Project description:We report the case of letrozole-induced radiation recall dermatitis (RRD) in a patient with a remote history of radiation therapy. There is only one previously known case of RRD triggered by letrozole in a patient with a recent (<3 month) history of radiation. Previously, only four other cases of aromatase-inhibitor-induced RRD have been reported. This case is significant for cancer care teams considering personalized treatments. In addition, improved long-term outcomes in cancer patients may lead to increases in and underdiagnoses of RRD. Likewise, RRD is patient specific, exacerbating health concerns, and can be difficult to recognize without proper awareness, documentation, and classification of triggering drugs. The authors hope to address these issues in this report.
Project description:Here we present a mouse model for T-cell targeting of hair follicles, linking the pathogenesis of alopecia to that of depigmentation disorders. Clinically, thymus transplantation has been successfully used to treat T-cell immunodeficiency in congenital athymia, but is associated with autoimmunity. We established a mouse model of thymus transplantation by subcutaneously implanting human thymus tissue into athymic C57BL/6 nude mice. These xenografts supported mouse T-cell development. Surprisingly, we did not detect multiorgan autoimmune disease. However, in all transplanted mice, we noted a striking depigmentation and loss of hair follicles. Transfer of T cells from transplanted nudes to syngeneic black-coated RAG(-/-) recipients caused progressive, persistent coat-hair whitening, which preceded patchy hair loss in depigmented areas. Further transfer experiments revealed that these phenomena could be induced by CD4+ T cells alone. Immunofluorescent analysis suggested that Trp2+ melanocyte-lineage cells were decreased in depigmented hair follicles, and pathogenic T cells upregulated activation markers when exposed to C57BL/6 melanocytes in vitro, suggesting that these T cells are not tolerant to self-melanocyte antigens. Our data raise interesting questions about the mechanisms underlying tissue-specific tolerance to skin antigens.
Project description:Rhodotorula mucilaginosa was isolated from a patient with onychomycosis, and identification was confirmed by morphological and cultural characteristics as well as by DNA molecular analysis. Antifungal agents naftifine (10 mg/mL, active substance in Exoderil) and bifonazole (10 mg/mL, active substance in Canespor) were tested in different concentrations to assess in vitro effects on fungal growth and carotenoid synthesis. The antifungal mechanisms of action of naftifine and bifonazole against R. mucilaginosa isolates were similar and affected the biosynthetic pathway of ergosterol. For the first time, this research demonstrates that naftifine affects the carotenoid biosynthetic pathway, producing depigmentation of R. mucilaginosa in solid and liquid media. Furthermore, depigmentation was a reversible process; naftifine-treated yeast cells that were depigmented resumed carotenoid production upon transfer to fresh media. Raman and UV-vis spectrophotometry in conjunction with chromatographic analysis detected changes in carotenoids in yeast cells, with torulene decreasing and B-carotene increasing after repigmentation. Transmission electron micrographs revealed critical ultrastructural modifications in the depigmented cells after naftifine treatment, i.e., a low-electron-density cell wall without visible mucilage or lamellate structure.
Project description:Melanocytes of the hair follicle produce melanin and are essential in determining the differences in hair color. Pigment cell-specific MELanocyte Protein (PMEL17) plays a crucial role in melanogenesis. One of the critical steps is the amyloid-like functional oligomerization of PMEL17. Beta Site APP Cleaving Enzyme-2 (BACE2) and γ-secretase have been shown to be key players in generating the proteolytic fragments of PMEL17. The β-secretase (BACE1) is responsible for the generation of amyloid-β (Aβ) fragments in the brain and is therefore proposed as a therapeutic target for Alzheimer's disease (AD). Currently BACE1 inhibitors, most of which lack selectivity over BACE2, have demonstrated efficacious reduction of amyloid-β peptides in animals and the CSF of humans. BACE2 knock-out mice have a deficiency in PMEL17 proteolytic processing leading to impaired melanin storage and hair depigmentation. Here, we confirm BACE2-mediated inhibition of PMEL17 proteolytic processing in vitro in mouse and human melanocytes. Furthermore, we show that wildtype as well as bace2(+/-) and bace2(-/-) mice treated with a potent dual BACE1/BACE2 inhibitor NB-360 display dose-dependent appearance of irreversibly depigmented hair. Retinal pigmented epithelium showed no morphological changes. Our data demonstrates that BACE2 as well as additional BACE1 inhibition affects melanosome maturation and induces hair depigmentation in mice.
Project description:Over half of all people diagnosed with cancer receive radiation therapy. Moderate to severe radiation dermatitis occurs in most human radiation patients, causing pain, aesthetic distress, and a negative impact on tumor control. No effective prevention or treatment for radiation dermatitis exists. The lack of well-characterized, clinically relevant animal models of human radiation dermatitis contributes to the absence of strategies to mitigate radiation dermatitis. Here, we establish and characterize a hairless SKH-1 mouse model of human radiation dermatitis by correlating temporal stages of clinical and pathological skin injury. We demonstrate that a single ionizing radiation treatment of 30 Gy using 6 MeV electrons induces severe clinical grade 3 peak toxicity at 12 days, defined by marked erythema, desquamation and partial ulceration, with resolution occurring by 25 days. Histopathology reveals that radiation-induced skin injury features temporally unique inflammatory changes. Upregulation of epidermal and dermal TGF-ß1 and COX-2 protein expression occurs at peak dermatitis, with sustained epidermal TGF-ß1 expression beyond resolution. Specific histopathological variables that remain substantially high at peak toxicity and early clinical resolution, including epidermal thickening, hyperkeratosis and dermal fibroplasia/fibrosis, serve as specific measurable parameters for in vivo interventional preclinical studies that seek to mitigate radiation-induced skin injury.
Project description:RationaleResistant cytomegalovirus-mediated infections are increasing in solid organ recipient with few available alternative treatments. Brincidofovir is an oral broad-spectrum antiviral in development for prevention and treatment of viral infection, particularly cytomegalovirus.Patients concernsAlthough brincidofovir is an analogue of cidofovir, previous studies reported no renal toxicity.DiagnosesHere, we report 2 cases of severe tubular necrosis in solid organ recipients, 1 heart and 1 kidney transplant.InterventionsBoth patients received brincidofovir for the treatment of cytomegalovirus infection with mutation of UL-97. They presented an acute kidney injury without any occurrence of other clinical event such as introduction of nephrotoxic drug, graft rejection, urinary tract obstruction or infection, and calcineurin inhibitor overdosage. In each case, renal biopsy showed extended tubular necrosis.OutcomesThe discontinuation of brincidofovir led to improve renal function without other any intervention. Reintroduction of brincidofovir in case 1, due to the absence of other medical alternative, led to a new episode of acute kidney injury. One more time, renal biopsy showed tubular necrosis and patient recovered renal function after discontinuation.LessonsTo our knowledge, this is the first report of brincidofovir-mediated renal adverse event. Clinicians may be aware of this severe complication in this specific population.
Project description:We present a case of mild radiation recall dermatitis triggered by cisplatin chemotherapy given simultaneously to re-irradiation. The dermatitis area correlated to skin exposure of the previous radiation therapy, characterizing the reaction clearly as a recall. Cisplatin has not yet been recognized as a potential trigger for recall reactions. Although it was part of several reported multidrug trigger combinations, all review works referred to cisplatin as not suspicious, suggesting the combination partner as the effector. We performed a focused systematic literature review aiming to re-evaluate the real role of cisplatin as a (co-)triggering factor. In total, 30 reported cases were found, 90% triggered by multidrug combinations. The latter tended to cause more severe symptoms. Besides findings supporting the 20 Gy-threshold theory, no correlation between radiation dose and severity or prevalence was found. Recognition of cisplatin as a trigger of the recall phenomenon and its supportive management may prevent unnecessary cessation of systemic chemotherapy. Systematic reporting of recall events as a secondary endpoint of prospective clinical trials applying radiation therapy could support understanding the recall phenomenon.
Project description:BackgroundLeptospirosis is a zoonotic spirochetal disease caused by Leptospira interrogans. The clinical presentation ranges from an asymptomatic state to a fatal multiorgan dysfunction. Neurological manifestations including aseptic meningitis, spinal cord and peripheral nerve involvement, cranial neuropathies and cerebellar syndrome are well recognized with varying frequencies among patients with this disease. Posterior reversible encephalopathy syndrome is a very rare occurrence in leptospirosis and only two cases are reported in the medical literature up to now. We report a case of posterior reversible encephalopathy syndrome in a patient with leptospirosis with rhabdomyolysis and acute kidney injury.Case presentationA 21 year-old male presented with fever and oliguric acute kidney injury with rhabdomyolysis. A diagnosis of leptospirosis was made and he was being managed according to the standard practice together with regular hemodialysis. The clinical condition was improving gradually. On day 8 of the illness, he developed headache and sudden painless complete bilateral vision loss followed by several brief generalized tonic clonic seizure attacks. Examination was significant for a Glasgow Coma Scale of 14/15, blood pressure of 150/90 mmHg and complete bilateral blindness. The findings of magnetic resonance imaging of the brain were compatible with posterior reversible encephalopathy syndrome. He was managed with blood pressure control and antiepileptics with supportive measures and standard treatment for leptospirosis and made a complete recovery.ConclusionPosterior reversible encephalopathy syndrome, though very rare with leptospirosis, should be considered as a differential diagnosis in a patient with new onset visual symptoms and seizures, especially during the immune phase. Optimal supportive care together with careful blood pressure control and seizure management would yield a favourable outcome in this reversible entity.