The role of social inequalities in the epidemiology of urological cancers: can this inform cancer screening?

Health inequalities are systematic and potentially remediable differences in health across populations. Understanding the origins of these discrepancies, the healthcare consequences and the manifestations of related diseases can help improve the outcomes of underserved communities. Here I discuss how social factors may be used to help identify particular at-risk populations with regards to urological malignancies, and how these can be potentially used as biomarkers that inform cancer screening targets.

¿Puede la cirugía mínimamente invasiva resultar en sitios inusuales de metástasis? / Does minimally invasive surgery for bladder cancer result in unusual sites of metastasis?

Objetivo: Comparar los sitios de metástasis desarrolladas tras procedimientos de abordaje laparoscópico (CRL) y abierto (CRA) en una cohorte de pacientes en un hospital distrital. La morbilidad y la mortalidad de los dos abordajes se evalúan utilizando las variables secundarias de tiempo de estancia hospitalaria y la tasa de complicaciones. Se comparan la tasa y el sitio de metástasis.MétodosSe llevó a cabo una revisión retrospectiva de las anotaciones clínicas de todos los pacientes sometidos a cistectomía por cáncer de vejiga en el Pinderfields General Hospital de Wakefield entre 2010 y 2016 (n=219). Fueron 150 hombres y 69 mujeres, y 107 casos tratados con abordaje mínimamente invasivo y 87 con abordaje abierto (faltan datos sobre 25 casos). Los datos fueron analizados usando Microsoft Excel XLSTAT.ResultadosLa tasa de recurrencia fue del 25,1% y no difirió significativamente respecto al abordaje (p=0,89). Los sitios de recurrencia tampoco difirieron respecto al abordaje quirúrgico, siendo los más frecuentes la pelvis, los pulmones y los huesos. Los sitios inusuales de recurrencia fueron la pared abdominal y el colon sigmoide, en ambos casos, desarrolladas tras procedimientos de CRL. El tiempo de estancia hospitalaria fue mayor para el abordaje abierto (mediana CRL=10, CRA=13, p<0,01). La supervivencia a 5 años fue del 74,9%. La distribución de la supervivencia no difirió significativamente entre los dos abordajes quirúrgicos (p=0,43), y no hubo una asociación significativa entre el abordaje quirúrgico y la muerte del paciente durante el período de seguimiento (p=0,09). La tasa de estenosis fue del 4,1%, sin presentar diferencias significativas entre los dos grupos (p=0,29). El tiempo hasta el desarrollo de la estenosis fue de 130 días. Las puntuaciones de Clavien-Dindo para las complicaciones no difirieron entre abordajes (p=0,93), y tampoco hubo una asociación significativa entre el abordaje quirúrgico y el desarrollo de complicaciones (p=0,19). (AU)

Objective: To compare sites of metastasis for the laparoscopic (LRC) and open (ORC) approaches in a cohort of patients at a district general hospital. Morbidity and mortality for the two approaches are assessed using secondary outcomes of length of stay and complication rate. Metastasis rate and site are compared.MethodsA retrospective case note review was carried out for all patients who underwent cystectomy for bladder malignancy at Pinderfields General Hospital, Wakefield between 2010 and 2016 (n=219). There were 150 males and 69 females in 107 minimally invasive cases and 87 open (missing data on 25 cases). Data were analysed using Microsoft Excel XLSTAT.ResultsRecurrence rate was 25.1% and did not differ significantly with approach (p=0.89). Sites of recurrence did not differ with operative approach, the most frequent being pelvis, chest and bone. Unusual sites of recurrence included abdominal wall and sigmoid colon which both occurred in LRC. Length of stay was greater for the open approach (median LRC=10, ORC=13, p<0.01). Five-year survival was 74.9%. Survival distribution did not significantly differ with operative approach (p=0.43), and there was no significant association between operative approach and patient death within the follow-up period (p=0.09). Stricture rate was 4.1% and was not significantly different between the two groups (p=0.29). Median time to stricture was 130 days. Clavien-Dindo scores for complications did not differ with approach (p=0.93), and there was no significant association between operative approach and whether complications developed (p=0.19). (AU)

Does minimally invasive surgery for bladder cancer result in unusual sites of metastasis?

BACKGROUND: To compare sites of metastasis for the laparoscopic (LRC) and open (ORC) approaches in a cohort of patients at a district general hospital. Morbidity and mortality for the two approaches are assessed using secondary outcomes of length of stay and complication rate. Metastasis rate and site are compared. METHODS: A retrospective case note review was carried out for all patients who underwent cystectomy for bladder malignancy at Pinderfields General Hospital, Wakefield between 2010 and 2016 (n = 219). There were 150 males and 69 females in 107 minimally invasive cases and 87 open (missing data on 25 cases). Data were analysed using Microsoft Excel XLSTAT. RESULTS: Recurrence rate was 25.1% and did not differ significantly with approach (p = 0.89). Sites of recurrence did not differ with operative approach, the most frequent being pelvis, chest and bone. Unusual sites of recurrence included abdominal wall and sigmoid colon which both occurred in LRC. Length of stay was greater for the open approach (median LRC = 10, ORC = 13, p < 0.01). Five-year survival was 74.9%. Survival distribution did not significantly differ with operative approach (p = 0.43), and there was no significant association between operative approach and patient death within the follow-up period (p = 0.09). Stricture rate was 4.1% and was not significantly different between the 2 groups (p = 0.29). Median time to stricture was 130 days. Clavien-Dindo scores for complications did not differ with approach (p = 0.93), and there was no significant association between operative approach and whether complications developed (p = 0.19). CONCLUSIONS: The adverse oncological outcomes in minimally invasive approaches suggested by some studies are not confirmed here. Those in the LRC group were discharged sooner, though this did not translate into differences in morbidity or survival. Analysis of the association between individual complications and length of stay may clarify this further. Shorter hospital stay is also likely to have significant financial implications. Despite no significant difference in outcomes, the findings demonstrate potential benefits of LRC. Extensions of this study could include: cost-benefit analysis, examination of individual complications' effect on length of stay; and analysis of approach-specific factors contributing to perioperative deaths.

Robotic prostatectomy after abandoned open radical prostatectomy-Technical aspects and outcomes.

Objective: To describe the technical aspects and outcomes of robotic-assisted radical prostatectomy (RARP) following abandoned open radical prostatectomy (ORP). Patients and Methods: A retrospective review was performed of patients who underwent RARP following abandonment of ORP between 2016 and 2020. RARP was undertaken by two highly experienced robotic surgeons. Analysis of patient and operative characteristics, outcomes, and reasons for abandonment of ORP were described. Results: Six patients were included for analysis with a median age of 63.5 years [50.3-67.5]. The median body mass index (BMI) was 34.7 [27.8-36.2]. All patients had intermediate-risk prostate cancer. Small prostate and deep pelvis were given as reasons for abandoning ORP in five cases (83.3%), with four of these also attributing increased BMI as a factor. Extensive mesh from previous bilateral inguinal hernia repair was cited as the reason for abandonment in the remaining patient. One patient had commenced androgen deprivation therapy following abandoned ORP. Extensive retropubic adhesions were noted at the time of RARP in five of six patients, with intraoperative complication of small bladder lacerations encountered in the patient with prior mesh hernia repair. The median time from abandoned ORP to RARP was 128 days [40-216]. Median operating time was 160 minutes [139-190] and estimated blood loss was 225 mL [138-375]. Negative margins were obtained in four of six cases, with further salvage treatment being required in one case at a median follow-up duration of 10.5 months [6.5-25.3]. Conclusion: Abandonment of ORP is an uncommonly reported event, however, in this small case series, we demonstrate that, in the hands of experienced surgeons, RARP is a safe and technically feasible alternative in such cases. Increased BMI, small prostate size and pelvic anatomical constraints appear to be common catalysts for abandonment of open surgery in this cohort. Identifying these high-risk patients early and considering referral to robotic centers may be preferred.

A multi-centre cohort study evaluating the role of inflammatory markers in patient's presenting with acute ureteric colic (MIMIC).

BACKGROUND: Spontaneous Stone Passage (SSP) rates in acute ureteric colic range from 47 to 75%. There is conflicting evidence on the role of raised inflammatory markers in acute ureteric colic. The use of an easily applicable biomarker that could predict SSP or need for intervention would improve the management of obstructing ureteric stones. Thus, there is a need to determine in an appropriately powered study, in patients who are initially managed conservatively, which factors at the time of acute admission can predict subsequent patient outcome such as SSP and the need for intervention. Particularly, establishing whether levels of white cell count (WBC) at presentation are associated with likelihood of SSP or intervention may guide clinicians on the management of these patients' stones. DESIGN: Multi-center cohort study disseminated via the UK British Urology Researchers in Surgical Training (BURST) and Australian Young Urology Researchers Organisation (YURO). PRIMARY RESEARCH QUESTION: What is the association between WBC and SSP in patients discharged from emergency department after initial conservative management? PATIENT POPULATION: Patients who have presented with acute renal colic with CT KUB evidence of a solitary ureteric stone. A minimum sample size of 720 patients across 15 centres will be needed. HYPOTHESIS: A raised WBC is associated with decreased odds of spontaneous stone passage. PRIMARY OUTCOME: The occurrence of SSP within six months of presentation with acute ureteric colic (YES/NO). SSP was defined as absence of need for intervention to assist stone passage. STATISTICAL ANALYSIS PLAN: A multivariable logistic regression model will be constructed, where the outcome of interest is SSP using data from patients who do not undergo intervention at presentation. A random effect will be used to account for clustering of patients within hospitals/institutions. The model will include adjustments for gender, age as control variables.

Digital pattern recognition-based image analysis quantifies immune infiltrates in distinct tissue regions of colorectal cancer and identifies a metastatic phenotype.

BACKGROUND: Several studies in colorectal cancer (CRC) indicate a relationship between tumour immune infiltrates and clinical outcome. We tested the utility of a digital pattern recognition-based image analysis (DPRIA) system to segregate tissue regions and facilitate automated quantification of immune infiltrates in CRC. METHODS: Primary CRC with matched hepatic metastatic (n=7), primary CRC alone (n=18) and primary CRC with matched normal (n=40) tissue were analysed immunohistochemically. Genie pattern recognition software was used to segregate distinct tissue regions in combination with image analysis algorithms to quantify immune cells. RESULTS: Immune infiltrates were observed predominately at the invasive margin. Quantitative image analysis revealed a significant increase in the prevalence of Foxp3 (P<0.0001), CD8 (P<0.0001), CD68 (<0.0001) and CD31 (<0.0001) positive cells in the stroma of primary and metastatic CRC, compared with tumour cell mass. A direct comparison between non-metastatic primary CRC (MET-) and primary CRC that resulted in metastasis (MET+) showed an immunosuppressive phenotype, with elevated Foxp3 (P<0.05) and reduced numbers of CD8 (P<0.05) cells in the stroma of MET+ compared with MET- samples. CONCLUSION: By combining immunohistochemistry with DPRIA, we demonstrate a potential metastatic phenotype in CRC. Our study accelerates wider acceptance and use of automated systems as an adjunct to traditional histopathological techniques.

No impairment of monocyte-derived Langerhans cell phenotype or function in early-onset psoriasis.

BACKGROUND: Migration of epidermal Langerhans cells (LCs) in response to the cytokines interleukin (IL)-1ß and tumour necrosis factor (TNF)-α is impaired in uninvolved skin of patients with early-onset psoriasis. AIM: To investigate whether this impairment is a reflection of a systemic defect in dendritic cells (DCs), using an established model of monocyte-derived LC-like cells (mLCs). METHODS: CD14+ monocytes isolated from both patients with psoriasis and healthy control volunteers were cultured in a cytokine cocktail for 5 days to promote their differentiation into mLCs, then stimulated for 24 h with TNF-α, IL-1ß (both 100 ng/mL) or medium alone. Cellular surface protein expression was quantified by flow cytometry, and the ability of cells to migrate to media supplemented with C-C motif ligand (CCL)19 was assessed using a Transwell migration assay. The cytokine and chemokine content of supernatants was analysed by cytokine array. RESULTS: CD14+ cells acquired an LC-like phenotype with high expression of CD1a and major histocompatibility complex (MHC) class II. There were no differences in the expression of activation markers or in the secretion of cytokines by mLCs isolated from patients with psoriasis and those isolated from healthy controls. Moreover, mLCs isolated from both groups displayed comparable ability to migrate in vitro. CONCLUSIONS: These data suggest that the failure of LCs to migrate in response to stimulation in patients with psoriasis is not attributable to a systemic defect in DC function, but is rather a reflection of local changes in the epidermal microenvironment.

Proteomic analysis of suction blister fluid isolated from human skin.

The regulation of cutaneous immune responses in health and disease is mediated locally by proteins such as cytokines and chemokines. We used a novel approach involving proteomic profiling of fluid drawn from suction blisters to compare and contrast protein expression in normal skin with that in nonlesional skin from a patient with plaque psoriasis. We also examined the impact of exogenous interleukin-1beta, a proinflammatory cytokine, on protein expression in these tissues. Described here are the results of proteomic profiling of 670 proteins from blister fluid, and the identification by differential expression of nine proteins between one volunteer with psoriasis and one normal volunteer. Although the apparent disease association of these nine proteins will require validation using additional volunteers, the identification of candidate protein biomarkers through proteomic analyses of blister fluid represents a promising approach for monitoring the disease activity and efficacy of therapeutic intervention in human skin diseases.

Cytokines and Langerhans cell mobilisation in mouse and man.

A critical event during the development of cutaneous immune responses, including those provoked by contact allergens, is the mobilisation of epidermal Langerhans cells (LC). These cells act as sentinels of the immune system in the skin, responding to a variety of local insults with migration and delivery of potentially foreign signals to draining lymph nodes. Experimental studies have revealed that the regulation of mobilisation and migration of LC display striking similarities in man and mouse. In both species it has been found that the successful induction of migration requires that LC receive (at least) 2 independent cytokine signals; provided by tumour necrosis factor-alpha (TNF-alpha) and interleukin 1beta. In addition, a similar heterogeneity in man and mouse is apparent with regard to the fraction of LC responding rapidly to mobilisation signals, with the same proportion of cells (20%-30%) being stimulated to migrate in each case. Other similarities exist between mice and humans with respect to LC function, including an age-related decrement in both LC frequency and responsiveness to TNF-alpha. Collectively these studies demonstrate that the mouse provides a valuable experimental surrogate for the human skin immune system, particularly with respect to LC biology, and suggest that it is possible to perform extrapolations between species with some confidence.

Dendritic cells and skin sensitisation hazard assessment.

Allergic contact dermatitis is an important occupational and environmental health disease. There is a need, therefore, to identify skin sensitisation hazard, and to assess accurately likely risks to human health. During the past 15 years very significant advances have been made in our understanding of the cellular and molecular mechanisms that serve to initiate and regulate cutaneous immune responses, including the acquisition of skin sensitisation. This has facilitated parallel advances in the identification and characterisation of skin sensitising chemicals and the development of more robust approaches to risk assessment. It is relevant to consider whether advances in immunobiology provide opportunities also for the design of alternative approaches to the toxicological evaluation of skin sensitisation, including the development of in vitro methods. Here we review the potential use of strategies based on analysis of responses induced in Langerhans cells and dendritic cells; professional antigen processing and presenting cells that are known to play pivotal roles during the induction phase of adaptive immune responses.

IL-1beta-induced Langerhans' cell migration and TNF-alpha production in human skin: regulation by lactoferrin.

In mice, the roles of cytokines in the initiation of epidermal Langerhans' cell (LC) migration are well documented; however, the mechanism of this response in humans is less well defined. The purpose of the present investigation was to examine the contribution of interleukin (IL)-1beta to human epidermal LC migration and to define further the mechanisms of this response. We demonstrate here that homologous recombinant IL-1beta administered intradermally to healthy human volunteers provides a stimulus for LC migration, with significant (P < 0.01) reductions in LC densities being observed at both 2 h and 4 h following treatment. At the later time-point of 4 h, injection of IL-1beta was also accompanied by activation of those LC remaining in the epidermis. Analysis of fluid aspirated from suction blisters formed at injection sites revealed significant (P < 0.01) tumour necrosis factor (TNF)-alpha production (2.99 +/- 1.18 pg TNF-alpha/mg protein; mean +/- s.d. of n = 10) in response to IL-1beta treatment compared with saline control injections (0.90 +/- 1.05 pg TNF-alpha/mg protein). Prior topical application of human recombinant lactoferrin (LF), an iron-binding protein found in exocrine secretions and skin, inhibited IL-1beta-mediated LC migration and also compromised the production of TNF-alpha protein as measured in suction blister fluids derived from each of the treatment sites. Taken together, these data demonstrate that IL-1beta is associated with both the stimulation of human epidermal LC migration and local TNF-alpha production. Topical treatment with LF compromises both these responses. These data suggest that topical LF may potentially represent a novel therapeutic in the treatment of skin inflammation where TNF-alpha is an important mediator.

Lactoferrin: influences on Langerhans cells, epidermal cytokines, and cutaneous inflammation.

It has been suggested previously that, in addition to other biological roles, lactoferrin (LF) may display antiinflammatory properties secondary to the regulation of cytokine expression. To explore this concept further, we have here examined in human volunteers the influence of recombinant homologous LF on the migration of epidermal Langerhans cells (LC), a process that is known to be dependent upon the local availability of certain proinflammatory cytokines including tumor necrosis factor alpha (TNF-alpha) and interleukin 1beta (IL-1beta). In common with previous studies in mice, it was found that topical administration of LF prior to exposure at the same site to the contact sensitizer diphenylcyclopropenone resulted in a significant reduction of allergen-induced LC migration from the epidermis (measured as a function of the frequency of CD1a+ or HLA-DR+ LC found in epidermal sheets prepared from punch biopsies of the treated skin sites). However, under the same conditions of exposure, LF was unable to influence migration of LC induced by the intradermal administration of TNF-alpha data consistent with the hypothesis that one action of LF in the skin is to regulate the local production of this cytokine. Further support for this hypothesis was derived from experiments conducted with IL-1beta. This cytokine is also able to induce the mobilization of LC following intradermal injection, although in this case, migration is known to be dependent upon the de novo production of TNF-alpha. We observed that prior exposure to LF resulted in a substantial inhibition of IL-1beta-induced LC migration, data again consistent with the regulation of TNF-alpha production by LF. Collectively, these results support the view that LF is able to influence cutaneous immune and inflammatory processes secondary to regulation of the production of TNF-alpha and possibly other cytokines.

Tumour necrosis factor-alpha-induced migration of human Langerhans cells: the influence of ageing.

BACKGROUND: Langerhans cells (LCs) play essential roles in the initiation and regulation of cutaneous immune responses mediated through their successful migration from the epidermis to draining lymph nodes while carrying antigen. Tumour necrosis factor (TNF)-alpha, a keratinocyte-derived cytokine, has recently been shown to play an important role in the mobilization of LCs from human epidermis. Although it is known that with age the immune system changes, the influence of increasing age on the function of human LCs has not been defined clearly. OBJECTIVES: To examine the influence of age on the ability of TNF-alpha to induce LC migration. METHODS: Ten elderly (six men, four women; mean age 76 years, range 72-79) and 10 young (six men, four women; mean age 23 years, range 18-35) volunteers received intradermal injections of 200 U of human recombinant TNF-alpha diluted in sterile saline, and control injections of sterile saline alone, at each of two paired sites identified on photoprotected buttock skin. Two hours later, paired injection sites were excised by punch biopsy. One set of paired biopsies was processed for assessment of the frequency and morphology of epidermal LCs, following preparation of epidermal sheets and immunofluorescence staining for the LC marker CD1a. The remaining paired biopsies were processed in formalin and the inflammatory response to TNF-alpha was assessed by standard histological examination. RESULTS: Mean +/- SEM baseline values for LC frequency within epidermal sheets were significantly different between young (1156.3 +/- 38.5 cells mm(-2)) and elderly subjects (835.7 +/- 48.2 cells mm(-2); P < 0.01). Intradermal injections of 200 U of TNF-alpha caused a significant reduction in the frequency of LCs in both elderly and young subjects (P < 0.01). However, the extent of TNF-alpha-induced LC migration was substantially different between the two groups, with a mean 9% reduction in LC frequency in elderly volunteers compared with a mean 23% decrease in young subjects. Exposure to TNF-alpha was associated with a perivascular polymorphonuclear infiltrate at 2 h in all young subjects; in contrast, only 50% of the elderly individuals showed evidence of such a response. CONCLUSIONS: There are significant differences between young and old skin with respect to both resting LC numbers and their response to TNF-alpha. These age-related changes in LC frequency and function may contribute to the altered cutaneous immune function observed in the elderly.

Chronic substance P (NK1) receptor antagonist and conventional antidepressant treatment increases burst firing of monoamine neurones in the locus coeruleus.

The mechanism of action of conventional antidepressants (e.g. imipramine) has been linked to modulation of central monoamine systems. Substance P (NK1) receptor antagonists may have antidepressant and anxiolytic effects in patients with major depressive disorder and high anxiety but, unlike conventional antidepressants, are independent of activity at monoamine reuptake sites, transporters, receptors, or monoamine oxidase. To investigate the possibility that substance P receptor antagonists influence central monoamine systems indirectly, we have compared the effects of chronic administration of imipramine with that of the substance P receptor antagonist L-760735 on the spontaneous firing activity of locus coeruleus neurones. Electrophysiological recordings were made from brain slices prepared from guinea-pigs that had been dosed orally every day for 4 weeks with either L-760735 (3 mg/kg), imipramine (10 mg/kg), or vehicle (water), or naive animals. Chronic, but not acute, treatment with the substance P receptor antagonist L-760735, induced burst firing of neurones in the locus coeruleus. This effect resembles that of the conventional antidepressant imipramine. However, their effects are dissociable since, in contrast to chronic imipramine treatment, chronic L-760735 treatment does not cause functional desensitisation of somatic alpha2 adrenoceptors. The mechanism by which chronic substance P receptor antagonist or conventional antidepressant treatment influences the pattern of firing activity of norepinephrine neurones remains to be elucidated. However, an indirect action in the periphery or distant brain nuclei has been excluded by the use of the in vitro slice preparation, suggesting a local site of action in the locus coeruleus.

Alternative approaches to the identification and characterization of chemical allergens.

Chemical allergy can take a variety of forms, those of greatest importance in an occupational setting being skin sensitization resulting in allergic contact dermatitis and sensitization of the respiratory tract associated with asthma and other symptoms. In both cases there is a need for predictive test methods that allow the accurate identification of sensitizing chemicals. Well characterized methods are available for skin sensitization testing, and although to date no tests for respiratory sensitization have been formally validated, progress has been made in defining suitable animal models. In recent years there have been significant advances in our understanding of the cellular and molecular mechanisms through which allergic sensitization to chemicals is induced and regulated. Such progress provides us now with new opportunities to consider alternative approaches to sensitization testing, including the design of in vitro test methods. The greatest investment has been in exploring novel methods for the identification of contact sensitizers and it is upon this aspect of chemical allergy that this article is focused. Described here are some of the general requirements of in vitro test methods for skin sensitization, and progress that has been made in developing suitable approaches with particular emphasis on the utility of dendritic cell culture systems.

Role of opioid receptors in neurogenic dural vasodilation and sensitization of trigeminal neurones in anaesthetized rats.

Migraine headache is thought to be caused by a distension of meningeal blood vessels, the activation of trigeminal sensory neurones and the the development of a central sensitization within the trigeminal nucleus caudalis (TNC). It has been proposed that clinically effective 5-HT(1B/1D) agonists act peripherally to inhibit the release of calcitonin gene-related peptide (CGRP) and neurogenic dural vasodilation, and to attenuate nociceptive neurotransmission within the TNC. Since opioids are also effective anti-migraine agents the present studies investigated the role of opioids within the trigemino-vascular system in anaesthetised rats. Electrical stimulation of the dura mater evoked neurogenic dural vasodilation which was significantly inhibited by morphine (1 mg kg(-1)) the selective mu-opioid agonist DAGO (10 microg kg(-1)) and the mixed agonist/antagonist butorphanol (1 mg kg(-1)) but not by the kappa- and delta-opioid agonists (+/-) U50488H (100 microg kg(-1)) and DPDPE (1 mg kg(-1)). Morphine had no effect on CGRP-evoked dural vasodilation. In electrophysiological studies morphine (1 - 10 mg kg(-1)) significantly attenuated brainstem neuronal activity in response to electrical stimulation of the dura by 65% at 10 mg kg(-1). Morphine (3 mg kg(-1)) also inhibited the TNC neuronal sensitization following CGRP-evoked dilation. The present studies have demonstrated that opioids block the nociceptive neurotransmission within the trigeminal nucleus caudalis and in addition inhibit neurogenic dural vasodilation via an action on mu-opioid receptors located on trigeminal sensory fibres innervating dural blood vessels. These peripheral and central actions are similar to those of the 'triptan' 5-HT(1B/1D) agonists and could account for the anti-migraine actions of opioids.

Exogenous topical lactoferrin inhibits allergen-induced Langerhans cell migration and cutaneous inflammation in humans.

BACKGROUND: Lactoferrin (LF), an iron-binding protein found in exocrine secretions, is known to possess antibacterial properties. It has recently been proposed that LF may also influence inflammatory reactions. OBJECTIVES: To characterize in humans the ability of recombinant homologous LF to inhibit the induced migration of epidermal Langerhans cells (LCs) from the skin, a process known to be dependent upon the proinflammatory cytokines tumour necrosis factor (TNF)-alpha and interleukin 1beta and to influence cutaneous inflammatory reactions. METHODS: We investigated the anti-inflammatory properties of LF in human volunteers. RESULTS: Topical exposure to LF 2 h prior to sensitization caused a significant reduction in contact allergen (diphenylcyclopropenone, DPC)-induced LC migration from the epidermis as judged by the altered frequency of cells expressing either HLA-DR or CD1a determinants. That this reduction was secondary to an inhibition of TNF-alpha production was indicated by the fact that LF failed to influence LC migration induced by intradermal injection of this cytokine. In approximately 50% of those volunteers who displayed local inflammation in response to DPC, LF was found to cause a discernible reduction in the clinical severity of the reaction, associated with reduced infiltration of inflammatory cells. CONCLUSIONS: These data demonstrate that LF is able to influence cutaneous immune and inflammatory responses, possibly because of an impaired production of local proinflammatory cytokines.

Interleukin (IL)-18 induces Langerhans cell migration by a tumour necrosis factor-alpha- and IL-1beta-dependent mechanism.

Following skin sensitization a proportion of epidermal Langerhans cells (LC) are stimulated to leave the skin and to migrate, via afferent lymphatics, to draining lymph nodes where they accumulate as immunostimulatory dendritic cells (DC). It has been demonstrated previously that tumour necrosis factor-alpha (TNF-alpha), an inducible product of epidermal keratinocytes, and interleukin (IL)-1beta, produced exclusively by LC in murine epidermis, provide important signals for the initiation of this response. Recently, it has been demonstrated that IL-18, a cytokine produced by both LC and keratinocytes within the epidermis, may also participate in immune responses induced following skin sensitization. In the present investigations, the ability of IL-18 to contribute to the regulation of LC migration and the accumulation of DC in draining lymph nodes has been examined. It was found that, like IL-1beta, IL-18 administered intradermally to mice resulted in a significant reduction in epidermal major histocompatibility complex (MHC) class II+ LC densities and a marked increase in lymph node DC numbers. Using neutralizing anti-TNF-alpha and blocking anti-type I IL-1 receptor (IL-1RI) antibodies, it was shown also that the induction by IL-18 of both LC mobilization and DC accumulation in regional lymph nodes was dependent upon availability of TNF-alpha and the integrity of IL-1RI signalling. Furthermore, using IL-1beta converting enzyme (caspase-1) knockout mice, IL-18-induced LC migration was found to have a mandatory requirement for active IL-1beta. Importantly, not only was IL-18 able to contribute to the regulation of LC migration, it was found to be essential for the manifestation of these processes in response to topical sensitization with the contact allergen oxazolone.