Blood and lymphatic vessels form a versatile transport network and provide inductive signals to regulate tissue-specific functions. Blood vessels in bone regulate osteogenesis and hematopoiesis, but current dogma suggests that bone lacks lymphatic vessels. Here, by combining high-resolution light-sheet imaging and cell-specific mouse genetics, we demonstrate presence of lymphatic vessels in mouse and human bones. We find that lymphatic vessels in bone expand during genotoxic stress. VEGF-C/VEGFR-3 signaling and genotoxic stress-induced IL6 drive lymphangiogenesis in bones. During lymphangiogenesis, secretion of CXCL12 from proliferating lymphatic endothelial cells is critical for hematopoietic and bone regeneration. Moreover, lymphangiocrine CXCL12 triggers expansion of mature Myh11+ CXCR4+ pericytes, which differentiate into bone cells and contribute to bone and hematopoietic regeneration. In aged animals, such expansion of lymphatic vessels and Myh11-positive cells in response to genotoxic stress is impaired. These data suggest lymphangiogenesis as a therapeutic avenue to stimulate hematopoietic and bone regeneration.

Fundamentals of bone vasculature: Specialization, interactions and functions.

Angiogenesis, hematopoiesis and osteogenesis are fundamental processes mediating complex and essential biological functions. In the bone marrow, endothelial cells (ECs) are a principal mediator of regulatory signals that govern hematopoietic and mesenchymal stem cells. EC and osteoblast interactions and niche functions of ECs are fundamental in maintaining bone health and coordinating repair and regeneration following injury. These cellular interactions are subject to dysregulation and deterioration under stress, aging, chronic disease states and malignancy. Thus, the prospect of manipulating the bone vasculature has tremendous potential to advance therapeutic interventions for the management of bone diseases. This review discusses the current state of vascular-skeletal tissue interactions focusing on osteoblast and hematopoietic stem cells interaction with ECs.

Age-related changes in the local milieu of inflamed tissues cause aberrant neutrophil trafficking and subsequent remote organ damage.

Aging is associated with dysregulated immune functions. Here, we investigated the impact of age on neutrophil diapedesis. Using confocal intravital microscopy, we found that in aged mice, neutrophils adhered to vascular endothelium in inflamed tissues but exhibited a high frequency of reverse transendothelial migration (rTEM). This retrograde breaching of the endothelium by neutrophils was governed by enhanced production of the chemokine CXCL1 from mast cells that localized at endothelial cell (EC) junctions. Increased EC expression of the atypical chemokine receptor 1 (ACKR1) supported this pro-inflammatory milieu in aged venules. Accumulation of CXCL1 caused desensitization of the chemokine receptor CXCR2 on neutrophils and loss of neutrophil directional motility within EC junctions. Fluorescent tracking revealed that in aged mice, neutrophils undergoing rTEM re-entered the circulation and disseminated to the lungs where they caused vascular leakage. Thus, neutrophils stemming from a local inflammatory site contribute to remote organ damage, with implication to the dysregulated systemic inflammation associated with aging.

Local microvascular leakage promotes trafficking of activated neutrophils to remote organs.

Increased microvascular permeability to plasma proteins and neutrophil emigration are hallmarks of innate immunity and key features of numerous inflammatory disorders. Although neutrophils can promote microvascular leakage, the impact of vascular permeability on neutrophil trafficking is unknown. Here, through the application of confocal intravital microscopy, we report that vascular permeability-enhancing stimuli caused a significant frequency of neutrophil reverse transendothelial cell migration (rTEM). Furthermore, mice with a selective defect in microvascular permeability enhancement (VEC-Y685F-ki) showed reduced incidence of neutrophil rTEM. Mechanistically, elevated vascular leakage promoted movement of interstitial chemokines into the bloodstream, a response that supported abluminal-to-luminal neutrophil TEM. Through development of an in vivo cell labeling method we provide direct evidence for the systemic dissemination of rTEM neutrophils, and showed them to exhibit an activated phenotype and be capable of trafficking to the lungs where their presence was aligned with regions of vascular injury. Collectively, we demonstrate that increased microvascular leakage reverses the localization of directional cues across venular walls, thus causing neutrophils engaged in diapedesis to reenter the systemic circulation. This cascade of events offers a mechanism to explain how local tissue inflammation and vascular permeability can induce downstream pathological effects in remote organs, most notably in the lungs.

Can health equity coexist with housing inequalities? A contemporary issue in historical context.

The housing policies established by the Federal Home Loan Bank Board, Federal Housing Administration, and the Veterans Administration transformed the American housing market. However, these policies intentionally excluded communities of color from the postwar American housing boom by defining them as contaminants eroding national property values. Hence, racially restrictive federal housing policies established an inequitable generational trajectory for residents in communities across the United States. Public health practitioners are faced with the monumental challenge of addressing health disparities that were in part created by non-public health policies. The purpose of this article is to examine how federal housing policies historically contributed to creating the built environment and therefore establishing a foundation for health disparities. These pervasive, exclusionary policies and the generational stigma associated with this issue raise serious questions about the ethics of contemporary policies, practices, and research aimed at achieving health equity.

Breaking the habit: a qualitative exploration of barriers and facilitators to smoking cessation in people with enduring mental health problems.

BACKGROUND: Smoking in people with mental health problems (MHPs) is an important public health concern as rates are two to three times higher than in the general population. While a strong evidence base exists to encourage and support smoking cessation in the wider population, there is limited evidence to guide the tailoring of interventions for people with MHPs, including minimal understanding of their needs. This paper presents findings from theoretically-driven formative research which explored the barriers and facilitators to smoking cessation in people with MHPs. The aim, guided by the MRC Framework for the development and evaluation of complex interventions, was to gather evidence to inform the design and content of smoking cessation interventions for this client group. METHODS: Following a review of the empirical and theoretical literature, and taking a critical realist perspective, a qualitative approach was used to gather data from key stakeholders, including people with enduring MHPs (n = 27) and professionals who have regular contact with this client group (n = 54). RESULTS: There was a strong social norm for smoking in participants with MHPs and most were heavily addicted to nicotine. They acknowledged that their physical health would improve if they stopped smoking and their disposable income would increase; however, more important was the expectation that, if they attempted to stop smoking, their anxiety levels would increase, they would lose an important coping resource, they would have given up something they found pleasurable and, most importantly, their mental health would deteriorate. Barriers to smoking cessation therefore outweighed potential facilitators and, as a consequence, impacted negatively on levels of motivation and self-efficacy. The potential for professionals to encourage cessation attempts was apparent; however, they often failed to raise the issue of smoking/cessation as they believed it would damage their relationship with clients. The professionals' own smoking status also appeared to influence their health promoting role. CONCLUSIONS: Many opportunities to encourage and support smoking cessation in people with MHPs are currently missed. The increased understanding provided by our study findings and literature review have been used to shape recommendations for the content of tailored smoking cessation interventions for this client group.

Secondary prevention of stroke and transient ischaemic attack.

Transient ischaemic attack (TIA) and stroke are clinical syndromes characterised by acute neurological deficits with vascular causes. People experiencing TIA or a first stroke are at significant risk of subsequent stroke. Risk factors have been identified and include factors associated with lifestyle such as tobacco use, diet, obesity, alcohol consumption, physical activity and stress. Targeted therapeutic interventions have the potential to reduce the burden of stroke substantially. The aim of this article is to provide an overview of the evidence relating to lifestyle risk factors for stroke. Health promotion theories and intervention techniques that nurses can use to address lifestyle behaviour change following stroke will also be discussed.

Diabetes risk, low fitness, and energy insufficiency levels among children from poor families.

BACKGROUND: Low-income populations have higher rates of type 2 diabetes and it is the hope of the investigators to increase support for the dissemination of evidence-based prevention programs aimed at children from poor families. OBJECTIVE: To determine the prevalence of high blood glucose, obesity, low fitness, and energy insufficiency levels among children from poor families. DESIGN: The cross-sectional study conducted in fall 2001 used fasting capillary glucose, body mass index, body fat, step test, and three 24-hour dietary recalls to assess diabetes risk factor levels. SUBJECTS: Participants were 1,402 fourth-grade students aged 8 to 10 years. The racial/ethnic backgrounds were 80% Mexican American, 10% African American, 5% Asian American, and 5% non-Hispanic white. STATISTICAL ANALYSIS PERFORMED: All data were analyzed for descriptive statistics and frequencies of distribution. Means were computed by sex for all diabetes risk factors and t test conducted to determine differences between sexes. RESULTS: Nearly 75% of participants lived in households with

Factors predicting anaphylaxis to peanuts and tree nuts in patients referred to a specialist center.

BACKGROUND: Although acute allergic reactions after ingestion of peanuts and tree nuts are common, fatalities are rare. Other than patients with coexisting asthma, it is currently not possible to predict which patients are most likely to develop severe reactions. OBJECTIVE: The aim of this study was to determine which clinical and laboratory parameters best predict the likelihood of severe allergic reactions. METHODS: From 1992 to 2004, we collected detailed information on the clinical severity and allergy test results of 1094 patients with peanut and tree nut allergy attending a regional allergy center. In a subgroup of 122 patients, sera were assayed for activity of enzymes involved in the catabolism of bradykinin. RESULTS: Severe pharyngeal edema was 3.8 (2.1-6.9) times more common in patients with severe rhinitis and 2.6 (1.8-3.7) more common after ingestion of tree nuts compared with peanuts. Patients with serum angiotensin-converting enzyme concentrations <37.0 mmol/L had a 9.6 (1.6-57)-fold risk of severe pharyngeal edema. Life-threatening bronchospasm was most likely in patients with severe asthma (relative risk, 6.8 [4.1-11.3]) and less so in patients with milder asthma (2.7 [1.7-4.0]). Altered levels of consciousness were more likely in patients with severe eczema (3.1 [1.1-8.4]). CONCLUSION: Severity of coexisting atopic diseases predicted which patients attending a tertiary referral clinic were most likely to develop life-threatening allergic reactions to peanuts and tree nuts. Patients with the lowest serum angiotensin-converting enzyme concentrations were more likely to develop life-threatening pharyngeal edema, suggesting that this complication may be partly mediated by bradykinin.