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As one article in a series on Global Mental Health Practice, Peter Ventevogel and colleagues provide a case study of their efforts to integrate brief, practice-oriented mental health training into the Afghanistan health care system at a time when the system was being rebuilt from scratch. [ABSTRACT FROM AUTHOR]

Frameworks conceptualising the quality of care abound and vary; some concentrate on specific aspects such as safety, effectiveness, others all-encompassing. However, to our knowledge, tailoring to systematically arrive at a comprehensive care for chronic conditions quality (CCCQ) framework has never been done. We conducted a scoping review and Delphi survey to produce a CCCQ framework, comprehensively delineating aims, determinants and measurable attributes. With the assumption that specific groups (people with chronic conditions, care providers, financiers, policy-makers, etc.) view quality of care differently, we analysed 48 scientific and 26 grey literature deductively and inductively using the Institute of Medicine's quality of care framework as the foundation. We produced a zero-version of the quality of chronic care framework, detailing aims, healthcare system determinants, and measurement mechanisms. This was presented in a Delphi survey to 49 experts with diverse chronic care expertise/experience around the world. Consensus was obtained after the first round, with the panel providing suggestions and justifications to expand the agreed-upon components. Through this exercise, a comprehensive CCCQ framework encompassing the journey through healthcare of people with chronic conditions was developed. The framework specifies seven CCCQ 'aims' and identifies health system determinants which can be acted upon with 'organising principles' and measured through chronic care quality 'attributes' related to structures, processes and outcomes. Tailoring quality of care based on the nature of the diseases/conditions and considering different views can be done to ensure a comprehensive offer of healthcare services, and towards better outcomes that are acceptable to both the health system and people with chronic conditions (PwCC).

There is a growing need to implement high quality chronic care to address the global burden of chronic conditions. However, to our knowledge, there have been no systematic attempts to define and specify aims for chronic care quality. To address this gap, we conducted a scoping review and Delphi survey to establish and validate comprehensive specifications. The Institute of Medicine's (IOM) quality of care definition and aims were used as the foundation. We purposively selected articles from the scientific (n=48) and grey literature (n=26). We sought papers that acknowledged and unpacked the plurality of quality in chronic care and proposed or utilised frameworks, studied their implementation, or investigated at least two IOM quality care aims and implementation. Articles were analysed both deductively and inductively. The findings were validated through a Delphi survey involving 49 international chronic care experts with varied knowledge of, and experience in, low-and-middle-income countries. Considering the natural history of chronic conditions and the journey of a person with a chronic condition, we defined and identified the aims of chronic care quality. The six IOM aims apply with specific meanings. We identified a seventh aim, continuity, which relates to the issue of chronicity. The group endorsed our specifications and several participants gave contextualised interpretations and concrete examples. Chronic conditions pose specific challenges underscoring the relevance of tailoring quality of care aims. The next steps require a tailored definition and specific aims to improve, measure and assure the quality of chronic care.

Background: Patients with facioscapulohumeral dystrophy (FSHD) suffer from slowly progressive muscle weakness. Approximately 20% of FSHD patients end up wheelchair-dependent. FSHD patients benefit from physical activity to maintain their muscle strength as much as possible. The impact of the COVID-19 pandemic on the health of FSHD patients was unknown., Objective: This study assessed changes in daily care received, perceived psychosocial stress, and worsening of FSHD complaints in 2020. Furthermore, we compared COVID-19 infection incidence and severity of symptoms between FSHD patients and non-FSHD housemates., Methods: Three online survey rounds were sent out to all adult participants of the Dutch FSHD registry regarding daily care received, perceived psychosocial stress, COVID-19 infection rate, and COVID-19 symptoms severity. They also included COVID-19-related questions regarding the participants' housemates, which served as control group., Results: Participation rate was 210 (61%), 186 (54%), and 205 (59%) for survey 1, 2, and 3, respectively. Care reduction was reported by 42.7%, 40%, and 28.8% of the participants in the respective surveys. Perceived psychosocial stress increased in 44%, 30%, and 40% of the participants. Compared to the 197 non-FSHD housemates, the 213 FSHD patients reported more possibly COVID-19-related symptoms (27% vs. 39%, p = 0.017) of mostly minimal severity (63%). No difference in (possible) COVID-19 infection incidence rates was found (2.0% vs. 2.8%, p = 0.527)., Conclusions: The COVID-19 pandemic negatively impacted care received and increased perceived psychosocial stress in FSHD patients. However, COVID-19 infection incidence in FSHD patients was similar to their non-FSHD housemates., (© 2024. The Author(s).)

Background: Telemedicine enables new forms of medical consultation and is expanding worldwide. Patients in sub-Saharan Africa could potentially benefit substantially from telemedicine., Objective: To improve primary healthcare services, especially referrals to the district hospital, for the population in three health centres in the rural district Kingandu in the Democratic Republic of the Congo (DRC) by introducing Smart Glasses, and leveraging them for telemedicine., Methods: The project involved the design and introduction of an intervention combining community engagement with technological innovation (Smart Glasses, communication equipment, moto-ambulances, and new diagnostic tests), and with staff training. Utilisation of the intervention, use of the health centres, and referrals to the hospital were monitored through the routine health information system and project-specific registers. Key stakeholders were interviewed and the project costs were analysed., Results: The use cases for the intervention were defined in consultation with the stakeholders. Smart Glasses were used in 10% of consultations in the health centres mostly for advice during curative consultations. The total number of consultations increased significantly in the intervention health centres. The number of referrals to the hospital remained stable, but an increased proportion effectively arrived in the hospital. The Smart Glasses and moto-ambulance greatly facilitated emergency referrals, often requiring a potentially life-saving intervention in the hospital. All stakeholders involved highly valued the intervention., Conclusion: Telemedicine can contribute to improving primary healthcare services in a remote rural area, as part of a more comprehensive intervention and with intensive participation of all stakeholders. It can increase acceptability and use of the existing services; improve diagnosis, treatment, and referral of patients; and can also facilitate on-the-job training and supportive supervision.

Background: Guinea undertook health workforce reform in 2016 following the Ebola outbreak to overcome decades-long shortages and maldistribution of healthcare workers (HCWs). Specifically, over 5000 HCWs were recruited and deployed to rural health districts and with a signed 5-year commitment for rural medical practice. Governance structures were also established to improve the supervision of these HCWs. This study assessed the effects of this programme on local health systems and its influence on HCWs turnover in rural Guinea., Methods: An exploratory study design using a mixed-method approach was conducted in five rural health districts. Data were collected through semi-structured questionnaires, in-depth interview guides, and documentary reviews., Results: Of the 611 HCWs officially deployed to the selected districts, 600 (98%) took up duties. Female HCWs (64%), assistant nurses (39%), nurses (26%), and medical doctors (20%) represented the majority. Findings showed that 69% of HCWs were posted in health centres and the remaining in district hospitals and the health office (directorate); the majority of which were medical doctors, nurses, and midwives. The deployment has reportedly enhanced quality and timely data reporting. However, challenges were faced by local health authorities in the posting of HCWs including the unfamiliarity of some with primary healthcare delivery, collaboration conflicts between HCWs, and high feminization of the recruitment. One year after their deployment, 31% of the HCWs were absent from their posts. This included 59% nurses, 29% medical doctors, and 11% midwives. The main reasons for absenteeism were unknown (51%), continuing training (12%), illness (10%), and maternity leave (9%). Findings showed a confusion of roles and responsibilities between national and local actors in the management of HCWs, which was accentuated by a lack of policy documents., Conclusion: The post-Ebola healthcare workers policy appears to have been successfully positive in the redistribution of HCWs, quality improvement of staffing levels in peripheral healthcare facilities, and enhancement of district health office capacities. However, greater attention should be given to the development of policy guidance documents with the full participation of all actors and a clear distinction of their roles and responsibilities for improved implementation and efficacy of this programme.

In Brussels, many migrant women without legal status have no or limited access to health care and other basic services. Their access to descent care is mainly hampered by a lack of information, limited financial resources and poor experiences in the past. Three non-governmental organisations joint efforts to help migrant women without legal status to come out of their isolation. Action research during the implementation process was conducted in order to know which elements contributed to increased feelings of trust and reinforced autonomy among the target group and more willingness to support migrants among a larger population. Our major conclusion is that mental health and well-being is largely defined by (the quality of) social relations and interactions - an aspect that is too often forgotten as a result of the medicalization of mental health related problems.

During inflammatory reactions, endogenously produced cytokines and chemokines act in a network and interact with hormones and neurotransmitters to regulate host immune responses. These signaling circuitries are even more interfaced during infections, when microbial agonists activate TLR, RLR, and NLR receptors. On the basis of the discovery of synergy between chemokines for neutrophil attraction, we extend here this phenomenon between the chemokine MCP-1/CCL2 and the GPCR ligand fMLP or the TLR4 agonist LPS on monocytes. In fact, the bacterial tripeptide fMLP, but not the cytokines IL-1beta or IFN-gamma, significantly and dose-dependently synergized with CCL2 in monocyte chemotaxis. Furthermore, LPS rapidly induced the expression of IL-8/CXCL8 but not of the CCL2 receptor CCR2 in monocytic cells. In turn, the induced CXCL8 synergized with CCL2 for mononuclear cell chemotaxis, and the chemotactic effect was mediated by CXCR1/CXCR2, because CXCL8 receptor antagonists or antibodies were capable of blocking the synergy, while keeping the responsiveness to CCL2 intact. These data recapitulate in vitro the complexity of innate immune regulation, provide a novel mechanism of enhancing monocyte chemotaxis during bacterial infections with gram-negative bacteria and demonstrate the importance of local contexts in inflammatory and infectious insults.

Chemokines are important in inflammation and in carcinogenesis. We hypothesized that besides oro-laryngeal cancer, oral inflammatory states, such as periodontitis, may also influence the chemokine profile of oral fluid. The aim of this study was to characterize the chemokine isoforms in the oral fluid of patients with periodontitis and in the oral fluid of patients with head and neck cancer. Using enzyme-linked immunosorbent assays (ELISA), it was found that the concentrations of CXCL8, CXCL10, and CCL14 were significantly elevated in the oral fluids of the cancer patients. However, periodontitis did not significantly alter the chemokine levels in oral fluid. Identification of chemokine isoforms by a proteomic approach using a newly developed three-step purification procedure was applied on the oral fluid of head and neck cancer and periodontitis patients and on the conditioned medium from carcinoma cells. Carcinoma cells produced predominantly intact CXCL1, CXCL2, CXCL8, and CCL2, whereas CXCL8 also appeared in a truncated, more active, form. Unfortunately, the chemokine concentrations in oral fluids were too low to allow full biochemical identification of the modified isoforms. However, the chemokine profile of head and neck cancer significantly changed after therapy, indicating that it is a useful parameter in clinical practice.

Interactions between chemokines and enzymes are vital in immunoregulation. Structural protein citrullination by peptidylarginine deiminase (PAD) has been associated with autoimmunity. In this report, we identified a novel naturally occurring posttranslational modification of chemokines, that is, the deimination of arginine at position 5 into citrulline of CXC chemokine ligand 10 (CXCL10) by rabbit PAD and human PAD2. Citrullination reduced (>/= 10-fold) the chemoattracting and signaling capacity of CXCL10 for CXC chemokine receptor 3 (CXCR3) transfectants; however, it did not affect CXCR3 binding. On T lymphocytes, though, citrullinated CXCL10 remained active but was again weaker than authentic CXCL10. PAD was also able to convert CXCL11, causing an impairment of CXCR3 signaling and T-cell activation, though less pronounced than for CXCL10. Similarly, receptor binding properties of CXCL11 were not altered by citrullination. However, deimination decreased heparin binding properties of both CXCL10 and CXCL11. Overall, chemokines are the first immune modulators reported of being functionally modified by citrullination. These data provide new structure-function dimensions for chemokines in leukocyte mobilization, disclosing an anti-inflammatory role for PAD. Additionally because citrullination has severe consequences for chemokine biology, this invites to reassess the involvement and impact of PAD and citrullinated peptides in inflammation, autoimmunity, and hematologic disorders.

Chemokines affect inflammation and cancer through leukocyte attraction and angiogenesis. Here, we demonstrate that CXCL4L1/platelet factor-4 variant (PF-4var), a highly angiostatic chemokine, is poorly chemotactic for phagocytes and is inducible in monocytes by inflammatory mediators but remained undetectable in macrophages and neutrophils. In addition, CXCL4L1/PF-4var production by mesenchymal tumor cells was evidenced in vitro and in vivo by specific ELISA and immunohistochemistry. CXCL4L1/PF-4var, but not CXCL4/PF-4, was coinduced with the angiogenic chemokine CXCL6/granulocyte chemotactic protein-2 (GCP-2) by cytokines, e.g., IL-1beta and IL-17, in sarcoma cells, but not in diploid fibroblasts. Furthermore, the induction of CXCL6/GCP-2 in endothelial cells by IL-1beta was enhanced synergistically by TNF-alpha but inhibited by IFN-gamma, which synergized with IL-1beta to produce the angiostatic CXCL10/IFN-gamma-induced protein-10. These findings indicate that the equilibrium between angiostatic and angiogenic factors during inflammation and tumor progression is rather complex and differs depending on the chemokine, cell type, and stimulus. Selective intervention in the chemokine network may drastically disturb this delicate balance of angiogenesis and tissue repair. Application of angiostatic CXCL4L1/PF-4var without attraction of protumoral phagocytes may be beneficial in cancer therapy.

CXCR3 ligands were secreted by tissue fibroblasts and peripheral blood-derived mononuclear leukocytes in response to interferon-gamma (IFN-gamma) and Toll-like receptor (TLR) ligands. Subsequent purification and identification revealed the presence of truncated CXCL11 variants missing up to 6 amino acids. In combination with CD26/dipeptidyl peptidase IV, the metalloprotease aminopeptidase N (APN), identical to the myeloid cell marker CD13, rapidly processed CXCL11, but not CXCL8, to generate truncated CXCL11 forms. Truncated CXCL11 had reduced binding, signaling, and chemotactic properties for lymphocytes and CXCR3- or CXCR7-transfected cells. CD13/APN-truncated CXCL11 failed to induce an intracellular calcium increase but was still able to bind and desensitize CXCR3 for intact CXCL11 signaling. CXCL11 efficiently bound to CXCR7, but CXCL11 was not able to induce calcium signaling or ERK1/2 or Akt phosphorylation through CXCR7. CD26-truncated CXCL11 failed to attract lymphocytes but still inhibited microvascular endothelial cell (HMVEC) migration. However, further processing of CXCL11 by CD13 resulted in significant reduction of inhibition of HMVEC migration. Taken together, during inflammation or cancer, CXCL11 processing by CD13 may lead to a reduced number of tumor-infiltrating lymphocytes and in a more angiogenic environment.

Mice with a disrupted IFN-gamma system are remarkably susceptible to experimental autoimmune diseases, such as collagen-induced arthritis (CIA), which rely on the use of CFA. The inflammatory lesions of these IFN-gamma knockout (KO) mice are characterized by an excessive proportion of neutrophils. Here, we show that the increased severity of CIA in IFN-gammaR KO as compared with wild-type mice is accompanied by increased levels of the CXC chemokine granulocyte chemotactic protein-2 (GCP-2), a major neutrophil-attracting chemokine in mice. We demonstrated that the heat-killed mycobacteria present in CFA elicited production of GCP-2 in mouse embryo fibroblast cultures and that this production was inhibited by IFN-gamma. Inhibition of GCP-2 production by IFN-gamma was STAT-1-dependent. IFN-gamma receptor KO mice treated with neutralizing anti-GCP-2 antibodies were protected from CIA, indicating the in vivo importance of GCP-2 in the pathogenesis of CIA. Our data support the notion that one of the mechanisms whereby endogenous IFN-gamma mitigates the manifestations of CIA consists of inhibiting production of GCP-2, thereby limiting mobilization and infiltration of neutrophils, which are important actors in joint inflammation. These results may also be applicable to other experimental models of autoimmunity that rely on the use of CFA.

CXC chemokines are potent attractants of neutrophil granulocytes, T cells or natural killer cells. Toll-like receptors (TLR) recognize microbial components and are also activated by endogenous molecules possibly implicated in autoimmune arthritis. In contrast to CXC chemokine ligand 8 (CXCL8), no CXC chemokine receptor 3 (CXCR3) ligand (ie CXCL9, CXCL10 and CXCL11) was induced by bacterial TLR ligands in human microvascular endothelial cells (HMVEC). However, peptidoglycan (PGN), double-stranded (ds) RNA or lipopolysaccharide (LPS) (TLR2, TLR3 or TLR4 ligands, respectively) synergized with interferon-gamma (IFN-gamma) at inducing CXCL9 and CXCL10. In contrast, enhanced CXCL11 secretion was only obtained when IFN-gamma was combined with TLR3 ligand. Furthermore, flagellin, loxoribine and unmethylated CpG oligonucleotide (TLR5, TLR7 and TLR9 ligands, respectively) did not enhance IFN-gamma-dependent CXCR3 ligand production in HMVEC. In analogy with TLR ligands, tumor necrosis factor-alpha (TNF-alpha) or interleukin-1beta (IL-1beta), in combination with IFN-gamma, synergistically induced CXCL9 and CXCL11 in HMVEC and human fibroblasts, two fundamental cell types delineating the joint cavity. Etanercept, a humanized soluble recombinant p75 TNF-receptor/IgG(1)Fc fusionprotein, neutralized synergistic CXCL9 production induced by TNF-alpha plus IFN-gamma, but not synergy between IFN-gamma and the TLR ligands PGN or LPS. Synovial chemokine concentrations exemplify the physiopathological relevance of the observed in vitro chemokine production patterns. In synovial fluids of patients with spondylarthropathies (ie ankylosing spondylitis or psoriatic arthritis) or rheumatoid arthritis, significantly enhanced CXCL9, but not CXCL11 levels, were detected compared to concentrations in synovial fluids of patients with metabolic crystal-induced arthritis. Thus, CXCL9 is an important chemokine in autoimmune arthritis.

The synovial cavity constitutes the ideal stage to study the interplay between microbial Toll-like receptor (TLR) ligands and cytokines. Infiltrated leukocytes and synovial fibroblasts produce cytokine- and chemokine-induced proteases for remodeling the extracellular matrix. The regulation of chemokine function for attraction and activation of leukocytes constitutes a key feature in host immunity and resolution of inflammation after infection. Enhanced levels of the CXC chemokine ligand (CXCL9)/monokine induced by interferon-gamma (IFN-gamma) and CXCL11/IFN-inducible T cell alpha chemoattractant, two chemoattractants for activated T cells and natural killer cells, and ligands for CXC chemokine receptor 3 (CXCR3) were detected in the synovial fluid of septic arthritis compared with osteo- and crystal arthritis patients. In vitro, IFN-gamma and TLR3 ligation by double-stranded RNA (dsRNA) induced the expression of CXCL9 and CXCL11 in leukocytes and skin-muscle fibroblasts, whereas ligation of TLR2, TLR4, TLR5, and TLR9 by peptidoglycan (PGN), lipopolysaccharide (LPS), flagellin, and unmethylated CpG oligonucleotides, respectively, did not. PGN and LPS, but not unmethylated CpG oligonucleotides, even inhibited IFN-gamma-induced CXCL9 and CXCL11 expression in leukocytes. In sharp contrast, in fibroblasts, the TLR ligands PGN, dsRNA, LPS, and flagellin synergized with IFN-gamma for the production of CXCL9 and CXCL11. Although TLR ligands stimulate leukocytes to produce CXCL8/interleukin-8 during the early innate defense, they contribute less to the production of CXCR3 ligands, whereas fibroblasts are important sources of CXCR3 ligands. These results illustrate the complex interaction between cytokines and TLR ligands in infection.

The collaborative program of the Transcultural Psychosocial Organization (TPO) provides a community-oriented and culturally sensitive public health response to the psychosocial problems of refugees and victims of organized violence. This paper describes the 9-step model that TPO has developed as a blueprint for each new intervention. Beneficiaries participate in determining priorities and there is an orientation toward culturally competent training, capacity-building, and sustainability. Two cases, one related to Sudanese refugees in Uganda and the other to internally displaced persons and returnees in postwar Cambodia, show how the TPO intervention protocol is adapted to local settings. The paper provides preliminary evaluative comments on the model's performance.

The CXC chemokine IFN-gamma-inducible protein-10 (IP-10/CXCL10) activates CXC chemokine receptor 3 (CXCR3) and attracts activated T cells and natural killer cells. Peripheral blood mononuclear cells (PBMC) produce low but significant amounts of IP-10/CXCL10 protein upon stimulation with double-stranded (ds) RNA, the Toll-like receptor 3 (TLR3) ligand. IFN-gamma is a superior IP-10/CXCL10inducer. The bacterial TLR4 and TLR2 ligands, LPS and peptidoglycan (PGN), inhibit IFN-gamma- or dsRNA-dependent IP-10/CXCL10 production in PBMC, whereas IL-8/CXCL8 production was enhanced. In fibroblasts a different picture emerges with IFN-gamma inducing moderate and dsRNA provoking strong IP-10/CXCL10 production. Furthermore, treatment of fibroblasts with IFN-gamma in combination with bacterial LPS or PGN results in a synergistic production of IP-10/CXCL10 and IL-8/CXCL8. The synergistic induction of IP-10/CXCL10 in fibroblasts is reflected by significantly enhanced IP-10/CXCL10 concentrations in synovial fluids of septic compared to osteoarthritis patients to reach on average higher levels than those of IL-8/CXCL8. These high amounts of IP-10/CXCL10 produced by connective tissue fibroblasts not only attract CXCR3 expressing activated Th1 cells and natural killer cells to sites of infection but may also antagonize the CCR3 dependent attraction of Th2 lymphocytes and exert CXCR3-independent, defensin-like antibacterial activity.

Human granulocyte chemotactic protein-2 (GCP-2)/CXCL6 is a CXC chemokine that functionally uses both of the IL-8/CXCL8 receptors to chemoattract neutrophils but that is structurally most related to epithelial cell-derived neutrophil attractant-78 (ENA-78)/CXCL5. This study provides the first evidence that GCP-2 protein is, compared with IL-8, weakly produced by some sarcoma, but less by carcinoma cells, and is tightly regulated in normal mesenchymal cells. IL-1beta was the predominant GCP-2 inducer in fibroblasts, chondrocytes, and endothelial cells, whereas IL-8 was equally well up-regulated in these cells by TNF-alpha, measles virus, or double-stranded RNA (dsRNA). In contrast, lipopolysaccharide (LPS) was a relatively better stimulus for GCP-2 versus IL-8 in fibroblasts. IFN-gamma down-regulated the GCP-2 production in fibroblasts induced by IL-1beta, TNF-alpha, LPS, or dsRNA. The kinetics of GCP-2 induction by IL-1beta, LPS, or dsRNA in fibroblasts differed from those of IL-8. Freshly isolated peripheral blood mononuclear leukocytes, which are a good source of IL-8 and ENA-78, failed to produce GCP-2. However, lung macrophages and blood monocyte-derived macrophages produced GCP-2 in response to LPS. Quantitatively, secretion of GCP-2 always remained inferior to that of IL-8, despite the fact that the ELISA recognized all posttranslationally modified GCP-2 isoforms. The expression of GCP-2 was confirmed in vivo by immunohistochemistry. The patterns of producer cell types, inducers and kinetics and the quantities of GCP-2 produced, suggest a unique role for GCP-2 in physiologic and pathologic processes.

The recently discovered CC chemokine, regakine-1, is constitutively present in bovine serum and synergizes with the CXC chemokine interleukin-8 (IL-8) to chemoattract neutrophils. Here we show that regakine-1 cooperates with the CXC chemokine receptor 2 ligand neutrophil activating protein-2 (NAP-2) and the anaphylatoxin C5a, two other mediators of inflammation present in the circulation. Neutrophil chemotaxis was 3-fold enhanced when regakine-1 (100 ng/ml) and C5a (30 ng/ml) were combined at concentrations present in bovine or human plasma, respectively. This synergy was also observed when neutrophils were preincubated with regakine-1. Plasma chemokines such as NAP-2, beta-thromboglobulin, and hemofiltrate CC-chemokine-1 did not affect C5a chemotactic activity. The capability of regakine-1 to synergize with C5a, NAP-2, or N-formyl-methionyl-leucyl-phenylalanine (fMLP) was not observed for monocyte chemotactic protein-3 (MCP-3), another CC chemokine that weakly chemoattracts neutrophils. Regakine-1 also failed to cooperate with MCP-3 and macrophage inflammatory protein-1alpha in neutrophil chemotaxis. The receptor of regakine-1 is not known yet. Competition with labeled fMLP or C5a for binding to neutrophils or receptor transfected cell lines demonstrated that regakine-1 did not alter receptor recognition. The protein kinase inhibitors 2'-amino-3'-methoxyflavone (PD98059), wortmannin and staurosporin had no effect on the synergy between C5a and regakine-1. Although NH2-terminal truncation affects the chemotactic potency of most chemokines, it did not affect the synergistic capacity of regakine-1 with C5a on neutrophils. These findings indicate that the constitutive plasma chemokine regakine-1 is a stable enhancer of the inflammatory response and that its blockade might be beneficial in acute and systemic inflammatory disorders.

Chemokines are mediators of innate and acquired immunity. CCL18, also designated pulmonary and activation-regulated chemokine (PARC), dendritic cell-derived CC chemokine-1 (DC-CK1), alternative macrophage activation-associated CC chemokine-1 (AMAC-1) and macrophage inflammatory protein-4 (MIP-4), was for the first time isolated from peripheral blood mononuclear cells (PBMC) and biochemically characterized. We found that CCL18/PARC protein is spontaneously secreted by PBMC and is selectively induced in PBMC by staphylococcal enterotoxins (SEA, SEB) and IL-4, but not by IFN-gamma and the CXCL8/IL-8 inducers lipopolysaccharide (LPS) or Concanavalin A. Human fibroblasts, chondrocytes and endothelial cells did not produce CCL18/PARC in response to inflammatory mediators such as measles virus, double-stranded RNA, LPS or IL-1beta, whereas up to 150 ng/ml of CCL2/MCP-1 was induced under these conditions. In synovial fluids from septic and rheumatoid arthritis patients, fourfold-enhanced CCL18/PARC levels (150 ng/ml) were detected compared to those in crystal-induced arthritis and osteoarthritis. In septic arthritis, the synovial levels of CCL18/PARC were fivefold higher than those of CXCL8/IL-8. Immunochemistry revealed CD68(+) monocytes/macrophages as the main CCL18/PARC-producing cell type in both PBMC and arthritic synovial tissue. In addition, CD1a(+) blood dendritic cells expressed CCL18/PARC. These findings suggest that monocytic cells respond to Gram-positive bacterial infection by the production of CCL18/PARC in the synovial cavity.

Context: Little is known about the impact of trauma in postconflict, low-income countries where people have survived multiple traumatic experiences., Objective: To establish the prevalence rates of and risk factors for posttraumatic stress disorder (PTSD) in 4 postconflict, low-income countries., Design, Setting, and Participants: Epidemiological survey conducted between 1997 and 1999 among survivors of war or mass violence (aged >/=16 years) who were randomly selected from community populations in Algeria (n = 653), Cambodia (n = 610), Ethiopia (n = 1200), and Gaza (n = 585)., Main Outcome Measure: Prevalence rates of PTSD, assessed using the PTSD module of the Composite International Diagnostic Interview version 2.1 and evaluated in relation to traumatic events, assessed using an adapted version of the Life Events and Social History Questionnaire., Results: The prevalence rate of assessed PTSD was 37.4% in Algeria, 28.4% in Cambodia, 15.8% in Ethiopia, and 17.8% in Gaza. Conflict-related trauma after age 12 years was the only risk factor for PTSD that was present in all 4 samples. Torture was a risk factor in all samples except Cambodia. Psychiatric history and current illness were risk factors in Cambodia (adjusted odds ratio [OR], 3.6; 95% confidence interval [CI], 2.3-5.4 and adjusted OR,1.6; 95% CI, 1.0-2.7, respectively) and Ethiopia (adjusted OR, 3.9; 95% CI, 2.0-7.4 and adjusted OR, 1.8; 95% CI, 1.1-2.7, respectively). Poor quality of camp was associated with PTSD in Algeria (adjusted OR, 1.8; 95% CI, 1.3-2.5) and in Gaza (adjusted OR, 1.7; 95% CI, 1.1-2.8). Daily hassles were associated with PTSD in Algeria (adjusted OR, 1.6; 95% CI, 1.1-2.4). Youth domestic stress, death or separation in the family, and alcohol abuse in parents were associated with PTSD in Cambodia (adjusted OR, 1.7; 95% CI, 1.1-2.6; adjusted OR, 1.7; 95% CI, 1.0-2.8; and adjusted OR, 2.2; 95% CI, 1.1-4.4, respectively)., Conclusions: Using the same assessment methods, a wide range of rates of symptoms of PTSD were found among 4 low-income populations who have experienced war, conflict, or mass violence. We identified specific patterns of risk factors per country. Our findings indicate the importance of contextual differences in the study of traumatic stress and human rights violations.

Recently, the LD78beta isoform of the CC chemokine macrophage inflammatory protein (MIP)-1alpha was shown to efficiently chemoattract lymphocytes and monocytes and to inhibit infection of mononuclear cells by R5 HIV-1 strains. We have now demonstrated that after cleavage of the NH2-terminal Ala-Pro dipeptide by CD26, LD78beta(3 - 70) became the most potent chemokine blocking HIV-1. LD78beta(3 - 70) competed tenfold more efficiently than LD78beta(1 - 70) with [125I] RANTES for binding to the CC chemokine receptors CCR5 and CCR1. Contrary to LD78alpha, LD78beta(1 - 70) at 30 ng/ml efficiently competed with [125I] RANTES for binding to CCR3 and mobilized calcium in CCR3 transfectants, whereas LD78beta(3 - 70) showed a 30-fold decrease in CCR3 affinity compared to LD78beta(1 - 70). This demonstrates the importance of the penultimate proline in LD78beta(1 - 70) for CCR3 recognition. Both LD78beta isoforms efficiently chemoattracted eosinophils from responsive donors. In contrast, only the CCR3 agonist LD78beta(1 - 70) and not LD78beta(3 - 70), induced calcium increases in eosinophils with low levels of CCR1. In responder neutrophils, LD78beta(3 - 70) elicited calcium fluxes at a 30-fold lower dose (10 ng/ml) compared to intact LD78beta and LD78alpha, whereas the three MIP-1alpha isoforms were equipotent neutrophil chemoattractants. Taken together, both LD78beta isoforms are potent HIV-1 inhibitors (CCR5) and activators for neutrophils (CCR1) and eosinophils (CCR1, CCR3), affecting infection and inflammation.

Liver and activation-regulated chemokine (LARC), also designated macrophage inflammatory protein-3alpha (MIP-3alpha), Exodus, or CCL20, is a C-C chemokine that attracts immature dendritic cells and memory T lymphocytes, both expressing CCR6. Depending on the cell type, this chemokine was found to be inducible by cytokines (IL-1beta) and by bacterial, viral, or plant products (including LPS, dsRNA, and PMA) as measured by a specific ELISA. Although coinduced with monocyte chemotactic protein-1 (MCP-1) and IL-8 by dsRNA, measles virus, and IL-1beta in diploid fibroblasts, leukocytes produced LARC/MIP-3alpha only in response to LPS. However, in myelomonocytic THP-1 cells LARC/MIP-3alpha was better induced by phorbol ester, whereas in HEp-2 epidermal carcinoma cells IL-1beta was the superior inducer. The production levels of LARC/MIP-3alpha (1-10 ng/ml) were, on the average, 10- to 100-fold lower than those of IL-8 and MCP-1, but were comparable to those of other less abundantly secreted chemokines. Natural LARC/MIP-3alpha protein isolated from stimulated leukocytes or tumor cell lines showed molecular diversity, in that NH(2)- and COOH-terminally truncated forms were purified and identified by amino acid sequence analysis and mass spectrometry. In contrast to other chemokines, including MCP-1 and IL-8, the natural processing did not affect the calcium-mobilizing capacity of LARC/MIP-3alpha through its receptor CCR6. Furthermore, truncated natural LARC/MIP-3alpha isoforms were equally chemotactic for lymphocytes as intact rLARC/MIP-3alpha. It is concluded that in addition to its role in homeostatic trafficking of leukocytes, LARC/MIP-3alpha can function as an inflammatory chemokine during host defense.

Cambodia has undergone massive psychosocial trauma in the last few decades, but has had virtually no western-style mental health services. For the first time in Cambodia a number of mental health clinics in rural areas have been started. This experience is used to discuss the risks and opportunities in introducing these services in the present war-torn situation. Basic statistics from the clinics are presented in the context of the historical and traditional setting, and the effort to maintain a culturally informed approach is described. The contrasting results in the clinics are analyzed in relation to factors intrinsic to the health care system and those related to the local population in order to highlight the issues involved in establishing future mental health services, both locally in other provinces and in situations similar to Cambodia. The efficacy of introducing low-cost, basic mental health care is shown, and related to the need to find solutions for prevailing problems on the psychosocial level. They can be introduced with modest means, and can be complementary to local health beliefs and traditional healing. In introducing mental health services, an approach is needed which adapts to the absorption potential of the health system as well as to the patients' need to find meaningful help. Existing resources, from the traditional healing sector to rudimentary village structures, cannot be neglected in the rehabilitation of the community, or in interventions to help the individual patient.

Chemokines are a family of chemotactic peptides affecting leukocyte migration during the inflammatory response. Post-translational modification of chemokines has been shown to affect their biological potency. Here, the isolation and identification of natural isoforms of the neutrophil chemoattractants GRO alpha and GRO gamma and the epithelial-cell-derived neutrophil attractant-78 (ENA-78), is reported. Cultured tumor cells produced predominantly intact chemokine forms, whereas peripheral blood monocytes secreted mainly NH2-terminally truncated forms. The order of neutrophil chemotactic potency of these CXC chemokines was GRO alpha > GRO gamma > ENA-78 both for intact and truncated forms. However, truncated GRO alpha (4,5,6-73), GRO gamma (5-73) and ENA-78(8,9-78) were 30-fold, fivefold and threefold more active than the corresponding intact chemokine. As a consequence, truncated GRO alpha (4,5,6-73) was 300-fold more potent than intact ENA-78 indicating that both the type of chemokine and its mode of processing determine the chemotactic potency. Similar observations were made when intact and truncated GRO alpha, GRO gamma and ENA-78 were compared for their capacity to induce an increase in the intracellular calcium concentration in neutrophilic granulocytes, and to desensitize the calcium response towards the CXC chemokine granulocyte chemotactic protein-2 (GCP-2). It must be concluded that physiological proteolytic cleavage of CXC chemokines in general enhances the inflammatory response, whereas for CC chemokines NH2-terminal processing mostly results in reduced chemotactic potency.

Monocyte chemotactic protein-3 (MCP-3) is a pluripotent CC chemokine, attracting most leukocytic cell types. With the use of a sensitive and specific ELISA, MCP-3 was found to be inducible in fibroblasts and peripheral blood mononuclear cells (PBMC) by cytokines and cytokine inducers. MCP-3 production levels (1-10 ng/ml) were tenfold lower compared to those of MCP-1. In diploid fibroblasts, synergistic induction of MCP-3, but not of MCP-1, mRNA and protein was observed by combined treatment with IL-1beta and IFN-gamma. In PBMC, IFN-alpha and IFN-beta (but not IFN-gamma), as well as measles virus and double-stranded RNA, were potent inducers of MCP-3, which suggests a role for this chemokine in an early stage of viral infections. In contrast, endotoxin failed to induce MCP-3 production in fibroblasts and PBMC. Purification of MCP-3 from PBMC revealed biochemical heterogeneity. In monocyte chemotaxis and calcium mobilization assays, pure 11-kDa MCP-3 from PBMC showed similar potencies as MCP-3 from tumor cells. It was concluded that the induction of MCP-3 by IFN is regulated differently in fibroblasts and PBMC. In view of the multiple target cells for MCP-3, local and strictly regulated chemokine production might be important to conduct selectively the immune response in infection or inflammation.

An effort is being made in Cambodia to involve grass-roots personnel in the integration of the care of the mentally ill into a broad framework of health services. This undertaking is examined with particular reference to the work of the Transcultural Psychosocial Organization.

Monocyte chemotactic protein (MCP)-1 and MCP-2, two closely related CC chemokines, are important mediators of monocyte and lymphocyte migration. These chemokines are secreted by various normal cell types, including fibroblasts, epithelial cells, and leukocytes, as well as by tumor cells. After stimulation with different cytokines and cytokine inducers the MCP-2 production levels are always lower than those of MCP-1. In human diploid fibroblasts cytokines differentially regulate chemokine induction, interleukin (IL)-1beta and interferon (IFN)-gamma being potent stimuli of MCP-1 and MCP-2, respectively. Co-stimulation of fibroblasts by 10 U/mL IL-1beta and 20 ng/mL IFN-gamma resulted in a synergistic induction of MCP-2, whereas the combined effect on MCP-1 and IL-6 production was rather additive. These findings were confirmed at the mRNA level by Northern blot analysis. In contrast, in human MG-63 fibroblastoid cells and HEp-2 epithelial cells, selected for their poor responsiveness to IL-1beta and IFN-gamma, MCP-2 as well as MCP-1 and IL-6 were synergistically induced, yielding protein levels that were increased 3- to 30-fold above the additive levels. When IFN-beta was used as a co-stimulant of IL-1beta, a similar synergistic induction of MCP-1 and MCP-2 was measured both at the protein and the mRNA level. It can be concluded that, when synergy occurred, the MCP-1 and MCP-2 expression levels reached a comparable maximum, indicative for an equal contribution of these chemokines in normal and pathological conditions.

Purpose: To investigate whether the chemokines monocyte chemotactic protein-1 (MCP-1) and interleukin-8 (IL-8) are involved in the pathogenesis of proliferative vitreoretinal disorders and to study their possible interaction with IL-6., Methods: In a prospective study of 125 consecutive patients (125 eyes), vitreous and paired serum samples were obtained and were assayed for MCP-1 and IL-8. Levels of IL-6 were determined by proliferation of the IL-6-dependent hybridoma cell line 7TD1., Results: Monocyte chemotactic protein-1 was detected in 13 (48%) of 27 vitreous samples from patients with retinal detachment, in five (63%) of eight samples from patients with macular pucker, in 31 (72%) of 43 samples from patients with proliferative vitreoretinopathy, and in 32 (76%) of 42 samples from patients with proliferative diabetic retinopathy, but not in samples from five patients with idiopathic epiretinal membrane. There was a significant (P = .049) correlation between the incidence of MCP-1 detection in retinal detachment, macular pucker, and proliferative vitreoretinopathy groups and the severity of proliferation. Interleukin-8 was detected in two vitreous samples from eyes with retinal detachment, in two samples from eyes with proliferative vitreoretinopathy, and in three samples from eyes with proliferative diabetic retinopathy. Monocyte chemotactic protein-1 levels in the vitreous samples were positively correlated with IL-6 levels (r = .31, P = .01). Interleukin-6 levels were significantly (P = .0097) greater in vitreous samples with than without detectable levels of MCP-1., Conclusion: Monocyte chemotactic protein-1 is present in a substantial percent of vitreous samples from eyes with proliferative vitreoretinal disorders and may help in stimulating the infiltration of monocytes and macrophages into eyes with these disorders.

A novel family of chemotactic cytokines or chemokines, essential for the directed migration of leukocytes to sites of inflammation, has been identified during the past decade. To obtain microgram amounts of natural chemokines, normal (e.g., freshly isolated leukocytes, connective tissue cell cultures) or malignant cell lines have to be selectively induced with endogenous (cytokines) or exogenous (bacterial, viral, or plant) products. We have developed a four-step procedure that allows for the complete purification of active C-C (MCP-1, MCP-2, MCP-3, RANTES, MIP-1alpha and MIP-1beta) and C-X-C (IL-8, GRO-alpha, GRO-beta, GRO-gamma, GCP-2, ENA-78, IP-10, PF-4, and CTAPIII/betaTG/NAP-2) chemokines from bulk volumes of culture supernatant. This method is applicable for the isolation of recombinant chemokines. Conditioned medium was first concentrated and partially purified on silicic acid or controlled pore glass beads. Further purification to homogeneity was achieved using heparin-Sepharose or antibody affinity chromatography, cation exchange FPLC, and reverse-phase HPLC. Purification of chemokines was monitored by testing column fractions for biological (chemotaxis) or immuno (RIA, ELISA) activity and protein content (SDS-PAGE). Homogeneous proteins were identified by amino-terminal or internal protein sequence analysis.

There is considerable evidence that Sertoli cell function is controlled not only by hormones, but also by locally produced growth factors and cytokines. To gain more insight into the nature and effects of cytokines potentially involved in the control of Sertoli cell function, we incubated rat Sertoli cells with media conditioned by activated human peripheral blood mononuclear cells. Such media (PBMC-CM) are known to be an extremely rich source of a variety of cytokines. It was demonstrated that PMBC-CM and protein fractions derived from them stimulate Sertoli cell transferrin secretion and messenger RNA production more potently then peritubular cell-conditioned medium or FIRT (a combination of FSH, insulin, retinol, and testosterone). Transferrin secretion expressed per mg cell DNA was stimulated approximately 5-fold by peritubular cell-conditioned medium or FIRT and nearly 20-fold by PBMC-CM. The effects of PBMC-CM were accompanied by a limited increase in cAMP and a noticeable rise in cGMP. Affinity chromatography on a column coated with an antiserum directed against interleukin-1 beta (IL-1 beta) showed that part of the activity in the PBMC-CM was related to IL-1 beta. The remainder of the activity was largely retained by an affinity column coated with an antiserum that recognizes IL-6 and a number of other known and unknown cytokines. Purified IL-1 beta provoked a 2- to 3-fold stimulation of Sertoli cell transferrin secretion. More limited stimulatory effects were observed with IL-6. Neither of these cytokines or their combination approached the degree of stimulation observed with crude PBMC-CM, suggesting that other cytokines are involved. It is concluded that the mixture of cytokines present in PBMC-CM is a more powerful stimulator of Sertoli cell transferrin secretion than any other agonist known at the present time. IL-1 and IL-6 may be responsible for part of the observed effects, but one or more other cytokines are probably involved.

The chemokine monocyte chemotactic protein 1 (MCP-1) is a cytokine with chemotactic activity specific for mononuclear phagocytes. To investigate the possible involvement of MCP-1 in the pathogenesis of sepsis, its course was studied in baboons challenged intravenously with a sublethal or lethal dose of Escherichia coli. Levels of MCP-1 started to increase in both groups of animals 2 h after injection of E. coli, reaching peak levels 4 and 6 h after a sublethal (186 +/- 21 ng/mL) or a lethal (213 +/- 24 ng/mL) dose, respectively. Levels of MCP-1 correlated significantly with plasma levels of another chemokine, interleukin-8 (IL-8; r = .826. P < .001), suggesting that common stimuli mediate the release of both cytokines in this model.

Phagocyte recruitment is an important immunological phenomenon in inflammation and cancer. A large family of selective chemotactic cytokines, designated chemokines, has recently emerged. Interleukin-8 (IL-8) is the prototype of such neutrophil activating factors, whereas MCP-1 is a well studied monocyte chemotactic protein. In vitro chemotactic assays were used to isolate and identify natural chemokines from mononuclear phagocytes and tumor cells. Additional new chemotactic proteins (MCP-2, MCP-3) attracting monocytes were also discovered by these methods. All chemokines are structurally related and show affinity for heparin. MCP-1, -2 and -3 have a comparable specific activity in monocyte chemotaxis assays. Specific and sensitive radioimmunoassays for MCP-1 and IL-8 were developed to study the regulation of their secretion by leukocytes. Monocytes or monocyte tumor cells produce MCP-1 and/or IL-8 in response to cytokines, virus, double stranded RNA, bacterial endotoxin, mitogen or phorbol ester. Granulocytes were found to secrete only minor amounts of MCP-1 and IL-8.

Monocyte chemotactic proteins (MCP) belong to a group of structurally and functionally related factors, called chemokines. To facilitate additional characterization of the recently identified MCP-2, the 76-residue protein was chemically synthesized. The synthetic 7-kDa monomeric protein was chemotactic for monocytes at 1 nM and was biochemically similar to natural MCP-2. Sensitive radioimmunoassays for both MCP-1 and MCP-2 were developed. These RIAs were specific in that no cross-reactivity could be observed, and other chemokines or cytokines were not detected. Induction of MCP-1 and MCP-2 in human diploid fibroblasts and peripheral blood leukocytes as well as osteosarcoma, epidermal carcinoma, and melanoma cells by the cytokines IL-1 beta, IFN-beta, and IFN-gamma and cytokine inducers such as dsRNA, virus, endotoxin, mitogen, and phorbol ester was studied. In connective tissue cells, IL-1 beta was the best inducer of MCP-1, but IFN-gamma was a superior inducer of MCP-2. Mononuclear cells also proved to be a source of MCP-1 and MCP-2 when stimulated by most of the inducers tested. Granulocytes, however, were inefficient producers. Measles virus induced MCP-1 and MCP-2 in most cell types. In general, the yields of MCP-2 were at least 10-fold lower than those of MCP-1. It is concluded that, although MCP-2 is often coproduced with MCP-1, regulation of expression of the two chemokines is not identical. It remains to be studied under which pathological conditions MCP-2 is released in vivo and whether MCP-1 and MCP-2 can activate different target cells.

Mice pretreated with monoclonal anti-interleukin-6 (IL-6) antibody and then challenged with lipopolysaccharide (LPS), paradoxically develop higher levels of circulating biological IL-6 activity, as measured by the hybridoma growth promotion assay, than mice similarly challenged but not pretreated with antibody. Here we provide evidence that this increased biological activity was entirely accounted for by the presence of increased amounts of IL-6 protein, which could be isolated by immunoaffinity chromatography and subsequently visualized after gel electrophoresis. Chromatography on a protein G matrix and a sandwich ELISA allowed to demonstrate that all IL-6 present in the serum was in the form of antigen-antibody complexes. Serum samples of antibody-treated animals which contained the highest biological activity typically contained near equimolar concentrations of IL-6 and antibody. In vitro neutralization tests with pure antibody and IL-6 demonstrated that, with both antibodies tested, more than 1000-fold molar excess of antibody is needed for neutralization in the hybridoma growth assay. It is concluded that increased biological activity in serum of the anti-IL-6 antibody-treated mice is due to sequestration of the endogenous IL-6 in the form of antigen-antibody complexes which, due to the lack of sufficient antibody excess, produce nearly full activity in the hybridoma growth assay.

Interleukin-1 beta (Il-1 beta) and interleukin-1 alpha (Il-1 alpha) were shown to act as motility factors for the human breast carcinoma cell lines SK-BR-3 and ZR-75-1 in vitro. Both cytokines induced transition from the stationary to the motile phenotype (spreading). Il-1 beta stimulated translocation, shape change and random migration (chemokinesis) of SK-BR-3 cells as demonstrated by time-lapse video recordings and by a modified Boyden chamber assay. Interleukin-6 (Il-6) stimulated spreading of the SK-BR-3 cells; an additive effect with Il-1 beta on spreading and fast plasma membrane movements was evidenced. In the SK-BR-3 cell line, the signal transduction of Il-1 beta and Il-6 differed, since only the effect of Il-6 on spreading was sensitive to pertussis toxin. Both Il-1 beta and Il-6 required protein synthesis to stimulate spreading, since cycloheximide inhibited the effect of the cytokines. Induction of an autocrine loop of Il-6 in the SK-BR-3 cells by Il-1 beta was unlikely, since after stimulation with Il-1 beta, no induction of Il-6 activity was measured, nor was inhibition of stimulated spreading seen in the presence of an antiserum against Il-6. Addition of Il-8 or of an antiserum against Il-8 did not affect spreading. We concluded that Il-1 and Il-6 could act as motility factors for human breast carcinoma cells, in both an independent and an additive way.(ABSTRACT TRUNCATED AT 250 WORDS)