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A concurrent outbreak of infection with Yersinia pseudotuberculosis occurred in adult captive African lions ( Panthera leo). Two 17-y-old male lions and one 14-y-old female lion developed respiratory distress, lethargy, ataxia, and hyporexia. Within 3–5 d of the onset of clinical signs, one male and the female lion died and were submitted for postmortem examination. Macroscopically, the liver and spleen had multifocal-to-coalescing, semi-firm, pale-tan nodules throughout the parenchyma. The lungs were non-collapsed and marked by petechiae. Histologic examination identified lytic, necrosuppurative foci in the liver, spleen, lungs, and kidney, with abundant intralesional gram-negative coccobacilli in the male lion. Similar findings were seen in the female lion in the liver, spleen, kidney, and mesenteric lymph node; however, the intralesional bacterial colonies were more pleomorphic, comprising rod and filamentous morphologies. Aerobic bacterial culture of the liver, spleen, and lung revealed Y. pseudotuberculosis growth. The source of infection is unknown, and an epidemiologic study was performed. Sources to be considered are from the predation of rodent and/or bird reservoirs, or contaminated soil or water. Mortality associated with Y. pseudotuberculosis has been described in an African lion cub, however, to our knowledge, Y. pseudotuberculosis has not been reported in adult African lions, and this is only the second report of Y. pseudotuberculosis with aberrant bacterial morphology observed histologically.

Gastrointestinal disorders are an important cause of morbidity in box turtles (Terrapene carolina Carolina), however published information is currently lacking on the normal radiographic anatomy, transit, and emptying times of the gastrointestinal tract. A total of 15 healthy box turtles were recruited for this prospective, anatomic, reference interval study. Three-view radiographic series (vertical beam dorsoventral, horizontal beam latero-lateral, and horizontal beam rostrocaudal views) were acquired prior to contrast administration, and following contrast administration at 0, 20, 40, 60, and 90 min, 2, 4, 8, 12, and 24 h post administration, and every 24 h thereafter until all contrast was eliminated (15 mL/kg barium sulfate diluted to 30% weight per volume was administered via orogastric gavage). Vertical beam dorsoventral and horizontal beam latero-lateral views were of excellent quality to identify gastrointestinal structures. The horizontal beam rostrocaudal view immediately postcontrast administration provided gastric and pyloric identification but had lesser diagnostic use at later time points due to anatomical superimposition. The gastrointestinal tract was composed of a tubular stomach, a pyloric sphincter near midline, a duodenum with a cranial flexure in the right cranial coelomic cavity, small intestines within the right coelom, a small cecal bulb, and a transverse and descending colon. Contrast media entered the large intestine by 24 h in all turtles, and a pyloro-colic indentation was noted at the proximal descending colon. The large intestinal emptying was highly variable due to the interindividual variability of contrast sequestration within the cecal bulb. Findings from the current study serve as a reference on the gastrointestinal anatomy, transit, and emptying times in healthy eastern box turtles; and introduce a novel, horizontal beam, rostrocaudal view for gastrointestinal contrast studies in chelonians.

The objective of this 20-yr retrospective study was to review and summarize causes of mortality in the North American (NA) snow leopard population to inform and enhance animal health and husbandry practices. Pathology reports were requested from all NA zoological institutions housing snow leopards that died between 01 January 1999 and 31 December 2019. Data were reviewed and cause of death (COD) and concurrent diseases were summarized and compared by age group, organ system, and disease process. The 241 snow leopards in this report include 109 males, 130 females, and two of undetermined sex. Among them were 116 geriatric snow leopards (>15 yr), 72 adults (15-3 yr), 16 juveniles (3 yr to 2 mo), 32 neonates (2 mo to 0 days), and five fetuses (

The objective of this 20-yr retrospective study was to review and summarize causes of mortality in the North American (NA) snow leopard population to inform and enhance animal health and husbandry practices. Pathology reports were requested from all NA zoological institutions housing snow leopards that died between 01 January 1999 and 31 December 2019. Data were reviewed and cause of death (COD) and concurrent diseases were summarized and compared by age group, organ system, and disease process. The 241 snow leopards in this report include 109 males, 130 females, and two of undetermined sex. Among them were 116 geriatric snow leopards (15 yr), 72 adults (15-3 yr), 16 juveniles (3 yr to 2 mo), 32 neonates (2 mo to 0 days), and five fetuses (0 days). Overall, noninfectious diseases were the most common COD across all age groups (73%). In adult and geriatric snow leopards, chronic renal disease (CRD) (38.8%) and malignant neoplasia (19.7%), including oral squamous cell carcinoma (6.4%), were a common COD. In juveniles and neonates, perinatal death and congenital diseases, including ocular coloboma (15.6%), were a common COD. Individuals with CRD were 13.5 and 4.36 times more likely to have veno-occlusive disease and cardiac fibrosis, respectively. Snow leopards with urolithiasis were 5.27 times more likely to have CRD. Infectious (14.1%) and inflammatory diseases (8.7%) for which no specific etiology was identified were less common overall and more common in juveniles and neonates (25% and 21%, respectively). Neoplasms not previously reported in snow leopards or that are generally uncommon in the veterinary literature included transitional cell carcinoma of the urinary bladder (

Lepidobatrachus laevis, commonly called the Budgett frog, is a member of the horned frog family (Ceratophryidae), which has become increasingly popular among amphibian hobbyists. L. laevis is also used in biologic research on embryonic development, providing a novel model species for the study of organogenesis, regeneration, evolution, and biologic scaling. However, little scientific literature details disease processes or histologic lesions in this species. Our objective was to describe spontaneous pathologic lesions in L. laevis to identify disease phenotypes. We performed a retrospective analysis of 14 captive L. laevis frogs (wild-caught and captive-bred), necropsied at the NC State University College of Veterinary Medicine between 2008 and 2018. The majority of frogs exhibited renal changes, including varying combinations of tubular epithelial binucleation, karyomegaly, and cytoplasmic vacuolation; polycystic kidney disease; and renal carcinoma. Many of the renal changes are reminiscent of a condition described in Japanese (Bufo japonicus) and Chinese (Bufo raddei) toad hybrids that progresses from tubular epithelial atypia and tubular dilation to polycystic kidney disease to renal carcinoma. A second common finding was variably sized, randomly distributed bile duct clusters (biliary proliferation). Other noteworthy findings included regional or generalized edema, intestinal adenocarcinoma, aspiration pneumonia, and parasitism. This retrospective analysis is the first description of histologic lesions identified in captive L. laevis populations, providing new insight into spontaneous disease processes occurring in this species for use in disease diagnosis and clinical management.

Internal organs exhibit left-right asymmetric sizes, shapes and anatomical positions, but how these different lateralities develop is poorly understood. Here we use the experimentally tractable Xenopus model to uncover the morphogenetic events that drive the left-right asymmetrical lobation of the liver. On the right side of the early hepatic diverticulum, endoderm cells become columnar and apically constricted, forming an expanded epithelial surface and, ultimately, an enlarged right liver lobe. In contrast, the cells on the left side become rounder, and rearrange into a compact, stratified architecture that produces a smaller left lobe. Side-specific gain- and loss-of-function studies reveal that asymmetric expression of the left-right determinant Pitx2c elicits distinct epithelial morphogenesis events in the left side of the diverticulum. Surprisingly, the cellular events induced by Pitx2c during liver development are opposite those induced in other digestive organs, suggesting divergent cellular mechanisms underlie the formation of different lateralities.

The digestive system comprises numerous cells, tissues and organs that are essential for the proper assimilation of nutrients and energy. Many aspects of digestive organ function are highly conserved among vertebrates, yet the final anatomical configuration of the gut varies widely between species, especially those with different diets. Improved understanding of the complex molecular and cellular events that orchestrate digestive organ development is pertinent to many areas of biology and medicine, including the regeneration or replacement of diseased organs, the etiology of digestive organ birth defects, and the evolution of specialized features of digestive anatomy. In this review, we highlight specific examples of how investigations using Xenopus laevis frog embryos have revealed insight into the molecular and cellular dynamics of digestive organ patterning and morphogenesis that would have been difficult to obtain in other animal models. Additionally, we discuss recent studies of gut development in non-model frog species with unique feeding strategies, such as Lepidobatrachus laevis and Eleutherodactylous coqui, which are beginning to provide glimpses of the evolutionary mechanisms that may generate morphological variation in the digestive tract. The unparalleled experimental versatility of frog embryos make them excellent, integrative models for studying digestive organ development across multiple disciplines.

Macrophages and dendritic cells (DC) are distributed throughout the body and play important roles in pathogen detection and tissue homeostasis. In tissues, resident macrophages exhibit distinct phenotypes and activities, yet the transcriptional pathways that specify tissue-specific macrophages are largely unknown. We investigated the functions and origins of two peritoneal macrophage populations in mice: small and large peritoneal macrophages (SPM and LPM, respectively). SPM and LPM differ in their ability to phagocytose apoptotic cells, as well as in the production of cytokines in response to LPS. In steady-state conditions, SPM are sustained by circulating precursors, whereas LPM are maintained independently of hematopoiesis; however, both populations are replenished by bone marrow precursors following radiation injury. Transcription factor analysis revealed that SPM and LPM express abundant CCAAT/enhancer binding protein (C/EBP)-β. Cebpb−/− mice exhibit elevated numbers of SPM-like cells but lack functional LPM. Alveolar macrophages are also missing in Cebpb−/− mice, although macrophage populations in the spleen, kidney, skin, mesenteric lymph nodes, and liver are normal. Adoptive transfer of SPM into Cebpb−/− mice results in SPM differentiation into LPM, yet donor SPM do not generate LPM after transfer into C/EBPβ-sufficient mice, suggesting that endogenous LPM inhibit differentiation by SPM. We conclude that C/EBPβ plays an intrinsic, tissue-restricted role in the generation of resident macrophages.

The Aicda gene product, activation-induced cytidine deaminase (AID), initiates somatic hypermutation, class-switch recombination, and gene conversion of Ig genes by the deamination of deoxycytidine, followed by error-prone mismatch- or base-excision DNA repair. These processes are crucial for the generation of genetically diverse, high affinity antibody and robust humoral immunity, but exact significant genetic damage and promote cell death. In mice, physiologically significant AID expression was thought to be restricted to antigen-activated, mature B cells in germinal centers. We now demonstrate that low levels of AID in bone marrow immature and transitional B cells suppress the development of autoreactivity. Aicda −/− mice exhibit significantly increased serum autoantibody and reduced capacity to purge autoreactive immature and transitional B cells. In vitro, AID deficient immature/transitional B cells are significantly more resistant to anti-IgM–induced apoptosis than their normal counterparts. Thus, early AID expression plays a fundamental and unanticipated role in purging self-reactive immature and transitional B cells during their maturation in the bone marrow.

During digestive organogenesis, the primitive gut tube (PGT) undergoes dramatic elongation and forms a lumen lined by a single-layer of epithelium. In Xenopus, endoderm cells in the core of the PGT rearrange during gut elongation, but the morphogenetic mechanisms controlling their reorganization are undetermined. Here, we define the dynamic changes in endoderm cell shape, polarity, and tissue architecture that underlie Xenopus gut morphogenesis. Gut endoderm cells intercalate radially, between their anterior and posterior neighbors, transforming the nearly solid endoderm core into a single layer of epithelium while concomitantly eliciting “radially convergent” extension within the gut walls. Inhibition of Rho/ROCK/Myosin II activity prevents endoderm rearrangements and consequently perturbs both gut elongation and digestive epithelial morphogenesis. Our results suggest that the cellular and molecular events driving tissue elongation in the PGT are mechanistically analogous to those that function during gastrulation, but occur within a novel cylindrical geometry to generate an epithelial-lined tube. Developmental Dynamics 238:3111–3125, 2009. © 2009 Wiley-Liss, Inc.

The large size and rapid development of amphibian embryos has facilitated ground-breaking discoveries in developmental biology. Here, we describe the embryogenesis of the Budgett's frog (Lepidobatrachus laevis), an unusual species with eggs that are over twice the diameter of laboratory Xenopus, and embryos that can tolerate higher temperatures to develop into a tadpole four times more rapidly. In addition to detailing their early development, we demonstrate that, like Xenopus, these embryos are amenable to explant culture assays and can express exogenous transcripts in a tissue-specific manner. Moreover, the steep developmental trajectory and large scale of Lepidobatrachus make it exceptionally well-suited for morphogenesis research. For example, the developing organs of the Budgett's frog are massive compared to those of most model species, and are composed of larger individual cells, thereby affording increased subcellular resolution of early vertebrate organogenesis. Furthermore, we found that complete limb regeneration, which typically requires months to achieve in most vertebrate models, occurs in a matter of days in the Budgett's tadpole, which substantially accelerates the pace of experimentation. Thus, the unusual combination of the greater size and speed of the Budgett's frog model provides inimitable advantages for developmental studies—and a novel inroad to address the mechanisms of spatiotemporal scaling during evolution.

Macrophages are dispersed throughout the body but exhibit tissue-specific phenotypes and functions. The extracellular and transcriptional pathways that regulate the generation of tissue-specific macrophages are largely unknown. In mice, the peritoneal cavity contains two distinct populations of macrophages, small (CD11b+F4/80lowCD93-) and large (CD11b+F4/80hiCD93+) peritoneal macrophages (SPM and LPM, respectively). Here, we show that mice deficient for the transcription factor C/EBPβ have increased numbers of SPM compared to control littermates, but lack LPM. In C/EBPβ-sufficient and deficient mice, however, splenic (MOMA-1+ and F4/80+) and liver (F4/80+) macrophage compartments are equivalent. When adoptively transferred into C/EBPβ-/- mice, wild-type SPM give rise to LPM, revealing a differentiative pathway from SPM to LPM that requires C/EBPβ. A role for C/EBPβ in the differentiation of certain macrophages is also evident in vitro, as bone marrow cells from C/EBPβ-sufficient and -deficient mice produce macrophages equivalently in cultures containing M-CSF, but C/EBPβ-/- bone marrow cells fail to generate normal macrophages in GM-CSF cultures. These findings demonstrate that tissue-specific macrophages arise through distinct transcriptional pathways, and reveal C/EBPβ as a master regulator of differentiation for a restricted subset of tissue macrophages.

Activation-induced cytidine deaminase (AID), the product of Aicda gene, is required for somatic hypermutation (SHM) and class-switch recombination (CSR) of immunoglobulin genes. Although crucial for humoral immunity, these processes exact genomic damage that often results in cell death, and occasionally oncogenesis. In mice, AID expression, SHM and CSR are thought to be restricted to mature B cells in germinal centers. We reported that developmentally immature B cells in mice and humans express low levels of AID, which support limited SHM and CSR. However, the physiological significance of AID expression and activity in these B-cell compartments is controversial. Here we show that low levels of AID in immature mouse bone marrow B cells suppress the development of autoreactivity. Aicda deficient mice exhibit significantly increased serum autoantibody and reduced capacity to purge autoreactive immature/transitional B cells; the clonal deletion and heavy chain receptor editing characteristics of autoimmune 3H9 VDJ knock-in mice is significantly impaired in the absence of AID expression. In vitro, AID deficient immature/transitional B cells are more resistant to anti-IgM induced apoptosis than their normal counterparts. Thus, early AID expression in immature B cells plays a fundamental and unanticipated role in purging self-reactive B cells during their development in the bone marrow. We are currently investigating signals that induce AID expression in immature B cells in vitro.