Atorvastatin-Associated Eosinophilic Spongiosis: A Case Report and a Relevant Literature Review of Dermatological Manifestations.

Atorvastatin, a widely prescribed 3-hydroxy-3-methyl-glutaryl-coenzyme A reductase inhibitor (HMG-CoA reductase inhibitor), is associated with various adverse effects, including many dermatologic manifestations. We present the case of a 73-year-old man who developed eosinophilic spongiosis shortly after initiating atorvastatin therapy, an adverse effect which to our knowledge has not yet been reported in association with atorvastatin. Our investigation explores the clinical and histopathologic characteristics of eosinophilic spongiosis induced by atorvastatin, delving into potential mechanisms behind statin-induced eosinophilia. A literature review, focusing on atorvastatin's dermatological side effects, revealed a limited number of relevant studies, emphasizing the scarcity of documented cases. Our aim is to raise awareness of eosinophilic spongiosis as a potential side effect of atorvastatin, emphasizing its impact on patients' quality of life. This case prompts further research into the mechanisms underlying such dermatologic reactions, contributing to a better understanding of atorvastatin's diverse adverse effects.

Cutaneous basophil infiltration in atopic dermatitis is associated with abundant epidermal infiltration of helper T cells: A preliminary retrospective study.

Atopic dermatitis (AD) is a heterogenous inflammatory skin disorder. Our previous study revealed that basophil infiltration in skin is observed in approximately 60% of AD cases. However, the clinical and histological characteristics of AD associated with basophil infiltration remain unclear. We examined basophil infiltration by immunohistochemical staining of 38 specimens from 34 patients who underwent skin biopsies to diagnose AD from April 2016 to September 2021 at Tokyo Medical and Dental University Hospital. The patients/specimens were divided into two groups, 17 patients/21 specimens associated with little or no basophil infiltration (basophil-low group) and 17 patients/17 specimens associated with marked basophil infiltration (basophil-high group). The clinical characteristics of the patients (age, sex, complications, blood biomarkers, skin symptoms, and treatment) and histological features of the specimens were compared between the groups. Basophil-high patients were significantly younger than basophil-low patients. Blood basophil counts were higher in basophil-high patients than in basophil-low patients. CD4+ T-cell infiltration was more marked in basophil-high specimens than in basophil-low specimens. CD4+ T cells infiltrated into the dermis as well as into the epidermis only in the basophil-high specimens. Thus, basophil-high AD can be characterized by skin lesions associated with abundant helper T-cell infiltration in younger patients.

Porcine Forebrain Vacuolization Associated with Wasting in Pigs: A Novel Pathological Outcome Associated with Vitamin-Mineral Deficiency?

The term wasting refers to a clinical sign used to describe a physical condition characterized by growth retardation, usually of multifactorial origin. The objective of the present study was to describe for the first time a pathological process characterized by forebrain neuropil vacuolization in pigs showing wasting without conspicuous neurological signs. To characterize the lesions pathologically, affected and non-affected pigs from eight of these farms were investigated. Histologically, the most consistent lesion was neuropil vacuolization of the prosencephalon, mainly located in the thalamic nuclei and in the transition between the white and grey matter of the neocortex (40/56 in sick and 4/30 in healthy pigs). In the most severe cases, the vacuolation also involved the midbrain, cerebellar nuclei and, to a lesser extent, the medulla oblongata. Vacuolization of the forebrain was associated with pigs experiencing marked emaciation and growth retardation. Although the specific cause of the present case remained unknown, the preventive use of multivitamin and mineral complexes in drinking water ameliorated the condition, strongly suggesting a metabolic origin of the observed condition.

Neuropathological report of propionic acidemia.

Propionic acidemia (PA) is an autosomal recessive inheritable metabolic disease caused by mutations in the propionyl CoA carboxylase gene (PCC) that affects multiple systems of the human body. Here, we report neuropathological findings of a PA patient. The patient was a male infant who presented with increasing lethargy and poor feeding from four days postpartum. He gradually became comatose and died from complications after liver transplantation at three months old. The results of laboratory examination were consistent with PA, and genetic analysis revealed compound heterozygous mutations in the gene for PCC subunit beta: c.838dupC (rs769968548) and c.1127G>T (rs142982097). Brain-restricted autopsy was performed 23 h after his death, and the neuropathological examination revealed distinct astrocytosis, oligodendrocytic loss, neuronal loss, and demyelination across the brainstem, motor cortex, basal ganglia, and thalamus. Spongiosis, vacuolization, and the appearance of Alzheimer type II astrocytes and activated microglia were observed as well. This is the first brain autopsy report of PA with a clear genetic cause.

An Observational Study of Dermoscopic and Histopathological Correlation in Spongiotic Disorders - A Hospital Based Cross Sectional Study.

Introduction: Spongiosis is defined as intercellular edema and vesicles in the epidermis. Histopathology is the gold standard for the diagnosis of spongiotic disorders. Clinical diagnosis of eczema is sometimes unclear and confused with other dermatoses; histopathology often shows spongiotic tissue reaction patterns; such conditions are called spongiotic disorders. It is challenging for a dermatologist to make the correct diagnosis noninvasively with a dermoscope and thus we have taken up the study to correlate the dermoscopic and histopathological findings in spongiotic disorders to set dermoscopic criteria for the diagnosis. Objective: To study the dermoscopic features of spongiotic disorders and correlate clinical, dermoscopic, and histopathological findings. Materials and Methods: Two hundred fifty two patients, with history and clinical presentation suggesting eczema were enrolled. They were classified as Acute (<6 weeks), Subacute (6 weeks to 3 months), and Chronic (>3 months) eczemas based on duration. Dermoscopy and skin biopsy were performed on representative lesions. Data were compiled and statistically analyzed using frequency distribution and Chi-square test. Results: We correlated the diagnosis based on acute, subacute, and chronic with three modalities, clinical examination, dermoscopy, and histopathology. On clinical examination, acute (27.4%), subacute (42.9%), and chronic (29.7%) dermatitis. On dermoscopy, acute (28.5%), subacute (40.4%), and chronic (31.1%) dermatitis. On histopathology, acute (29.5%), subacute (44.2%), and chronic (26.3%) spongiosis. A positive correlation of 99%, 96.2%, and 95% was observed on dermoscopy and histopathology, in acute, subacute, and chronic eczemas, respectively. Dermoscopy of acute eczemas showed linear vessels (100%) and red background (100%). White-Clods (98.9%) and excoriation marks (70.1%). Dermoscopy of subacute eczemas showed white scales (99.1%), irregular pigment network (98.3%), vascular changes with irregular dots (97.4%), a brown-white background (93.1%), and black/brown/grey dots (91.4%). Dermoscopy of chronic eczema showed brown-white background (100%), irregular pigment network (100%), and black/brown/grey blotches (100%). Conclusion: Definitive dermoscopic patterns are observed consistently with spongiotic diseases and these can be used additionally to set dermoscopic criteria and confirm the diagnosis. Also, dermoscopic findings are well correlated with the already established histopathological features.

Spongiotic Pattern in Pemphigus: A Retrospective Observational Single-Center Study.

Pemphigus is a chronic blistering disorder caused by autoantibodies that target desmosomal proteins in the epidermis. Acantholysis may be absent, and pemphigus may present only with spongiosis and vesiculation, thereby leading to a misdiagnosis of eczema. Herein, we conducted a retrospective, observational, single-center study to establish a pattern of spongiosis in cases of pemphigus confirmed by direct immunofluorescence. Immunopathologically diagnosed pemphigus specimens from 2001 to 2020 were retrieved, and specimens with spongiosis were analyzed for the following features: vesiculation, acantholysis, spongiosis, inflammatory cells in the epidermis, and inflammation in the dermis. Cases of spongiotic dermatitis were used as control. Out of 99 immunopathologically diagnosed pemphigus specimens, 41 samples with spongiosis were identified. About one quarter of the specimens did not have acantholysis. Spongiosis in the middle to lower thirds of the perilesional epidermis (p = 0.030), exocytosis with either neutrophils or eosinophils (p = 0.016), dermal infiltrates composed of lymphocytes, eosinophils, and neutrophils (p = 0.012), and absence of Langerhans cell microabscesses (p < 0.001) were more common in pemphigus than control. Spongiosis in pemphigus may mimic eczema in patients without acantholysis. The subtle histological findings in this study provide diagnostic clues and suggest that further immunofluorescence should be performed to confirm pemphigus diagnosis.

Immunological Pathomechanisms of Spongiotic Dermatitis in Skin Lesions of Atopic Dermatitis.

Atopic dermatitis (AD) is a chronic pruritic skin disease with a complex pathogenesis underlying its heterogeneous clinical phenotypes and endotypes. The skin manifestation of AD reflects the cytokine milieu of a type-2-dominant immunity axis induced by genetic predisposition, innate immunity dysregulation, epidermal barrier defects, and allergic inflammation. However, the detailed pathomechanism of eczematous dermatitis, which is the principal characteristic of AD, remains unclear. This review examines previous studies demonstrating research progress in this area and considers the immunological pathomechanism of "spongiotic dermatitis", which is the histopathological hallmark of eczematous dermatitis. Studies in this field have revealed the importance of IgE-mediated delayed-type hypersensitivity, the Fas/Fas-ligand system, and cell-mediated cytotoxicity in inducing the apoptosis of keratinocytes in spongiotic dermatitis. Recent studies have demonstrated that, together with infiltrating CD4 T cells, IgE-expressing dendritic cells (i.e., inflammatory dendritic epidermal cells and Langerhans cells) that capture specific allergens (i.e., house dust mites) are present in the spongiotic epidermis of lichenified eczema in patients with IgE-allergic AD. These findings suggest that IgE-mediated delayed-type hypersensitivity plays a pivotal role in the pathogenesis of spongiotic dermatitis in the skin lesions of AD.

A case of spontaneous autoimmune skin disease in a cynomolgus monkey (Macaca fascicularis).

Pemphigus is an autoimmune blistering disease characterized by lesions on the skin and mucous membranes. To date, no spontaneous cases of this disease have been reported in cynomolgus monkeys. This report describes the histopathological characteristics of spontaneous pemphigus in a cynomolgus monkey. Macroscopically, redness and scaling with pruritus were observed on the skin of the entire body. Histopathologically, the epidermis showed intercellular edema, and eosinophils and mononuclear cells infiltrated the epidermis. There was no obvious acantholysis in the epidermis. The perivascular area showed edema, and eosinophils and mononuclear cells infiltrated the vessels in the dermis. Immunohistochemically, the intercellular area in the epidermis was positive for Immunoglobulin G and Complement component 3. Serologically, anti-desmoglein 1 and desmoglein 3 antibodies in the serum were negative. From these findings, this case was diagnosed as an autoimmune skin disease, suspected to be pemphigus, and concluded as lesions being similar to those in human "pemphigus herpetiformis".

Histopathologic features of inverse psoriasis.

BACKGROUND: Inverse psoriasis represents a less commonly described form of psoriasis in intertriginous areas. The pathologic findings of inverse psoriasis are typically grouped in with those of plaque psoriasis, as the histopathologic features specific to inverse psoriasis have not received significant investigation. METHODS: A single institution, retrospective cohort study was performed to review biopsy slides for psoriasis occurring in typical intertriginous areas. Patient's charts were reviewed and only those where the clinical diagnosis of inverse psoriasis was also favored were included. RESULTS: Twelve patients met inclusion criteria: 58% male and 42% female, 18 to 86 years of age. Classic features of psoriasis such as hypogranulosis, confluent parakeratosis, and thinning of the suprapapillary plate were seen in 100%. Regular psoriasiform acanthosis and dilated tortuous dermal vessels were seen in 92%. Neutrophils were present in the scale in 83% and in the dermis in 100%. Features considered atypical for psoriasis included spongiosis in 83%, eosinophils in 67%, and focal serum in the scale in 42%. CONCLUSIONS: While inverse psoriasis commonly exhibits features considered to be classic for psoriasis, it is not unusual for inverse psoriasis to show features considered atypical for plaque psoriasis such as dermal eosinophils, epidermal spongiosis, and focal serum in the scale.

Spongiotic reaction patterns in autoimmune bullous dermatoses (Review).

Spongiosis or a spongiotic reaction pattern is the histological hallmark of intercellular epidermal edema, viewed as clear spaces within the epidermis. Although considered a histopathological term, spongiosis has clinical correlations, with the variable degrees of spongiotic reaction leading to different dermatological findings. This review aimed to highlight the spongiotic reactive patterns found in different autoimmune bullous dermatoses, considering the paucity of publications in this domain. The pathogenesis of spongiosis assumes the passage of extravasated edema fluid from the dermis into the epidermis, frequently accompanied by dermal inflammatory cells, and classification of the spongiotic reaction patterns, as well as their associated spongiotic dermatitis, take into consideration the type and distribution of these inflammatory cells. It is mandatory to consider different reactive processes, specific for other skin disorders, which act as simulants of different spongiotic patterns for the diagnosis. Considering the possible transient occurrence, the heterogeneity and non-specificity of the histopathological features of these diseases, the diagnosis is very complex, requiring clinicopathological correlations and additional analyses. A deep insight into spongiosis pathogeny may open the perspectives of a classification refinement of autoimmune bullous dermatoses.

ß-RA Targets Mitochondrial Metabolism and Adipogenesis, Leading to Therapeutic Benefits against CoQ Deficiency and Age-Related Overweight.

Primary mitochondrial diseases are caused by mutations in mitochondrial or nuclear genes, leading to the abnormal function of specific mitochondrial pathways. Mitochondrial dysfunction is also a secondary event in more common pathophysiological conditions, such as obesity and metabolic syndrome. In both cases, the improvement and management of mitochondrial homeostasis remain challenging. Here, we show that beta-resorcylic acid (ß-RA), which is a natural phenolic compound, competed in vivo with 4-hydroxybenzoic acid, which is the natural precursor of coenzyme Q biosynthesis. This led to a decrease in demethoxyubiquinone, which is an intermediate metabolite of CoQ biosynthesis that is abnormally accumulated in Coq9R239X mice. As a consequence, ß-RA rescued the phenotype of Coq9R239X mice, which is a model of primary mitochondrial encephalopathy. Moreover, we observed that long-term treatment with ß-RA also reduced the size and content of the white adipose tissue (WAT) that is normally accumulated during aging in wild-type mice, leading to the prevention of hepatic steatosis and an increase in survival at the elderly stage of life. The reduction in WAT content was due to a decrease in adipogenesis, an adaptation of the mitochondrial proteome in the kidneys, and stimulation of glycolysis and acetyl-CoA metabolism. Therefore, our results demonstrate that ß-RA acted through different cellular mechanisms, with effects on mitochondrial metabolism; as such, it may be used for the treatment of primary coenzyme Q deficiency, overweight, and hepatic steatosis.

Immunohistopathological Analysis of Immunoglobulin E-Positive Epidermal Dendritic Cells with House Dust Mite Antigens in Naturally Occurring Skin Lesions of Adult and Elderly Patients with Atopic Dermatitis.

The immunopathogenic role of house dust mite (HDM) allergens in the development of skin lesions in atopic dermatitis (AD) has not yet been precisely clarified. We immunohistopathologically evaluated the localization of immunoglobulin E (IgE)-positive epidermal dendritic cells with HDM antigens in the skin lesions of patients with IgE-allergic AD. Using double-immunofluorescence and single-immunochemical staining methods, we analyzed biopsy specimens from the skin lesions of six patients with IgE-allergic AD and HDM allergy and 11 control subjects with inflammatory skin disorders. Inflammatory dendritic epidermal cells (IDECs; CD11c+ and CD206+ cells) were markedly observed in the central area of the spongiotic epidermis of skin lesions in all AD patients. Furthermore, IgE-positive IDECs with HDM antigens in the central areas of the spongiosis were found in four of the six (66.7%) AD patients. Langerhans cells (LCs; CD207+ cells) with HDM antigens were also observed in the peripheral areas of the spongiosis. Infiltration of CD4+ and CD8+ T cells in association with IgE-positive IDECs and LCs with HDM antigens was seen in the spongiotic epidermis. An IgE-mediated delayed-type hypersensitivity reaction, in combination with IgE-bearing dendritic cells, specific T cells, keratinocytes, and HDM antigens, may lead to spongiotic tissue formation in eczematous dermatitis in AD.

Loss of PIKfyve drives the spongiform degeneration in prion diseases.

Brain-matter vacuolation is a defining trait of all prion diseases, yet its cause is unknown. Here, we report that prion infection and prion-mimetic antibodies deplete the phosphoinositide kinase PIKfyve-which controls endolysosomal maturation-from mouse brains, cultured cells, organotypic brain slices, and brains of Creutzfeldt-Jakob disease victims. We found that PIKfyve is acylated by the acyltransferases zDHHC9 and zDHHC21, whose juxtavesicular topology is disturbed by prion infection, resulting in PIKfyve deacylation and rapid degradation, as well as endolysosomal hypertrophy and activation of TFEB-dependent lysosomal enzymes. A protracted unfolded protein response (UPR), typical of prion diseases, also induced PIKfyve deacylation and degradation. Conversely, UPR antagonists restored PIKfyve levels in prion-infected cells. Overexpression of zDHHC9 and zDHHC21, administration of the antiprion polythiophene LIN5044, or supplementation with the PIKfyve reaction product PI(3,5)P2 suppressed prion-induced vacuolation and restored lysosomal homeostasis. Thus, PIKfyve emerges as a central mediator of vacuolation and neurotoxicity in prion diseases.

Pathological changes within two weeks following spinal cord injury in a canine model.

PURPOSES: This study aimed to investigate the histopathological changes that occur within 2 weeks following spinal cord injury (SCI) in dogs. METHODS: Eight adult female Beagle dogs were included in this study, and SCI was induced using an epidural balloon catheter. Two dogs were killed at each of the following four time points: immediately after the procedure and 1 day, 1 week, and 2 weeks after the procedure. Neurological status was evaluated with five categories. Histopathological changes were visually observed for stained sections of formalin-fixed spinal cord to evaluate hemorrhage, spongiosis, necrosis, and gliosis morphologically. RESULTS: Along the 2 weeks post-injury, severe hemorrhage was observed at the primary injury site, the average diameter of which expanded quickly from 8 to 10 mm in 1 day and then decreased to 5 mm in 1 week. This indicates that the bleeding cavity expanded at the initial injury site to produce ascending and descending hemorrhage. The hemorrhage at the injury site resolved in 2 weeks. In contrast, spongiosis, parenchymal necrosis, and gliosis were first inconspicuous or mild and then became severe in 1 week or 2 weeks. Hemorrhage, hematoma, and other similar changes occurred at the regions approximately 20-mm rostral and caudal to the primary injury site. These changes were observed in both gray matter and white matter. CONCLUSIONS: This study is the first to assess the sequential histopathological changes in the acute and intermediate phases following SCI in dogs. Our findings enhance the usefulness of the canine intervertebral disk disease model in the assessment of secondary spinal cord histopathology in human SCI.

Reflections on Cerebellar Neuropathology in Classical Scrapie.

In this review, the most important neuropathological changes found in the cerebella of sheep affected by classical natural scrapie are discussed. This disease is the oldest known of a group of unconventional "infections" caused by toxic prions of different origins. Scrapie is currently considered a "transmissible spongiform encephalopathy" (due to its neuropathological characteristics and its transmission), which is the paradigm of prion pathologies as well as many encephalopathies (prion-like) that present aberrant deposits of insoluble protein with neurotoxic effects due to errors in their catabolization ("misfolding protein diseases"). The study of this disease is, therefore, of great relevance. Our work data from the authors' previous publications as well as other research in the field. The four most important types of neuropathological changes are neuron abnormalities and loss, neurogliosis, tissue vacuolization (spongiosis) and pathological or abnormal prion protein (PrP) deposits/deposition. These findings were analyzed and compared to other neuropathologies. Various aspects related to the presentation and progression of the disease, the involution of different neuronal types, the neuroglial responses and the appearance of abnormal PrP deposits are discussed. The most important points of controversy in scrapie neuropathology are presented.

Characterisation of an ischemia reperfusion model for the formation of a stage I pressure ulcer in mouse skin.

Pairs of magnets were applied to the loose skin on the backs of mice in order to cause ischemia for periods of 1.5, 2, 2.5 and 3 h followed by reperfusion. We found 1.5 h of ischemia resulted in the most reliable outcome of blanched skin but no redness or skin breakdown. Histological analysis at 4 h of reperfusion showed, in the centre of the insult, condensed nuclei in the epidermis and sebaceous glands with a build up of neutrophils in the blood vessels, and a reduction in the number of fibroblasts. At 24 h, spongiosis was seen in the epidermis and pockets of neutrophils began to accumulate under it, as well as being scatted through the dermis. In the centre of the insult there was a loss of sebaceous gland nuclei and fibroblasts. Four days after the insult, spongiosis was reduced in the epidermis at the edge of the insult but enhanced in the centre and in hair follicles. Leukocytes were seen throughout the central dermis. At 8 days, spongiosis and epidermal thickness had reduced and fibroblasts were reappearing. However, blood vessels still had leukocytes lining the lumen. The gap junction protein connexin 43 was significantly elevated in the epidermis at 4 h and 24 h reperfusion. Ischemia of 1.5 h generates a sterile inflammatory reaction causing the loss of some cell types but leaving the epidermis intact reminiscent of a stage I pressure ulcer.

Dipeptidyl peptidase-4 inhibitor-related bullous pemphigoid: A comparative study of 100 patients with bullous pemphigoid and diabetes mellitus.

Dipeptidyl peptidase-4 inhibitor (DPP4i)-associated bullous pemphigoid (BP) has been emerging but whether it has genotype or phenotype differences from idiopathic BP (IBP) remains to be determined. We aimed to compare clinical characteristics, genetic susceptibility, laboratory features, disease activity, and outcomes between DPP4i-associated BP (DBP) and IBP occurring among patients with diabetes mellitus type 2 (T2DM). Medical records of patients diagnosed with BP and T2DM from January 2009 to December 2019 were retrospectively reviewed, and patients were categorized into DBP or IBP groups. Of 100 patients, 23 had DBP and 77 had IBP. There was no difference in the Bullous Pemphigoid Disease Activity Index score between the two groups; however, the score for urticaria and erythema was less in DBP (p < 0.001), indicating a non-inflammatory phenotype. The HLA-DQB1*03:01 allele was more commonly present in the DBP than IBP cases (odds ratio = 5.33 [95% confidence interval, 1.11-28.59], p = 0.016). The absolute eosinophil count was significantly lower in the DBP group (p = 0.002). Likewise, eosinophilic spongiosis was found less frequently in DBP cases (p = 0.005). Patients in the DBP group had a significantly higher percentage of complete remission on therapy compared to the IBP counterpart (p = 0.026) after DPP4i discontinuation. Moreover, the mean maximum dosage of prednisolone administrated per patient was significantly lower in drug-related cases (p = 0.012). In conclusion, our cohort in Thai patients with T2DM confirms the differences between phenotype and genotype characteristics of DBP and IBP. We emphasize the importance of drug discontinuation in all DPP4i-related cases because doing so may lead to a better disease outcome.