Comparison of diagnostic algorithms in clinically suspected viral myocarditis: agreement between cardiac magnetic resonance, endomyocardial biopsy and troponin T.

AIMS: Myocardial inflammation is increasingly detected non-invasively by tissue mapping with cardiovascular magnetic resonance (CMR). Intraindividual agreement with endomyocardial biopsy (EMB) or marker of myocardial injury, high-sensitive troponin (hs-cTnT) in patients with clinically suspected viral myocarditis not understood. METHODS AND RESULTS: Prospective multicentre study of consecutive patients with clinically suspected myocarditis who underwent blood testing for hs-cTnT, CMR and EMB as a part of diagnostic work-up. EMB was considered positive based on immunohistological criteria in line with the ESC definitions. CMR diagnoses employed tissue mapping using sequence-specific cut-off for native T1 and T2 mapping; active inflammation was defined as T1≥2SD and T2≥2SD above the mean of normal range. Hs-cTnT of greater than 13.9ng/1 was considered significant. A total of 114 patients (age (mean±SD) 54±16, 65% males) were included, of which 79(69%) had positive EMB-criteria, 64(56%) CMR criteria, and a total of 58 (51%) positive troponin. Agreement between EMB and CMR diagnostic criteria was poor (CMR vs. ESC: AUCs: 0.51 (0.39-0.62)). The agreement between the significant hs-cTnT rise and CMR-based diagnosis of myocarditis was good (AUC: 0.84 (0.68-0.92); p<0.001), but poor for EMB (0.50 (0.40-0.61). Hs-cTnT was significantly associated with native T1 and T2, hs-CRP and NT-pro BNP (r=0.37, r=0.35, r=0.30, r=0.25 p<0.001), but not immunohistochemical criteria or viral presence. CONCLUSIONS: In clinically suspected viral myocarditis, all diagnostic approaches reflect the pathophysiological elements of myocardial inflammation, however the differing underlying drivers only partially overlap. The EMB and CMR diagnostic algorithms are neither interchangeable in terms of interpretation of myocardial inflammation nor in their relationship with myocardial injury.

Metabolic Deficits in the Retina of a Familial Dysautonomia Mouse Model.

Neurodegenerative retinal diseases such as glaucoma, diabetic retinopathy, Leber's hereditary optic neuropathy (LHON), and dominant optic atrophy (DOA) are marked by progressive death of retinal ganglion cells (RGC). This decline is promoted by structural and functional mitochondrial deficits, including electron transport chain (ETC) impairments, increased oxidative stress, and reduced energy (ATP) production. These cellular mechanisms associated with progressive optic nerve atrophy have been similarly observed in familial dysautonomia (FD) patients, who experience gradual loss of visual acuity due to the degeneration of RGCs, which is thought to be caused by a breakdown of mitochondrial structures, and a disruption in ETC function. Retinal metabolism plays a crucial role in meeting the elevated energetic demands of this tissue, and recent characterizations of FD patients' serum and stool metabolomes have indicated alterations in central metabolic processes and potential systemic deficits of taurine, a small molecule essential for retina and overall eye health. The present study sought to elucidate metabolic alterations that contribute to the progressive degeneration of RGCs observed in FD. Additionally, a critical subpopulation of retinal interneurons, the dopaminergic amacrine cells, mediate the integration and modulation of visual information in a time-dependent manner to RGCs. As these cells have been associated with RGC loss in the neurodegenerative disease Parkinson's, which shares hallmarks with FD, a targeted analysis of the dopaminergic amacrine cells and their product, dopamine, was also undertaken. One dimensional (1D) proton (1H) nuclear magnetic resonance (NMR) spectroscopy, mass spectrometry, and retinal histology methods were employed to characterize retinae from the retina-specific Elp1 conditional knockout (CKO) FD mouse model (Pax6-Cre; Elp1LoxP/LoxP). Metabolite alterations correlated temporally with progressive RGC degeneration and were associated with reduced mitochondrial function, alterations in ATP production through the Cahill and mini-Krebs cycles, and phospholipid metabolism. Dopaminergic amacrine cell populations were reduced at timepoints P30-P90, and dopamine levels were 25-35% lower in CKO retinae compared to control retinae at P60. Overall, this study has expanded upon our current understanding of retina pathology in FD. This knowledge may apply to other retinal diseases that share hallmark features with FD and may help guide new avenues for novel non-invasive therapeutics to mitigate the progressive optic neuropathy in FD.

Microphthalmia and disrupted retinal development due to a LacZ knock-in/knock-out allele at the Vsx2 locus.

Visual System Homeobox 2 (Vsx2) is a transcription factor expressed in the developing retina that regulates tissue identity, growth, and fate determination. Several mutations in the Vsx2 gene exist in mice, including a spontaneous nonsense mutation and two targeted missense mutations originally identified in humans. Here, we expand the genetic repertoire to include a LacZ reporter allele (Vsx2 LacZ ) designed to express beta-Galactosidase (b-GAL) and simultaneously disrupt Vsx2 function (knock-in/knock-out). The retinal expression pattern of b-GAL is concordant with VSX2, and the mutant allele is recessive. Vsx2 LacZ homozygous mice have congenital bilateral microphthalmia accompanied by defects in retinal development including ectopic expression of non-retinal genes, reduced proliferation, delayed neurogenesis, aberrant tissue morphology, and an absence of bipolar interneurons - all hallmarks of Vsx2 loss-of-function. Unexpectedly, the mutant VSX2 protein is stably expressed, and there are subtle differences in eye size and early retinal neurogenesis when compared to the null mutant, ocular retardation J. The perdurance of the mutant VSX2 protein combined with subtle deviations from the null phenotype leaves open the possibility that Vsx2 LacZ allele is not a complete knock-out. The Vsx2 LacZ allele exhibits loss-of-function characteristics and adds to the genetic toolkit for understanding Vsx2 function.

[Current WHO classification (2022) of neuroendocrine neoplasms]. / Aktuelle WHO-Klassifikation (2022) neuroendokriner Neoplasien.

CLINICAL ISSUE: After the first description of the "carcinoid tumors" by the pathologist Siegfried Oberndorfer in Munich, the classification system of neuroendocrine neoplasms (NENs) is still a challenge and an evolving concept. METHODICAL INNOVATIONS: The new WHO classification system proposed a framework for universal classification. ACHIEVEMENTS: The new WHO classification system recognizes two distinct families distinguished by genetic, morphology and clinical behaviour: Well differentiated NENs are defined as neuroendocrine tumor (NET G1, G2, G3), while poorly differentiated ones are defined as neuroendocrine carcinoma (NEC, G3) and further subdivided into small and large cell carcinoma. All NENs are characterized by the expression of synaptophysin and chromogranin A, Ki-67 and morphology. MOLECULAR PATHOLOGY: The morphological NEN dichotomy is supported by genetic alterations. NECs show TP53 and RB1 alterations that are absent in NETs and are therefore useful for differentiating between NETs and NECs. PRACTICAL RECOMMENDATIONS: All NENs are divided into well-differentiated neuroendocrine tumor (NET G1, G2, G3) or poorly differentiated neuroendocrine carcinoma (NEC, G3). They are categorized by morphology, mitotic count and immunohistochemistry with synaptophysin, chromogranin and Ki-67.

Case Study of Atypical Fibroxanthoma: Presentation and Management.

Atypical fibroxanthoma (AFX) is a rare spindle cell proliferation arising from significant sun exposure. AFX often appears as a red papule, typically found in the head and neck region of elderly patients. Since there is no specificity in immunohistology, various stains differentiate AFX from other skin cancers. The stains include cluster of differentiation 68 (CD68), cluster of differentiation 163 (CD163), vimentin, cytokeratin epithelial (CKAE), and melanin. While local recurrence is common, AFX rarely metastasizes. Thus, the treatment options are complete surgical excision or micrographically oriented histographic surgery.

[Introduction to renal pathology]. / Einführung in die Nierenpathologie.

In recent decades, nephropathology has developed worldwide as a subspeciality of pathology, which requires special methodological and technical equipment to process the material and specific clinical and pathological expertise to interpret the findings. These special requirements mean that nephropathology is not available at all pathology institutes, but is carried out on a large scale in a few highly specialised centres. The history of nephropathology, or in a narrower sense the specialised histopathological examination of kidney biopsies, began in 1958 with the first use or performance of a kidney biopsy [1]. It thus replaced the practice of urinalysis, which had been common since the Middle Ages, as a diagnostic tool for kidney diseases. Specialised techniques such as immunofluorescence or immunohistology but also electron microscopy are required to assess specific renal changes, for which the examination of renal biopsies is one of the few remaining routine applications today. In Germany and German-speaking countries, the discipline developed thanks to the work of outstanding people in the field of pathology who were primarily involved in this discipline and had the necessary technical and human resources in their laboratories to ensure that these biopsies could be analysed.

Immunohistological Analysis of Lichen Sclerosus of the Foreskin in Pediatric Age: Could It Be Considered a Premalignant Lesion?

BACKGROUND: A major worry of juvenile penile LS is potential malignant degeneration to spinocellular carcinoma (SCC) in adulthood. LS is characterized by increased CD8+ and CD57+ cells, dermal sclerosis, epidermal atrophy, and hyperkeratosis. p53 and Ki67 are reliable premalignant markers. Our aim was to define the LS immunohistochemical profile of foreskin in children, focusing on tissue immune response and cell proliferation. METHODS: Thirty specimens of foreskins removed from pediatric patients during circumcision were included: six from ritual operation (A), twelve from phimosis (B), and twelve from phimosis with LS (C). Formalin-fixed paraffin-embedded sections were stained for histomorphology and immunohistochemistry. A quantitative evaluation for CD8, CD57, p53, and Ki-67 and a statistical analysis were performed. RESULTS: As compared to groups A and B, the samples from group C patients showed an acanthotic epidermis, a dermal band of lymphoid infiltrate with a significant enhancement of CD8+ CD57+ lymphocytes, and a keratinocytic hyperplasia with an overexpression of Ki67+ and p53+ cells. CONCLUSIONS: Immunohistological findings confirmed an immune reaction and proliferative behavior in juvenile LS of foreskin. We believe that radical circumcision should be the first treatment of choice in pediatric patients with clinical suspicious of LS for the potential risk of transformation to SCC in adulthood.

The postnatal development of the compartments in human lymph nodes up to 15 years of age.

The postnatal development of normal human lymph nodes (LN) is largely unknown but is of relevance for intranodal desensitization and for comparison to lymphoma. Superficial inguinal lymphoid (LN) of 25 children (newborn up to 14 years) were studied by routine histology and immunohistology for T and B lymphocytes. The LN were obtained from the legal medicine department at necropsy. The cortex and medulla were identifiable in LN of children of less than 1 month of age. Later high endothelial venules as typical structures for the T cell area are present. Secondary follicles were obvious from 3 months of age onwards in lymph nodes of adolescents also the histology of the LN was similar to adults. The structural elements for an intranodal desensitization are given in human children. The normal development of LN structure is essential to identify pathology like lymphoma in children.

Evaluation and Validation of Commercially Available Dopamine Transporter Antibodies.

With a wide variety of dopamine transporter (DAT) antibodies available commercially, it is important to validate which antibodies provide sufficient immunodetection for reproducibility purpose and for accurate analysis of DAT levels and/or location. Commercially available DAT antibodies that are commonly used were tested in western blotting (WB) on wild-type (WT) and DAT-knock-out (DAT-KO) brain tissue and with immunohistology (IH) techniques against coronal slices of unilaterally lesioned 6-OHDA rats, in addition to wild-type and DAT-knock-out mice. DAT-KO mice and unilateral 6-OHDA lesions in rats were used as a negative control for DAT antibody specificity. Antibodies were tested at various concentrations and rated based on signal detection varying from no signal to optimal signal detection. Commonly used antibodies, including AB2231 and PT-22 524-1-AP, did not provide specific DAT signals in WB and IH. Although certain antibodies provided a good DAT signal, such as SC-32258, D6944, and MA5-24796, they also presented nonspecific bands in WB. Many DAT antibodies did not detect the DAT as advertised, and this characterization of DAT antibodies may provide a guide for immunodetection of DAT for molecular studies.

Two mechanisms of retinal photoreceptor plasticity underlie rapid adaptation to novel light environments.

Fishes experience different light environments over short time periods that may require quick modulation of photoreceptor properties to optimize visual function. Previous research has shown that the relative expression of different visual pigment protein (opsin) transcripts can change within several days following exposure to new light environments, but whether such changes are mirrored by analogous modulation in opsin protein expression is unknown. Here, Atlantic halibut larvae and juveniles raised under white light were exposed to blue light for 1 week and their retina compared to that of controls, which remained under white light. Blue light-treated larvae showed increased expression of all cone opsin transcripts, except rh2, over controls. They also had longer outer segments, and higher density of long wavelength sensitive (L) cones in the dorsal retina. In contrast, only the lws transcript was upregulated in juveniles exposed to blue light compared to controls but their L cone density was greater throughout the retina. These results demonstrate two mechanisms of rapid photoreceptor plasticity as a function of developmental stage associated with improved perception of achromatic or chromatic contrasts in line with the animal's ecological needs.

A case of mediastinal mesenchymal tumor with pericytic neoplasm feature that responded to radiation therapy.

Here, we report a case of mediastinal mesenchymal tumor with a pericytic neoplasm feature that responded to radiation therapy. A 43-year-old man visited our hospital with a complaint of esophageal obstruction and chest pain. Chest computed tomography revealed a middle mediastinal tumor and a mesenchymal tumor was diagnosed with a pericytic neoplasm feature by video-assisted thoracoscopic biopsy. The definitive treatment for soft tissue tumor is surgical resection; however, the mediastinal tumor was unresectable because of esophageal and tracheal invasion. Radiation therapy was administered and there was a partial tumor response and 2 years disease-free status. With a review of the literature, we discuss the clinical and pathological characteristics of this rare tumor and its treatment.

Chromatic organization of retinal photoreceptors during eye migration of Atlantic halibut (Hippoglossus hippoglossus).

The retinas of fishes often have single and double cone photoreceptors that are organized in lattice-like mosaics. In flatfishes experiencing eye migration (i.e., the metamorphic process whereby one eye migrates to the other side of the head), the hexagonal lattice of single cones present in the larva undergoes major restructuring resulting in a dominant square mosaic postmetamorphosis consisting of four double cones surrounding each single cone. The expression of different opsin types during eye migration has not been examined despite its importance in understanding photoreceptor plasticity and whether cell fate (in terms of spectral phenotype) could influence square mosaic formation. Here, we probed the retina of Atlantic halibut undergoing eye migration for opsin expression using two antibodies, AHblue and AB5407, that labeled short wavelength sensitive 2 (SWS2) opsin and longer wavelength (predominantly middle wavelength sensitive, RH2) opsins, respectively. Throughout the retina, double and triple cones labeled with AB5407 exclusively, whereas the vast majority of single cones labeled with AHblue. A minority (<5%) of single cones in the square mosaic of the centroventral retina labeled with AB5407. In regions of mosaic transition and near peripheral growth zones, some single cones co-expressed at least two opsins as they labeled with both antibodies. Short wavelength (SWS2 expressing, or S) cones formed a nonrandom mosaic gradient from central to dorsal retina in a region dominated by the larval single cone mosaic. Our results demonstrate the expression of at least two opsins throughout the postmetamorphic retina and suggest opsin switching as a mechanism to create new cone spectral phenotypes. In addition, the S cone gradient at the onset of eye migration may underlie a plastic, cell induction mechanism by which a cone's phenotype determines that of its neighbors and the formation of the square mosaic.

Histological Methods to Assess Skeletal Muscle Degeneration and Regeneration in Duchenne Muscular Dystrophy.

Duchenne muscular dystrophy (DMD) is a progressive disease caused by the loss of function of the protein dystrophin. This protein contributes to the stabilisation of striated cells during contraction, as it anchors the cytoskeleton with components of the extracellular matrix through the dystrophin-associated protein complex (DAPC). Moreover, absence of the functional protein affects the expression and function of proteins within the DAPC, leading to molecular events responsible for myofibre damage, muscle weakening, disability and, eventually, premature death. Presently, there is no cure for DMD, but different treatments help manage some of the symptoms. Advances in genetic and exon-skipping therapies are the most promising intervention, the safety and efficiency of which are tested in animal models. In addition to in vivo functional tests, ex vivo molecular evaluation aids assess to what extent the therapy has contributed to the regenerative process. In this regard, the later advances in microscopy and image acquisition systems and the current expansion of antibodies for immunohistological evaluation together with the development of different spectrum fluorescent dyes have made histology a crucial tool. Nevertheless, the complexity of the molecular events that take place in dystrophic muscles, together with the rise of a multitude of markers for each of the phases of the process, makes the histological assessment a challenging task. Therefore, here, we summarise and explain the rationale behind different histological techniques used in the literature to assess degeneration and regeneration in the field of dystrophinopathies, focusing especially on those related to DMD.

Perivascular Epithelioid Cell Tumor (PEComa) of the Lung in a 56-Year-Old Female Patient: A Case Report.

Perivascular epithelioid cell tumors, best known as PEComas, are extremely uncommon mesenchymal tumors The etiology of PEComas remains unestablished and its clinical presentation is usually benign. PEComas lack a distinctive symptomatic presentation; thus, the diagnosis of these tumors relies mainly on pathological examinations. These neoplasms have a very distinct immunoreactivity for melanocytic markers critical for their identification. Due to the rarity of these tumors and lack of a distinct disease presentation, we discuss the diagnostic relevance of imaging and pathologic findings in a 56-year-old woman diagnosed with a PEComa in the right middle lobe of the lung.

[Chordoma-An update]. / Chordome ­ Ein Update.

Chordomas are rare malignant tumors of the axial skeleton with notochordal differentiation. From a morphological point of view, chordomas display a broad spectrum ranging from the classical, conventional form not otherwise specified (NOS) to forms with hepatoid or renal carcinoma-like differentiation or even poorly or dedifferentiated variants. The detection of brachyury is highly characteristic, though not exclusive. The morphological differential diagnosis from a benign notochordal tumor (BNCT) requires integration of imaging since BNCT is limited to the vertebral bodies and is not osteolytic. Targeted therapy is a current research focus and cell lines as in vitro models are a precondition for the establishment and validation of this approach.

Preventive Effects of Ginkgo-Extract EGb 761® on Noise Trauma-Induced Cochlear Synaptopathy.

Noise trauma-induced loss of ribbon synapses at the inner hair cells (IHC) of the cochlea may lead to hearing loss (HL), resulting in tinnitus. We are convinced that a successful and sustainable therapy of tinnitus has to treat both symptom and cause. One of these causes may be the mentioned loss of ribbon synapses at the IHC of the cochlea. In this study, we investigated the possible preventive and curative effects of the Ginkgo biloba extract EGb 761® on noise-induced synaptopathy, HL, and tinnitus development in Mongolian gerbils (Meriones unguiculatus). To this end, 37 male animals received EGb 761® or placebo orally 3 weeks before (16 animals) or after (21 animals) a monaural acoustic noise trauma (2 kHz, 115 dB SPL, 75 min). Animals' hearing thresholds were determined by auditory brainstem response (ABR) audiometry. A possible tinnitus percept was assessed by the gap prepulse inhibition acoustic startle reflex (GPIAS) response paradigm. Synaptopathy was quantified by cochlear immunofluorescence histology, counting the ribbon synapses of 15 IHCs at 11 different cochlear frequency locations per ear. We found a clear preventive effect of EGb 761® on ribbon synapse numbers with the surprising result of a significant increase in synaptic innervation on the trauma side relative to placebo-treated animals. Consequently, animals treated with EGb 761® before noise trauma did not develop a significant HL and were also less affected by tinnitus compared to placebo-treated animals. On the other hand, we did not see a curative effect (EGb 761® treatment after noise trauma) of the extract on ribbon synapse numbers and, consequently, a significant HL and no difference in tinnitus development compared to the placebo-treated animals. Taken together, EGb 761® prevented noise-induced HL and tinnitus by protecting from noise trauma-induced cochlear ribbon synapse loss; however, in our model, it did not restore lost ribbon synapses.

In Vitro Model of Human Skeletal Muscle Tissue for the Study of Resident Macrophages and Stem Cells.

Findings from studies of muscle regeneration can significantly contribute to the treatment of age-related loss of skeletal muscle mass, which may predispose older adults to severe morbidities. We established a human experimental model using excised skeletal muscle tissues from reconstructive surgeries in eight older adults. Muscle samples from each participant were preserved immediately or maintained in agarose medium for the following 5, 9, or 11 days. Immunofluorescence analyses of the structural proteins, actin and desmin, confirmed the integrity of muscle fibers over 11 days of maintenance. Similarly, the numbers of CD80-positive M1 and CD163-positive M2 macrophages were stable over 11 days in vitro. However, the numbers of PAX7-positive satellite cells and MYOD-positive myoblasts changed in opposite ways, suggesting that satellite cells partially differentiated in vitro. Further experiments revealed that stimulation with unsaturated fatty acid C18[2]c (linoleic acid) increased resident M1 macrophages and satellite cells specifically. Thus, the use of human skeletal muscle tissue in vitro provides a direct experimental approach to study the regulation of muscle tissue regeneration by macrophages and stem cells and their responses to therapeutic compounds.

Significant Sex Differences in the Efficacy of the CSF1R Inhibitor-PLX5622 on Rat Brain Microglia Elimination.

Microglia play pivotal roles in central nervous system development, homeostasis, responses to trauma, and neurodegenerative and neuropsychiatric disorders with significant sex-bias in their symptoms and prevalence. Survival of the microglia in adult brains depends on the expression of the colony-stimulating factor 1 receptor (CSF1R). The inhibition of CSF1R by brain-permeant PLX5622 in the chow eliminates, within 5-10 days, ~90% of the microglia in female and male mice, thereby enabling the investigation of the roles of the microglia in health and pathological mice models. Because of a prevailing "impression" that PLX5622 is ineffective in rats, it has hardly been used in studies of adult rats. Here, we report that effective microglia elimination by PLX5622-chow in rats is highly sex-dependent. Our observations provide missing information for the limited use and interpretation of PLX5622 in biomedical studies of the microglia in rat models. The sex differences that are too often overlooked must be carefully considered and clearly emphasized.

Neuroendocrine neoplasms of the pancreas: diagnosis and pitfalls.

Common to neuroendocrine neoplasms of the pancreas is their expression of synaptophysin, chromogranin A, and/or INSM1. They differ, however, in their histological differentiation and molecular profile. Three groups can be distinguished: well-differentiated neuroendocrine neoplasms (neuroendocrine tumors), poorly differentiated neuroendocrine neoplasms (neuroendocrine carcinomas), and mixed neuroendocrine-non-neuroendocrine neoplasms. However, the expression of synaptophysin and, to a lesser extent, also chromogranin A is not restricted to the neuroendocrine neoplasms, but may also be in a subset of non-neuroendocrine epithelial and non-epithelial neoplasms. This review provides the essential criteria for the diagnosis of pancreatic neuroendocrine neoplasms including diagnostic clues for the distinction of high-grade neuroendocrine tumors from neuroendocrine carcinomas and an algorithm avoiding diagnostic pitfalls in the delineation of non-neuroendocrine neoplasms with neuroendocrine features from pancreatic neuroendocrine neoplasms.

Piloleiomyosarcoma in cats: Histological and immunohistochemical features.

This study describes the histomorphology and immunohistochemical profile of 9 cases of feline piloleiomyosarcoma. Cats ranged in age from 7 to 16 years (mean 10), and tumors were 7 to 24 mm in diameter (mean 15). Tumors were composed of fusiform cells that were haphazardly arranged or in variably sized interwoven bundles. Neoplastic cells had eosinophilic and fibrillar cytoplasm, and elongated blunt-ended nuclei. Entrapment of hair follicles and absence of vascular components support an origin from the smooth muscle cells of the arrector pili. Additional findings included bizarre nuclei and giant cells (7/9 cases), atypical mitoses (7/9 cases), ulceration (3/9 cases), and intratumoral necrosis (6/9 cases). Neoplastic cells expressed calponin, desmin, α-smooth muscle actin, and vimentin, but not CD18, CD31, cytokeratins, glial fibrillary acidic protein, neuron-specific enolase, Melan A, p63, or S-100 protein. Surgical excision was curative in 6/9 cases, with local recurrence in 2/9 cases and metastasis to local lymph nodes in 1/9 case. Clinical outcome was influenced by mitotic count, infiltration of subcutaneous tissue, and intensity of nuclear immunolabeling for p53.