Estimating Intra-Urban Inequities in PM2.5-Attributable Health Impacts: A Case Study for Washington, DC.

Air pollution levels are uneven within cities, contributing to persistent health disparities between neighborhoods and population sub-groups. Highly spatially resolved information on pollution levels and disease rates is necessary to characterize inequities in air pollution exposure and related health risks. We leverage recent advances in deriving surface pollution levels from satellite remote sensing and granular data in disease rates for one city, Washington, DC, to assess intra-urban heterogeneity in fine particulate matter (PM2.5)- attributable mortality and morbidity. We estimate PM2.5-attributable cases of all-cause mortality, chronic obstructive pulmonary disease, ischemic heart disease, lung cancer, stroke, and asthma emergency department (ED) visits using epidemiologically derived health impact functions. Data inputs include satellite-derived annual mean surface PM2.5 concentrations; age-resolved population estimates; and statistical neighborhood-, zip code- and ward-scale disease counts. We find that PM2.5 concentrations and associated health burdens have decreased in DC between 2000 and 2018, from approximately 240 to 120 cause-specific deaths and from 40 to 30 asthma ED visits per year (between 2014 and 2018). However, remaining PM2.5-attributable health risks are unevenly and inequitably distributed across the District. Higher PM2.5-attributable disease burdens were found in neighborhoods with larger proportions of people of color, lower household income, and lower educational attainment. Our study adds to the growing body of literature documenting the inequity in air pollution exposure levels and pollution health risks between population sub-groups, and highlights the need for both high-resolution disease rates and concentration estimates for understanding intra-urban disparities in air pollution-related health risks.

Factors Increasing Risk of Suicide after Traumatic Brain Injury: A State-of-the-Science Review of Military and Civilian Studies.

Primary Objective: Survey TBI literature to identify evidence of risk for post-injury suicide.Literature Selection: Search terms ((traumatic brain injury OR TBI) AND (suicidality OR suicidal behaviour OR suicidal ideation)) entered in PubMed, OVID Medline, PsychInfo, and Web of Science for papers published in print 01/01/1997 to 06/30/2019.Analysis of Literature: Authors screened abstracts, excluding duplicates and articles not meeting inclusion/exclusion criteria. Full papers were reviewed to make final exclusions. Data were extracted from 40 papers included co- and premorbid disorders, demographics, injury-related and psychological factors.Results: Persons with TBI have a higher risk for suicide than the general population. Reviewed articles reported comorbid depression and/or PTSD as risk factors for post-TBI suicide. Co- or premorbid substance misuse, sex, and sleep disturbance moderate risk. Quality of the literature was limited by sample size, the predominance of male participants, and inconsistency in reporting of findings.Conclusions: Comorbid depression and PTSD are significant post-TBI risk factors for suicide. Several variables combine to moderate or mediate TBI's connection with suicide. Civilian and military clinician cross-talk and consistent reporting of results from reproducible studies of post-TBI suicide risk factors could improve prevention and treatment efforts in veterans and civilians.

Juvenile-onset motor polyneuropathy in Siberian cats.

BACKGROUND: Polyneuropathies are infrequently described in cats. There is a genetic predisposition in several breeds. OBJECTIVE: To clinically characterize a novel motor polyneuropathy in a family of Siberian cats. ANIMALS: Thirteen closely related Siberian cats, 4 clinically affected and 9 clinically unaffected individuals. METHODS: Retrospective study. Clinical data and pedigree information were obtained from the medical records and breeder. Electrodiagnostic testing and muscle and peripheral nerve biopsy samples were obtained from 1 affected cat. Follow-up information was obtained for all affected cats. RESULTS: Onset of signs was 4 to 10 months in affected cats. Clinical signs were progressive or waxing/waning neuromuscular weakness (4/4), normal sensory function (4/4), and variably decreased withdrawal reflexes (3/4). All cats returned to normal neurologic function within 1 to 4 weeks. All cats had a recurrence of weakness (3/4 had 1 recurrent episode, 1/4 had 3 relapses) from which they recovered fully. In 1 cat, electromyography and motor nerve conduction studies showed multicentric spontaneous activity, normal motor nerve conduction velocity, reduced compound muscle action potential amplitude, and polyphasia. Histologic evaluation of muscle and nerve in that cat showed mild muscle atrophy consistent with recent denervation, endoneurial and perineurial edema, and mild mononuclear cell infiltration within intramuscular nerve branches and a peripheral nerve. Pedigree analysis suggests an autosomal recessive mode of inheritance, although neither a genetically complex/polygenic condition nor an acquired inflammatory polyneuropathy can be ruled-out. CONCLUSIONS AND CLINICAL IMPORTANCE: We describe a motor polyneuropathy in juvenile Siberian cats characterized by self-limiting weakness with potential relapse.

Angiogenesis and Vascular Endothelial Growth Factor-A Expression Associated with Inflammation in Pediatric Crohn's Disease.

BACKGROUND AND AIMS: Angiogenesis is a component of chronic inflammatory diseases including inflammatory bowel disease. Some studies describe increased angiogenesis associated with acute disease in adult Crohn's disease and ulcerative colitis, while animal models aid investigations of mechanism and pathophysiology of angiogenesis. We aim to explore the role of angiogenesis and its pathways in pediatric Crohn's disease. METHODS: Surgical specimens were obtained from pediatric Crohn's disease (both inflamed and non-inflamed regions of ileum) and control patients. Samples were examined for inflammation, microvessel density, and molecular expression of vascular endothelial growth factor-A, platelet-derived growth factor-ß, angiopoietin-1, and angiopoietin-2. RESULTS: Angiogenesis and inflammation were increased in parallel in Crohn's disease compared to controls. We also discovered increased angiogenesis in Crohn's disease tissue that was relatively free of inflammatory disease. Vascular endothelial growth factor-A gene expression (P = 0.034) was elevated in Crohn's disease over controls, while gene expression of platelet-derived growth factor-ß (P = 0.069), angiopoietin-1 (P = 0.206), and angiopoietin-2 (P = 0.082) was not significantly elevated. CONCLUSIONS: We confirm that inflammation-associated angiogenesis is upregulated in pediatric Crohn's disease. This population also exhibits elevated mucosal angiogenesis at the surgical margin with limited inflammation. This suggests that angiogenesis is an additional pathologic characteristic to potentially identify normal mucosa and margins of surgical resection that are uninvolved with disease and, furthermore, may have implications for monitoring complete disease remission. We further identify the vascular endothelial growth factor-A pathway involvement in the disease process, which may serve as a future molecular target for anti-angiogenic therapy in inflammatory bowel disease.

Murine colitis treated with multitargeted tyrosine kinase inhibitors.

BACKGROUND: Angiogenesis, a known pathogenic component of neoplastic and nonneoplastic diseases, serves as a therapeutic target. Vascular endothelial growth factor (VEGF) and angiogenesis are clinically elevated in inflammatory bowel disease. By targeting vascular endothelial growth factor receptor (VEGFR) and platelet-derived growth factor receptor (PDGFR) with receptor tyrosine kinase inhibitors in a murine model of colitis, we hypothesize that angiogenesis will be suppressed and disease severity improved. METHODS AND METHODS: Sorafenib, sunitinib, and axitinib were administered by oral gavage in a murine model of dextran sodium sulfate (DSS) colitis. Inflammation score, microvessel density (MVD), and gene expression of VEGF, VEGFR, platelet-derived growth factor, PDGFR, Ang-2, and epidermal growth factor receptor was assessed. RESULTS: Inflammation and MVD were elevated in groups receiving DSS, but were similar between DSS-only and treatment cohorts. Unexpected weight loss was present in the gavaged groups versus DSS only. In treated groups, VEGFR was significantly decreased (P = 0.002) and VEGF gene expression trended down (P = 0.213) versus DSS only. Neither the platelet-derived growth factor/PDGFR pathway nor the alternative pathways, Ang-2 and epidermal growth factor receptor, were significantly changed from DSS control in treatment cohorts. CONCLUSIONS: This study confirms the association between inflammation and MVD. Antiangiogenic receptor tyrosine kinase inhibitors suppressed the VEGF/VEGFR pathway but the expected decrease in colonic MVD did not follow, suggesting possible involvement of other angiogenic pathway(s). In the DSS model of colitis, vehicle selection and mouse strain can impact disease response.

Mouse strain influences angiogenic response to dextran sodium sulfate-induced colitis.

BACKGROUND: Angiogenesis is a known pathologic factor in chronic inflammatory diseases. Regarding the murine dextran sodium sulfate (DSS) colitis model, different mouse strains produce variable clinical and inflammatory responses. We hypothesize that DSS colitis applied to diverse mouse strains will similarly elevate colonic microvessel density in parallel with inflammation, but will do so with different angiogenic profiles. MATERIALS AND METHODS: We induced DSS colitis in 129S2/SvPas, BALB/c, and C57BL/6 mice, then performed histologic and molecular analysis at day 7 to evaluate colonic inflammation and angiogenesis. RESULTS: Inflammation and microvessel density were similarly increased in DSS groups. The C57BL/6 cohort mounted a more severe colitis with 25% weight loss and greater colonic ulceration. Gene expression of angiogenic factors at baseline and in colitis groups were widely variable among strains. BALB/c mice exhibited higher angiogenic gene expression in control and DSS groups compared with other strains, specifically platelet-derived growth factor, angiopoietin-1, angiopoietin-1 (Ang-2), vascular endothelial growth factor receptor, and PDGF receptor. When evaluating the effect of DSS relative to controls, BALB/c mice were not significantly affected. 129S2/SvPas mice exhibited broad suppression of growth factors, significantly platelet-derived growth factor, Ang-2, and PDGF receptor. In contrast, C57BL/6 mice displayed increased gene expression, especially for angiopoietin-1 and Ang-2. CONCLUSIONS: Genetic heterogeneity influences the angiogenic profile elicited by DSS colitis. We demonstrate that within a model of murine colitis, mouse strain significantly affects inflammation-associated angiogenesis. These results may impact strain selection when using a colitis model focusing on inflammation and angiogenesis. Future studies to further define the angiogenesis pathway and potentially alter the disease course with targeted antiangiogenics are warranted.

Vascular endothelial growth factor receptor-2 inhibition in experimental murine colitis.

BACKGROUND: In the setting of inflammatory bowel disease, inflammation is associated with a simultaneous increase in angiogenesis; moreover, elevated vascular endothelial growth factor (VEGF) levels implicate angiogenesis as a pathologic contributor to disease severity. We hypothesize that selectively inhibiting vascular endothelial growth factor receptor-2 (VEGFR2) in a model of murine colitis will reduce angiogenesis, resulting in decreased inflammation and disease severity, providing mechanistic insight into the role of pathologic angiogenesis in IBD. MATERIALS AND METHODS: In a dextran sodium sulfate model of murine colitis, anti-VEGFR2 monoclonal antibody (DC101) or placebo was administered. Clinical assessments followed by histologic and molecular tissue analysis were performed to quantify inflammation, microvessel density (MVD), VEGF and VEGFR2 gene expression, and phosphorylated mitogen-activated protein kinase protein expression. RESULTS: Weight loss began after d 6 with the treatment group demonstrating a more favorable percent weight change. Inflammation and MVD were similar between cohorts, both increasing in parallel toward a plateau. VEGF and VEGFR2 messenger RNA expression were not significantly different, but phosphorylated mitogen-activated protein kinase was elevated in the DC101 cohort (P = 0.03). CONCLUSIONS: Despite a more favorable weight change profile in the treated group, no difference was observed between cohorts regarding clinical disease severity. However, a parallel rise in inflammation and MVD was observed coinciding with weight loss, suggesting their relationship in IBD. VEGFR2 downstream signaling was significantly elevated in the treated cohort, possibly by VEGF-independent signal transduction. Early and effective inhibition of angiogenesis by limiting downstream VEGF signaling or targeting multiple angiogenic pathways may block angiogenesis, thereby reducing disease severity and provide evidence toward the mechanism and clinical benefit of antiangiogenics in the setting of IBD.

VEGF blockade enables oncolytic cancer virotherapy in part by modulating intratumoral myeloid cells.

Understanding the host response to oncolytic viruses is important to maximize their antitumor efficacy. Despite robust cytotoxicity and high virus production of an oncolytic herpes simplex virus (oHSV) in cultured human sarcoma cells, intratumoral (ITu) virus injection resulted in only mild antitumor effects in some xenograft models, prompting us to characterize the host inflammatory response. Virotherapy induced an acute neutrophilic infiltrate, a relative decrease of ITu macrophages, and a myeloid cell-dependent upregulation of host-derived vascular endothelial growth factor (VEGF). Anti-VEGF antibodies, bevacizumab and r84, the latter of which binds VEGF and selectively inhibits binding to VEGF receptor-2 (VEGFR2) but not VEGFR1, enhanced the antitumor effects of virotherapy, in part due to decreased angiogenesis but not increased virus production. Neither antibody affected neutrophilic infiltration but both partially mitigated virus-induced depletion of macrophages. Enhancement of virotherapy-mediated antitumor effects by anti-VEGF antibodies could largely be recapitulated by systemic depletion of CD11b(+) cells. These data suggest the combined effect of oHSV virotherapy and anti-VEGF antibodies is in part due to modulation of a host inflammatory reaction to virus. Our data provide strong preclinical support for combined oHSV and anti-VEGF antibody therapy and suggest that understanding and counteracting the innate host response may help enable the full antitumor potential of oncolytic virotherapy.

Pretreatment with anti-VEGF therapy may exacerbate inflammation in experimental acute colitis.

AIM: Our previous investigations of angiogenesis in inflammatory bowel disease showed that vascular endothelial growth factor (VEGF) blockade reduced colonic neovascularization and inflammation. We hypothesized that pretreatment with bevacizumab, a monoclonal anti-VEGF antibody, would attenuate the severity of angiogenesis and inflammation in a murine model of colitis. METHODS: C57BL/6 mice were treated with intraperitoneal injections of bevacizumab (250 µg/dose) before induction of colitis with dextran sulfate sodium (DSS). The colons were examined at predetermined time points. Colonic inflammation and microvessel density were assessed microscopically. RESULTS: All mice acutely developed melena and weight loss (18.8% ± 1.1% control vs 20.2% ± 1.1% treated, P = .37) and regained a similar weight percentage after the recovery (26.5% ± 4.0% vs 20.9% ± 4.4%, P = .37). Microvessel density acutely increased in both groups in response to DSS, with a trend toward inhibited angiogenesis in the treated group at the conclusion of the acute phase (194,100 ± 14,240 vs 149,400 ± 17,590 µm(2), P = .11). Bevacizumab-treated mice exhibited significantly increased inflammation after the acute phase (8.3 ± 0.8 vs 13.0 ± 2.0, P = .05), but were similar to control after the recovery (7.3 ± 1.5 vs 5.5 ± 1.0, P = .27). CONCLUSIONS: Preemptive VEGF inhibition does not significantly attenuate angiogenesis and, in fact, worsens inflammation in a model of acute colitis. Preventive VEGF blockade may disrupt healing and exacerbate injury via alternative angiogenic or inflammatory pathways.

EGFR inhibition fails to suppress vascular proliferation and tumor growth in a Ewing's sarcoma model.

BACKGROUND: Expression of epidermal growth factor receptor (EGFR), a potent regulator of cellular homeostasis, is associated with aggressive tumor behavior. The mechanism by which EGFR inhibition functions is unclear, with controversial results demonstrating an effect on the tumor cells, endothelial cells, or pericytes. EGFR activation has been linked to the expression of vascular endothelial growth factor (VEGF), a known mitogen of angiogenesis, but the relationship between these factors and their effect on tumor vessel development is vague. We hypothesized that using an EGFR inhibitor on a human Ewing's sarcoma model would inhibit tumor growth by suppressing vessel proliferation. METHODS: A cell proliferation assay was performed on the Ewing's sarcoma (SK-NEP-1) cell line. Tumor cells were implanted intrarenally in athymic mice. Animals received daily gavage with vehicle or gefitinib 1 wk following implantation. Mice (n = 12/cohort) were euthanized 6 wk following implantation. Remaining mice were maintained without treatment for 2 wk. Vascular changes were assessed by angiography and immunohistochemically. EGFR and vascular endothelial growth factor (VEGF) expression were quantified using quantitative polymerase chain reaction (qPCR). RESULTS: Gefitinib suppressed in vitro cell growth with an IC(50) = 1.36 µM. Minimal tumor growth suppression was noted at 6 wk (6.01 ± 1.2 g in control versus 4.61 ± 0.9 g treated, P = 0.36). After cessation of gefitinib, tumor growth was increased in both groups (7.37 ± 1.62 g versus 6.77 ± 1.53 g, P = 0.79). Microvessel density was unchanged despite EGFR inhibition (161,000 ± 16,000 pixels versus 135,000 ± 18,000 pixels, P = 0.31). At 6 wk, the vascular maturity index was similar in both groups (3.63 ± 1.12 versus 4.09 ± 1.71, P = 0.83). A downward trend in EGFR expression (49% of control) and an upward trend in VEGF levels (50% of control) occurred in the treated group. CONCLUSIONS: EGFR expression was suppressed in cultured cells and xenograft tumors. Despite a cytotoxic effect on cell lines, gefitinib had little effect on tumor growth. No effects on the tumor vasculature were noted in the setting of EGFR suppression, suggesting that angiogenesis induced by SK-NEP-1 cells is refractory to EGFR inhibition. Interestingly, the resulting increase in VEGF expression following EGFR blockade, provides an alternative pro-angiogenic pathway promoting tumor survival.

Rescue of skeletal muscle alpha-actin-null mice by cardiac (fetal) alpha-actin.

Skeletal muscle alpha-actin (ACTA1) is the major actin in postnatal skeletal muscle. Mutations of ACTA1 cause mostly fatal congenital myopathies. Cardiac alpha-actin (ACTC) is the major striated actin in adult heart and fetal skeletal muscle. It is unknown why ACTC and ACTA1 expression switch during development. We investigated whether ACTC can replace ACTA1 in postnatal skeletal muscle. Two ACTC transgenic mouse lines were crossed with Acta1 knockout mice (which all die by 9 d after birth). Offspring resulting from the cross with the high expressing line survive to old age, and their skeletal muscles show no gross pathological features. The mice are not impaired on grip strength, rotarod, or locomotor activity. These findings indicate that ACTC is sufficiently similar to ACTA1 to produce adequate function in postnatal skeletal muscle. This raises the prospect that ACTC reactivation might provide a therapy for ACTA1 diseases. In addition, the mouse model will allow analysis of the precise functional differences between ACTA1 and ACTC.

Double aortic arch and nasogastric tubes: a fatal combination.

Double aortic arch is a common form of complete vascular ring that encircles both the trachea and the esophagus, and presents with various respiratory and esophageal symptoms, usually in the pediatric population. We present a case of double aortic arch in an adult patient that manifested as massive upper gastrointestinal bleeding after prolonged nasogastric intubation.

Malabsorption work-up: utility of small bowel biopsy.

A wide variety of small intestinal mucosal diseases lead to malabsorption. Although stool studies, especially stool for excess fat, and functional tests for deficiency states are important clues to malabsorption, small intestinal biopsies are probably the most crucial part of the diagnostic process. Many mucosal disorders have distinctive histologic features that allow for precise diagnosis. However, these histologic changes might be subtle. The role of the gastroenterologist is to provide the pathologist with adequate clinical information and tissue material to ensure a complete examination pathologically. Celiac disease is the most common mucosal cause of chronic malabsorption in the western world. Celiac disease can present classically as large volume fatty diarrhea, but it more commonly presents with subtle clinical symptoms or iron deficiency anemia. Although the histologic hallmark of celiac disease is increased intraepithelial lymphocytosis along with villous atrophy, increased intraepithelial lymphocytosis alone in an appropriate clinical context might suggest the diagnosis of celiac disease. The aim of this review is to highlight the importance of close cooperation and communication between the gastroenterologist and the pathologist to optimize the diagnosis of mucosal diseases that result in malabsorption.

Ca(2+) activation and tension cost in myofilaments from mouse hearts ectopically expressing enteric gamma-actin.

To determine the significance of actin isoforms in chemomechanical coupling, we compared tension and ATPase rate in heart myofilaments from nontransgenic (NTG) and transgenic (TG) mice in which enteric gamma-actin replaced >95% of the cardiac alpha-actin. Enteric gamma-actin was expressed against three backgrounds: mice expressing cardiac alpha-actin, heterozygous null cardiac alpha-actin mice, and homozygous null cardiac alpha-actin mice. There were no differences in maximum Ca(2+) activated tension or maximum rate of tension redevelopment after a quick release and rapid restretch protocol between TG and NTG skinned fiber bundles. However, compared with NTG controls, Ca(2+) sensitivity of tension was significantly decreased and economy of tension development was significantly increased in myofilaments from all TG hearts. Shifts in myosin isoform population could not fully account for this increase in the economy of force production of TG myofilaments. Our results indicate that an exchange of cardiac alpha-actin with an actin isoform differing in only five amino acids has a significant impact on both Ca(2+) regulation of cardiac myofilaments and the cross-bridge cycling rate.

MDON: a network of community partnerships.

This model for strengthening diabetes care in communities teams the public health system with the professional and lay community to address prevention, early detection, and treatment of diabetes. This article describes how the Michigan Diabetes Outreach Network (MDON) develops local, regional, and statewide partnerships to increase professional and public knowledge and to improve care delivery for this chronic and complex disease.