Imidacloprid unique and repeated treatment produces cholinergic transmission disruption and apoptotic cell death in SN56 cells.

Imidacloprid (IMI), the most widely used worldwide neonicotinoid biocide, produces cognitive disorders after repeated and single treatment. However, little was studied about the possible mechanisms that produce this effect. Cholinergic neurotransmission regulates cognitive function. Most cholinergic neuronal bodies are present in the basal forebrain (BF), regulating memory and learning process, and their dysfunction or loss produces cognition decline. BF SN56 cholinergic wild-type or acetylcholinesterase (AChE), ß-amyloid-precursor-protein (ßAPP), Tau, glycogen-synthase-kinase-3-beta (GSK3ß), beta-site-amyloid-precursor-protein-cleaving enzyme 1 (BACE1), and/or nuclear-factor-erythroid-2-related-factor-2 (NRF2) silenced cells were treated for 1 and 14 days with IMI (1 µM-800 µM) with or without recombinant heat-shock-protein-70 (rHSP70), recombinant proteasome 20S (rP20S) and with or without N-acetyl-cysteine (NAC) to determine the possible mechanisms that mediate this effect. IMI treatment for 1 and 14 days altered cholinergic transmission through AChE inhibition, and triggered cell death partially through oxidative stress generation, AChE-S overexpression, HSP70 downregulation, P20S inhibition, and Aß and Tau peptides accumulation. IMI produced oxidative stress through reactive oxygen species production and antioxidant NRF2 pathway downregulation, and induced Aß and Tau accumulation through BACE1, GSK3ß, HSP70, and P20S dysfunction. These results may assist in determining the mechanisms that produce cognitive dysfunction observed following IMI exposure and provide new therapeutic tools.

Histopathologic Findings of Evolving Mpox Lesions.

ABSTRACT: This article reports two cases of the 2022 mpox virus with notable histopathology, and includes a novel description of mpox pseudotumor in the perianal region which is not previously described. This article additionally includes literature review of characteristic histopathology through evolving lesions, as it is sparsely described in relation to the 2022 mpox outbreak. Case one describes a 42-year-old man who presented with umbilicated, smooth papules on the trunk and extremities, and milia-like papules on the face. Histopathology of an umbilicated lesion revealed epidermal acanthosis with keratinocyte pallor, ballooning degeneration, keratinocyte necrosis, and neutrophilic epitheliotropism. Case two describes a 51-year-old man who presented with scattered eroded papules as well as a perianal mass. Histopathology of the mass revealed ulceration with keratinocyte enlargement and pallor with a mixed inflammatory cell infiltrate. It additionally revealed rare multinucleated keratinocytes with nuclear molding. These cases are remarkable and contribute to literature as reports of the histopathology of the atypical 2022 mpox outbreak are rare. A combination of clinical, laboratory, and histopathologic evidence is useful in diagnosing mpox, and these cases contribute to describing the evolution of viral lesions.

Metastatic Adrenocortical Carcinoma to the Skin: A Case Report and Review of This Unusual Neoplasm.

ABSTRACT: Adrenocortical carcinoma is a very rare oncologic condition with poor prognosis that usually metastasizes to the lungs, liver, local lymph nodes, and peritoneum at initial presentation. However, skin metastasis is very uncommon and has rarely been reported even in advanced stages of the disease. We present a case of a 41-year-old man with a known history of adrenocortical carcinoma of the right adrenal gland that presented with an arm mass. The histopathologic sections showed a multinodular necrotic malignant neoplasm in dermis and subcutaneous fat composed of atypical epithelioid cells with ample granular cytoplasm and pleomorphic vesicular nuclei with frequent intranuclear inclusions and atypical mitoses. The immunohistochemical stains showed tumor cells that were strongly positive for synaptophysin and inhibin, only focally positive for Melan-A, and negative for AE1/AE3. The histopathologic features and the immunohistochemical profile confirmed the diagnosis of metastatic carcinoma consistent with adrenal cortical origin. The diagnosis can be difficult (especially when no clinical data are provided), and an immunohistochemical battery is often useful in distinguishing this tumor from other tumors with similar cytomorphological features.

A Case Series of Primary Cutaneous Sarcomatoid Carcinoma With Aberrant Smooth Muscle Actin Expression: A Clinicopathologic and Immunophenotypic Study.

ABSTRACT: Primary cutaneous sarcomatoid squamous cell carcinoma can show significant histologic overlap with other malignant spindle cell tumors, posing a diagnostic challenge. Even with a wide array of immunohistochemical markers, the exact line of differentiation can be a challenge to identify in some cases. The picture is further complicated by the aberrant expression of myofibroblastic markers [such as smooth muscle actin (SMA)] by these neoplasms, along with a concomitant loss of conventional epithelial markers. The histologic differential diagnoses of primary cutaneous sarcomatoid squamous cell carcinoma include desmoplastic melanoma, leiomyosarcoma, and spindle cell atypical fibroxanthoma/pleomorphic dermal sarcoma (AFX/PDS). A retrospective analysis of 16 cases of PCSSCCs with SMA expression, obtained from large academic institutions, was performed and is summarized below. The tumors were in the scalp (6 cases), arm (4 cases), leg (2 cases), face (2 cases), hand (1 case), and neck (1 case). Immunohistochemical studies were performed in all cases with the following antibodies: AE1/AE3, CAM 5.2, MNF-116, p63, p40, CK5/6, S-100, SOX10, SMA, desmin, calponin, H-caldesmon, CD10, CD68, CD163, and CD34. Histopathologically, all cases were classified as high-grade malignant poorly differentiated neoplasms. Tumors were characterized by an infiltrative neoplasm that involved the entire reticular dermis and, in 7 cases, the subcutaneous fat. Three cases were associated with a well-differentiated squamous cell component. The neoplasms were composed of atypical spindle and epithelioid cells arranged in long and intersecting fascicles. All neoplasms were positive for epithelial markers (at least 1 marker), and all cases were strongly positive for SMA. Our data emphasize the diagnostic utility of multiple epithelial markers as a first screening tool in the detection and workup of malignant cutaneous sarcomatoid neoplasms. Awareness of SMA expression in these tumors can complicate its diagnosis, and it is important to recognize this aberrant immunophenotype to facilitate definitive diagnosis and avoid misdiagnosis.

Increased Levels of Phosphorylated-P38α Induce WNT/ß-Catenin and NGF/P75NTR/TrkA Pathways Disruption and SN56 Cell Death following Single and Repeated Chlorpyrifos Treatment.

Chlorpyrifos (CPF) biocide, exposure to which is mainly produced in the human population through diet, induces several neurotoxic effects. CPF single and repeated exposure induces memory and learning disorders, although the mechanisms that produce these outcomes are complex and not well understood. CPF treatment (single and repeated) of cholinergic septal SN56 cells induced an increase in phosphorylated-P38α levels that led to WNT/ß-Catenin and NGF/P75NTR/TrkA pathways disruption and cell death. These results provide new knowledge on the mechanisms that mediate CPF basal forebrain cholinergic neuronal loss induced by CPF single and repeated exposure and can help unravel the way through which this compound produces cognitive decline and develop efficient treatments against these effects.

Cuboids Prevail When Unraveling the Influence of Microchip Geometry on Macrophage Interactions and Metabolic Responses.

Drug delivery advances rely on using nano- and microsized carriers to transfer therapeutic molecules, although challenges persist in increasing the availability of new and even approved pharmaceutical products. Particle shape, a critical determinant in how these carriers distribute within the body after administration, raises opportunities of using, for instance, micrometer-sized nonspherical particles for vascular targeting and thereby creating new prospects for precise drug delivery to specific targeted areas. The versatility of polycrystalline silicon microfabrication allows for significant variation in the size and shape of microchips, and so, in the current work, photolithography was employed to create differently shaped polysilicon microchips, including cuboids, cubes, bars, and cylinders, to explore the influence of particle shape on cellular interactions. These microchips with different shapes and lateral dimensions, accounting for surface areas in the range of ca. 15 to 120 µm2 and corresponding total volumes of 0.4 to 27 µm3, serve as ideal models for investigating their interactions with macrophages with diameters of ca. 20 µm. Side-scattering imaging flow cytometry was employed for studying the interaction of label-free prepared microchips with RAW 264.7 macrophages. Using a dose of 3 microchips per cell, results show that cuboids exhibit the highest cellular association (ca. 25%) and uptake (ca. 20%), suggesting their potential as efficient carriers for targeted drug delivery to macrophages. Conversely, similarly sized cylinders and bar-shaped microchips exhibit lower uptakes of about 8% and about 6%, respectively, indicating potential benefits in evading macrophage recognition. On average, 1-1.5 microchips were internalized, and ca. 1 microchip was surface-bound per cell, with cuboids showing the higher values overall. Macrophages respond to microchips by increasing their metabolic activity and releasing low levels of intracellular enzymes, indicating reduced toxicity. Interestingly, increasing the particle dose enhances macrophage metabolic activity without significantly affecting enzyme release.

Exploring the influence of silicon oxide microchips shape on cellular uptake using imaging flow cytometry.

Nano- and micro-carriers of therapeutic molecules offer numerous advantages for drug delivery, and the shape of these particles plays a vital role in their biodistribution and their interaction with cells. However, analysing how microparticles are taken up by cells presents methodological challenges. Qualitative methods like microscopy provide detailed imaging but are time-consuming, whereas quantitative methods such as flow cytometry enable high-throughput analysis but struggle to differentiate between internalised and surface-bound particles. Instead, imaging flow cytometry combines the best of both worlds, offering high-resolution imaging with the efficiency of flow cytometry, allowing for quantitative analysis at the single-cell level. This study focuses on fluorescently labelled silicon oxide microchips of various morphologies but related surface areas and volumes: rectangular cuboids and apex-truncated square pyramid microchips fabricated using photolithography techniques, offering a reliable basis for comparison with the more commonly studied spherical particles. Imaging flow cytometry was utilised to evaluate the effect of particle shape on cellular uptake using RAW 264.7 cells and revealed phagocytosis of particles with all shapes. Increasing the particle dose enhanced the uptake, while macrophage stimulation had minimal effect. Using a ratio particle:cell of 10:1 cuboids and spheres showed an uptake rate of approximately 50%, in terms of the percentage of cells with internalised particles, and the average number of particles taken up per cell ranging from about 1-1.5 particle/cell for all the different shapes. This study indicates how differently shaped micro-carriers offer insights into particle uptake variations, demonstrating the potential of non-spherical micro-carriers for precise drug delivery applications.

Acute Interstitial Inflammation on Skin Biopsies and Positive Tissue Cultures in Cellulitis Patients Are Associated a Worse Prognosis.

BACKGROUND: Cellulitis is a significant public health burden and lacks a gold standard for diagnosis. Up to 1/3 of patients are incorrectly diagnosed. The skin biopsy has been proposed as the gold standard. OBJECTIVE: In this study, we evaluate the histopathologic characteristics and tissue culture positivity of biopsies in patients diagnosed with cellulitis seen by our inpatient dermatology consultation service. METHODS: This retrospective cohort study examined patients who were hospitalized with a skin and soft tissue infection at our institution between 2011 and 2020 and underwent a skin biopsy. RESULTS: Those with a positive tissue culture were more likely to die within 30 days compared with those with negative tissue cultures (26% vs. 6%, P = 0.048). Patients who died within 30 days were more likely to have acute interstitial inflammation as a feature on histopathology (38%, P = 0.03). LIMITATIONS: Single institutional design, unintentional exclusion of patients with organism-specific diagnosis, and selection for a medically complex patient population because of the nonroutine collection of biopsies. CONCLUSION: Positive tissue cultures and histopathology showing acute interstitial space inflammation on skin and soft tissue infection (SSTI) biopsies are associated with increased mortality and thus may serve as indicators of poor prognosis.

Late-Onset Reactions after Hyaluronic Acid Dermal Fillers: A Consensus Recommendation on Etiology, Prevention and Management.

Hyaluronic acid (HA) dermal fillers, generally considered low-risk, can lead to rare late-onset reactions (LORs) manifesting between 3 and 4 months postinjection, occasionally even as early as 24 h postinjection. The Complication Assessment and Risk Evaluation (CARE) board was established to review these reactions. In this publication, the authors aims to explore the etiological hypotheses underlying LORs, associated risk factors, prevention, and management approaches suggested by the CARE board. The CARE board identified three etiological hypotheses contributing to LORs. Firstly, the physicochemical structure of the filler, particularly low molecular weight HA, which may trigger an immune response. Secondly, infection, potentially introduced during injection or by dormant biofilm activation. Lastly, an imbalance in the host immune system, caused by factors like autoimmune diseases or viral infections, may lead to extended foreign body reactions, delayed type IV hypersensitivity, or adjuvant-based reactions. Based on these hypotheses, the board categorized various risk factors as patient-related (e.g., recent dental treatment, current medical status, active autoimmune disease), product-related (e.g., molecular weight), and procedure-related (e.g., aseptic technique and trauma). To reduce the risk of LORs, the CARE board recommends diligent patient selection, including comprehensive medical history assessment and informed consent. Practitioners should maintain an effective aseptic technique, and choose an appropriate product and injection depth for the anatomical location. Post-procedure, patients should receive education on proper filler care. Management of LORs depends on the suspected etiology, and the CARE board has proposed an algorithm to determine the most appropriate treatment. Hyaluronidase is recommended for noninflammatory reactions in the absence of active infection, while watchful waiting and/or steroid treatment may be preferred for inflammatory reactions. Hyaluronidase is not recommended as a first-line treatment for infections, which require drainage, bacterial culture, and antibiotic treatment. However, the board emphasizes the need for individualized evaluation and treatment in all cases.

Effects of balance constraints during a double-step reaching task.

BACKGROUND: In daily life tasks of the upper limb, we must make quick corrections with our hands in unstable postural situations. Postural and reaching control mechanisms are involved in the accurate execution of upper-limb tasks. RESEARCH QUESTION: This research aimed to determine the effect of different postural stability conditions on the motor performance of the upper limb in a reaching task with non-static targets. METHODOLOGY: 19 young participants performed a reaching task toward targets that exhibited a change in position (at 200 or 600 ms) in different postural conditions (bipedal-firm, bipedal-foam, and unipedal-foam surface). Performance on the screen (motion time and spatial error), balance (center of pressure displacements, CoP), and index finger movements were recorded during the reaching task. RESULTS: The instability affects the finger kinematic (displacements) and CoP kinematic (displacements, speed, and smoothness) without affecting the performance on the screen (precision and duration). The timing of target change affects the performance on the screen, finger kinematic (speed and smoothness), and CoP kinematic (displacements, speed, and smoothness). SIGNIFICANCE: Postural and reaching control systems enable accurate hand motions in less stable situations, even in reaching tasks with non-static targets. The postural and reaching control systems can protect the end-effector performance during unstable conditions but not during trials with less time to correct the motion.

Diagnostic discordance among histopathological reviewers of melanocytic lesions.

BACKGROUND: Histopathological examination is adequate for the diagnosis of most cutaneous melanocytic neoplasms. However, there is a subset that is either difficult to definitively diagnose or would have diagnostic disagreement upon review by multiple dermatopathologists if a more exhaustive review was performed. METHODS: Melanocytic lesions underwent an independent, blinded diagnostic histopathological review of hematoxylin and eosin-stained sections. Each lesion was reviewed by three to six dermatopathologists and categorized as benign, malignant, or unknown malignant potential (UMP). Diagnoses were grouped as concordant (all the same designation); opposing (received benign and malignant designations); majority (single designation with the highest number of diagnoses, no benign/malignant opposing designations); and non-definitive (equal number of non-opposing designations [i.e., benign/UMP or malignant/UMP]). Lesions with equivocal designations (concordant or majority UMP, opposing, majority, and non-definitive) were utilized in a patient treatment model of projected surgical treatment discrepancies. RESULTS: In total, 3317 cases were reviewed, and 23.8% of lesions received equivocal diagnoses. Of these, 7.3% were majority benign, 4.8% were majority malignant, 2.7% were majority UMP, 0.5% were concordant UMP, 6.9% were opposing, and 1.6% were non-definitive. Patient treatment models of those with equivocal lesions (n = 788) revealed a potential of overall surgical treatment variations ranging from 18% to 72%, with the highest variation amongst lesions with opposing, non-definitive, or majority UMP (40%-72%) diagnoses. CONCLUSION: Histopathologic review in this large cohort demonstrated substantial diagnostic variation, with 23.8% of cases receiving equivocal diagnoses. We identified diagnostic ambiguity even in lesions where a definitive diagnosis was previously rendered by a single real-world dermatopathologist. The combined clinical impact of diagnostic discordance or a final diagnosis of UMP is highlighted by high diagnosis-dependent treatment variation in the patient treatment model, which could be underreported in a real-world setting, where review by more than one to two dermatopathologists is relatively rare.

Gene Expression Profile of Benign, Intermediate, and Malignant Spitz and Spitzoid Melanocytic Lesions.

Spitz and Spitzoid lesions represent one of the most challenging melanocytic neoplasms in dermatopathology. Nosologic classification has been more recently improved by the discovery of novel molecular drivers, particularly translocations. In the current study, we aimed to use an unbiased approach to explore the gene expression profile of a group of melanocytic Spitz and Spitzoid melanocytic lesions ranging from benign lesions to melanoma, including intermediate lesions such as SPARK nevi and atypical Spitz tumors/melanocytomas. Using unsupervised analysis of gene expression data, we found some distinct hierarchical clusters of lesions, including groups characterized by ALK and NTRK translocations. Few non-ALK translocated tumors demonstrated increased ALK expression, confirmed by immunohistochemistry. Spitz tumors with overlapping features of dysplastic nevi, so-called SPARK nevi, appear to have a common gene expression profile by hierarchical clustering. Finally, weighted gene correlation network analysis identified gene modules variably regulated in subtypes of these cases. Thus, gene expression profiling of Spitz and Spitzoid lesions represents a viable instrument for the characterization of these lesions.

Mitogen-Activated Protein Kinase Inhibitor-Induced Inflammatory Alopecia in Woman With Ovarian Cancer.

Inflammatory alopecia is an increasingly reported side effect of targeted cancer therapies. Here we report one case of inflammatory alopecia secondary to mitogen-activated protein kinase kinase (MEK) inhibitor agent Trametinib in a woman with ovarian cancer. Biopsies of the scalp were consistent with early scarring alopecia compatible with drug-induced alopecia. Significant improvement in hair loss occurred after treatment with intralesional Kenalog (ILK) injections and oral isotretinoin. Though acute alopecia has been described in patients using MEK inhibitors, this is the first reported case of inflammatory alopecia.  J Drugs Dermatol. 2024;23(4):7802.     doi:10.36849/JDD.7802e  .

Lymphomatoid Papulosis With T-cell Receptor-Gamma Delta Expression: A Clinicopathologic Case-series of 26 Patients of an Underrecognized Immunophenotypic Variant of Lymphomatoid Papulosis.

Lymphomatoid papulosis (LyP) has several histopathologic presentations. LyP featuring gamma-delta (γδ) T-cell receptor expression may masquerade as and may be misdiagnosed as aggressive cutaneous T-cell lymphoma, particularly primary cutaneous γδ T-cell lymphoma (PCGDTL) or γδ mycosis fungoides. We performed a clinicopathologic analysis of the largest series of LyP featuring γδ T-cell expression. We identified 26 patients with a diagnosis of LyP with γδ T cells from our institutions, as well as through a comprehensive review of the literature, and characterized these cases. Most cases were treated with topical steroids or not treated at all. The majority of cases showed a CD4 - CD8 + phenotype and featured at least one cytotoxic marker. Histopathologic features included an intraepidermal or dermal infiltrate with large cells and frequent angiotropism. One case was initially misdiagnosed as PCGDTL, requiring further therapy. Our case series, the largest international cohort of γδ T cell predominant LyP cases, confirms marked clinicopathologic heterogeneity that may contribute to misdiagnosis, reasserting the need to identify classic clinical features, CD30 + T-cell components, and markers of cytotoxicity when dealing with this differential diagnosis. A limitation of this study includes somewhat limited follow-up, histologic, and immunophenotypic information for some cases.

Cutaneous Manifestations of Rheumatoid Arthritis: Diagnosis and Treatment.

Rheumatoid arthritis (RA) is a chronic, systemic autoimmune disorder characterized by inflammatory arthritis and periarticular structural damage. Available evidence suggests that RA results from complex interactions between genetic susceptibility (e.g., HLA-DRB1), environmental factors (e.g., smoking), and immune dysregulation. Alongside joint-related symptoms, individuals with RA may also experience a wide array of skin issues, including the development of nodules, neutrophilic dermatoses, vasculitis, and vasculopathy. Treatment strategies for these manifestations vary but routinely involve corticosteroids, disease-modifying anti-rheumatic drugs, and biologics, with individualized approaches guided by disease severity. In this review, we provide comprehensive insights into the skin-related issues associated with RA, outlining their clinical characteristics and histopathological findings. Our aim is to facilitate early diagnosis and personalized treatment to improve the quality of life of affected individuals.

PRAME Expression Is a Useful Tool in the Diagnosis of Primary and Metastatic Dedifferentiated and Undifferentiated Melanoma.

Although mostly recognized in the metastatic setting dedifferentiated and undifferentiated melanomas are increasingly recognized as cutaneous and, less commonly, mucosal primary tumors. Their diagnosis is challenging and dependent on sampling and recognition of a conventional melanoma precursor and/or detection of a mutation in a conventional melanoma driver gene. PRAME immunohistochemistry has recently become an important ancillary tool in the separation of melanoma from benign nevi, but no comprehensive studies exist regarding its value in the detection of dedifferentiated and undifferentiated melanomas and their separation from atypical fibroxanthoma and pleomorphic dermal sarcoma, the main differential diagnoses on sun-damaged skin. After retrieval from archival files, we performed PRAME immunohistochemistry on 11 primary and 10 metastatic dedifferentiated and undifferentiated melanomas, 11 atypical fibroxanthomas, and 10 pleomorphic dermal sarcomas. Nuclear staining was assigned extent (ranging from 0 to 4 and reflecting the percentage of PRAME-positive tumor nuclei) and intensity scores (graded as absent, weak, moderate, and strong, with assigned scores ranging from 0 to 3) with combined scores ranging from 0 to 7. Both primary and metastatic dedifferentiated and undifferentiated melanomas showed strong and diffuse nuclear PRAME staining with median combined scores of 7. Strong and diffuse staining was also seen in all conventional melanoma precursors except for desmoplastic melanoma. In contrast, PRAME staining in atypical fibroxanthoma and pleomorphic dermal sarcoma was patchy and weak with median combined scores of 2. Our data emphasize the diagnostic utility of PRAME staining as a first screening tool in the detection and workup of dedifferentiated and undifferentiated melanomas, both in the primary and metastatic settings. PRAME immunohistochemistry is particularly helpful as it is also positive in tumors without a recognizable conventional melanoma precursor and in those associated with desmoplastic melanomas, where PRAME is typically found to be negative.

Spiradenoma With Adenoid Cystic Carcinoma-like Changes: A Case Series of This Rare Variant With a Potential Diagnostic Pitfall.

Spiradenomas are benign cutaneous adnexal neoplasms with sweat gland differentiation that can manifest a broad spectrum of histomorphologic appearances. While they show a characteristic histopathologic phenotype and clinical management involves surgical excision with a low risk of recurrence, there have been unusual histopathologic variants of spiradenoma reported, including cases with adenoid cystic carcinoma (ACC)-like changes. Primary cutaneous ACC is a low-grade malignancy presenting as a subcutaneous mass with the potential for local invasion, perineural invasion, and high rates of local recurrence after excision. The diagnosis of spiradenomas with ACC-like features can be challenging, especially when only the ACC-like component is present for evaluation. A retrospective analysis of 21 cases of spiradenoma with ACC-like changes were obtained from large academic institutions, was performed, and summarized below. All cases showed background of conventional spiradenoma, and the ACC-like areas represented a component in all lesions. The percentage of ACC-like component ranged from 5% to 40% in all cases. The ACC-like component was multifocal and without pleomorphism, perineural and/or vascular invasion, necrosis, or increased mitotic activity. MYB translocation and protein expression was studied in 16 cases by fluorescence in situ hybridization, polymerase chain reaction, and immunohistochemistry. All studied cases were negative for MYB / NFIB , MYB L1, and MYB F by fluorescence in situ hybridization and polymerase chain reaction and 3 cases were positive for MYB expression by immunohistochemistry. Our study expands on spiradenomas with ACC-like features that ought to be considered in the differential diagnosis of cutaneous neoplasms such as primary cutaneous ACC. Our results indicate that a thorough histopathologic inspection and strict application of well-defined histologic criteria are necessary to support the diagnosis of this unusual histopathologic variant. These tumors can be difficult to diagnose, and awareness of their histomorphologic spectrum will facilitate definitive diagnosis and avoid misdiagnosis with other conditions.