Brimonidine Eye Drops Causing Encephalopathy in a Patient With Advanced Chronic Kidney Disease.

Brimonidine eye drops are frequently prescribed for the treatment of glaucoma and ocular hypertension in adults. Systemic toxicities including neurological side effects have been reported with its use, especially in the paediatric population. In this report, we present a case of encephalopathy secondary to the use of brimonidine eye drops in a patient with underlying advanced chronic kidney disease, who recovered promptly after drug cessation. Herein, we also review the pharmacokinetics of eye drops leading to their systemic side effects, especially in the context of renal impairment. We also explore the possibility of extracorporeal treatment, such as by haemodialysis, for the treatment of these manifestations. This case demonstrates the need to clarify a patient's drug history and stop offending medications early on in a patient with delirium, while treatments such as antidotes or extracorporeal treatment are being considered.

Placental chemokine compartmentalisation: A novel mammalian molecular control mechanism.

Atypical chemokine receptor 2 (ACKR2) is a chemokine-scavenging receptor. ACKR2-/-embryos display a reduction in size of a novel, to our knowledge, embryonic skin macrophage population referred to as 'intermediate' cells. CC chemokine receptor 2 (CCR2)-/-embryos display an identical phenotype, indicating that these cells require CCR2 to enable them to populate embryonic skin. Further analysis revealed that ACKR2-/-embryos have higher circulating concentrations of the CCR2 ligand, CC ligand 2 (CCL2); thus, ACKR2 regulates intraembryonic CCL2 levels. We show that ACKR2 is strongly expressed by trophoblasts and that it blocks movement of inflammatory chemokines, such as CCL2, from the maternal decidua into the embryonic circulation. We propose that trophoblastic ACKR2 is responsible for ensuring chemokine compartmentalisation on the maternal decidua, without which chemokines enter the embryonic circulation, disrupting gradients essential for directed intraembryonic cell migration. Overall, therefore, we describe a novel, to our knowledge, molecular mechanism whereby maternal decidual chemokines can function in a compartmentalised fashion without interfering with intraembryonic leukocyte migration. These data suggest similar functions for other atypical chemokine receptors in the placenta and indicate that defects in such receptors may have unanticipated developmental consequences.

Chemokine Receptor Redundancy and Specificity Are Context Dependent.

Currently, we lack an understanding of the individual and combinatorial roles for chemokine receptors in the inflammatory process. We report studies on mice with a compound deletion of Ccr1, Ccr2, Ccr3, and Ccr5, which together control monocytic and eosinophilic recruitment to resting and inflamed sites. Analysis of resting tissues from these mice, and mice deficient in each individual receptor, provides clear evidence for redundant use of these receptors in establishing tissue-resident monocytic cell populations. In contrast, analysis of cellular recruitment to inflamed sites provides evidence of specificity of receptor use for distinct leukocyte subtypes and no indication of comprehensive redundancy. We find no evidence of involvement of any of these receptors in the recruitment of neutrophils or lymphocytes to resting or acutely inflamed tissues. Our data shed important light on combinatorial inflammatory chemokine receptor function and highlight Ccr2 as the primary driver of myelomonocytic cell recruitment in acutely inflamed contexts.

The Atypical Chemokine Receptor Ackr2 Constrains NK Cell Migratory Activity and Promotes Metastasis.

Chemokines have been shown to be essential players in a range of cancer contexts. In this study, we demonstrate that mice deficient in the atypical chemokine receptor Ackr2 display impaired development of metastasis in vivo in both cell line and spontaneous models. Further analysis reveals that this relates to increased expression of the chemokine receptor CCR2, specifically by KLRG1+ NK cells from the Ackr2-/- mice. This leads to increased recruitment of KLRG1+ NK cells to CCL2-expressing tumors and enhanced tumor killing. Together, these data indicate that Ackr2 limits the expression of CCR2 on NK cells and restricts their tumoricidal activity. Our data have important implications for our understanding of the roles for chemokines in the metastatic process and highlight Ackr2 and CCR2 as potentially manipulable therapeutic targets in metastasis.

An analysis of the function and expression of D6 on lymphatic endothelial cells.

The mechanisms by which CC chemokine receptor (CCR)7 ligands are selectively presented on lymphatic endothelium in the presence of inflammatory chemokines are poorly understood. The chemokine-scavenging receptor D6 is expressed on lymphatic endothelial cells (LEC) and contributes to selective presentation of CCR7 ligands by suppressing inflammatory chemokine binding to LEC surfaces. As well as preventing inappropriate inflammatory cell attachment to LECs, D6 is specifically involved in regulating the ability of LEC to discriminate between mature and immature dendritic cells (DCs). D6 overexpression reduces immature DC (iDC) adhesion to LECs, whereas D6 knockdown increases adhesion of iDCs that displace mature DCs. LEC D6 expression is regulated by growth factors, cytokines, and tumor microenvironments. In particular, interleukin-6 and interferon-γ are potent inducers, indicating a preferential role for D6 in inflamed contexts. Expression of the viral interleukin-6 homolog from Kaposi sarcoma-associated herpesvirus is also sufficient to induce significant D6 upregulation both in vitro and in vivo, and Kaposi sarcoma and primary effusion lymphoma cells demonstrate high levels of D6 expression. We therefore propose that D6, which is upregulated in both inflammatory and tumor contexts, is an essential regulator of inflammatory leukocyte interactions with LECs and is required for immature/mature DC discrimination by LECs.

D6: the 'crowd controller' at the immune gateway.

The chemokine-scavenging receptor, D6, is reported to regulate resolution of inflammatory responses. However, recent data also point to an unanticipated role for D6 in coordinating innate and adaptive immune responses. Here, we propose that D6 is essential for preventing inflammatory leukocyte association with lymphatic vasculature. In the absence of D6, inappropriate inflammatory leukocyte accumulation around lymphatic endothelium congests the lymphatic system, impairing fluid and cellular flow from inflamed sites to lymph nodes and reducing efficiency of antigen presentation. Thus, the inability of D6-deficient mice to resolve inflammation may be a byproduct of impaired fluid drainage from inflamed sites and thus we provide a model unifying D6 function in innate and adaptive immune responses.

Elevated expression of the chemokine-scavenging receptor D6 is associated with impaired lesion development in psoriasis.

D6 is a scavenging-receptor for inflammatory CC chemokines that are essential for resolution of inflammatory responses in mice. Here, we demonstrate that D6 plays a central role in controlling cutaneous inflammation, and that D6 deficiency is associated with development of a psoriasis-like pathology in response to varied inflammatory stimuli in mice. Examination of D6 expression in human psoriatic skin revealed markedly elevated expression in both the epidermis and lymphatic endothelium in "uninvolved" psoriatic skin (ie, skin that was more than 8 cm distant from psoriatic plaques). Notably, this increased D6 expression is associated with elevated inflammatory chemokine expression, but an absence of plaque development, in uninvolved skin. Along with our previous observations of the ability of epidermally expressed transgenic D6 to impair cutaneous inflammatory responses, our data support a role for elevated D6 levels in suppressing inflammatory chemokine action and lesion development in uninvolved psoriatic skin. D6 expression consistently dropped in perilesional and lesional skin, coincident with development of psoriatic plaques. D6 expression in uninvolved skin also was reduced after trauma, indicative of a role for trauma-mediated reduction in D6 expression in triggering lesion development. Importantly, D6 is also elevated in peripheral blood leukocytes in psoriatic patients, indicating that upregulation may be a general protective response to inflammation. Together our data demonstrate a novel role for D6 as a regulator of the transition from uninvolved to lesional skin in psoriasis.

D6 facilitates cellular migration and fluid flow to lymph nodes by suppressing lymphatic congestion.

Lymphatic endothelial cells are important for efficient flow of antigen-bearing fluid and antigen-presenting cells (APCs) from peripheral sites to lymph nodes (LNs). APC movement to LNs is dependent on the constitutive chemokine receptor CCR7, although how conflicting inflammatory and constitutive chemokine cues are integrated at lymphatic surfaces during this process is not understood. Here we reveal a previously unrecognized aspect of the regulation of this process. The D6 chemokine-scavenging receptor, which is expressed on lymphatic endothelial cells (LECs), maintains lymphatic surfaces free of inflammatory CC-chemokines and minimizes interaction of inflammatory leukocytes with these surfaces. D6 does not alter the level of CCR7 ligands on LECs, thus ensuring selective presentation of homeostatic chemokines for interaction with CCR7(+) APCs. Accordingly, in D6-deficient mice, inflammatory CC-chemokine adherence to LECs results in inappropriate perilymphatic accumulation of inflammatory leukocytes at peripheral inflamed sites and draining LNs. This results in lymphatic congestion and impaired movement of APCs, and fluid, from inflamed sites to LNs. We propose that D6, by suppressing inflammatory chemokine binding to lymphatic surfaces, and thereby preventing inappropriate inflammatory leukocyte adherence, is a key regulator of lymphatic function and a novel, and indispensable, contributor to the integration of innate and adaptive immune responses.

Factors contributing to hospital readmission in a Hong Kong regional hospital: a case-controlled study.

BACKGROUND: As many as 50% of total hospital admissions are readmissions. Because the factors contributing to hospital readmission are multiple, and research findings are not conclusive, it is important for clinicians to gain an understanding of the key factors that contribute to readmission. OBJECTIVES: This study explores the factors contributing to hospital readmission and derives an explanatory model that can best identify characteristics of patients at high risk for hospital readmission. METHODS: This research was a case-controlled study with readmitted patients (n = 168) as the readmitted group and non-readmitted patients (n = 98) as the control group. The variables included demographic data, health assessment data, medical diagnosis, frequency of admissions, severity of illness, intensity of service and improvement of condition. The study sample was also interviewed to explore the patients' views on their repeated hospitalization. RESULTS: In the bivariate analysis significant differences between the study and control groups were multiple and generally consistent with findings in other studies. Using multiple logistic regression, however, the final model shows that only three factors best predict readmissions: frequency (3-4 times) of readmissions (OR = 9.96, p < .0001) and frequency (more than 5 times) of readmissions (OR = 15.73, p < .0001), financial assistance (OR = 5.03, p < .001), and severity of illness (OR = 3.12, p < .01). Our interview data suggest that the readmitted patients required assistance to accomplish daily living activities upon discharge and often returned to the hospital for the same health reason. CONCLUSION: The study findings suggest that patients who are frequently readmitted to the hospital are severely ill; are on public assistance; and may need special attention when discharged in order to attenuate repeated hospital readmission.