Unmet needs in treating itch: reaching beyond eczema.

PURPOSE: Pruritus is an unpleasant sensation that creates the urge to scratch. In many chronic conditions, relentless pruritus and scratching perpetuates a vicious itch-scratch cycle. Uncontrolled itch can detrimentally affect quality of life and may lead to sleep disturbance, impaired concentration, financial burden, and psychological suffering. Recent strides have been made to develop guidelines and investigate new therapies to treat some of the most common severely pruritic conditions, however, a large group of diseases remains underrecognized and undertreated. The purpose of this article is to provide a comprehensive review of the challenges hindering the treatment of pruritus. METHODS: An online search was performed using PubMed, Web of Science, Google Scholar, and ClinicalTrials.gov from 1994 to 2024. Included studies were summarized and assessed for quality and relevance in treating pruritus. RESULTS: Several barriers to treating pruritus emerged, including variable presentation, objective measurement of itch, and identifying therapeutic targets. Itch associated with autoimmune conditions, connective tissue diseases, genodermatoses, cutaneous T-cell lymphoma, and pruritus of unknown origin were among the etiologies with the greatest unmet needs. CONCLUSION: Treating pruritus poses many challenges and there are many itchy conditions that have no yet been addressed. There is an urgent need for large-scale controlled studies to investigate potential targets for these conditions and novel therapies.

Modeling the single and multiple scattering properties of soot-laden mineral dust aerosols.

Fractal particle morphologies are employed to study the light scattering properties of soot-laden mineral dust aerosols. The applicability of these models is assessed in comparison with measurements and other numerical studies. To quantify the dust-soot mixing effects on the single and multiple scattering properties, a parameterization of the effective bulk properties is developed. Based on the parameterized bulk properties, polarized one-dimensional radiative transfer simulations are performed. The results indicate that small uncertainties in conjunction with soot contamination parameters may lead to large uncertainties in both forward and inverse modeling involving mineral dust contaminated with soot.

Anti-hIgE gene therapy of peanut-induced anaphylaxis in a humanized murine model of peanut allergy.

BACKGROUND: Peanuts are the most common food to provoke fatal or near-fatal anaphylactic reactions. Treatment with an anti-hIgE mAb is efficacious but requires frequent parenteral administration. OBJECTIVE: Based on the knowledge that peanut allergy is mediated by peanut-specific IgE, we hypothesized that a single administration of an adeno-associated virus (AAV) gene transfer vector encoding for anti-hIgE would protect against repeated peanut exposure in the host with peanut allergy. METHODS: We developed a novel humanized murine model of peanut allergy that recapitulates the human anaphylactic response to peanuts in NOD-scid IL2Rgammanull mice transferred with blood mononuclear cells from donors with peanut allergy and then sensitized with peanut extract. As therapy, we constructed an adeno-associated rh.10 serotype vector coding for a full-length, high-affinity, anti-hIgE antibody derived from the Fab fragment of the anti-hIgE mAb omalizumab (AAVrh.10anti-hIgE). In the reconstituted mice peanut-specific IgE was induced by peanut sensitization and hypersensitivity, and reactions were provoked by feeding peanuts to mice with symptoms similar to those of human subjects with peanut allergy. RESULTS: A single administration of AAVrh.10anti-hIgE vector expressed persistent levels of anti-hIgE. The anti-hIgE vector, administered either before sensitization or after peanut sensitization and manifestation of the peanut-induced phenotype, blocked IgE-mediated alterations in peanut-induced histamine release, anaphylaxis scores, locomotor activity, and free IgE levels and protected animals from death caused by anaphylaxis. CONCLUSION: If this degree of persistent efficacy translates to human subjects, AAVrh.10anti-hIgE could be an effective 1-time preventative therapy for peanut allergy and possibly other severe, IgE-mediated allergies.

Effects of chemical aging on the ice nucleation activity of soot and polycyclic aromatic hydrocarbon aerosols.

The role of soot particles as ice nuclei (IN) in heterogeneous freezing processes in the atmosphere remains uncertain. Determination of the freezing efficiency of soot is complicated by the changing properties of soot particles undergoing atmospheric aging processes. In this study, the heterogeneous freezing temperatures of droplets in contact with fresh and oxidized soot particles were determined using an optical microscope apparatus equipped with a sealed cooling stage and a CCD video camera. Experiments were also conducted using fresh and oxidized polycyclic aromatic hydrocarbons (PAHs), including anthracene, pyrene, and phenanthrene, as potential ice nuclei. Chemical changes at the surface of the aerosols caused by exposure to ozone were characterized using Fourier transform infrared spectroscopy with horizontal attenuated total reflectance (FTIR-HATR). In addition, Brunauer-Emmett-Teller (BET) measurements were used to determine the specific surface areas of the soot particles. Mean freezing temperatures on fresh particles ranged from -19 to -24 °C, depending on the IN composition and size. In all cases, exposure to ozone facilitated ice nucleation at warmer temperatures, by 2-3 °C, on average. In addition, nucleation rate coefficients for a single temperature and IN type increased by as much as 4 orders of magnitude because of oxidation. Furthermore, a fraction of the oxidized soot particles froze at temperatures above -10 °C. A modified version of classical nucleation theory that accounts for a range of contact angles on nucleation sites within an IN population was used to derive the probability of freezing as a function of temperature for each type of IN. In summary, our results suggest that atmospheric oxidation processes may both extend the range over which particles can act as ice nuclei to warmer temperatures and increase heterogeneous nucleation rates on soot and pollutant aerosols.

Renal metastasis of an ovarian granulosa cell tumour inducing growth of a cystic nephroma.

A 44-year-old woman presented with a large pelvic mass. Pathology revealed a granulosa cell tumour of the left ovary. The patient was followed after surgery with inhibin B levels and interval imaging. Six years later, she began to experience severe back pain. A vertebral biopsy was positive for metastatic granulosa cell tumour. She underwent radiation to the spine. Inhibin B levels began to rise and, several months later, a CT scan showed a large heterogeneous mass essentially replacing the left kidney. She underwent an open left radical nephrectomy. Pathology revealed a 12 cm cystic nephroma with a 5 cm nodule of metastatic granulosa cell tumour. Immunohistochemistry demonstrated that the mass was inhibin and oestrogen receptor positive. This is a novel presentation of these coexisting pathologies. This unique case sheds light on the possibility of induction of cystic nephroma by the altered hormonal environment created by a granulosa cell tumour metastasis.

Prolonged exposure to sphingosine 1-phosphate receptor-1 agonists exacerbates vascular leak, fibrosis, and mortality after lung injury.

Sphingosine 1-phosphate (S1P) is a key endogenous regulator of the response to lung injury, maintaining endothelial barrier integrity through interaction with one of its receptors, S1P(1). The short-term administration of S1P or S1P(1) receptor agonists enhances endothelial monolayer barrier function in vitro, and attenuates injury-induced vascular leak in the lung and other organ systems in vivo. Although S1P(1) agonists bind to and activate S1P(1), several of these agents also induce receptor internalization and degradation, and may therefore act as functional antagonists of S1P(1) after extended exposure. Here we report on the effects of prolonged exposure to these agents in bleomycin-induced lung injury. We demonstrate that repeated administration of S1P(1) agonists dramatically worsened lung injury after bleomycin challenge, as manifested by increased vascular leak and mortality. Consistent with these results, prolonged exposure to S1P(1) agonists in vitro eliminated the ability of endothelial cell monolayers to respond appropriately to the barrier-protective effects of S1P, indicating a loss of normal S1P-S1P(1) signaling. As bleomycin-induced lung injury progressed, continued exposure to S1P(1) agonists also resulted in increased pulmonary fibrosis. These data indicate that S1P(1) agonists can act as functional antagonists of S1P(1) on endothelial cells in vivo, which should be considered in developing these agents as therapies for vascular leak syndromes. Our findings also support the hypothesis that vascular leak is an important component of the fibrogenic response to lung injury, and suggest that targeting the S1P-S1P(1) pathway may also be an effective therapeutic strategy for fibrotic lung diseases.

Induction of robust cellular and humoral virus-specific adaptive immune responses in human immunodeficiency virus-infected humanized BLT mice.

The generation of humanized BLT mice by the cotransplantation of human fetal thymus and liver tissues and CD34(+) fetal liver cells into nonobese diabetic/severe combined immunodeficiency mice allows for the long-term reconstitution of a functional human immune system, with human T cells, B cells, dendritic cells, and monocytes/macrophages repopulating mouse tissues. Here, we show that humanized BLT mice sustained high-level disseminated human immunodeficiency virus (HIV) infection, resulting in CD4(+) T-cell depletion and generalized immune activation. Following infection, HIV-specific humoral responses were present in all mice by 3 months, and HIV-specific CD4(+) and CD8(+) T-cell responses were detected in the majority of mice tested after 9 weeks of infection. Despite robust HIV-specific responses, however, viral loads remained elevated in infected BLT mice, raising the possibility that these responses are dysfunctional. The increased T-cell expression of the negative costimulator PD-1 recently has been postulated to contribute to T-cell dysfunction in chronic HIV infection. As seen in human infection, both CD4(+) and CD8(+) T cells demonstrated increased PD-1 expression in HIV-infected BLT mice, and PD-1 levels in these cells correlated positively with viral load and inversely with CD4(+) cell levels. The ability of humanized BLT mice to generate both cellular and humoral immune responses to HIV will allow the further investigation of human HIV-specific immune responses in vivo and suggests that these mice are able to provide a platform to assess candidate HIV vaccines and other immunotherapeutic strategies.

Gemcitabine-induced radiation recall.

PURPOSE: To study and report 6 patients with radiation recall in unique sites, secondary to gemcitabine chemotherapy. METHODS AND MATERIALS: The clinical presentations and outcomes of 6 patients with radiation recall secondary to gemcitabine chemotherapy were retrospectively analyzed over the course of a 1-year period. RESULTS: Radiation recall reactions were seen in the central nervous system, skin, gastrointestinal tract, and in the lymphatic and musculoskeletal systems. The time between initiation of radiation and recall of the radiation phenomenon ranged from 3 weeks to 8 months from the time gemcitabine was initiated. The usual dosage of gemcitabine in these cases was 1000 mg/m(2) given on a weekly basis. No radiation therapy was given concomitantly with gemcitabine. Treatment of the recall reaction consisted of discontinuing gemcitabine and initiating steroid therapy, supportive therapy, and/or nonsteroidal anti-inflammatory agents. Minimal improvement was seen in 3 out of 6 patients, and resolution of the radiation recall was seen in 3 out of 6 patients. A comprehensive review of the literature revealed that radiation recall with gemcitabine has been related to skin reactions only; no previous cases of radiation recall occurring in the central nervous system have been reported with any chemotherapy agent. CONCLUSION: Radiation recall from gemcitabine chemotherapy is rare, but can potentially arise in any site that has been previously irradiated. Treating physicians must be aware of this potential toxicity from gemcitabine and radiation and discontinue the gemcitabine if radiation recall is observed.