Angiogenic markers and maternal echocardiographic indices in women with hypertensive disorders of pregnancy.

OBJECTIVE: The maternal cardiovascular system of women with hypertensive disorders of pregnancy (HDP) can be impaired, with higher rates of left ventricular (LV) remodeling and diastolic dysfunction compared to those with normotensive pregnancy. The primary objective of this prospective study was to correlate cardiac indices obtained by transthoracic echocardiography (TTE) and circulating angiogenic markers, such as soluble fms-like tyrosine kinase-1 (sFlt-1) and placental growth factor (PlGF). METHODS: In this study, 95 women with a pregnancy complicated by HDP and a group of 25 with an uncomplicated pregnancy at term underwent TTE and blood tests to measure sFlt-1 and PlGF during the peripartum period (before delivery or within a week of giving birth). Spearman's rank correlation was used to derive correlation coefficients between biomarkers and cardiac indices in the HDP and control populations. RESULTS: The HDP group included 61 (64.2%) pre-eclamptic patients and, among them, 42 (68.9%) delivered before 37 weeks' gestation. Twelve women with HDP (12.6%) underwent blood sampling and TTE after delivery, and, as they showed significantly lower levels of angiogenic markers, they were excluded from the analysis. There was a correlation between sFlt-1 and LV mass index (LVMI) (r = 0.246; P = 0.026) and early diastolic mitral inflow velocity (E) and early diastolic mitral annular velocity (e') ratio (r = 0.272; P = 0.014) in the HDP group (n = 83), while in the controls, sFlt-1 showed a correlation with relative wall thickness (r = 0.409; P = 0.043), lateral e' (r = -0.562; P = 0.004) and E/e' ratio (r = 0.417; P = 0.042). PlGF correlated with LVMI (r = -0.238; P = 0.031) in HDP patients and with lateral e' (r = 0.466; P = 0.022) in controls. sFlt-1/PlGF ratio correlated with lateral e' (r = -0.568; P = 0.004) and E/e' ratio (r = 0.428; P = 0.037) in controls and with LVMI (r = 0.252; P = 0.022) and E/e' ratio (r = 0.269; P = 0.014) in HDP. CONCLUSIONS: Although the current data are not able to infer causality, they confirm the intimate relationship between the maternal cardiovascular system and angiogenic markers that are used both to diagnose and indicate the severity of HDP. © 2023 The Authors. Ultrasound in Obstetrics & Gynecology published by John Wiley & Sons Ltd on behalf of International Society of Ultrasound in Obstetrics and Gynecology.

The relationship between meniscal pathologies, cartilage loss, joint replacement and pain in knee osteoarthritis: a systematic review.

OBJECTIVE: We conducted a systematic review in order to understand the relationship between imaging-visualised meniscus pathologies, hyaline cartilage, joint replacement and pain in knee osteoarthritis (OA). DESIGN: A search of the Medline, Excerpta Medica database (EMBASE) and Cochrane library databases was performed for original publications reporting association between imaging-detected meniscal pathology (extrusion or tear/damage) and longitudinal and cross-sectional assessments of hyaline articular cartilage loss [assessed on magnetic resonance imaging (MRI)], incident joint replacement and pain (longitudinal and cross-sectional) in knee OA. Each association was qualitatively characterised by a synthesis of data from each analysis, based upon study design and quality scoring (including risk of bias assessment and adequacy of covariate adjustment using Cochrane recommended methodology). RESULTS: In total 4,878 abstracts were screened and 82 publications were included (comprising 72 longitudinal analyses and 49 cross-sectional). Using high quality, well-adjusted data, meniscal extrusion and meniscal tear/damage were associated with longitudinal progression of cartilage loss, cross-sectional cartilage loss severity and joint replacement, independently of age, sex and body mass index (BMI). Medial and lateral meniscal tears were associated with cartilage loss when they occurred in the body and posterior horns, but not the anterior horns. There was a lack of high quality, well-adjusted meniscal pathology and pain publications and no clear independent association between meniscal extrusion or tear/damage with pain severity, progression in pain or incident frequent knee symptoms. CONCLUSION: Meniscal features have strong associations with cartilage loss and joint replacement in knee OA, but weak associations with knee pain. Systematic review PROSPERO registration number: CRD 42020210910.

Nuclear F-actin Cytology in Oral Epithelial Dysplasia and Oral Squamous Cell Carcinoma.

Oral cavity cancer has a low 5-y survival rate, but outcomes improve when the disease is detected early. Cytology is a less invasive method to assess oral potentially malignant disorders relative to the gold-standard scalpel biopsy and histopathology. In this report, we aimed to determine the utility of cytological signatures, including nuclear F-actin cell phenotypes, for classifying the entire spectrum of oral epithelial dysplasia and oral squamous cell carcinoma. We enrolled subjects with oral potentially malignant disorders, subjects with previously diagnosed malignant lesions, and healthy volunteers without lesions and obtained brush cytology specimens and matched scalpel biopsies from 486 subjects. Histopathological assessment of the scalpel biopsy specimens classified lesions into 6 categories. Brush cytology specimens were analyzed by machine learning classifiers trained to identify relevant cytological features. Multimodal diagnostic models were developed using cytology results, lesion characteristics, and risk factors. Squamous cells with nuclear F-actin staining were associated with early disease (i.e., lower proportions in benign lesions than in more severe lesions), whereas small round parabasal-like cells and leukocytes were associated with late disease (i.e., higher proportions in severe dysplasia and carcinoma than in less severe lesions). Lesions with the impression of oral lichen planus were unlikely to be either dysplastic or malignant. Cytological features substantially improved upon lesion appearance and risk factors in predicting squamous cell carcinoma. Diagnostic models accurately discriminated early and late disease with AUCs (95% CI) of 0.82 (0.77 to 0.87) and 0.93 (0.88 to 0.97), respectively. The cytological features identified here have the potential to improve screening and surveillance of the entire spectrum of oral potentially malignant disorders in multiple care settings.

Porphyromonas gingivalis Outer Membrane Vesicles Increase Vascular Permeability.

Periodontitis is increasingly associated with increased risk of cardiovascular and other systemic diseases. The Gram-negative anaerobe, Porphyromonas gingivalis, is a key periodontal pathogen, and several lines of evidence link the presence of this bacterium in the circulation with vascular disease. The outer membrane vesicles (OMVs) produced by P. gingivalis have been shown to play a role in periodontitis, although, to date, little is known about their interaction with the vasculature; therefore, this study assessed the effects of P. gingivalis OMVs on the endothelium. OMVs were isolated from wild-type strain W83 and the gingipain-deficient strain ΔK/R-ab. Immunoblotting along with cryo-EM showed gingipain expression in W83 but not ΔK/R-ab-derived OMVs, where gingipains were localized to the cell wall surface. Confluent endothelial cell monolayers infected with either W83 or W83-derived OMV displayed significantly increased dextran permeability over those infected with ΔK/R-ab or its OMV. Moreover, W83-derived OMVs induced significantly more vascular disease in a zebrafish larvae systemic infection model over 72 h compared to those injected with gingipain-deficient OMVs or controls. In line with these data, human microvascular endothelial cells (HMEC-1) displayed an OMV-associated, gingipain-dependent decrease in cell surface levels of the intercellular adhesion molecule PECAM-1 (CD31) when examined by flow cytometry. These data show, for the first time, that OMVs from P. gingivalis mediate increased vascular permeability, leading to a diseased phenotype both in vitro and in vivo. Moreover, these data strongly implicate gingipains present on the OMV surface in mediating these vascular events, most likely via a mechanism that involves proteolytic cleavage of endothelial cell-cell adhesins such as PECAM-1. These data provide important evidence for the role of bacterial-derived OMVs in mediating systemic disease.

The Effect of Early Rounds of ex vivo Expansion and Cryopreservation on the Adipogenic Differentiation Capacity of Adipose-Derived Stromal/Stem Cells.

Multipotent adipose-derived stromal/stem cells (ASCs) are candidates for use in cellular therapies for the treatment of a variety of conditions/diseases. Ex vivo expansion of freshly isolated ASCs may be necessary prior to clinical application to ensure that clinically relevant cell numbers are administered during treatment. In addition, cryopreserving cells at early passages allows for storage of freshly isolated cells for extended periods of time before expanding these cells for clinical usage. There are however several concerns that these laboratory-based procedures may alter the characteristics of the cells and in so doing decrease their regenerative potential. In this study we report on the impact of early rounds of cryopreservation (P0) and ex vivo expansion (P0 to P5) on the phenotypic characteristics and adipogenic differentiation potential of ASCs. Our results show that ASCs that upregulate CD36 expression during adipogenic differentiation gradually decrease with increasing expansion rounds. The consequent decrease in adipogenic differentiation capacity was evident in both gene expression and flow cytometry-based phenotypic studies. Successive rounds of expansion did not however alter cell surface marker expression of the cells. We also show that early cryopreservation of ASCs (at P0) does not affect the adipogenic differentiation potential of the cells.

Identification of Novel Bacteriophages with Therapeutic Potential That Target Enterococcus faecalis.

The Gram-positive opportunistic pathogen Enterococcus faecalis is frequently responsible for nosocomial infections in humans and represents one of the most common bacteria isolated from recalcitrant endodontic (root canal) infections. E. faecalis is intrinsically resistant to several antibiotics routinely used in clinical settings (such as cephalosporins and aminoglycosides) and can acquire resistance to vancomycin (vancomycin-resistant enterococci). The resistance of E. faecalis to several classes of antibiotics and its capacity to form biofilms cause serious therapeutic problems. Here, we report the isolation of several bacteriophages that target E. faecalis strains isolated from the oral cavity of patients suffering root canal infections. All phages isolated were Siphoviridae with similar tail lengths (200 to 250 nm) and icosahedral heads. The genome sequences of three isolated phages were highly conserved with the exception of predicted tail protein genes that diverge in sequence, potentially reflecting the host range. The properties of the phage with the broadest host range (SHEF2) were further characterized. We show that this phage requires interaction with components of the major and variant region enterococcal polysaccharide antigen to engage in lytic infection. Finally, we explored the therapeutic potential of this phage and show that it can eradicate E. faecalis biofilms formed in vitro on a standard polystyrene surface but also on a cross-sectional tooth slice model of endodontic infection. We also show that SHEF2 cleared a lethal infection of zebrafish when applied in the circulation. We therefore propose that the phage described here could be used to treat a broad range of antibiotic-resistant E. faecalis infections.

Pre-clinical evaluation of novel mucoadhesive bilayer patches for local delivery of clobetasol-17-propionate to the oral mucosa.

Oral lichen planus (OLP) and recurrent aphthous stomatitis (RAS) are chronic inflammatory conditions often characterised by erosive and/or painful oral lesions that have a considerable impact on quality of life. Current treatment often necessitates the use of steroids in the form of mouthwashes, creams or ointments, but these are often ineffective due to inadequate drug contact times with the lesion. Here we evaluate the performance of novel mucoadhesive patches for targeted drug delivery. Electrospun polymeric mucoadhesive patches were produced and characterised for their physical properties and cytotoxicity before evaluation of residence time and acceptability in a human feasibility study. Clobetasol-17-propionate incorporated into the patches was released in a sustained manner in both tissue-engineered oral mucosa and ex vivo porcine mucosa. Clobetasol-17 propionate-loaded patches were further evaluated for residence time and drug release in an in vivo animal model and demonstrated prolonged adhesion and drug release at therapeutic-relevant doses and time points. These data show that electrospun patches are adherent to mucosal tissue without causing tissue damage, and can be successfully loaded with and release clinically active drugs. These patches hold great promise for the treatment of oral conditions such as OLP and RAS, and potentially many other oral lesions.

Can thyroid surgery be decided based on ultrasonographic findings, irrespective of cytopathological findings? Five-year retrospective study in a district general hospital.

AIM: To evaluate whether thyroid surgery be decided based on ultrasonographic criteria of the nodule(s), irrespective of cytopathological findings. MATERIALS AND METHODS: The histopathological findings of resected thyroid lobes were retrospectively reviewed and the findings were compared with the preoperative ultrasonographic and cytopathological findings. RESULTS: The results suggest that the decision to operate on thyroid lesions based on suspicious sonographic findings was correct in a significant number of patients irrespective of the preoperative cytopathological findings. CONCLUSION: Sonographic features suspicious for malignancy should be taken seriously even if the cytopathological results are inconclusive or are suggestive of benignity.

Gingipain-dependent degradation of mammalian target of rapamycin pathway proteins by the periodontal pathogen Porphyromonas gingivalis during invasion.

Porphyromonas gingivalis and Tannerella forsythia are gram-negative pathogens strongly associated with periodontitis. Their abilities to interact, invade and persist within host cells are considered crucial to their pathogenicity, but the mechanisms by which they subvert host defences are not well understood. In this study, we set out to investigate whether P. gingivalis and T. forsythia directly target key signalling molecules that may modulate the host cell phenotype to favour invasion and persistence. Our data identify, for the first time, that P. gingivalis, but not T. forsythia, reduces levels of intracellular mammalian target of rapamycin (mTOR) in oral epithelial cells following invasion over a 4-h time course, via the action of gingipains. The ability of cytochalasin D to abrogate P. gingivalis-mediated mTOR degradation suggests that this effect is dependent upon cellular invasion. We also show that levels of several other proteins in the mTOR signalling pathway are modulated by gingipains, either directly or as a consequence of mTOR degradation including p-4E-BP1. Taken together, our data suggest that P. gingivalis manipulates the mTOR pathway, providing evidence for a potentially novel mechanism by which P. gingivalis mediates its effects on host cell responses to infection.

Cigarette smoke condensate promotes pro-tumourigenic stromal-epithelial interactions by suppressing miR-145.

BACKGROUND: Exposure to factors released from tobacco during chewing or smoking is recognized as a major risk factor for oral carcinogenesis and influences the phenotype of oral epithelial cells and fibroblasts within the underlying stroma. Micro(mi)RNA can regulate the expression of genes within cells, and previous studies show that tobacco products can alter the miRNA profiles in lung epithelial cells. However, the molecular alterations occurring in oral fibroblasts exposed to tobacco constituents remain to be elucidated. METHODS: Oral fibroblasts were exposed to cigarette smoke condensate (CSC) and miRNA expression compared to untreated controls using tiling low-density arrays (TLDA). Expression of miRNA-145 was confirmed by quantitative (q)RT-PCR. The effect of CSC on fibroblast cell viability, motility and matrix metalloproteinase (MMP)-2 expression was measured using MTS, a wound scratch assay and qRT-PCR, respectively. Oral cancer cell migration in response to culture supernatants from mock, control or pre-miR-145-transfected CSC-treated fibroblasts was analysed by chemotaxis assay. RESULTS: TLDA analysis identified widespread changes in the miRNA expression profile of fibroblasts exposed to CSC. Pri-, pre- and mature miRNA-145 were significantly down-regulated in response to CSC, and this was accompanied by up-regulated expression of MMP-2 and increased migration of fibroblasts compared to untreated controls. Re-expression of miR-145 abrogated the ability of fibroblasts to promote oral cancer cell chemotaxis in response to CSC. CONCLUSION: These findings suggest that tobacco constituents influence the expression of miRNA within oral fibroblasts promoting a phenotype that increases oral cancer migration and sheds new light on the mechanisms underlying oral cancer pathogenesis.

Tissue-engineered oral mucosa.

Advances in tissue engineering have permitted the three-dimensional (3D) reconstruction of human oral mucosa for various in vivo and in vitro applications. Tissue-engineered oral mucosa have been further optimized in recent years for clinical applications as a suitable graft material for intra-oral and extra-oral repair and treatment of soft-tissue defects. Novel 3D in vitro models of oral diseases such as cancer, Candida, and bacterial invasion have been developed as alternatives to animal models for investigation of disease phenomena, their progression, and treatment, including evaluation of drug delivery systems. The introduction of 3D oral mucosal reconstructs has had a significant impact on the approaches to biocompatibility evaluation of dental materials and oral healthcare products as well as the study of implant-soft tissue interfaces. This review article discusses the recent advances in tissue engineering and applications of tissue-engineered human oral mucosa.

Development of tissue-engineered models of oral dysplasia and early invasive oral squamous cell carcinoma.

BACKGROUND: Current organotypic models of dysplasia and oral squamous cell carcinoma (OSCC) lack the complexity that mimics in vivo tissue. Here we describe a three-dimensional in vitro model of the oral epithelium that replicates tumour progression from dysplasia to an invasive phenotype. METHODS: The OSCC cell lines were seeded as a cell suspension (D20, Cal27) or as multicellular tumour spheroids (FaDu) with oral fibroblasts on to a de-epidermised acellular dermis to generate tissue-engineered models and compared with patient biopsies. RESULTS: The D20 and Cal27 cells generated a model of epithelial dysplasia. Overtime Cal27 cells traversed the basement membrane and invaded the connective tissue to reproduce features of early invasive OSCC. When seeded onto a model of the normal oral mucosa, FaDu spheroids produced a histological picture mimicking carcinoma in situ with severe cellular atypia juxtaposed to normal epithelium. CONCLUSION: It is possible to culture in vitro models with the morphological appearance and histological characteristics of dysplasia and tumour cell invasion seen in vivo using native dermis. Such models could facilitate study of the molecular processes involved in malignant transformation, invasion and tumour growth as well as in vitro testing of new treatments, diagnostic tests and drug delivery systems for OSCC.

A novel magnetic approach to enhance the efficacy of cell-based gene therapies.

Attempts have been made to use various forms of cellular vectors to deliver therapeutic genes to diseased tissues like malignant tumours. However, this approach has proved problematic due to the poor uptake of these vectors by the target tissue. We have devised a novel way of using magnetic nanoparticles (MNPs) to enhance the uptake of such 'therapeutically armed' cells by tumours. Monocytes naturally migrate from the bloodstream into tumours, so attempts have been made to use them to deliver therapeutic genes to these sites. However, transfected monocytes injected systemically fail to infiltrate tumours in large numbers. Using a new in vitro assay for assessing monocyte extravasation, we show that the ability of transfected human monocytes to migrate across a human endothelial cell layer into a 3D tumour spheroid is markedly increased when cells are pre-loaded with MNPs and a magnetic force is applied close to the spheroid. Furthermore, systemic administration of such 'magnetic' monocytes to mice bearing solid tumours led to a marked increase in their extravasation into the tumour in the presence of an external magnet. This new magnetic targeting approach could be used to increase the targeting, and thus the efficacy, of many cell-based gene therapies in vivo.

Myriad and the mass media: the covering of a gene patent controversy.

PURPOSE: We explore how the print media in four jurisdictions framed the controversy surrounding Myriad Genetic's BRCA patents and consider the possible influence of media on public perceptions and policy reform. METHOD: We used a broad search strategy to collect newspaper articles from Factiva and Lexis/Nexis on Myriad Genetics and the BRCA gene and identified the main triggers for those articles. We then selected articles on the BRCA gene patents for coding. The coding frame queried the presence or absence of either positive or negative statements about gene patenting and a subjective assessment of the tone of the article. We compared the differences in tone and number of positive and negative statements between jurisdictions (Australia, Canada, United Kingdom, and United States). RESULTS: Myriad Genetic's BRCA1/2 gene patents sparked significant international newspaper coverage in comparison to other stories on gene patenting controversies. Only 55.9% of 143 articles presented a variety of perspectives. The majority of articles (77.6%) had a negative overall tenor; only 6.29% had a positive overall tenor, whereas 16.1% were neutral. There were significant differences in the overall tenor between jurisdictions, with Canadian coverage being overwhelmingly negative in comparison with the other three jurisdictions. The main triggers for news coverage were largely local licensing deals, actions at regional patent offices, and statements and publications by prominent figures. CONCLUSION: Myriad's patents were largely portrayed as a negative story, except in Utah where Myriad Genetics is located, and as an example of the problems associated with gene patents. The story was primarily framed as a social dilemma that needed to be addressed. In Canada there was a disproportionate level of coverage of the political response to the threat of patent infringement action against government testing laboratories and potential impacts on public health care. In Europe and elsewhere in the United States, the opposition to gene patenting at the European Patent Office predominated. In these contexts, our data provide some support that the media coverage helped to drive the policy agenda, although the resultant policy response received almost no media attention.

Parents and carers' choice of drinks for infants and toddlers, in areas of social and economic disadvantage.

BACKGROUND: Sugar rich drinks are a recognised risk factor in early childhood caries. Currently, in depth knowledge of factors influencing parents' choice of infant drinks is incomplete. OBJECTIVES: This study investigated parents and carers understanding of feeding practices potentially detrimental to oral health; barriers to adopting safe feeding practices and commercial factors influencing feeding bottle and cup contents. METHODOLOGY: A qualitative approach using semi-structured interviews was employed. Interviews were conducted by an experienced researcher and tape recorded. Following full transcription, emerging themes were identified, systematically explored and validated within the verbatim accounts. Thirty-three parents/carers of children aged three years and under, resident in areas of high caries prevalence in Cardiff, Wales, were interviewed. RESULTS: Overall understanding of the prolonged effect of exposure to sugared drinks in feeding bottles and cups was poor. Greater concern was expressed over the use of bottles on the development of the occlusion. Milk was viewed as a food rather than as a drink. Many barriers to giving water were described: children reject it; mothers don't like it; it was 'cruel' to offer water instead of sweet drinks; water in feeding bottles or cups was seen as a sign of poverty. Commercial influences on choices were strong. Products offered by baby food manufacturers were viewed as safe, but a recently marketed "Toothsafe" drink was viewed with suspicion. CONCLUSIONS: There are significant barriers to adopting the traditional oral health education message, that only milk and water are truly safe for teeth. Future oral health education and promotion programmes must recognise and account for these factors.

Pneumococcal nasopharyngeal carriage in children following heptavalent pneumococcal conjugate vaccination in infancy.

AIMS: To ascertain whether the reduction in nasopharyngeal carriage of vaccine serotypes induced by pneumococcal conjugate vaccine (PnCV) administered to infants persists beyond the age of 2 years. METHODS: Non-randomised, unblinded controlled study of 2-5 year old children who had received three doses of heptavalent PnCV (7VPnCV) in infancy and 23-valent pneumococcal polysaccharide vaccine at 13 months, and unimmunised controls. Nasopharyngeal swabs were taken in summer (150 vaccinated subjects, 126 controls) and winter (143 vaccinated subjects, 188 controls). The swabs were cultured and serotyped for Streptococcus pneumoniae. RESULTS: Carriage rates (vaccinated subjects: 24.7% and 43.4%; controls: 27.0% and 41.0%, in summer and winter respectively) and carriage of vaccine serotypes (subjects: 10.0% and 30.0%; controls: 13.5% and 31.5%, in summer and winter respectively) were similar in the two groups. CONCLUSIONS: Effects of vaccination in infancy on rates of nasal carriage of pneumococcus and serotype replacement in children living in a largely unvaccinated population are no longer evident by 2-5 years of age.

Effect of the addition of ketamine to morphine in patient-controlled analgesia.

This randomised, double-blind, prospective study compared morphine (1 mg x m(-1)) with the combination of morphine (1 mg x m(-1)) and ketamine (0.75 mg x m(-1)) via a patient-controlled analgesia system (PCAS) for postoperative pain control. A total of 42 female patients, ASA grade I and II, undergoing elective total abdominal hysterectomy was studied. During a standardised anaesthetic, a loading dose from the PCA syringe of 10 ml x m(-2) of body surface area was given. A PCAS with a background infusion was commenced postoperatively. Pain and side-effects were assessed using numerical scoring systems and cardiovascular and respiratory parameters were recorded. There was no statistically significant difference between the groups in total morphine consumption or pain scoring. Side-effect profiles and time to mobilisation were similar. This study concludes that the addition of ketamine to morphine, in this dosage regimen, administered via PCAS for postoperative pain control, does not confer benefit following total abdominal hysterectomy.

Uropathogenic Escherichia coli-induced neutrophil adhesion to urinary epithelium is strain-specific and mediated by CD11b/CD18.

Adherence of Escherichia coli to urinary tract epithelium induces neutrophil migration across the uroepithelium to combat bacterial infection. Neutrophil adherence to the apical membrane of uroepithelial cells may be an important factor for bacterial clearance. We used an in vitro model of urinary tract infection to examine the effects of uropathogenic E. coli on neutrophil adhesion to the uroepithelial cell line RT4. We found that distinct clinical isolates caused different levels of neutrophil adherence. One particular isolate caused significant neutrophil adhesion in a dose- and time-dependent manner. The neutrophil adhesion-promoting effect induced by this isolate was not caused by bacterial secreted products, suggesting that contact between intact E. coli and uroepithelial cells is required for promoting neutrophil adhesion. This adhesion was almost exclusively mediated by CD11b/CD18, suggesting that E. coli upregulates CD11b/CD18 counterligands on the uroepithelial surface. These data suggest that certain uropathogenic E. coli selectively promote adhesion of neutrophils to ligands on uroepithelial cells by a CD11b/CD18-dependent mechanism.

Chemokine receptors and their role in inflammation and infectious diseases.

Chemokines are small peptides that are potent activators and chemoattractants for leukocyte subpopulations and some nonhemopoietic cells. Their actions are mediated by a family of 7-transmembrane G-protein-coupled receptors, the size of which has grown considerably in recent years and now includes 18 members. Chemokine receptor expression on different cell types and their binding and response to specific chemokines are highly variable. Significant advances have been made in understanding the regulation of chemokine receptor expression and the intracellular signaling mechanisms used in bringing about cell activation. Chemokine receptors have also recently been implicated in several disease states including allergy, psoriasis, atherosclerosis, and malaria. However, most fascinating has been the observation that some of these receptors are used by human immunodeficiency virus type 1 in gaining entry into permissive cells. This review will discuss structural and functional aspects of chemokine receptor biology and will consider the roles these receptors play in inflammation and in infectious diseases.