Treating chronic wounds in an acute care setting: the forgotten diagnosis.

BACKGROUND: Chronic wounds include lower extremity ulcers, diabetic foot ulcers, and pressure injuries, and can take months or years to heal. Wounds place a high burden on outpatient and inpatient care settings. This burden is expected to increase markedly in the United States as the population ages and with increased rates of diabetes, obesity, and COVID-19. PURPOSE: To articulate the effect of chronic, hard-to-heal wounds on acute care facilities, and how a few days of inpatient care can have a significant effect on the healing trajectory. METHODS: An expert panel of 7 members, all with extensive knowledge and experience in the assessment and treatment of chronic wounds in an acute care setting, was convened in March 2022. The panel discussed the role of hospitals as part of the longer-term healing pathway of chronic wounds. RESULTS: Chronic wounds have a significant effect on hospitals that includes unseen costs, bed occupancy, demands on bedside nurses, and wound complications that lead to extended stays or readmissions. A successful inpatient wound program offers appropriate identification of previously undiagnosed wounds, elevation of bedside care through simplified protocols, quickly and easily understood education and easy dressing selection, and comprehensive discharge planning with a multidisciplinary team for continuity of care and reduced risk of readmission. CONCLUSION: Hospitals can play a key role in the management of chronic wounds, thus reducing the effect on each facility and the wider care network.

Phallus preservation and reconstruction: 5-year outcomes of national penile cancer centralisation in the Republic of Ireland.

INTRODUCTION: Penile cancer is a rare urological malignancy with an age-standardised incidence of 0.8 per 100,000 person-years [1]. Given this low incidence it has been suggested that centralised care may improve patient outcomes in relation to phallus sparing surgery and nodal assessment [2]. We aim to assess the outcomes after 5-years of national centralisation of penile cancer care. METHODS: A retrospective analysis of prospectively collected data was performed. All patients undergoing penile cancer surgery from January 2018 to December 2022 following centralisation of care were included. The primary outcome was proportion of phallus sparing procedures performed. Secondary outcomes were patient characteristics, histologic outcomes and procedures performed. RESULTS: 124 patients underwent surgery in the study period. Mean age was 64.49 (±13.87). Overall, 82.3% of patients underwent phallus sparing surgery. This remained stable over the 5-year period from 2018 to 2022 â€‹at 92%, 85%, 76%, 79% and 78% respectively (p â€‹= â€‹0.534). 62.7% had reconstruction performed, including split-thickness skin graft neoglans formation, (57.8% [n â€‹= â€‹37]), preputial flap (32.8% [n â€‹= â€‹21]), glans resurfacing (4.7% [n â€‹= â€‹3]), shaft advancement flap (1.6% [n â€‹= â€‹1]), penile shaft skin graft (1.6% [n â€‹= â€‹1]), and partial penectomy with urethral centralisation (1.6% [n â€‹= â€‹1]). Phallus preservation was not affected by positive nodal status (OR 0.75 [95% CI 0.249-2.266], p â€‹= â€‹0.564) or T-stage ≥1b (OR 0.51 [95% CI 0.153-1.711], p â€‹= â€‹0.276). There has been a significant reduction in Nx nodal status from 64% in 2017 to 15% in 2021 (p â€‹= â€‹0.009). CONCLUSION: Centralisation of treatment for rare malignancies such as penile cancer may improve oncologic outcomes and rates of phallus preservation. This study has shown centralisation to has a high rate of phallus preservation. Further long-term analysis of outcomes in Ireland is required.

Kidney transplantation using ipsilateral arterial and contralateral venous anastomosis in a patient with failing vascular access.

Herein, we describe our surgical technique and outcome of a kidney transplant in a patient with failing vascular access. A right donor kidney was transplanted into the right iliac fossa with an end-to-side arterial anastomosis to the ipsilateral right common iliac artery and end-to-side venous anastomosis to the contralateral left common iliac vein. The possibility of performing an ipsilateral arterial and contralateral venous anastomosis has been shown here to be successful. No post-operative surgical complications were encountered.

Surgical management and post-operative functional outcomes of patients with a penile fracture-a single centre experience over 10 years.

BACKGROUND: Penile fractures are uncommon urological emergencies which occur when there has been a breach in the tunica albuginea of the corpora cavernosum that may be unilateral and bilateral and can extend to involve the urethra. AIM: To assess the management and outcomes of penile fractures in a single institution in Ireland. METHODS: A retrospective review of the emergency theatre logbooks was performed between 2011 and 2021 to identify patients who had undergone an exploration for a suspected penile fracture. OUTCOMES: Seventeen patients were initially identified on review of theatre logbooks as having an exploration for a suspected penile fracture. Two patients were excluded from the study due to a lack of clinical notes being available. A further 4 patients on chart review were found to not have a penile fracture at exploration. RESULTS: Eleven patients had a confirmed penile fracture intra-operatively, four of whom had an associated urethral injury. Nine (9/11) patients had preserved normal erections post-operatively documented on follow-up; two, however, reported erectile dysfunction requiring phosphodiesterase inhibitors. CLINICAL IMPLICATIONS: Our study supports urgent surgical exploration for penile fractures to ensure good functional outcomes. STRENGTHS AND LIMITATIONS: This is a retrospective review of theatre logbooks to identify patients with a suspected penile fracture. CONCLUSION: The results of our cohort show a good outcome of erectile function following surgical repair of a penile fracture (9/11; 82%). Four patients (4/11; 36%) had a urethral injury diagnosed intra-operatively, one of whom required a formal urethroplasty.

Outcome of acute epididymo-orchitis: risk factors for testicular loss.

PURPOSE: Acute epididymo-orchitis (AEO) is a common urological condition characterised by pain and swelling of the epididymis which can affect men of any age. The aetiology and to some extent the management of the patient differ between paediatric and young and older adult groups. METHODS: A retrospective analysis was performed at the University Hospital Limerick from 2012 to 2016. Hospital In-Patient Enquiry (HIPE) data were obtained for all patients diagnosed with orchitis, epididymitis, epididymo-orchitis or testicular abscess over this 5-year period. RESULTS: 140 patients were identified, the age range was 0-89, median age 35.6. These were then split into 3 clinical groups, pre-pubertal (Group 1, 0-15-year-olds), sexually active young men (Group 2a, 16-35-year-olds) and men over 35 (Group 2b). Nine patients had an abscess on ultrasound investigation. There was a significant correlation between the presence of an abscess and the need for an orchidectomy (2 patients, P = 0.035). Two patients were reported as having an atrophic testis following AEO and both were in Group 2b. CONCLUSION: Overall, 7/131 (5%) patients had loss or atrophy of a testicle following an episode of AEO. Nineteen patients had further readmissions with AEO (14%).

Community health workers can be trained to identify patients eligible for tuberculosis preventive therapy, but encounter barriers to programme implementation in KwaZulu-Natal, South Africa.

Tuberculosis (TB) remains one of the top 10 causes of death worldwide, ranking as the leading cause of death from infectious disease, above HIV and AIDS. South Africa has the sixth highest TB incidence rate in the world and the world's largest HIV epidemic. This study sought to demonstrate the feasibility of community health workers (CHWs) contributing to the implementation of tuberculosis preventive therapy (TPT) among people living with HIV and AIDS. Twelve community health workers were trained to test for communicable and non-communicable diseases and screen for TPT eligibility. They visited a select number of homes monthly to conduct screening for HIV, TB and non-communicable diseases. We recorded screening results, rates of referral for TPT, linkage to care - defined as being seen in the clinic for TPT - and treatment initiation. Among the 1 279 community members screened, 248 were identified as living with HIV, 99 (39.9%) individuals were identified as eligible for TPT, and 46 (46.5%) were referred to care. Among those referred, the median age was 39 (IQR 30-48) and 29 (63%) linked to care; 11 (37.9%) of those linked subsequently initiated treatment. In rural South Africa, it is feasible to train CHWs to identify and refer patients eligible for TPT, but losses occurred at each step of the cascade. CHWs can facilitate TPT implementation, although further implementation research exploring and addressing barriers to TPT (on an individual, provider and systems level) should be prioritised to optimise their role in rural resource-limited settings.

Managing Exudate Pooling: A Simplified Practical Guide.

BACKGROUND: Exudate pooling is the collection of wound fluid in the wound bed. Wounds with irregular depth, pockets, or cavities can create a dead space between the dressing and the wound bed where exudate can accumulate. Exudate pooling could lead to increased risk of infection or biofilm formation, maceration of the periwound skin, and delayed wound healing. PURPOSE: This article aims to offer a simplified yet practical summary for the prevention and management of exudate pooling by using advanced wound dressings. METHODS: Following a review of published literature, consensus statements, and best practice guidelines, the authors put their learnings into practice by translating the findings into a practical guide for the prevention and management of exudate pooling. RESULTS: Nearly half (49.6%) of all wounds have depth beyond the epidermis (0.22 cm), a characteristic that increases the risk of exudate pooling. In addition, approximately 12% of chronic wounds are undermined by tunneling or cavities underneath the skin where exudate could pool. Appropriate dressing selection can help manage exudate and prevent exudate pooling. In particular, dressings that provide a moist environment, manage the dead space, and maintain close contact with the wound bed may help reduce the risks associated with exudate pooling. A practical guide is presented that could be used by nurses at all levels to help select appropriate dressings. CONCLUSION: This practical guide could help prevent and manage exudate pooling and associated risk factors.

Where are the paediatric patients with testicular torsion during the COVID-19 pandemic?

INTRODUCTION: The Irish people were put on lockdown in mid-March 2020 due to concern of the spread of coronavirus. With these societal changes came a notable reduction in emergency department attendance. Our aim was to analyse emergency urological procedures performed during the COVID-19 era versus the previous year. METHODS: A retrospective review of theatre logbooks was undertaken comparing numbers of emergency urological procedures performed between 1 March 2020 and 31 May 2020 (i.e. the COVID-19 era) with the corresponding 3-month period in 2019. RESULTS: A total of 173 cases were analysed between the two time periods. Similar overall numbers of cases were performed in 2019 (n = 90) and 2020 (n = 83). In particular, similar patient case numbers are also noted in both scrotal explorations (13 vs 9) and ureteric stone surgeries (69 vs 70). However, orchidectomies for testicular cancers were reduced by 63% (3/8). On further analysis of the scrotal exploration group, only 3 were performed in the period after lockdown regulations were instated. CONCLUSION: Whilst patients with ureteric colic continue to present, those with acute testis pain requiring exploration attended less frequently, raising the possibility of undiagnosed testicular torsion in the community.

Preliminary efficacy of the "SitLess with MS" intervention for changing sedentary behaviour, symptoms, and physical performance in multiple sclerosis.

PURPOSE: People with multiple sclerosis (MS) sit (i.e., are sedentary) more than peers. We examined the preliminary efficacy of an internet-based intervention that focuses on sitting less and moving more for changing sedentary behaviour outcomes, symptoms, QOL, and physical performance in adults with MS. METHODS: Persons with mild-to-moderate disability from MS took part in a 15-week pre-post trial. Outcomes including sedentary behaviour, representative symptoms (e.g., fatigue, pain), QOL and physical performance measures (e.g., walking speed) were measured at three time points: pre-post intervention and at follow-up. An unstructured linear mixed-effects model was used to determine change over time per outcome. RESULTS: Forty-one persons with MS participated (age 50 ± 10.3 years). There were significant reductions in total sedentary time (d = 0.34) and the number of long (≥30 min) bouts of sedentary time (d = 0.39) post-intervention. All symptoms and physical performance measures were significantly improved following the intervention, with effects sizes greatest for fatigue (d = 0.61) and depression (d = 0.79). Changes were maintained during the 7-week follow-up, except for all sedentary behaviour outcomes and sleep quality. Cognition did not change. CONCLUSIONS: This study provides preliminary support for the efficacy of an intervention focused on sitting less and moving more for improving symptoms in adults with MS.IMPLICATIONS FOR REHABILITATIONThis research provides preliminary evidence that an intervention aimed at reducing sedentary behaviour and increasing light intensity activity throughout the day can have an impact.Fatigue, depression and anxiety, symptoms frequently encountered by people with MS, showed the greatest improvement following the intervention.Weekly coaching sessions including discussions about results from activity monitoring provided motivation for participants. TRIAL REGISTRATION: The "SitLess with MS" feasibility study was registered at ClinicalTrials.gov Trial Registration Number: NCT03136744. Date of registration was 2 May 2017. Find at https://clinicaltrials.gov/ct2/show/NCT03136744.

Recommendations for Reporting on Rehabilitation Interventions.

ABSTRACT: Clear reporting on rehabilitation treatments is critical for interpreting and replicating study results and for translating treatment research into clinical practice. This article reports the recommendations of a working group on improved reporting on rehabilitation treatments. These recommendations are intended to be combined with the efforts of other working groups, through a consensus process, to arrive at a reporting guideline for randomized controlled trials in physical medicine and rehabilitation (Randomized Controlled Trials Rehabilitation Checklist). The work group conducted a scoping review of 156 diverse guidelines for randomized controlled trial reporting, to identify themes that might be usefully applied to the field of rehabilitation. Themes were developed by identifying content that might improve or enhance existing items from the Template for Intervention Description and Replication. Guidelines addressing broad research domains tended to define reporting items generally, from the investigator's perspective of relevance, whereas those addressing more circumscribed domains provided more specific and operationalized items. Rehabilitation is a diverse field, but a clear description of the treatment's separable components, along with distinct treatment theories for each, can improve reporting of relevant information. Over time, expert consensus groups should develop more specific guideline extensions for circumscribed research domains, around coalescing bodies of treatment theory.

The SitLess With MS Program: Intervention Feasibility and Change in Sedentary Behavior.

OBJECTIVES: This study reports on the feasibility of the SitLess with MS trial, an intervention targeting sedentary behavior in individuals with multiple sclerosis (MS). DESIGN: Single group, pre-post intervention design. SETTING: Community. PARTICIPANTS: Participants (N=41) with mild to moderate disability from MS. INTERVENTION: The intervention was 15 weeks, with a 7-week follow-up, and included 2 stages: SitLess and MoveMore. During the SitLess stage, participants were encouraged to break up prolonged sitting bouts over a 7-week period, whereas the MoveMore stage promoted increased steps per day and interrupting sitting over a 7-week period. The intervention was delivered through weekly one-on-one coaching sessions via telerehabilitation and an accompanying newsletter based on social-cognitive theory. Activity was monitored throughout the program using a Fitbit. MAIN OUTCOME MEASURES: Process (eg, recruitment) and resource and management (eg, personnel requirements) metrics were assessed, along with efficacy outcomes (eg, effect). Progression criteria were set a priori and were related to safety, fatigue, satisfaction, and attrition. Sedentary behavior, measured using the ActivPal, was reported pre- and postintervention, as well as 7 weeks postintervention. Effect sizes (pre to post, pre to 7 weeks post) were calculated for the sedentary behavior outcomes (eg, time sitting, transitions from sitting to standing, number of long sitting bouts). Experiences with the intervention were explored through an online survey. RESULTS: Forty-one participants enrolled, 39 of whom completed the intervention. All participants but 1 were satisfied with the experience. Pre-post intervention effect sizes for change in total sedentary time, number of transitions from sit to stand, and number of long (>30 min) sedentary bouts were 0.34, 0.02, and 0.39 respectively. All a priori progression criteria were met. CONCLUSIONS: The SitLess with MS program, a novel intervention that emphasized and facilitated sitting less and moving more, was feasible and resulted in small changes in sedentary behavior in individuals with MS.

Male urethral stricture disease in a regional centre: 10 years of experience.

BACKGROUND: Male urethral stricture disease is a challenging condition with a propensity for recurrence following endoscopic management. In recent years, earlier definitive urethral reconstruction has been advocated through international guidelines, prompted by series suggesting the underutilization of urethroplasty at rates of 0.6-0.8%. However, little local data exists to characterize our urethral stricture patients and we aimed to characterize the management of patients with urethral stricture disease presenting over a 10-year period to a single regional centre. METHODS: Patients with urethral stricture disease and admitted to a regional health service were identified. Retrospective chart review was undertaken for patients detailing basic demographics, stricture characteristics, clinical management and follow up. RESULTS: We identified 360 patients with median age 69 years (interquartile range 56-77). A total of 191 (53%) presented with lower urinary tract symptoms, 122 (34%) urethral strictures were incidental, and 13% presented in urinary retention. Bulbar urethral strictures were the commonest strictures at 40% with most being spontaneous or idiopathic (67%). A total of 339 patients had treatment during their first admission, 48% of patients had subsequent treatment on a second episode, and over 20% had a third or subsequent treatment. Only 21 (5.8%) underwent urethroplasty. Urethral dilatation and optical urethrotomy were most commonly performed (54%). With follow up 19 months (interquartile range 2-56), 205 (57%) were voiding, 38 (11%) were performing intermittent catheterization, and 59 were catheterized permanently. CONCLUSION: Definitive urethral reconstruction appears underutilized in our cohort of patients. A high proportion of incidentally presenting urethral strictures emphasizes the importance of wider education to optimize patient outcomes.

Myeloid-derived suppressor cells enhance IgE-mediated mast cell responses.

Mast cells and MDSCs are increased by parasitic infection and tumor growth. We previously demonstrated that enhanced MDSC development in ADAM10 transgenic mice yielded resistance to Nb infection and that coculturing MDSCs and mast cells enhanced cytokine production. In the current work, we show that MDSC-mast cell coculture selectively enhances IgE-mediated cytokine secretion among mast cells, without increasing MDSC cytokine production. This effect was independent of cell contact and elicited by Ly6C(+) and Ly6C/G+ MDSC subsets. These interactions were functionally important. MDSC depletion with the FDA-approved drug gemcitabine exacerbated Nb or Trichinella spiralis infection and reduced mast cell-dependent AHR and lung inflammation. Adoptive transfer of MDSC worsened AHR in WT but not mast cell-deficient Wsh/Wsh mice. These data support the hypothesis that MDSCs enhance mast cell inflammatory responses and demonstrate that this interaction can be altered by an existing chemotherapeutic.

Epoxyeicosatrienoic acids are involved in the C(70) fullerene derivative-induced control of allergic asthma.

BACKGROUND: Fullerenes are molecules being investigated for a wide range of therapeutic applications. We have shown previously that certain fullerene derivatives (FDs) inhibit mast cell (MC) function in vitro, and here we examine their in vivo therapeutic effect on asthma, a disease in which MCs play a predominant role. OBJECTIVE: We sought to determine whether an efficient MC-stabilizing FD (C(70)-tetraglycolate [TGA]) can inhibit asthma pathogenesis in vivo and to examine its in vivo mechanism of action. METHODS: Asthma was induced in mice, and animals were treated intranasally with TGA either simultaneously with treatment or after induction of pathogenesis. The efficacy of TGA was determined through the measurement of airway inflammation, bronchoconstriction, serum IgE levels, and bronchoalveolar lavage fluid cytokine and eicosanoid levels. RESULTS: We found that TGA-treated mice have significantly reduced airway inflammation, eosinophilia, and bronchoconstriction. The TGA treatments are effective, even when given after disease is established. Moreover, we report a novel inhibitory mechanism because TGA stimulates the production of an anti-inflammatory P-450 eicosanoid metabolites (cis-epoxyeicosatrienoic acids [EETs]) in the lung. Inhibitors of these anti-inflammatory EETs reversed TGA inhibition. In human lung MCs incubated with TGA, there was a significant upregulation of CYP1B gene expression, and TGA also reduced IgE production from B cells. Lastly, MCs incubated with EET and challenged through FcεRI had a significant blunting of mediator release compared with nontreated cells. CONCLUSION: The inhibitory capabilities of TGA reported here suggest that FDs might be used a platform for developing treatments for asthma.

A new class of human mast cell and peripheral blood basophil stabilizers that differentially control allergic mediator release.

Treatments for allergic disease block the effects of mediators released from activated mast cells and blood basophils. A panel of fullerene derivatives was synthesized and tested for their ability to preempt the release of allergic mediators in vitro and in vivo. The fullerene C(70)-tetraglycolic acid significantly inhibited degranulation and cytokine production from mast cells and basophils, while C(70)-tetrainositol blocked only cytokine production in mast cells and degranulation and cytokine production in basophils. The early phase of FcepsilonRI inhibition was dependent on the blunted release of intracellular calcium stores, elevations in reactive oxygen species, and several signaling molecules. Gene microarray studies further showed the two fullerene derivatives inhibited late phase responses in very different ways. C(70)-tetraglycolic acid was able to block mast cell-driven anaphylaxis in vivo, while C(70)-tetrainositol did not. No toxicity was observed with either compound. These findings demonstrate the biological effects of fullerenes critically depends on the moieties added to the carbon cage and suggest they act on different FcepsilonRI-specific molecules in mast cells and basophils. These next generation fullerene derivatives represent a new class of compounds that interfere with FcepsilonRI signaling pathways to stabilize mast cells and basophils. Thus, fullerene-based therapies may be a new approach for treating allergic diseases.

IL-4 and TGF-beta 1 counterbalance one another while regulating mast cell homeostasis.

Mast cell responses can be altered by cytokines, including those secreted by Th2 and regulatory T cells (Treg). Given the important role of mast cells in Th2-mediated inflammation and recent demonstrations of Treg-mast cell interactions, we examined the ability of IL-4 and TGF-beta1 to regulate mast cell homeostasis. Using in vitro and in vivo studies of mouse and human mast cells, we demonstrate that IL-4 suppresses TGF-beta1 receptor expression and signaling, and vice versa. In vitro studies demonstrated that IL-4 and TGF-beta1 had balancing effects on mast cell survival, migration, and FcepsilonRI expression, with each cytokine cancelling the effects of the other. However, in vivo analysis of peritoneal inflammation during Nippostrongylus brasiliensis infection in mice revealed a dominant suppressive function for TGF-beta1. These data support the existence of a cytokine network involving the Th2 cytokine IL-4 and the Treg cytokine TGF-beta1 that can regulate mast cell homeostasis. Dysregulation of this balance may impact allergic disease and be amenable to targeted therapy.

Uptake and distribution of fullerenes in human mast cells.

Fullerenes are carbon cages of variable size that can be derivatized with various side chain moieties resulting in compounds that are being developed into nanomedicines. Although fullerene use in several preclinical in vitro and in vivo models of disease has demonstrated their potential as diagnostic and therapeutic agents, little is known about how they enter cells, what organelles they target, and the time course for their cellular deposition. Fullerenes (C(70)) that have already been shown to be potent inhibitors of mast cell (MC)-mediated allergic inflammation were conjugated with Texas red (TR) and used in conjunction with confocal microscopy to determine mechanisms of uptake, the organelle localization, and the duration they can be detected in situ. We show that C(70)-TR are nonspecifically endocytosed into MCs, where they are shuttled throughout the cytoplasm, lysosomes, mitochondria, and into endoplasmic reticulum at different times. No nuclear or secretory granule localization was observed. The C(70)-TR remained detectable within cells at 1 week. These studies show that MCs endocytose fullerenes, where they are shuttled to organelles involved with calcium and reactive oxygen species production, which may explain their efficacy as cellular inhibitors. From the clinical editor: Fullerenes are carbon cages of variable size that have already been shown to be potent inhibitors of mast cell (MC)-mediated allergic inflammation. These were conjugated with Texas red (TR) and used in conjunction with confocal microscopy to determine mechanisms of uptake, the organelle localization, and duration, demonstrating that MCs endocytose fullerenes, which are shuttled to organelles involved with calcium and reactive oxygen species production. This intracellular trafficking may explain the efficacy of fullerenes as cellular inhibitors.

Cutting edge: CD4 T cell-mast cell interactions alter IgE receptor expression and signaling.

Mast cell activation is associated with atopic and inflammatory diseases, but the natural controls of mast cell homeostasis are poorly understood. We hypothesized that CD4(+)CD25(+) regulatory T cells (Treg) could function in mast cell homeostasis. In this study, we demonstrate that mast cells can recruit both Treg and conventional CD4(+) T cells (Tconv). Furthermore, Treg, but not Tconv, suppress mast cell FcepsilonRI expression. Despite the known inhibitory functions of IL-10 and TGFbeta1, FcepsilonRI suppression was independent of IL-10 and TGF-beta1 and required cell contact. Surprisingly, coculture with either Treg or Tconv cells suppressed IgE-mediated leukotriene C(4) production but enhanced cytokine production by mast cells. This was accompanied by a selective increase in FcepsilonRI-mediated Stat5 phosphorylation, which is a critical mediator of IgE-mediated cytokine secretion. These data are the first direct demonstration that mast cells can recruit Treg and illustrate that T cell interactions can alter the mast cell response.

IL-10 suppresses mast cell IgE receptor expression and signaling in vitro and in vivo.

Mast cells are known for their roles in allergy, asthma, systemic anaphylaxis, and inflammatory disease. IL-10 can regulate inflammatory responses and may serve as a natural regulator of mast cell function. We examined the effects of IL-10 on in vitro-cultured mouse and human mast cells, and evaluated the effects of IL-10 on FcepsilonRI in vivo using mouse models. IgE receptor signaling events were also assessed in the presence or absence of IL-10. IL-10 inhibited mouse mast cell FcepsilonRI expression in vitro through a Stat3-dependent process. This down-regulation was consistent in mice tested in vivo, and also on cultured human mast cells. IL-10 diminished expression of the signaling molecules Syk, Fyn, Akt, and Stat5, which could explain its ability to inhibit IgE-mediated activation. Studies of passive systemic anaphylaxis in IL-10-transgenic mice showed that IL-10 overexpression reduced the IgE-mediated anaphylactic response. These data suggest an important regulatory role for IL-10 in dampening mast cell FcepsilonRI expression and function. IL-10 may hence serve as a mediator of mast cell homeostasis, preventing excessive activation and the development of chronic inflammation.

Fullerene nanomaterials inhibit the allergic response.

Fullerenes are a class of novel carbon allotropes that may have practical applications in biotechnology and medicine. Human mast cells (MC) and peripheral blood basophils are critical cells involved in the initiation and propagation of several inflammatory conditions, mainly type I hypersensitivity. We report an unanticipated role of fullerenes as a negative regulator of allergic mediator release that suppresses Ag-driven type I hypersensitivity. Human MC and peripheral blood basophils exhibited a significant inhibition of IgE dependent mediator release when preincubated with C(60) fullerenes. Protein microarray demonstrated that inhibition of mediator release involves profound reductions in the activation of signaling molecules involved in mediator release and oxidative stress. Follow-up studies demonstrated that the tyrosine phosphorylation of Syk was dramatically inhibited in Ag-challenged cells first incubated with fullerenes. In addition, fullerene preincubation significantly inhibited IgE-induced elevation in cytoplasmic reactive oxygen species levels. Furthermore, fullerenes prevented the in vivo release of histamine and drop in core body temperature in vivo using a MC-dependent model of anaphylaxis. These findings identify a new biological function for fullerenes and may represent a novel way to control MC-dependent diseases including asthma, inflammatory arthritis, heart disease, and multiple sclerosis.