A Series of 69 COVID-related Dermatoses With Biopsy, Immunohistochemistry With Anti-spike 3, in situ Hybridization and PCR: A Critical Reappraisal of Viral Involvement in COVID-19 Skin Lesions.

BACKGROUND: Despite the large number of articles published on skin lesions related to COVID-19, clinicopathological correlation has not been performed consistently and immunohistochemistry to demonstrate spike 3 protein expression has not been validated through RT-PCR. MATERIAL AND METHODS: We compiled 69 cases of patients with confirmed COVID-19, where skin lesions were clinically and histopathologically studied. Immunohistochemistry (IHC) and RT-PCR was performed in skin biopsies. RESULTS: After a careful review of the cases, 15 were found to be dermatosis not related to COVID-19, while the rest of the lesions could be classified according to their clinical characteristics as vesicular (4), maculopapular eruptions (41), urticariform (9), livedo and necrosis (10) and pernio-like (5). Although histopathological features were similar to previously reported results, we found two previously unreported findings, maculopapular eruptions with squamous eccrine syringometaplasia and neutrophilic epitheliotropism. IHC showed in some cases endothelial and epidermal staining but RT-PCR was negative in all the tested cases. Thus, direct viral involvement could not be demonstrated. CONCLUSIONS: Despite presenting the largest series of confirmed COVID-19 patients with histopathologically studied skin manifestations, direct viral involvement was difficult to establish. Vasculopathic and urticariform lesions seem to be those more clearly related to the viral infection, despite IHC or RT-PCR negative results failed to demonstrate viral presence. These findings, as in other dermatological areas, highlight the need of a clinico-pathological correlation to increase knowledge about viral involvement in COVID-19 skin-related lesions.

A Series of 69 COVID-related Dermatoses With Biopsy, Immunohistochemistry With Anti-spike 3, in situ Hybridization and PCR: A Critical Reappraisal of Viral Involvement in COVID-19 Skin Lesions. / [Articulo traducido] Serie de 69 dermatosis relacionadas con la COVID-19 con biopsia, estudio inmunohistoquímico con anti-spike 3, hibridación in situ y PCR: Una revisión crítica de la afectación cutánea relacionada con la COVID-19.

BACKGROUND: Despite the large number of articles published on skin lesions related to COVID-19, clinicopathological correlation has not been performed consistently and immunohistochemistry to demonstrate spike 3 protein expression has not been validated through RT-PCR. MATERIAL AND METHODS: We compiled 69 cases of patients with confirmed COVID-19, where skin lesions were clinically and histopathologically studied. Immunohistochemistry (IHC) and RT-PCR was performed in skin biopsies. RESULTS: After a careful review of the cases, 15 were found to be dermatosis not related to COVID-19, while the rest of the lesions could be classified according to their clinical characteristics as vesicular (4), maculopapular eruptions (41), urticariform (9), livedo and necrosis (10) and pernio-like (5). Although histopathological features were similar to previously reported results, we found two previously unreported findings, maculopapular eruptions with squamous eccrine syringometaplasia and neutrophilic epitheliotropism. IHC showed in some cases endothelial and epidermal staining but RT-PCR was negative in all the tested cases. Thus, direct viral involvement could not be demonstrated. CONCLUSIONS: Despite presenting the largest series of confirmed COVID-19 patients with histopathologically studied skin manifestations, direct viral involvement was difficult to establish. Vasculopathic and urticariform lesions seem to be those more clearly related to the viral infection, despite IHC or RT-PCR negative results failed to demonstrate viral presence. These findings, as in other dermatological areas, highlight the need of a clinico-pathological correlation to increase knowledge about viral involvement in COVID-19 skin-related lesions.

SARS-CoV-2 endothelial infection causes COVID-19 chilblains: histopathological, immunohistochemical and ultrastructural study of seven paediatric cases.

BACKGROUND: Chilblains ('COVID toes') are being seen with increasing frequency in children and young adults during the COVID-19 pandemic. Detailed histopathological descriptions of COVID-19 chilblains have not been reported, and causality of SARS-CoV-2 has not yet been established. OBJECTIVES: To describe the histopathological features of COVID-19 chilblains and to explore the presence of SARS-CoV-2 in the tissue. METHODS: We examined skin biopsies from seven paediatric patients presenting with chilblains during the COVID-19 pandemic. Immunohistochemistry for SARS-CoV-2 was performed in all cases and electron microscopy in one. RESULTS: Histopathology showed variable degrees of lymphocytic vasculitis ranging from endothelial swelling and endotheliitis to fibrinoid necrosis and thrombosis. Purpura, superficial and deep perivascular lymphocytic inflammation with perieccrine accentuation, oedema, and mild vacuolar interface damage were also seen. SARS-CoV-2 immunohistochemistry was positive in endothelial cells and epithelial cells of eccrine glands. Coronavirus particles were found in the cytoplasm of endothelial cells on electron microscopy. CONCLUSIONS: Although the clinical and histopathological features were similar to other forms of chilblains, the presence of viral particles in the endothelium and the histological evidence of vascular damage support a causal relation of the lesions with SARS-CoV-2. Endothelial damage induced by the virus could be the key mechanism in the pathogenesis of COVID-19 chilblains and perhaps also in a group of patients severely affected by COVID-19 presenting with features of microangiopathic damage. What is already known about this topic? Despite the high number of cases of chilblains seen during the COVID-19 pandemic, a definite causative role for SARS-CoV-2 has not yet been proven. Different pathogenetic hypotheses have been proposed, including coagulation anomalies, interferon release and external factors. What does this study add? The demonstration of SARS-CoV-2 in endothelial cells of skin biopsies by immunohistochemistry and electron microscopy confirms that these lesions are part of the spectrum of COVID-19. Virus-induced vascular damage and secondary ischaemia could explain the pathophysiology of COVID-19 chilblains. Our findings support the hypothesis that widespread endothelial infection by SARS-CoV-2 could have a pathogenetic role in the severe forms of COVID-19. Linked Comment: Wetter. Br J Dermatol 2020; 183:611.

[Guideline: Auditory Processing and Perception Disorders: Differential Diagnosis : S1 guideline of the German Society of Phoniatrics and Pediatric Audiology]. / Leitlinie "Auditive Verarbeitungs- und Wahrnehmungsstörungen": Differenzialdiagnose : S1-Leitlinie der Deutschen Gesellschaft für Phoniatrie und Pädaudiologie.

As a prerequisite for diagnosing auditory processing disorders (APD), differential diagnostic considerations are essential, especially with regard to language comprehension disorders, attention deficit hyperactivity disorder, specific cognitive impairments (e. g., in memory or multi-modal perception performance), specific learning disorders affecting reading and/or spelling, and autistic-type diseases. The current clinical management is presented in detail in the updated APD guidelines, as are the resulting conclusions for the interpretation of individual test results.

[Morphological and genetic aspects of Spitz tumors]. / Morphologische und genetische Aspekte bei Spitz-Tumoren.

BACKGROUND: Spitzoid melanocytic neoplasms (i.e. Spitz nevi, atypical Spitz tumors and spitzoid melanoma) are a clinical, histopathological and molecular genetic heterogeneous group of melanocytic skin tumors. OBJECTIVES: Correlation of the histological features of spitzoid neoplasms with molecular genetic aberrations. MATERIAL AND METHODS: A review and summary of the scientific literature. RESULTS: Several histopathological and molecular genetic distinct subtypes of spitzoid lesions have been defined. Epithelioid Spitz tumors commonly show a loss of the BAP1 gene and BRAF mutations and are associated with a hereditary tumor predisposition syndrome. Desmoplastic Spitz tumors frequently harbor HRAS mutations and gains of the chromosome arm 11p. Plexiform Spitz tumors often display ALK translocations. The morphology of Spitz tumors with ROS1, NTRK1, RET and BRAF fusion genes seems to be unspecific and is currently not well characterized. CONCLUSION: Morphological features offer valuable clues to the underlying genetic aberrations in spitzoid neoplasms. Genetic aberrations can be found in the entire biological spectrum of spitzoid neoplasms (i.e. Spitz nevi, atypical Spitz tumors and spitzoid melanoma) and are, therefore, probably not useful for distinguishing benign from malignant tumors; however, genetic aberrations represent important targets for therapeutic interventions and offer investigational treatment options for patients with metastatic disease. The appearance of multiple epithelioid melanocytic tumors with BAP1 loss indicates a hereditary tumor syndrome and warrants genetic counseling and preventive screening of affected individuals.

[Auditory processing and perception disorders (APPD): summary and updated overview]. / Auditive Verarbeitungs- und Wahrnehmungsstörungen (AVWS): Zusammenfassung und aktualisierter Überblick.

The APD guideline of 2009 was supplemented by the statements listed here. The addition is based on current knowledge and findings. Otherwise, the Guideline 2009 remains valid. Here, a summary of the updated APD guideline is given, thus proving an overview of the definition of APD, diagnosis, differential diagnosis and recommended for APD management.

[Objective hearing tests in pediatric audiology: AGERA recommendations for follow-up diagnosis in infants that fail newborn hearing screening tests]. / Empfehlungen der AGERA zum Einsatz objektiver Hörprüfmethoden im Rahmen der pädaudiologischen Konfirmationsdiagnostik (Follow-up) nach nicht bestandenem Neugeborenen-Hörscreening.

This paper presents the recommendations compiled by the German Electric Response Audiometry Working Group (Arbeitsgruppe Elektrische Reaktions-Audiometrie, AGERA) and the Association of German Audiologists and Neuro-otologists (Arbeitsgemeinschaft Deutschsprachiger Audiologen und Neurootologen, ADANO) for infants that fail newborn hearing screening (NHS) tests. Outlined are procedures for follow-up diagnosis using objective hearing tests to rule out or confirm a therapeutically relevant auditory defect and assessment of the severity thereof.

Absence of BRAF and HRAS mutations in eruptive Spitz naevi.

BACKGROUND: Eruptive Spitz naevi have been reported rarely in the literature. In solitary Spitz naevi, BRAF and HRAS mutations, as well as increased copy numbers of chromosome 11p have been identified. OBJECTIVES: To investigate the genetic changes underlying eruptive Spitz naevi. METHODS: We report on a 16-year-old boy who developed multiple disseminated eruptive Spitz naevi within a few months. We analysed BRAF, HRAS, KRAS and NRAS genes in 39 naevi from this patient for hotspot mutations. Furthermore, comparative genomic hybridization analysis was performed in three lesions. RESULTS: None of the Spitz naevi displayed a mutation in the analysed genes, and no chromosomal imbalances were observed. Conclusions Our results indicate that the typical genetic alterations described in solitary Spitz naevi appear to be absent in eruptive Spitz naevi. Yet unknown alternative genetic alterations must account for this rare syndrome.

[Quality assurance of a universal newborn hearing screening. Recommendations of the German Society of Phoniatrics and Pediatric Audiology]. / Qualitätssicherung eines universellen Neugeborenen-Hörscreenings. Empfehlungen der Deutschen Gesellschaft für Phoniatrie und Pädaudiologie.

Statutory implementation of a universal newborn hearing screening requires a continuous quality assurance monitoring. Therefore, at the Annual Meeting in 2007, the members of the German Society of Phoniatrics and Pediatric Audiology passed a recommendation on measures of quality assurance applied to newborn hearing screening. This recommendation describes the procedures, performance, location, time frame, and technical prerequisites of the screening and of potentially necessary follow-ups, the definition of hearing loss to be detected, the performing and responsible professional groups and their qualifications for the screening, the regulation of repeat and control screenings, the confirmation diagnostics and initiation of therapy, the information of parents, the documentation of screening results, the aims and organization of a tracking system, the tasks of regional screening centers and of a supraregional institution for the quality assurance of the hearing screening, the central collection of person and screening-related quality relevant data, and the accessibility of defined data sets as predisposition for cost analyses and quality reports.

Potentiation of Ca(2+) release by cADP-ribose in the heart is mediated by enhanced SR Ca(2+) uptake into the sarcoplasmic reticulum.

cADP-Ribose (cADPR) is a novel endogenous messenger that is believed to mobilize Ca(2+) from ryanodine-sensitive Ca(2+) stores. Despite intense research, the precise mechanism of action of cADPR remains uncertain, and experimental findings are contradictory. To elucidate the mechanism of cADPR action, we performed confocal Ca(2+) imaging in saponin-permeabilized rat ventricular myocytes. Exposure of the cells to cADPR resulted in a slow (>2 minutes) and steady increase in the frequency of Ca(2+) sparks. These effects on local release events were accompanied by a significant increase in sarcoplasmic reticulum (SR) Ca(2+) content. In comparison, sensitization of ryanodine receptors (RyRs) by caffeine, a true RyR agonist, caused a rapid (<1 second) and transient potentiation of Ca(2+) sparks followed by a decrease in SR Ca(2+) content. When the increase in the SR load was prevented by partial inhibition of the SR Ca(2+) with thapsigargin, cADPR failed to produce any increase in sparking activity. cADPR had no significant impact on activity of single cardiac RyRs incorporated into lipid bilayers. However, it caused a significant increase in the rate of Ca(2+) uptake by cardiac SR microsomes. Our results suggest that the primary target of cADPR is the SR Ca(2+) uptake mechanism. Potentiation of Ca(2+) release by cADPR is mediated by increased accumulation of Ca(2+) in the SR and subsequent luminal Ca(2+)-dependent activation of RyRs.

Interobserver variation for ultrasound determination of thyroid nodule volumes.

Thyroid ultrasound is used in the routine clinical assessment and the follow-up of thyroid disorders. The follow- up of patients with thyroid nodules is mostly based on thyroid nodule volume determinations performed by different observers. However, for the judgment of treatment effects there is uncertainty about the interobserver variation of thyroid nodule volume measurements by ultrasound because there are no prospective blinded studies available comparing the interobserver variation in thyroid nodule volume measurement. The aim of our study was therefore to determine the variation of thyroid nodule volume determinations for different observers. We conducted a prospective blinded trial. Our study population consisted of 42 probands (8 men, 34 women) with an uniform distribution of thyroid nodule sizes (25 uninodular and 17 multinodular thyroid glands). We compared the results of 3 ultrasonographers with certified experience in thyroid ultrasound. The interobserver variation for the determination of thyroid nodule volume (n = 38) was 48.96% for the ellipsoid method and 48.64% for the planimetric method. The interobserver variation for determining thyroid volume (n = 40) was 23.69% for the ellipsoid method and 17.82% for the planimetric method. A regression analysis revealed that the probability for the identification of the same nodule in nodular thyroids by all sonographers is 90%, if the nodule is at least 15mm in greatest diameter. Future investigations should not describe changes in nodule volume less than 50% as therapy effects because only volume changes of at least 49% or more can be interpreted as nodule shrinkage or growth. Reporting of nodule volume modification 50% or more and lack of information for ultrasound procedures introduce a bias in studies evaluating the effects of nodule treatments. The clinical interpretation of a shrinking/growing thyroid nodule based on volume determinations by ultrasound is not well established because it is difficult to reproduce a two-dimensional image plane for follow-up studies.

Impact of the Thr789Ala variant of the von Willebrand factor levels, on ristocetin co-factor and collagen binding capacity and its association with coronary heart disease in patients with diabetes mellitus type 2.

A Thr789Ala variant in the von Willebrand Factor (vWF) gene is associated with increased vWF plasma concentrations and might therefore affect the risk of coronary heart disease (CHD) in the general population. Patients with type 2 diabetes have an increased risk for premature atherosclerosis and are characterized by alterations of the coagulation system. However, it is not known whether the Thr789Ala variant in the vWF gene contributes to the increased CHD risk in patients with type 2 diabetes. We therefore investigated the potential relationship between the Thr789Ala variant in the vWF gene and the occurrence of CHD in 356 patients with type 2 diabetes, either with (DM+/CHD+, n = 204) or without evidence for CHD (DM+/CHD-, n = 152). In addition, two control groups without type 2 diabetes, with (DM-/CHD+, n = 22) or without CHD (DM-/CHD-, n = 100), were investigated. Individuals with the vWF Thr789Ala variant have significantly higher von Willebrand factor plasma concentrations (p < 0.001). In addition, ristocetin co-factor was significantly increased in vWF Thr789Ala variant carriers (p < 0.05). Ristocetin co-factor levels and collagen binding capacity were also increased in individuals affected with either type 2 diabetes, CHD or both (DM+/CHD+, DM+/CHD-, DM-/CHD+) as compared to healthy controls (DM-/CHD-) (p < 0.001). However, we did not find an association between the vWF Thr789Ala variant and the occurrence of CHD in patient with type 2 diabetes (p = 0.34). In conclusion, although the Thr789Ala vWF gene variant is associated with increased plasma concentrations of vWF, ristocetin co factor levels and collagen binding capacity in patients with type 2 diabetes and CHD, a direct effect of this variant on the occurrence of CHD in patients with type 2 diabetes, could not be detected.

Improvement of insulin sensitivity after adrenalectomy in patients with pheochromocytoma.

OBJECTIVE: Decreased insulin secretion is considered to be the main cause for pheochromocytoma-associated diabetes mellitus. Data from animal and evidence from clinical studies suggest that catecholamines can induce insulin resistance. However, there is no study investigating the effect of catecholamine excess on insulin resistance in patients with pheochromocytopma by the euglycemic hyperinsulinaemic clamp technique. RESEARCH DESIGN AND METHODS: We characterized the effect of high catecholamine plasma concentrations on glucose metabolism and insulin resistance. Euglycemic hyperinsulinemic clamps were performed in 10 patients with pheochromocytoma with and without diabetes mellitus before and 5 wk after adrenalectomy. RESULTS: In five patients with diabetes mellitus, glucose infusion rate required to maintain euglycemia during the clamp (mean +/- SEM) significantly improved from 27.5 +/- 6.5 micro mol/kg.min before surgery to 44.6 +/- 12.3 micro mol/kg.min 5 wk after adrenalectomy (P < 0.05). In five individuals without diabetes, total glucose disposal improved from 105 +/- 13.6 to 130 +/- 11.2 (P < 0.05). Improved insulin sensitivity after surgery was confirmed by a decrease of fasting hyperinsulinemia from 210 +/- 74 pmol/liter (diabetes mellitus) and 69 +/- 9 pmol/liter (no diabetes) before to 134 +/- 56 pmol/liter and 54 +/- 8 after surgery respectively (P < 0.01). In three patients, diabetes and hyperinsulinemia were reversed by the surgical removal of the pheochromocytoma. CONCLUSION: Our data provide evidence that endogenous catecholamine excess in patients with pheochromocytoma can induce or aggravate insulin resistance both in patients with type 2 diabetes and patients with normal glucose tolerance.

Circulating endocannabinoids and N-acyl-ethanolamides in patients with sleep apnea--specific role of oleoylethanolamide.

OBJECTIVE: The endocannabinoid system promotes diverse effects on fat and glucose metabolism as well as on energy balance and sleep regulation. The role of N-acylethanolamides like oleoylethanolamide (OEA) and other endocannabinoids such as anandamide (AEA) and 2-arachidonyl-glycerol (2-AG) has not yet been investigated in patients with sleep apnea. DESIGN AND METHODS: We measured circulating OEA, AEA and 2-AG in patients with sleep apnea (n = 20) and healthy control subjects (n = 57). Respiratory distress index (RDI) as measured by polysomnography was used as a quantitative index of sleep apnea. RESULTS: In patients with sleep apnea OEA serum concentrations were significantly higher than in control subjects (8.4 pmol/ml (95% CI 6.9;9.9) vs. 4.0 (3.5;4.5); p<0.0001, adjusted for body mass index (BMI), fasting insulin, HDL and LDL cholesterol). In contrast, AEA (2.9 (95% CI 1.9;3.9) vs. 1.8 (1.4;2.1), p = 0.09) and 2-AG (20.0 (-14.5;54.5) vs. 32.8 (21.4;44.2), p = 0.56) were not significantly different between patients with sleep apnea and control subjects after adjustment. In the sleep apnea group, OEA serum concentrations were associated with RDI (r (2) = 0.28, p = 0.02) and BMI (r (2) = 0.32, p = 0.01). However, OEA was not associated with BMI in the control group (p = 0.10). CONCLUSIONS: These results indicate that among the three analyzed fatty acid derivatives, OEA plays a specific role in patients with sleep apnea. Together with animal data, the 2-fold elevation of OEA serum concentrations could be interpreted as a neuroprotective mechanism against chronic oxidative stressors and a mechanism to promote wakefulness in patients with nocturnal sleep deprivation and daytime hypersomnolence.

Cutaneous lymphomas: from morphology to chip technology.

Cutaneous lymphomas represent a heterogeneous group of malignant lymphoid diseases with particular tropism for the skin. Prognosis and treatment depend on the type of lymphoma, thus precise diagnosis and classification are of paramount importance. Classification of cutaneous lymphomas relies on a synthesis of all available information, including clinical history and presentation, histopathology, immunophenotype, and molecular data. Thanks to the efforts of the lymphoma groups of both the World Health Organization (WHO) and the European Organization for Research and Treatment of Cancer (EORTC), a joint WHO-EORTC classification for primary cutaneous lymphomas has been proposed in 2005. The WHO-EORTC classification has been adsorbed with minor changes in the 2008 WHO classification of tumours of haematopoietic and lymphoid tissues, thus including for the first time primary cutaneous lymphomas as distinct subtypes of extranodal lymphomas in a general classification of lymphomas.

[High-caloric nutrition in radiochemotherapy, nasogastric tube and parenteral nutrition versus PEG (percutaneous endoscopic controlled gastrostomy)]. / Hochkalorische Ernährung bei Radiochemotherapie, nasale Magensonde und parenterale Ernährung kontra PEG (perkutane endoskopisch kontrollierte Gastrostomie).

The advantages and problems of different types of artificial feeding are discussed. For patients needing long-term nutritional support, we see the following special advantages of PEG: physiological enteral nutrition with an only small risk of tube dislocation, no additional handicap of the natural swallowing procedure and without stigmatizing the patient by an external visible tube (Tab. 3). To help to spread this method of artificial feeding for the benefit of the patient, this article gives some informations on how to cope with the problems that might occur when using PEG (for example: a diet plan for building up the tube food nutrition (Tab. 4).