Global climate change is expected to affect waterborne enteric diseases, yet to date there has been no comprehensive, systematic review of the epidemiological literature examining the relationship between meteorological conditions and diarrheal diseases. We searched PubMed, Embase, Web of Science and the Cochrane Collection for studies describing the relationship between diarrheal diseases and four meteorological conditions that are expected to increase with climate change: ambient temperature, heavy rainfall, drought, and flooding. We synthesized key areas of agreement and evaluated the biological plausibility of these findings, drawing from a diverse, multidisciplinary evidence base. We identified 141 articles that met our inclusion criteria. Key areas of agreement include a positive association between ambient temperature and diarrheal diseases, with the exception of viral diarrhea; and an increase in diarrheal disease following heavy rainfall and flooding events. Insufficient evidence was available to evaluate the effects of drought on diarrhea. There is evidence to support the biological plausibility of these associations, but publication bias is an ongoing concern. Future research evaluating whether interventions, such as improved water and/or sanitation access, modify risk would further our understanding of the potential impacts of climate change on diarrheal diseases and aid in the prioritization of adaptation measures.

Changes in temperature due to global climate change can and may already be affecting diarrhoeal disease incidence. The vulnerability of populations may depend, in part, on local pathogen distribution. However, evidence of publication bias and the uneven geographical distribution of studies limit the precision and generalizability of the pooled estimates.

Catecholamines released from the sympathetic nervous system in response to stress or injury affect expression of inflammatory cytokines generated by immune cells. ␣ 1 -Adrenergic receptors (ARs) are expressed on innate immune cell populations, but their subtype expression patterns and signaling characteristics are not well characterized. Primary human monocytes, a human monocytic cell line, and monocyte-derived macrophage cells were used to measure expression of the proinflammatory mediator interleukin (IL)-1␤ responding to lipopolysaccharide (LPS) in the presence or absence of ␣ 1 -AR activation. Based on our previous findings, we hypothesized that ␣ 1 -AR stimulation on innate immune cells positively regulates LPS-initiated IL-1␤ production. IL-1␤ production in response to LPS was synergistically higher for both monocytes and macrophages in the presence of the selective ␣ 1 -AR agonist (R)-(Ϫ)-phenylephrine hydrochloride (PE). This synergistic IL-1␤ response could be blocked with a selective ␣ 1 -AR antagonist as well as inhibitors of protein kinase C (PKC). Radioligand binding studies characterized a homogenous ␣ 1B -AR subtype population on monocytes, which changed to a heterogeneous receptor subtype expression pattern when differentiated to macrophages. Furthermore, increased p38 mitogenactivated protein kinase (MAPK) activation was observed only with concurrent PE and LPS stimulation, peaking after 120 and 30 min in monocytes and macrophages, respectively. Blocking the PKC/p38 MAPK signaling pathway in both innate immune cell types inhibited the synergistic IL-1␤ increase observed with concurrent PE and LPS treatments. This study characterizes ␣ 1 -AR subtype expression on both human monocyte and macrophage cells and illustrates a mechanism by which increased IL-1␤ production can be modulated by ␣ 1 -AR input.

Stress induced circulating catecholamines are hypothesized to selectively activate adrenergic receptors (ARs) on immunocompetent cells modulating their inflammatory response to trauma or environmental toxins. We characterized changes in expression of a pro-inflammatory cytokine modulated by β-AR activation in human primary and immortalized monocytes that had been simultaneously stimulated with lipopolysaccharide (LPS). Results from cytokine antibody arrays demonstrated that half-maximal effective concentrations of the selective β-AR agonist isoproterenol (Iso) qualitatively increased LPS-mediated expression of the soluble cytokine, interleukin-1β (IL-1β). Semi-quantitative immunoblot techniques confirmed a synergistic increase of IL-1β production in both LPS stimulated THP-1 cells and primary human monocytes co-incubated with Iso. Immunoblot techniques as well as radioligand binding studies were also used to characterize the heterogeneous expression of β 1 -and β 2 -AR subtypes on THP-1 cells. β-AR activation is classically associated with generation of cAMP in many tissues and cell types. Therefore, using the method of Schild, we generated Iso concentration-response curves in the presence of fixed subtype-selective β-AR antagonist concentrations to demonstrate that β 1 -AR activation was exclusively linked with the generation of cAMP in THP-1 cells. Furthermore, use of a selective kinase inhibitor demonstrated that Iso potentiated the expression of soluble IL-1β through activation of cAMP-dependent protein kinase A. Finally, discriminating concentrations of subtype-selective β-AR antagonists revealed that β 1 -AR stimulation alone accounted for the synergistic production of IL-1β in LPS stimulated monocytes co-incubated with Iso. These results demonstrate a unique synergistic pro-inflammatory Publisher's Disclaimer: This is a PDF file of an unedited manuscript that has been accepted for publication. As a service to our customers we are providing this early version of the manuscript. The manuscript will undergo copyediting, typesetting, and review of the resulting proof before it is published in its final citable form. Please note that during the production process errors may be discovered which could affect the content, and all legal disclaimers that apply to the journal pertain. CONFLICT OF INTEREST STATEMENT NIH-PA Author ManuscriptNIH-PA Author Manuscript NIH-PA Author Manuscript response mediated through a β 1 -AR cAMP-dependent mechanism in LPS challenged monocytic cells.

Peroxisome proliferator-activated receptor gamma (PPARc) agonists are known to inhibit select pro-inflammatory changes in models of CNS and systemic inflammation. Recent reports suggest that these anti-inflammatory effects are due to mechanisms other than canonical nuclear receptormediated transcriptional alteration. Using primary microglia and the monocytic cell line, THP-1, we demonstrate that rosiglitazone, a PPARc-activating thiazolidinedione, decreases pro-inflammatory cytokine secretion as measured by ELISA. Cells were pre-treated with various thiazolidinediones, including rosiglitazone, prior to stimulation with lipopolysaccharide or phorbol 12-myristate 13-acetate (PMA) to stimulate cytokine production. Tumor necrosis factor alpha (TNFa) secretion was significantly inhibited in both primary microglia and THP-1 cells differentiated for 72 h in the presence of PMA to induce a macrophage-like phenotype. No reduction in TNFa secretion was observed in undifferentiated THP-1 cells with rosiglitazone pre-treatment. Electrophoretic mobility shift assay revealed no significant difference in PPARc activation between PMA-differentiated and undifferentiated THP-1 cells. When PMA-differentiated and undifferentiated THP-1 cells were treated with the irreversible PPARc antagonist, GW 9662, a significant, dose-dependent decrease in TNFa secretion was observed. These results suggest that the anti-inflammatory benefit of PPARc ligands occur independently of classical PPARc activation.