Case report: Androgen-secreting adrenocortical tumors in eight cats

Urine marking, aggression, and other behavioral concerns are common reasons for cat owners to seek veterinary care. Empiric treatment for lower urinary tract disease or primary behavior disorders are commonly pursued, especially in those cases with normal routine laboratory evaluations. Herein, we report the clinicopathologic findings in eight sexually altered cats that were diagnosed with androgen-secreting adrenocortical tumors. Nearly all cats (n = 7) initially were evaluated for inappropriate urination and pungent urine, with additional behavioral concerns including aggression (n = 3) and excess vocalization (n = 4) commonly reported. Penile barbs (n = 5) were identified in all five male cats, and an enlarged clitoris was observed in one female cat. Testing of serum androgen concentrations revealed abnormally high androstenedione (n = 1) or testosterone (n = 7) concentrations. In the five cases with available adrenal tissue, histopathologic evaluation identified either an adrenocortical adenoma (n = 3) or adrenocortical carcinoma (n = 2). Hormonal abnormalities resolved and clinical signs improved in the four cats that underwent surgical adrenalectomy, with each of these cats surviving >1 year. However, clinical signs were minimally impacted with medical treatments, including one cat in which trilostane treatment failed to improve clinical signs or testosterone concentrations. This collection of cases underscores the importance of a detailed physical examination as well as the consideration of endocrine disturbances in cats undergoing evaluation for inappropriate urination or aggression. Furthermore, this report adds to the growing body of evidence that sex-hormone secreting adrenal tumors in cats may be an under-recognized syndrome

Human Thrombomodulin Knock-In Mice Reveal Differential Effects of Human Thrombomodulin on Thrombosis and Atherosclerosis

We sought to develop a murine model to examine the antithrombotic and antiinflammatory functions of human thrombomodulin in vivo

Unraveling structural rearrangements of the CFH gene cluster in atypical hemolytic uremic syndrome patients using molecular combing and long-fragment targeted sequencing

Complement factor H (CFH) and its related proteins have an essential role in regulating the alternative pathway of the complement system. Mutations and structural variants (SVs) of the CFH gene cluster, consisting of CFH and its five related genes (CFHR1-5), have been reported in renal pathologies as well as in complex immune diseases like age-related macular degeneration and systemic lupus erythematosus. SV analysis of this cluster is challenging due to its high degree of sequence homology. Following first-line NGS gene panel sequencing, we applied Genomic Vision's Molecular Combing Technology, to detect and visualize SVs within the CFH gene cluster and resolve its structural haplotypes completely. This approach was tested in three patients with atypical hemolytic uremic syndrome (aHUS) and known SVs, and 18 patients with aHUS or complement factor 3 glomerulopathy with unknown CFH gene cluster haplotypes. Three SVs, a CFH/CFHR1 hybrid gene in two patients and a rare heterozygous CFHR4/CFHR1 deletion in trans with the common CFHR3/CFHR1 deletion in a third patient were newly identified. For the latter, the breakpoints were determined using a targeted enrichment approach for long DNA fragments (Samplix Xdrop) in combination with Oxford Nanopore sequencing. Molecular combing in addition to NGS was able to improve the molecular genetic yield in this pilot study. This (cost-)effective approach warrants validation in larger cohorts with CFH/CFHR-associated disease

Transcriptomic analysis of the temporal host response to skin infestation with the ectoparasitic mite Psoroptes ovis

<p>Abstract</p> <p>Background</p> <p>Infestation of ovine skin with the ectoparasitic mite <it>Psoroptes ovis </it>results in a rapid cutaneous immune response, leading to the crusted skin lesions characteristic of sheep scab. Little is known regarding the mechanisms by which such a profound inflammatory response is instigated and to identify novel vaccine and drug targets a better understanding of the host-parasite relationship is essential. The main objective of this study was to perform a combined network and pathway analysis of the <it>in vivo </it>skin response to infestation with <it>P. ovis </it>to gain a clearer understanding of the mechanisms and signalling pathways involved.</p> <p>Results</p> <p>Infestation with <it>P. </it>ovis resulted in differential expression of 1,552 genes over a 24 hour time course. Clustering by peak gene expression enabled classification of genes into temporally related groupings. Network and pathway analysis of clusters identified key signalling pathways involved in the host response to infestation. The analysis implicated a number of genes with roles in allergy and inflammation, including pro-inflammatory cytokines (<it>IL1A, IL1B, IL6, IL8 </it>and <it>TNF</it>) and factors involved in immune cell activation and recruitment (<it>SELE, SELL, SELP, ICAM1, CSF2, CSF3, CCL2 </it>and <it>CXCL2</it>). The analysis also highlighted the influence of the transcription factors NF-kB and AP-1 in the early pro-inflammatory response, and demonstrated a bias towards a Th2 type immune response.</p> <p>Conclusions</p> <p>This study has provided novel insights into the signalling mechanisms leading to the development of a pro-inflammatory response in sheep scab, whilst providing crucial information regarding the nature of mite factors that may trigger this response. It has enabled the elucidation of the temporal patterns by which the immune system is regulated following exposure to <it>P. ovis</it>, providing novel insights into the mechanisms underlying lesion development. This study has improved our existing knowledge of the host response to <it>P. ovis</it>, including the identification of key parallels between sheep scab and other inflammatory skin disorders and the identification of potential targets for disease control.</p

Severe neurological outcomes after very early bilateral nephrectomies in patients with autosomal recessive polycystic kidney disease (ARPKD)

To test the association between bilateral nephrectomies in patients with autosomal recessive polycystic kidney disease (ARPKD) and long-term clinical outcome and to identify risk factors for severe outcomes, a dataset comprising 504 patients from the international registry study ARegPKD was analyzed for characteristics and complications of patients with very early (� 3 months; VEBNE) and early (4�15 months; EBNE) bilateral nephrectomies. Patients with very early dialysis (VED, onset � 3 months) without bilateral nephrectomies and patients with total kidney volumes (TKV) comparable to VEBNE infants served as additional control groups. We identified 19 children with VEBNE, 9 with EBNE, 12 with VED and 11 in the TKV control group. VEBNE patients suffered more frequently from severe neurological complications in comparison to all control patients. Very early bilateral nephrectomies and documentation of severe hypotensive episodes were independent risk factors for severe neurological complications. Bilateral nephrectomies within the first 3 months of life are associated with a risk of severe neurological complications later in life. Our data support a very cautious indication of very early bilateral nephrectomies in ARPKD, especially in patients with residual kidney function, and emphasize the importance of avoiding severe hypotensive episodes in this at-risk cohort. © 2020, The Author(s)

Clinical Characteristics and Courses of Patients With Autosomal Recessive Polycystic Kidney Disease-Mimicking Phenocopies

[No abstract available]We thank the German Society for Pediatric Nephrology (GPN), the ESCAPE Network, and the European Society for Pediatric Nephrology (ESPN; Working Groups CAKUT and Inherited Renal Diseases) for their support. ML was supported by grants of the GPN, ESPN (Grant ESPN 2014.2), and the German PKD foundation. KB and ML were supported by the Medical Faculty of the University of Cologne (Koeln Fortune program), and the Marga and Walter Boll-Foundation. FS and ML are supported by the German Federal Ministry of Research and Education (BMBF grant 01GM1515 and 01GM1903). This work was generated within the European Reference Network for Rare Kidney Disorders (ERKNet). Parts of the underlying data of this analysis have been described in Burgmaier et al. Kidney International 2021 Sep;100(3): 650-659. doi: 10.1016/j.kint.2021.04.019. Parts of the data have been presented at the annual meeting of the German Society for Pediatric Nephrology 2021 (GPN, Abstract in Nieren- und Hochdruckkrankheiten, Jahrgang 50, Nr. 9/2021, S. 353–399). The datasets generated and/or analyzed during the current study are available from the corresponding author on reasonable request.ESPN 2014.2; PKD Foundation, PKDF; Bundesministerium für Bildung und Forschung, BMBF: 01GM1515, 01GM1903; Universität zu Köln, UoC; Marga und Walter Boll-StiftungWe thank the German Society for Pediatric Nephrology (GPN), the ESCAPE Network, and the European Society for Pediatric Nephrology (ESPN; Working Groups CAKUT and Inherited Renal Diseases) for their support. ML was supported by grants of the GPN, ESPN (Grant ESPN 2014.2), and the German PKD foundation. KB and ML were supported by the Medical Faculty of the University of Cologne (Koeln Fortune program), and the Marga and Walter Boll-Foundation. FS and ML are supported by the German Federal Ministry of Research and Education (BMBF grant 01GM1515 and 01GM1903). This work was generated within the European Reference Network for Rare Kidney Disorders (ERKNet). Parts of the underlying data of this analysis have been described in Burgmaier et al. Kidney International 2021 Sep;100(3): 650-659. doi: 10.1016/j.kint.2021.04.019 . Parts of the data have been presented at the annual meeting of the German Society for Pediatric Nephrology 2021 (GPN, Abstract in Nieren- und Hochdruckkrankheiten, Jahrgang 50, Nr. 9/2021, S. 353–399)

Severe autonomic failure in a patient compound heterozygous for a frame shift mutation and deletion of the ganglionic acetylcholine receptor alpha-3 subunit

The alpha-3 subunit is a crucial component of the ganglionic acetylcholine receptor. Indeed, pharmacological ganglionic blockade or antagonistic antibodies against the alpha-3 subunit virtually abolish postganglionic sympathetic and parasympathetic traffic in human beings. Mutations of the CHRNA3 gene encoding the alpha-3 subunit appear to be a rare cause of autonomic failure. We encountered an 18-year-old woman who had exhibited a fixed heart rate in utero and a rocky clinical course with repeated hypoglycemic episodes following birth. She presented with warm skin, hypohidrosis, pupillary rigidity, accommodation disorder, severe orthostatic hypotension, gastrointestinal dysmotility with a megacolon, and suprapubic catheter for urinary drainage. Intraneural nerve recordings from skin and muscle fascicles showed normal afferent but missing sympathetic activity. Isometric handgrip did not increase blood pressure. Axon reflex sweating and respiratory sinus arrhythmia were minimal. Very low supine and upright plasma norepinephrine but normal levels of related precursors and metabolites as well as skin biopsy suggested the presence of biochemically intact postganglionic neurons yet defective ganglionic neurotransmission. We performed trio whole exome sequencing using the Agilent SureSelect Human All Exon v8 enrichment chemistry on an Illumina NovaSeq6000 platform. Variant calling and copy number variant detection was done using the QIAGEN CLC Genomics Workbench, variant annotation and filtering with in-house developed software. We detected the hemizygous frameshift variant c.907_908delCT (p.Lys303Asnfs*115) in trans with a heterozygous deletion of exons 5–6 in the CHRNA3 (NM_000743.5) gene in the index patient. The frameshift variant was inherited paternally, the deletion maternally. Both variants were classified as pathogenic. We describe the first case of a patient compound heterozygous for previously described frame shift mutation and a deletion of the gene encoding the alpha-3 subunit of the ganglionic acetylcholine receptor. Clinically, the condition is associated with life-long autonomic failure with severe cardiovascular, gastrointestinal, and urogenital involvemen