Clinicopathological and pedigree investigation of a novel spinocerebellar neurological disease in juvenile Quarter Horses in North America.

BACKGROUND: In 2020, a novel neurologic disease was observed in juvenile Quarter Horses (QHs) in North America. It was unknown if this was an aberrant manifestation of another previously described neurological disorder in foals, such as equine neuroaxonal dystrophy/equine degenerative myeloencephalopathy (eNAD/EDM). HYPOTHESIS/OBJECTIVES: To describe the clinical findings, outcomes, and postmortem changes with Equine Juvenile Spinocerebellar Ataxia (EJSCA), differentiate the disease from other similar neurological disorders, and determine a mode of inheritance. ANIMALS: Twelve neurologically affected QH foals and the dams. METHODS: Genomic DNA was isolated and pedigrees were manually constructed. RESULTS: All foals (n = 12/12) had a history of acute onset of neurological deficits with no history of trauma. Neurological deficits were characterized by asymmetrical spinal ataxia, with pelvic limbs more severely affected than thoracic limbs. Clinicopathological abnormalities included high serum activity of gamma-glutamyl transferase and hyperglycemia. All foals became recumbent (median, 3 days: [0-18 days]), which necessitated humane euthanasia (n = 11/12, 92%; the remaining case was found dead). Histological evaluation at postmortem revealed dilated myelin sheaths and digestion chambers within the spinal cord, most prominently in the dorsal spinocerebellar tracts. Pedigree analysis revealed a likely autosomal recessive mode of inheritance. CONCLUSIONS AND CLINICAL IMPORTANCE: EJSCA is a uniformly fatal, rapidly progressive, likely autosomal recessive neurological disease of QHs <1 month of age in North America that is etiologically distinct from other clinically similar neurological disorders. Once the causative variant for EJSCA is validated, carriers can be identified through genetic testing to inform breeding decisions.

Human Salmonellosis Outbreak Linked to Salmonella Typhimurium Epidemic in Wild Songbirds, United States, 2020-2021.

Salmonella infection causes epidemic death in wild songbirds, with potential to spread to humans. In February 2021, public health officials in Oregon and Washington, USA, isolated a strain of Salmonella enterica serovar Typhimurium from humans and a wild songbird. Investigation by public health partners ultimately identified 30 illnesses in 12 states linked to an epidemic of Salmonella Typhimurium in songbirds. We report a multistate outbreak of human salmonellosis associated with songbirds, resulting from direct handling of sick and dead birds or indirect contact with contaminated birdfeeders. Companion animals might have contributed to the spread of Salmonella between songbirds and patients; the outbreak strain was detected in 1 ill dog, and a cat became ill after contact with a wild bird. This outbreak highlights a One Health issue where actions like regular cleaning of birdfeeders might reduce the health risk to wildlife, companion animals, and humans.

Amdoparvovirus-associated disease in striped skunks (Mephitis mephitis).

Disease caused by the archetypical amdoparvovirus (APV), Aleutian mink disease virus (AMDV), has been well studied, but APV infections in other carnivores are poorly understood. Skunk amdoparvovirus (SKAV), one of a handful of newly discovered APVs, is apparently species-specific in striped skunks (Mephitis mephitis) and has a high prevalence across North America. We have evaluated the infection status and viral tissue distribution in a cohort of 26 free-ranging California skunks from a single rehabilitation facility who were euthanized due to poor prognosis for recovery from neurologic disease. SKAV was detected in the majority of this cohort, and virus was associated with a spectrum of lesions including tubulointerstitial nephritis, meningoencephalitis, myocarditis, and arteritis. Affected tissue and patterns of inflammation were partially overlapping with those of AMDV infection but were notably distinct in the kidney.

How we approach complex vascular anomalies and overgrowth syndromes.

Vascular anomalies, both vascular tumors and vascular malformations, can occur in isolation or as part of syndromes including those which feature phenotypic overgrowth. To update what is known about vascular anomalies associated with overgrowth, PubMed was searched for "overgrowth syndromes and vascular anomalies or malformations." PubMed, OMIM, and the Rare Disease Database also were searched for specific diagnoses. We review individual overgrowth syndromes, provide a case-based approach to the clinical, radiographic, pathologic, and genetic basis for diagnosis, to complications of both the vascular anomalies and the overgrowth, and emphasize the need for a multidisciplinary approach to care.

Pathology in Practice.

In collaboration with the American College of Veterinary Pathologists.

Generalized dermatophytosis caused by Trichophyton equinum in 8 juvenile black bears in California.

From 2014-2019, 8 juvenile black bears (Ursus americanus) from different geographic regions were presented to the California Department of Fish and Wildlife because of emaciation, alopecia, and exfoliative dermatitis that resulted in death or euthanasia. Autopsy and histopathology revealed that all 8 bears had generalized hyperkeratotic dermatitis, folliculitis, and furunculosis. Skin structures were heavily colonized by fungal hyphae and arthrospores; fungal cultures of skin from 7 bears yielded Trichophyton equinum, a zoophilic dermatophyte reported only rarely in non-equid species. Additional skin conditions included mites (5), ticks (2), and coagulase-negative Staphylococcus sp. infections (2). No other causes of morbidity or mortality were identified. Molecular comparisons performed at the University of Texas Fungal Reference Laboratory determined that all isolates produced identical banding patterns, potentially representing a clonal population. Dermatophytosis is commonly localized and limited to the stratum corneum of the epidermis and hair follicles. Generalized disease with dermal involvement is rare in immunocompetent individuals; illness, malnutrition, age, or immunosuppression may increase susceptibility. Underlying causes for the severe disease impact in these bears were not evident after physical or postmortem examination. The mechanism by which bears from different geographic locations had severe, T. equinum-associated dermatophytosis from a potentially clonal dermatophyte could not be explained and warrants further investigation.

LIQUID NITROGEN CRYOSURGERY FOR CUTANEOUS AND OCULAR NEOPLASMS IN KOI (CYPRINUS CARPIO) AND GOLDFISH (CARASSIUS AURATUS): EIGHT CASES (2018-2019).

Cryosurgery, also known as cryotherapy and cryoablation, is a promising surgical technique that employs highly localized freezing to destroy damaged and diseased tissue, including benign and malignant neoplasms. This procedure has been reported in the treatment of chromatophoromas, fibromas, and peripheral nerve sheath tumors in piscine patients. This study presents eight clinical cases of cryosurgery on cyprinid pet fish for a wide array of neoplastic masses, including chromatophoromas, squamous cell carcinoma, and sarcomas that were diagnosed by histopathology. Surgical excision of external masses, liquid nitrogen cryotherapy, injectable medications (meloxicam and danofloxacin), and topical medical-grade honey were applied to the patients after biopsy sampling. Five out of seven cutaneous cases and two out of three ocular cases had complete resolution without recurrence for at least three months posttreatment. Treatment was unsuccessful for two of the cutaneous cases in which the cutaneous masses were extremely invasive, resulting in severe ulceration and deep invasion into the coelomic cavity. One of the ocular cases involved a corneal mass that did not change in size and had no complications after treatments, suggesting that the treatment might be useful in limiting growth. The effectiveness of cryotherapy appears to correlate with the tumor type, as well as the stage and progression of tumor invasion.

Delayed Hemolytic Transfusion Reaction in a Patient With Sickle Cell Disease and the Role of the Classical Complement Pathway: A Case Report.

A 14-year-old female patient with sickle cell disease developed a severe delayed hemolytic transfusion reaction (DHTR) leading to multiple transfusions and intensive care management. To better understand the extent to which the classical complement pathway was contributing to her DHTR, we utilized the complement hemolysis using human erythrocytes (CHUHE) assay and the classical complement pathway inhibitor, PIC1. Residual discarded de-identified plasma and erythrocytes from the patient obtained from routine phlebotomy was acquired. These reagents were used in the CHUHE assay in the presence of increasing concentrations of PIC1. Complement-mediated hemolysis of the patient's erythrocytes occurred in her plasma and complement permissive buffer. Increasing concentrations of PIC1 dose-dependently inhibited hemolysis to levels found for the negative control - complement inhibitor buffer. Complement-mediated hemolysis was demonstrated by the CHUHE assay for this patient with sickle cell disease and severe DHTR. PIC1 inhibition of hemolysis suggested that the classical complement pathway was contributing to her DHTR.

Poisoning Crimes and Forensic Toxicology Since the 18th Century.

The easy availability of deadly poisons in 19th-century Britain, Western Europe, and the United States led to widespread public anxiety about the prevalence of murder by poison, resulting in what might be termed a "poison panic." The fear was fed by well-publicized reports of trials and executions which, though not especially numerous, seemed indicative of the dangerous incidence of a unique type of homicide, one that was particularly difficult to prevent or detect. As a result, poisoning crimes stimulated the development of the earliest medicolegal specialism, forensic toxicology, and consequently the careers of some of the best known expert witnesses of the Victorian era, including Mathieu Orfila, Alfred Swaine Taylor, Thomas Stevenson, and Theodore Wormley. This article traces the history of poisoning crimes and the related medico-scientific discipline of forensic toxicology using textbooks, key trials, and crime statistics to examine and evaluate their contribution to the historical development of forensic expertise and practice.

A nonsense variant in Rap Guanine Nucleotide Exchange Factor 5 (RAPGEF5) is associated with equine familial isolated hypoparathyroidism in Thoroughbred foals.

Idiopathic hypocalcemia in Thoroughbred (TB) foals causes tetany and seizures and is invariably fatal. Based upon the similarity of this disease with human familial hypoparathyroidism and occurrence only in the TB breed, we conducted a genetic investigation on two affected TB foals. Familial hypoparathyroidism was identified, and pedigree analysis suggested an autosomal recessive (AR) mode of inheritance. We performed whole-genome sequencing of the two foals, their unaffected dams and four unaffected, unrelated TB horses. Both homozygosity mapping and an association analysis were used to prioritize potential genetic variants. Of the 2,808 variants that significantly associated with the phenotype using an AR mode of inheritance (P<0.02) and located within a region of homozygosity, 1,507 (54%) were located in a 9.7 Mb region on chr4 (44.9-54.6 Mb). Within this region, a nonsense variant (RAPGEF5 c.2624C>A,p.Ser875*) was significantly associated with the hypoparathyroid phenotype (Pallelic = 0.008). Affected foals were homozygous for the variant, with two additional affected foals subsequently confirmed in 2019. Necropsies of all affected foals failed to identify any histologically normal parathyroid glands. Because the nonsense mutation in RAPGEF5 was near the C-terminal end of the protein, the impact on protein function was unclear. Therefore, we tested the variant in our Xenopus overexpression model and demonstrated RAPGEF5 loss-of-function. This RAPGEF5 variant represents the first genetic variant for hypoparathyroidism identified in any domestic animal species.

Obstructive Tracheal Necrosis in a Dog Secondary to Smoke Inhalation Injury-Case Report.

A 4-year-old Siberian Husky mix was referred to the emergency service of the University of California Davis Veterinary Medical Teaching Hospital after being found unconscious in a housefire. Upon arrival, the dog was conscious and panting with normal breathing effort. The dog was initially treated with oxygen therapy to minimize the risk of carbon monoxide toxicosis. Progressive agitation with paroxysmal episodes of increased respiratory effort and increased upper airway sounds were noted ~48 h after presentation. Hypoxemia was then documented. Clinical signs continued to progress despite supportive measures, and five days after initial presentation mechanical ventilation was deemed indicated. Following anesthetic induction, endotracheal intubation was performed. Capnography and peak inspiratory pressures recorded on the mechanical ventilator were consistent with airway obstruction. Diffuse intraluminal tracheal obstruction with grossly necrotic tracheal tissue was confirmed using fiber optic tracheoscopy. The patient was humanely euthanized due to grave prognosis. At necropsy, the tracheal lumen was obstructed by sloughed, necrotic tracheal mucosa. This is the first report describing a severe delayed intrathoracic large airway complication secondary to smoke inhalation in a dog.

Immunohistochemical analysis of pigment cell tumors in two cyprinid species.

Pigment cell tumors, also known as chromatophoromas, are cutaneous spindle cell neoplasms originating from pigment cells (chromatophores) in the dermis of teleosts, amphibians, and reptiles. Chromatophoromas share similar histologic morphology to other spindle cell tumors and are not always pigmented. Therefore, immunohistochemical analysis may be useful in distinguishing these neoplasms from tumors of other cellular origin when poorly pigmented. We performed 3 immunohistochemistry assays (PNL-2, melan A, and SOX10) on 8 cutaneous neoplasms from 8 teleosts diagnosed as chromatophoromas based on histologic morphology. Semiquantitative analysis of immunoreactivity was evaluated on each immunohistochemical assay using a 0-3 scale. PNL-2 exhibited mild-to-moderate (1 or 2) immunoreactivity in 7 of the cases, and resident chromatophores (internal control) were also immunoreactive in these cases. Melan A exhibited mild-to-moderate (1 or 2) immunoreactivity in 4 cases (and with resident chromatophores in these cases); SOX10 was not immunoreactive in any cases. Our results indicate that PNL-2 may be a useful marker in teleosts to distinguish tumors of chromatophore origin. Melan A could also be useful, but appears to be less sensitive, and SOX10 is likely not a useful marker for these neoplasms in teleosts.

Association between image-defined risk factors and neuroblastoma outcomes.

BACKGROUND: The current neuroblastoma (NBL) staging system employs image-defined risk factors (IDRFs) to assess numerous anatomic features, but the impact of IDRFs on surgical and oncologic outcomes is unclear. METHODS: The Vanderbilt Cancer Registry identified children treated for NBL from 2002 to 2017. Tumor volume (TV) and IDRFs were measured radiographically at diagnosis and before resection. Perioperative and oncologic outcomes were evaluated. RESULTS: At diagnosis of 106 NBL, 61% were IDRF positive. MYCN-amplified and undifferentiated NBL had more IDRFs than nonamplified and more differentiated tumors (p = 0.001 and p = 0.01). Of 86 NBLs resected, 43% were IDRF positive, which associated with higher stage, risk, and TV (each p < 0.001). The presence of IDRF at resection was also associated with increased blood loss (p < 0.001), longer operating times (p < 0.001), greater incidence of intraoperative complications (p = 0.03), more frequent ICU admissions postoperatively (p < 0.001), and longer hospital stays (p < 0.001). IDRF negative and positive tumors did not have significantly different rates of gross total resection (p = 0.2). Five-year relapse-free and overall survival was similar for IDRF negative and positive NBL (p = 0.9 and p = 0.8). CONCLUSIONS: IDRFs at diagnosis were associated with larger, less differentiated, advanced stage, and higher risk NBL and at resection with increased operative difficulty and perioperative morbidity. However, the frequency of gross total resection and patient survival after resection were not associated with the presence of IDRFs. TYPE OF STUDY: Retrospective cohort study. LEVEL OF EVIDENCE: Level III.

Clinical, histopathologic, cystoscopic, and fluorescence in situ hybridization analysis of proliferative urethritis in 22 dogs.

BACKGROUND: Proliferative urethritis (PU) is a lower urinary tract disease of dogs characterized by frond-like lesions in the urethra. The etiology of PU is unknown, although an association with bacterial cystitis is reported. OBJECTIVES: Deep-seated bacterial cystitis is associated with PU, particularly in dogs with neutrophilic or granulomatous inflammation. ANIMALS: Twenty-two client-owned dogs with PU and 5 control dogs euthanized for non-urinary disease. METHODS: In retrospective analysis, medical records of dogs with PU from 1986 to 2016 were reviewed. Signalment, clinical signs, cystoscopic findings, antimicrobial use, and results of urine, bladder, or urethral tissue cultures, if available, were recorded. Histopathology was reviewed and classified as lymphocytic-plasmacytic (LP), neutrophilic, LP-neutrophilic (LPN), granulomatous, or pleocellular. Eubacterial fluorescence in situ hybridization (FISH) was performed on 18 tissue samples (13 cases, 5 controls), with subsequent evaluation of bacterial species. RESULTS: Of the 22 dogs, 9 had LP urethritis, 6 had LPN, 4 had pleocellular, and 3 had neutrophilic urethritis. Of note, 7 of 13 PU samples were FISH+ for adherent or invasive bacteria; 1 of 5 controls were FISH+ for adherent bacteria. Five dogs had negative urine and tissue cultures when FISH was positive. There was no association detected between the type of urethral inflammation and the results of urine and tissue culture or FISH. CONCLUSIONS AND CLINICAL IMPORTANCE: The type of inflammation varied widely in these 22 PU cases. Deep-seated bacterial urethritis could be contributing to the inflammatory process in some dogs, regardless of the inflammation type. Urine and tissue cultures likely underestimate bacterial colonization of the urethra in dogs.

Maintaining oncologic integrity with minimally invasive resection of pediatric embryonal tumors.

BACKGROUND: Embryonal tumors arise typically in infants and young children and are often massive at presentation. Operative resection is a cornerstone in the multimodal treatment of embryonal tumors but potentially disrupts therapeutic timelines. When used appropriately, minimally invasive surgery can minimize treatment delays. The oncologic integrity and safety attainable with minimally invasive resection of embryonal tumors, however, remains controversial. METHODS: Query of the Vanderbilt Cancer Registry identified all children treated for intracavitary, embryonal tumors during a 15-year period. Tumors were assessed radiographically to measure volume (mL) and image-defined risk factors (neuroblastic tumors only) at time of diagnosis, and at preresection and postresection. Patient and tumor characteristics, perioperative details, and oncologic outcomes were compared between minimally invasive surgery and open resection of tumors of comparable size. RESULTS: A total of 202 patients were treated for 206 intracavitary embryonal tumors, of which 178 were resected either open (n = 152, 85%) or with minimally invasive surgery (n = 26, 15%). The 5-year, relapse-free, and overall survival were not significantly different after minimally invasive surgery or open resection of tumors having a volume less than 100 mL, corresponding to the largest resected with minimally invasive surgery (P = .249 and P = .124, respectively). No difference in margin status or lymph node sampling between the 2 operative approaches was detected (p = .333 and p = .070, respectively). Advantages associated with minimally invasive surgery were decreased blood loss (P < .001), decreased operating time (P = .002), and shorter hospital stay (P < .001). Characteristically, minimally invasive surgery was used for smaller volume and earlier stage neuroblastic tumors without image-defined risk factors. CONCLUSION: When selected appropriately, minimally invasive resection of pediatric embryonal tumors, particularly neuroblastic tumors, provides acceptable oncologic integrity. Large tumor volume, small patient size, and image-defined risk factors may limit the broader applicability of minimally invasive surgery.

Was Jack the Ripper a Slaughterman? Human-Animal Violence and the World's Most Infamous Serial Killer.

Hundreds of theories exist concerning the identity of "Jack the Ripper". His propensity for anatomical dissection with a knife-and in particular the rapid location and removal of specific organs-led some to speculate that he must have been surgically trained. However, re-examination of a mortuary sketch of one of his victims has revealed several aspects of incisional technique highly inconsistent with professional surgical training. Related discrepancies are also apparent in the language used within the only letter from Jack considered to be probably authentic. The techniques he used to dispatch his victims and retrieve their organs were, however, highly consistent with techniques used within the slaughterhouses of the day. East London in the 1880s had a large number of small-scale slaughterhouses, within which conditions for both animals and workers were exceedingly harsh. Modern sociological research has highlighted the clear links between the infliction of violence on animals and that inflicted on humans, as well as increased risks of violent crimes in communities surrounding slaughterhouses. Conditions within modern slaughterhouses are more humane in some ways but more desensitising in others. The implications for modern animal slaughtering, and our social reliance on slaughterhouses, are explored.

Priming is key to effective incorporation of image-guided thermal ablation into immunotherapy protocols.

Focal therapies play an important role in the treatment of cancers where palliation is desired, local control is needed, or surgical resection is not feasible. Pairing immunotherapy with such focal treatments is particularly attractive; however, there is emerging evidence that focal therapy can have a positive or negative impact on the efficacy of immunotherapy. Thermal ablation is an appealing modality to pair with such protocols, as tumors can be rapidly debulked (cell death occurring within minutes to hours), tumor antigens can be released locally, and treatment can be conducted and repeated without the concerns of radiation-based therapies. In a syngeneic model of epithelial cancer, we found that 7 days of immunotherapy (TLR9 agonist and checkpoint blockade), prior to thermal ablation, reduced macrophages and myeloid-derived suppressor cells and enhanced IFN-γ-producing CD8+ T cells, the M1 macrophage fraction, and PD-L1 expression on CD45+ cells. Continued treatment with immunotherapy alone or with immunotherapy combined with ablation (primed ablation) then resulted in a complete response in 80% of treated mice at day 90, and primed ablation expanded CD8+ T cells as compared with all control groups. When the tumor burden was increased by implantation of 3 orthotopic tumors, successive primed ablation of 2 discrete lesions resulted in survival of 60% of treated mice as compared with 25% of mice treated with immunotherapy alone. Alternatively, when immunotherapy was begun immediately after thermal ablation, the abscopal effect was diminished and none of the mice within the cohort exhibited a complete response. In summary, we found that immunotherapy begun before ablation can be curative and can enhance efficacy in the presence of a high tumor burden. Two mechanisms have potential to impact the efficacy of immunotherapy when begun immediately after thermal ablation: mechanical changes in the tumor microenvironment and inflammatory-mediated changes in immune phenotype.

Feasibility of quantitative contrast ultrasound imaging of bladder tumors in dogs.

The purpose of this pilot study was to assess the feasibility of Cadence contrast pulse sequencing ultrasound to predict clinical and angiogenic tumor response in dogs undergoing chemotherapy. Contrast ultrasound facilitated visualization of bladder tumors but failed to identify a straightforward relationship between ultrasound measures and clinical outcome.

Faisabilité de l'échographie de contraste quantitative des tumeurs des reins chez les chiens. Cette étude pilote avait pour but d'évaluer la faisabilité de l'échographie de contraste par séquençage des pulsations (CadenceTM) pour prédire la réponse clinique et angiogénique de la tumeur chez les chiens subissant la chimiothérapie. L'échographie de contraste a facilité la visualisation des tumeurs rénales mais n'a pas réussi à identifier un lien direct entre les mesures de l'échographie et le résultat clinique.(Traduit par Isabelle Vallières).