Imaging VEGF Receptors and α<Subscript>v</Subscript>β<Subscript>3</Subscript> Integrins in a Mouse Hindlimb Ischemia Model of Peripheral Arterial Disease

Purpose

To compare targeted imaging of vascular endothelial growth factor (VEGF) receptors vs. α_vβ₃ integrins in a mouse hindlimb ischemia model of peripheral artery disease.

Procedures

Male wild-type (WT) C57BL/6 mice (8- to 10-week old) (n?=?24) underwent left femoral artery ligation. The right leg served as control. Five days later, mice were injected with either VEGF receptor targeting [^99mTc]DOTA-PEG-scVEGF ([^99mTc]scV) (n?=?8) or with α_vβ₃-targeting tracer [^99mTc]HYNIC-cycloRGD ([^99mTc]RGD) (n?=?8) and underwent single photon emission computed tomography (SPECT) x-ray computed tomography imaging. To assess non-specific [^99mTc]scV uptake, six additional mice received a mixture of [^99mTc]scV and 30-fold excess of targeting protein, scVEGF. Tracer uptake as %ID was measured using volumetric regions encompassing the hindlimb muscles and as %ID/g from harvested limb muscles. Double and triple immunofluorescent analysis on tissue sections established localization of α_vβ₃, VEGFR-1, VEGFR-2, as well as certain cell lineage markers.

Results

Tracer uptake, as %ID/g, was higher in ligated limbs of mice injected with [^99mTc]scV compared to ligated hindlimbs in mice injected with [^99mTc]RGD (p?=?0.02). The ratio of tracer uptake for ligated/control hindlimb was borderline higher for [^99mTc]scV than for [^99mTc]RGD (p?=?0.06). Immunofluorescent analysis showed higher prevalence of VEGFR-1, VEGFR-2, and α_vβ₃, in damaged vs. undamaged hindlimb tissue, but with little co-localization of these markers. Double immunofluorescent staining showed partial co-localization of VEGFR-1, VEGFR-2, and α_vβ_3, with endothelial cell marker FVIII, but not with CD31. Immunostaining for VEGFR-1 and VEGFR-2 additionally co-localized with lineage markers for endothelial progenitor cell and monocytes/macrophages, with a more diverse pattern of co-localization for VEGFR-2.

Conclusion

In a mouse hindlimb ischemia model of peripheral artery disease, [^99mTc]scV SPECT tracer-targeting VEGF receptors showed a more robust signal than [^99mTc]RGD tracer-targeting α_vβ₃. Immunofluorescent analysis suggests that uptake of [^99mTc]scV and [^99mTc]RGD in damaged tissue is due to non-overlapping cell populations and reflects different dynamic processes and that enhanced uptake of [^99mTc]scV may be due to the presence of VEGF receptors on additional cell types.

     

Cadazolid: A new hope in the treatment of Clostridium difficile infection

Clostridium difficile infection (CDI) is a potential life-threatening consequence of antibiotic therapy. Although the risk increases with duration of treatment, it can also occur after a short treatment course. In addition to broad-spectrum antibiotics, anti-neoplastic agents, proton pump inhibitors, H² blockers, and several other drugs have been reported to induce intestinal dysbiosis, which is central to the pathogenesis of CDI. There is an increase in incidence and mortality attributed to CDI globally. Moreover, the epidemiology of C. difficile-associated diseases has changed significantly with an increasing occurrence of community-acquired CDI. Metronidazole and oral vancomycin are the first-line antibiotics used to treat CDI. However, metronidazole has limited effectiveness in severe cases and vancomycin use is associated with increasing risk of vancomycin resistance among Enterococcus spp. Cadazolid, a novel oxazolidinone antibiotic, has recently shown potent antimicrobial activity against C. difficile and has a lower propensity to induce resistance. The implications of its use in treating CDI have been reviewed based on current evidence.     

Community Factors and Hospital Readmission Rates

Objective

To examine the relationship between community factors and hospital readmission rates.

Data Sources/Study Setting

We examined all hospitals with publicly reported 30-day readmission rates for patients discharged during July 1, 2007, to June 30, 2010, with acute myocardial infarction (AMI), heart failure (HF), or pneumonia (PN). We linked these to publicly available county data from the Area Resource File, the Census, Nursing Home Compare, and the Neilsen PopFacts datasets.

Study Design

We used hierarchical linear models to assess the effect of county demographic, access to care, and nursing home quality characteristics on the pooled 30-day risk-standardized readmission rate.

Data Collection/Extraction Methods

Not applicable.

Principal Findings

The study sample included 4,073 hospitals. Fifty-eight percent of national variation in hospital readmission rates was explained by the county in which the hospital was located. In multivariable analysis, a number of county characteristics were found to be independently associated with higher readmission rates, the strongest associations being for measures of access to care. These county characteristics explained almost half of the total variation across counties.

Conclusions

Community factors, as measured by county characteristics, explain a substantial amount of variation in hospital readmission rates.     

Household Crowding and Food Insecurity Among Inuit Families With School-Aged Children in the Canadian Arctic

Objectives. We examined the relation of household crowding to food insecurity among Inuit families with school-aged children in Arctic Quebec.Methods. We analyzed data collected between October 2005 and February 2010 from 292 primary caregiver–child dyads from 14 Inuit communities. We collected information about household conditions, food security, and family socioeconomic characteristics by interviews. We used logistic regression models to examine the association between household crowding and food insecurity.Results. Nearly 62% of Inuit families in the Canadian Arctic resided in more crowded households, placing them at risk for food insecurity. About 27% of the families reported reducing the size of their children’s meals because of lack of money. The likelihood of reducing the size of children’s meals was greater in crowded households (odds ratio = 3.73; 95% confidence interval = 1.96, 7.12). After we adjusted for different socioeconomic characteristics, results remained statistically significant.Conclusions. Interventions operating across different levels (community, regional, national) are needed to ensure food security in the region. Targeting families living in crowded conditions as part of social and public health policies aiming to reduce food insecurity in the Arctic could be beneficial.Inadequate housing conditions (e.g., crowding and structural damage) are prevalent among First Nations and Inuit communities in Canada and elsewhere.1 In Nunavik, the Inuit homeland in Arctic Quebec, Canada, the government promoted the relocation of many Inuit families to fledgling communities during the 1950s. Relocated families were moved to small, poorly heated and insulated accommodations. Since then, different programs have been designed by the federal, provincial, territorial, and regional governments to address the housing problem in Nunavik and across the Canadian Arctic.2 At present, more than 90% of the Nunavik population has reported living in social (subsidized) housing.3 In this region, social housing units are allocated locally through a point-based system set according to specific criteria, so that applicants most in need are given first priority (e.g., families with lower income, with young children, and living in overcrowded dwellings).2 Rent is set according to household income, while also considering the cost of living.4 Thus, in Nunavik, housing tenure does not differentiate between households on the basis of financial security or income level, given that nearly all of the population resides in social housing. Such organization rather highlights the high degree of financial need throughout this population and a limited private residential market unattainable by most of the population.Household overcrowding, generally defined as more than 1 person per room,5 is particularly problematic in Nunavik. According to Statistics Canada, 49% of the 2006 population lived in overcrowded houses.5 Often, overcrowding is approached as a consequence of economic difficulties. Living in smaller homes or in shared accommodation has been known as a way to lower living costs to dedicate the available financial resources to other basic necessities.6 In such situations, overcrowded households may experience higher food insecurity as a result of a precarious economic situation. In the particular case of Nunavik, however, crowding is a direct consequence of an underlying, and persistent, lack of housing. Household crowding in Nunavik is not only a product of financial difficulties but also an effect of the rapidly growing and young population. Between 2001 and 2006, the population in Nunavik increased by 12% compared with 4% for the province of Quebec. During the past 3 decades, the population has doubled from 5860 in 1986 to 12 090 in 2011.7 In 2008, it was estimated that more than 900 new housing units were needed, but only 239 units were constructed.8 The housing backlog is further compounded by high costs of construction and short building seasons.The housing situation in Nunavik and throughout the Canadian Arctic raises concerns, in terms of both public health and the health of each individual resident, especially that of children.9–14 Indeed, studies have shown that household crowding is associated with poorer respiratory health, especially among children.12,15 In crowded dwellings, the lack of privacy and the difficulty of withdrawing from (unwanted) social interactions may limit the ability of controlling one’s home situation and lead to “overarousal.”16 Household crowding also has been identified as eliciting chronic stress responses in adults,17 anger and depression18 with possible repercussions on behaviors,19–22 withdrawal,23 and reduced social support24 that, we contend, could influence household food insecurity.Food insecurity occurs when it is not possible to obtain safe, sufficient, and nutritiously adequate foods for a healthy life in socially and culturally acceptable ways.25–27 Studies have shown that in a situation of food insecurity, adults generally first reduce their own food consumption. As the situation becomes more severe, children’s diets also will be reduced, particularly in low-income households with single mothers.28,29 In 2012, 14% of the households in Canada experienced food insecurity.30 In Canadian Arctic communities, food insecurity is high: 62.2% and 31.6% of children live in food-insecure households in Nunavut and Northwest Territories, respectively.30 In Nunavik, the proportion of Inuit children experiencing food insecurity reached 30% in 2006.31 Studies emphasize that a reduction of the quality in diet and nutrient intake resulting from food insecurity is linked to various health issues in children, including poor health,25,32–34 developmental delays,35 and poor mental health.36Access to food products supplied from southern regions of Quebec comes at a very high cost to Nunavik, with an average price 57% higher than in the provincial capital.37 Despite efforts to redress this situation, food costs remain very high and often inaccessible to many Nunavik families who must resort to reducing the amount of food supplies or buying products of lower nutritional quality,38 which compromises health and well-being.36,37,39In a study conducted among low-income families in the United States, Cutts et al.40 found a higher risk of food insecurity and child food insecurity in households with higher housing insecurity. In their study, crowding and multiple moves were considered as indicators of housing insecurity. This association was independent of maternal and family characteristics such as education and household employment. In a recent study involving Inuit households from Nunavut, in the eastern Canadian Arctic, Huet et al.41 reported higher food insecurity among Inuit living in overcrowded households and in houses requiring major repairs. This observation, however, was based on bivariate associations between housing conditions and food insecurity and did not account for other factors such as socioeconomic conditions. These studies nonetheless suggest that food insecurity is not only explained in terms of low socioeconomic status and poverty.40,42We examined whether household crowding was associated with food insecurity among Inuit families with school-aged children, independently of socioeconomic disadvantage.     

Association of Roadway Proximity with Fasting Plasma Glucose and Metabolic Risk Factors for Cardiovascular Disease in a Cross-Sectional Study of Cardiac Catheterization Patients

Background

The relationship between traffic-related air pollution (TRAP) and risk factors for cardiovascular disease needs to be better understood in order to address the adverse impact of air pollution on human health.

Objective

We examined associations between roadway proximity and traffic exposure zones, as markers of TRAP exposure, and metabolic biomarkers for cardiovascular disease risk in a cohort of patients undergoing cardiac catheterization.

Methods

We performed a cross-sectional study of 2,124 individuals residing in North Carolina (USA). Roadway proximity was assessed via distance to primary and secondary roadways, and we used residence in traffic exposure zones (TEZs) as a proxy for TRAP. Two categories of metabolic outcomes were studied: measures associated with glucose control, and measures associated with lipid metabolism. Statistical models were adjusted for race, sex, smoking, body mass index, and socioeconomic status (SES).

Results

An interquartile-range (990 m) decrease in distance to roadways was associated with higher fasting plasma glucose (β = 2.17 mg/dL; 95% CI: –0.24, 4.59), and the association appeared to be limited to women (β = 5.16 mg/dL; 95% CI: 1.48, 8.84 compared with β = 0.14 mg/dL; 95% CI: –3.04, 3.33 in men). Residence in TEZ 5 (high-speed traffic) and TEZ 6 (stop-and-go traffic), the two traffic zones assumed to have the highest levels of TRAP, was positively associated with high-density lipoprotein cholesterol (HDL-C; β = 8.36; 95% CI: –0.15, 16.9 and β = 5.98; 95% CI: –3.96, 15.9, for TEZ 5 and 6, respectively).

Conclusion

Proxy measures of TRAP exposure were associated with intermediate metabolic traits associated with cardiovascular disease, including fasting plasma glucose and possibly HDL-C.

Citation

Ward-Caviness CK, Kraus WE, Blach C, Haynes CS, Dowdy E, Miranda ML, Devlin RB, Diaz-Sanchez D, Cascio WE, Mukerjee S, Stallings C, Smith LA, Gregory SG, Shah SH, Hauser ER, Neas LM. 2015. Association of roadway proximity with fasting plasma glucose and metabolic risk factors for cardiovascular disease in a cross-sectional study of cardiac catheterization patients. Environ Health Perspect 123:1007–1014; http://dx.doi.org/10.1289/ehp.1306980