Spontaneous Glomerular and Tubulointerstitial Lesions in Common Marmosets (Callithrix jacchus)

Spontaneous progressive nephropathy dominated by glomerular lesions in common marmosets has been reported. However, the histopathologic characteristics, including the relationship between glomerular and tubulointerstitial lesions, have not been described in detail. In the present study, the authors examined the histopathologic characteristics of the background renal lesions in common marmosets (3 males and 9 females, 3 to 8 years old). The severity of glomerular lesions was graded into 3 classes: grade I, no alteration; grade II, hilar/focal increase of mesangial matrix; grade III, global/diffuse increase of mesangial matrix. Tubulointerstitial lesions (tubular regeneration and hyperplasia and interstitial inflammation and fibrosis) were scored according to the area of each lesion. The renal lesions were characterized by enlargement of glomeruli, expanded mesangial area with increase of periodic acid-Schiff reaction-positive matrix, tubular regeneration and hyperplasia, and interstitial inflammation and fibrosis. Glomerular lesions progressed with increasing mesangial matrix and aging. Additionally, the tubulointerstitial lesions became exacerbated with progressing glomerular lesions. Tubular hyperplasia was divided into 4 types according to the structure of the cell layer (simple or stratified-like), the area of increased lining cells (partial or entire), cytoplasmic staining (eosinophilic or basophilic), brush border and thickness of basement membrane, and the activity of cell proliferation. In conclusion, the background renal lesions in common marmosets were characterized by glomerular lesions with increase of mesangial matrix, which progressed with aging, and secondary tubulointerstitial lesions, including tubular hyperplasia. Those lesions were thus diagnosed as progressive glomerulonephropathy in common marmosets.     

Relationship to growth performance of pneumonia and atrophic rhinitis lesions detected in pigs at slaughter among four seasons.

A commercial swine herd was selected for study, because pigs at slaughter repeatedly had lung lesions consistent with enzootic pneumonia and had snout lesions typical of atrophic rhinitis. Pigs born during various seasons of the year were allotted to 4 investigations and were evaluated from birth to slaughter. Individual lungs and snouts were identified and collected at the slaughter plant and later examined for gross lesions of bronchopneumonia and atrophic rhinitis, respectively. Each lesion was scored, and the following comparisons were made within investigations: prevalence and mean scores for lung lesions; prevalence and mean grades for snout lesions; correlations between lung lesion scores and growth indicators; correlations between snout lesion grades and growth indicators; and correlations between lung lesion scores and snout grade scores. Included in the growth indicators were average daily gain during the growing phase, average daily gain during the finishing phase, average daily gain during growing and finishing phases, and days to attain 104.5 kg of body weight. Prevalence of lung or snout lesions, mean values for lung lesion scores, mean values for snout lesion grades, and mean values for the various growth indicators were tested for statistical differences among the 4 investigations. Prevalence of lung lesions was highest (96%) for winter-slaughtered and lowest (81%) for autumn-slaughtered pigs. Mean scores for lung lesions were 7% (summer), 5% (autumn), 9% (winter), and 16% (spring). Prevalence of snout lesions was highest (85%) for spring-slaughtered pigs and lowest (42%) for autumn-slaughtered pigs.(ABSTRACT TRUNCATED AT 250 WORDS)     

Use of concurrent scintigraphic and magnetic resonance imaging evaluation to improve understanding of the pathogenesis of injury of the podotrochlear apparatus

REASONS FOR PERFORMING STUDY: Use of physiological methods of diagnostic imaging could provide insight into the pathogenesis of foot pain in live horses. OBJECTIVES: To describe patterns and intensity of increased radiopharmaceutical uptake (IRU) in the navicular bone, and relate this to distribution and types of signal intensity change in the navicular bone and to the presence or absence of lesions of the related soft tissue structures detected using MRI. MATERIALS AND METHODS: Scintigraphic and MR images of 264 horses with unilateral or bilateral foot pain were analysed and graded. A Spearman rank correlation was used to test for relationships between scintigraphic grade of the navicular bone and MRI scores for each region of the bone. Chi-square tests were used to test for associations between scintigraphy grade and presence of increased signal intensities, for differences in the proportion of focal and diffuse IRU between MRI grades, and for associations between an abnormal scintigraphic grade of the navicular bone and presence or absence of a lesion. RESULTS: There were significant positive correlations between scintigraphy grade and both maximum and total MRI grades for the navicular bone and between scintigraphy grade and the MRI grades for the flexor border, the distal border and medulla. However, there was no difference in the proportions of focal and diffuse IRU between navicular bone MRI grades, although diffuse IRU was relatively under-represented in Grade 3 navicular bones. There was no association between IRU in the navicular bone and MR lesions of either the DSIL origin or the CSL insertion, however there was an association between IRU in the navicular bone and combined lesions of the CSL, DSIL and navicular bursa. In limbs with a DDFT lesion, navicular bone scintigraphic Grades 2 and 3 were over-represented. CONCLUSIONS AND CLINICAL RELEVANCE: Scintigraphy and MRI provide complementary information about the pathogenesis of lesions of the podotrochlear apparatus. Further understanding of these disease processes may eventually permit more targeted treatments.     

Histologic features of mammary carcinomas in zoo felids treated with melengestrol acetate (MGA) contraceptives

Melengestrol acetate (MGA), a potent synthetic progestin, has been used as a contraceptive in zoo felids since 1975. Mammary gland carcinomas have been linked to MGA treatment in zoo felids, but the histologic features of these tumors and steroid receptor expression have not been described. Zoo felid mammary tumors were requested from participating zoos from 1986 through 1998, and 31 mammary carcinomas from 28 MGA-treated and 3 untreated felids were received. The carcinomas were evaluated on the basis of histologic pattern, tumor grade, and occurrence of metastasis; then features of the tumors were compared to determine if carcinomas in MGA-treated felids differed from those that occur spontaneously. Estrogen- and progesterone-receptor expression was evaluated in 17 of the 31 carcinomas. Of the 31 tumors, 22 (70.9%) had multiple histologic patterns, 29 (93.5%) were high grade, and 28 (90.3%) had metastasized. Within tumors, the tubulopapillary pattern was most common (87.1%, n = 27); solid (61.3%, n = 19), cribriform (38.7%, n = 12), and comedone (25.8%, n = 8) patterns were less common; and the mucinous (3.2%, n = 1) pattern was rare. Both MGA-treated and untreated zoo felids had similar patterns and grades of mammary gland cancer as well as prevalence of metastasis. These results indicate that mammary carcinomas in zoo felids are high grade with a predominant tubulopapillary pattern and aggressive behavior. Five of 17 carcinomas expressed progesterone receptors, and 1 of 17 expressed estrogen receptors. Although more zoo felids with cancer had been exposed to MGA in this study, mammary carcinomas were similar in appearance and behavior in untreated and MGA-treated zoo felids. The association of MGA with the development of malignant mammary gland tumors should be considered when using this contraceptive in zoo felids.     

COMPARISON OF RADIOGRAPHIC AND SCINTIGRAPHIC FINDINGS OF THE SPINOUS PROCESSES IN THE EQUINE THORACOLUMBAR REGION

Back pain is common in horses, but there has been no large‐scale in‐depth study describing radiographic changes of the spinous processes, the relationship between radiographic and scintigraphic findings, and the effect of size, age, breed, or discipline. The objectives were to investigate the frequency of occurrence in horses with perceived back pain of: (1) radiographic alteration of the spinous process structure; (2) increased radiopharmaceutical uptake (IRU) in the spinous processes; and (3) to compare radiographic and scintigraphic findings; and to determine if there was breed, gender, age, bodyweight, height, or work discipline predisposition for close, impinging, or overriding spinous processes. Radiographic and scintigraphic images of the thoracolumbar spine of 604 horses were graded. A radiographic grade for each spinous process (T8–L6) was assigned (0–7). The maximum radiographic grade for each horse was defined as the highest grade assigned to any spinous process; the total radiographic grade was the sum of all grades for each horse. A scintigraphic grade for each spinous process was determined (0–3). The maximum scintigraphic grade for each horse was defined as the highest grade assigned to any spinous process; the total scintigraphic grade was the sum of all grades for each horse. Associations between radiology and scintigraphy and age, gender, breed, height, weight, and discipline were analyzed statistically. The severity of radiographic lesions of the spinous processes was associated with the severity of scintigraphic abnormalities. The caudal thoracic spine (T14–T17) was most frequently affected. There was a significant breed and age effect, with Thoroughbreds and older horses having higher total and maximum radiographic grades. The severity of the lesions of the spinous processes was significantly associated with the presence of osteoarthritis of the articular process joints. It was concluded that there is a wide range of radiographic abnormalities of the spinous processes seen in horses with or without back pain. There is an association between radiographic and scintigraphic grades of the spinous processes.     

Enthesophytosis and Impingement of the Dorsal Spinous Processes in the Equine Thoracolumbar Spine

Impingement of the dorsal spinous processes (DSPs) is a common cause of pain and poor performance in sport horses, but there is limited information regarding regional differences in the prevalence and severity of DSP osseous lesions in the equine thoracolumbar spine. It was hypothesized that lesion severity would increase with horse age and height, and that severe lesions would be more prevalent in the mid-caudal thoracic region. The thoracolumbar spines of 33 horses were removed postmortem, disarticulated, and boiled out. The thoracic and lumbar DSPs were examined for the presence of proliferative or lytic osseous lesions of the DSPs. Age and height of the horses were recorded, and severity of pathologic changes at each vertebral level was scored using an ordinal grading system (grades 0–3) and a continuous visual analog scale (VAS). Osseous lesions of the DSPs were present at every vertebral level from C7–T1 to L6–S1, and 70% of horses had at least one lesion of severity grade 2 or higher. Grade 3 lesions were found in the cranial thoracic (T2–T4), mid-thoracic to cranial lumbar (T11–L1) and mid-lumbar (L4–L5) segments. Analysis of VAS data using analysis of variance indicated that increasing age and height were associated with more severe osseous lesions (P < .001). DSP osseous lesions occur frequently in horses with more severe lesions in the cranial thoracic, mid to caudal thoracic, and mid-lumbar regions. Lesions in the cranial thoracic and lumbar regions present a challenge for diagnostic imaging and may be underdiagnosed clinically.     

Juvenile nephropathy in a Weimaraner dog

A case of juvenlle nephropathy In a two-year-old Welmaraner bitch Is reported. Although juvenlle nephropathy has been described in several breeds of dogs, this is the first report In a Welmaraner. Clinical aspects, blood analysis, renal pathology and extrarenal changes are described. The renal changes consisted of tubular as well as glomerular lesions, similar to those described in the miniature schnauzer. The main extrarenal lesion was degeneration and necrosis of subendocardial myocytes in the left atrial wail associated with an inflammatory reaction and focal necrotising arteritis.     

The application of a scintigraphic grading system to equine tibial stress fractures: 42 cases

REASONS FOR PERFORMING STUDY: Tibial stress fractures are an important cause of lameness in the Thoroughbred racehorse. While it is recognised that these injuries can vary in clinical presentation and radiographic or scintigraphic appearance, little has been done to quantify lesion severity. By contrast the scintigraphic grading of tibial stress fractures in human athletes is widely reported and assists in the selection of appropriate management regimes. OBJECTIVES: To determine the relationship between scintigraphic grade, clinical severity and radiographic appearance of tibial stress fractures. METHODS: The current study involved the retrospective analysis of records from 42 Thoroughbreds with abnormal tibial scintigraphic activity. RESULTS: There was a significant association between lesion site and scintigraphic grade and good correlation of scintigraphic scoring between investigators. No significant association was found between scintigraphic grade and either radiographic grade or degree of lameness. CONCLUSIONS: The study confirmed that radiographic appearance is an unreliable measure of clinical severity or stage of progression of lesions. The scintigraphic grading system used in the study was not of use in defining stress fracture severity in the equine tibia. POTENTIAL RELEVANCE: Despite this finding, there is clearly a need for prospective investigations to explore the potential for targeted management regimes for tibial injuries based on lesion site or clinical criteria.     

Post mortem evaluation of palmar osteochondral disease (traumatic osteochondrosis) of the metacarpo/metatarsophalangeal joint in Thoroughbred racehorses

Reasons for performing study: Thoroughbred racehorses are commonly affected by subchondral bone injury, but the exact prevalence and the distribution of palmar/plantar osteochondral disease (POD) lesions are unknown. The relationship between pathologies has not been elucidated, although it is widely accepted that POD is a manifestation of traumatic overload arthrosis. Hypothesis: There is an association between grade of POD and other pathologies affecting the third metacarpal and metatarsal (MC/MTIII) condyles (wear lines, cartilage loss, marginal remodelling, dorsal impact injuries and linear fissures). Objectives: To evaluate the pathology found affecting the distal MC/MTIII condyles of Thoroughbred racehorses at post mortem examination, to describe the prevalence and distribution of POD lesions within a population of racing Thoroughbreds and to determine relationships between pathologies of the distal condyles of the third metacarpal and metatarsal bones. Methods: The metacarpo/metatarsophalangeal joints of 64 Thoroughbred racehorses were examined at routine post mortem examination and graded for third metacarpal and metatarsal condylar pathology. Associations between pathologies were determined. Results: POD had a within horse prevalence of 67%. There was a significant linear relationship between grade of POD and grades of wear lines, cartilage ulceration and dorsal impact injuries. There was a significant relationship, but this was not linear, between grade of POD and grade of linear fissures. Using ordinal logistic regression, compared to condyles with grade 0 or grade 2 linear fissures, condyles with grade 1 linear fissures were found to be more likely to have a lower POD grade. Potential relevance: POD can be considered to be a manifestation of traumatic overload arthrosis, but the role of subchondral bone adaptation is complex and warrants further investigation.     

Safety of reduced-dosage ketoprofen for long-term oral administration in healthy dogs

OBJECTIVE: To evaluate the safety of reduced-dosage ketoprofen (RDKET) for long-term oral administration in healthy dogs. ANIMALS: 14 healthy Beagles. PROCEDURES: Racemic ketoprofen (0.25 mg/kg, PO) and gelatin capsules, as a drug-free placebo, were each administered to 7 dogs for 30 days. Dogs were periodically monitored via physical examination, blood analyses, endoscopic examinations, fecal occult blood tests (tetramethylbenzidine and guaiac methods), renal function tests (effective renal plasma flow and glomerular filtration rate), urinalyses, urinary enzyme indices (N-acetyl-beta-D-glucosaminidase and gamma-glutamyl-transferase), and hemostatic function tests (buccal mucosa bleeding time, cuticle bleeding time, prothrombin time, activated partial thromboplastin time, and fibrinogen concentration). RESULTS: Pyloric antrum lesion grade was significantly higher in the RDKET group on day 28, compared with the pretreatment and control group grades. Fecal occult blood grade measured by use of the tetramethylbenzidine method was significantly higher in the RDKET group on day 30, compared with the pretreatment grade. No other significant differences were detected between treatment groups. CONCLUSIONS AND CLINICAL RELEVANCE: RDKET induced mild to moderate gastric mucosal injuries especially in the pyloric antrum in healthy Beagles, whereas no adverse effects were observed in renal function or hemostasis. Fecal occult blood tests may be useful as screening tests for adverse gastrointestinal effects induced by RDKET in dogs.     

High field magnetic resonance imaging contributes to diagnosis of equine distal tarsus and proximal metatarsus lesions: 103 horses

Injury of the distal tarsus and proximal metatarsus commonly causes lameness. Magnetic resonance imaging (MRI) allows concurrent assessment of both the distal tarsal joints and suspensory ligament origin, and aids identification of lesions that may otherwise go undetected by other modalities. In this retrospective observational study, the medical records of a veterinary imaging center were searched for MRI exams of the distal tarsus and proximal metatarsus for the years 2012 through 2014. Studies for 125 limbs of 103 horses were identified and retrospectively evaluated by two board‐certified veterinary radiologists. Soft tissue and osseous changes were characterized and graded by degree of severity. The patients’ signalment, lameness severity, and results of diagnostic analgesia were recorded. Osteoarthritic changes of the distal intertarsal and tarsometatarsal joints were the most common findings. Other findings included bone marrow lesions, degenerative changes of the small cuboidal bones, subchondral cystic lesions, and intertarsal desmopathy. Suspensory ligament desmopathy was found in 53% of limbs. Fourty‐seven percent of limbs that responded to analgesia of the proximal suspensory ligament had more severe lesions in the distal tarsus. Bone marrow lesions of the third tarsal bone were the only MRI finding that correlated with grade of lameness in patients for which lameness grade was reported. The grade of lameness has a poor correlation with the severity of lesions found on MRI. The findings support the use of MRI for simultaneous evaluation of the proximal metatarsus and distal tarsus, particularly given the difficulty of lesion localization with diagnostic analgesia.     

Evaluation of the global DNA methylation in canine mast cell tumour samples by immunostaining of 5‐methyl cytosine

Cutaneous mast cell tumours (MCT) are the most common skin tumour in dogs, and to our knowledge, there are no previous studies regarding the global methylation of these tumours. DNA hypomethylation and hypermethylation have been described in several tumours and both mechanisms can lead to carcinogenesis. The purpose of this study was to evaluate the global DNA methylation in canine MCT. A total of 48 MCT samples were classified in grades 1, 2 and 3 or high‐grade or low‐grade. Monoclonal antibodies were used for the immunohistochemical detection of the 5‐methylcytosine. The immunostained nuclei were classified in strong, weak or negative pattern, and these were quantified in five distinct microscopic fields (40× objective) in each slide. The results showed that global DNA hypomethylation was predominant in grade 3, high‐grade, less differentiated MCT. These epigenetic changes in neoplastic mast cells warrant further detailed investigation aiming the establishment of tumour epigenetic therapies.     

Renal fibrosis in feline chronic kidney disease: Known mediators and mechanisms of injury

Chronic kidney disease (CKD) is a common medical condition of ageing cats. In most cases the underlying aetiology is unknown, but the most frequently reported pathological diagnosis is renal tubulointerstitial fibrosis. Renal fibrosis, characterised by extensive accumulation of extra-cellular matrix within the interstitium, is thought to be the final common pathway for all kidney diseases and is the pathological lesion best correlated with function in both humans and cats. As a convergent pathway, renal fibrosis provides an ideal target for the treatment of CKD and knowledge of the underlying fibrotic process is essential for the future development of novel therapies. There are many mediators and mechanisms of renal fibrosis reported in the literature, of which only a few have been investigated in the cat. This article reviews the process of renal fibrosis and discusses the most commonly cited mediators and mechanisms of progressive renal injury, with particular focus on the potential significance to feline CKD.     

Oxalate nephropathy in a laboratory colony of common marmoset monkeys (Callithrix jacchus) following the ingestion of Eucalyptus viminalis

Seven common marmoset monkeys (Callithrix jacchus) from a laboratory colony of 17 died over a period of eight months. Death of six of these monkeys was attributed to kidney failure from an oxalate-induced nephropathy. The epidemiology of this outbreak suggested an exogenous source and there was strong evidence that the source was bark and leaves from an Eucalyptus viminalis tree. Branches of this tree were introduced one month before the first death. The branches were removed one month after deaths commenced, but deaths continued for another five months. Urinalysis of all surviving marmosets at 80 and 122 days after initial contact with the E viminalis branches suggested that these monkeys had renal impairment. In the cases described here, the eating behaviour of common marmosets apparently exposed the animals to toxic levels of oxalate in the bark and leaves of an E viminalis tree.     

Clinical signs and results of treatment in cats with patellar luxation: 42 cases (1992-2002)

OBJECTIVE: To describe clinical signs and results of treatment in cats with patellar luxation. DESIGN: Retrospective case series. ANIMALS: 42 cats in which patellar luxation had been diagnosed on the basis of results of palpation of the stifle joints. PROCEDURES: Degree of luxation was graded on a scale from 1 to 4, and severity of lameness was graded on a scale from 0 to 5. Radiographs of stifle joints were evaluated for signs of osteoarthritis. Long-term function was classified as poor, fair, good, or excellent. RESULTS: 34 cats had bilateral luxation and 8 had unilateral luxation. Only 7 (17%) cats had a history of trauma. Mean age of the cats was 3.3 years, and mean weight was 4.26 kg (9.4 lb); 26 (62%) were domestic shorthairs. Seventy-three of the 76 (95%) affected joints had medial patellar luxation. Luxation grades could be assigned to 65 joints, with grade 2 (30 joints) and 3 (22 joints) luxation being most common. Lameness grades could be assigned to 73 joints, with grade 1 lameness (27 joints) most common. Outcome was excellent for 8 of 17 joints treated without surgery and for 23 of 35 joints treated surgically. Complications attributable to surgery were reported in 8 cats. CONCLUSIONS AND CLINICAL RELEVANCE: Patellar luxation should be considered as a cause of hind limb lameness in cats. Low-grade luxation can be associated with lameness of the same severity as high-grade luxation. Surgical correction of patellar luxation in cats with grade 2 or 3 lameness can result in a favorable outcome.     

Cutaneous angiomatosis in a young dog

A 1-year-old, spayed, female, mixed-breed dog had two reddish-purple cutaneous lesions, one on the right dorsal antebrachium and the other on the right shoulder. The lesions consisted of approximately 13 x 3 cm and 15 x 10 cm, irregular, patchy regions of 0.5-3.0 cm, circular, sometimes raised, reddish-purple swellings resembling ecchymoses. The lesion on the antebrachium had been noticed since the dog was adopted at 6 months of age and appeared to have increased in size over an 11-week period, at which time skin punch biopsy revealed an infiltrative pattern of well-differentiated blood vessels leading to an interpretation that the lesion was a well-differentiated hemangiosarcoma. The second lesion was revealed when the dog had its fur shaved in that area during surgical preparation to excise the antebrachial lesion. No other skin lesions were found on the dog. Microscopically, there was a widely disseminated and infiltrative-like pattern of benign-appearing small blood vessels, which were throughout the superficial and deep dermis and subcutis. Although the disseminated nature suggested malignancy, the histologic appearance of well-differentiated small blood vessels and nonprogressive clinical features indicate that the lesions were benign. The dog has been followed for 6 years and to date has no evidence of progression of the antebrachial lesion or shoulder lesion. To the authors' knowledge, this is the first report of a congenital angiomatosis-like lesion in a young dog, with extensive involvement of the forelimb.     

Proteinuria in the dog: a clinicopathological study in 51 proteinuric dogs

In 51 dogs with predominantly massive urinary protein loss, the daily loss was quantified and glomerular and tubulointerstitial lesions from renal biopsies were characterised and graded using histology, immune fluorescence and electron microscopy. The highest median daily urinary protein loss occurred in dogs with membranous glomerulonephritis (median 380 mg kg-1 d-1) and renal amyloidosis (median 257 mg kg-1 d-1). Although in nine febrile dogs the urinary protein loss was transient, both glomerular and tubular lesions were diagnosed in five and seven of these dogs, respectively. The pattern of urinary proteins was determined using sodium dodecyl-sulphate polyacrylamide gel electrophoresis. The albumin fractional clearance (FC) was raised in 46 dogs, whereas the FCS of the low molecular weight (MW) protein fraction (MW less than 66,000) and high molecular weight protein fraction (MW more than 66,000) were raised in 42 and 28 dogs, respectively. Both the high molecular weight protein FC and albumin FC significantly correlated to the grade of glomerular lesions, whereas the low molecular weight protein FC only moderately significantly correlated to the grade of tubular lesions. The selectivity index, calculated as (formula; see text) did not differentiate between the various forms of glomerulopathies. The urinary lysozyme concentration was significantly correlated to the grade of tubular lesions. It is concluded that although quantitative and qualitative measurements of urinary proteins can provide additional clinical information, they do not have a reliable predictive value and histopathological examination of renal tissue is still necessary for the final diagnosis.     

Reduced differentiation of intestinal epithelial cells in wasting marmoset syndrome

Wasting marmoset syndrome (WMS) is a serious disease in captive common marmoset (Callithrix jacchus) colonies. Because of the high mortality rates, elucidation of the underlying mechanisms is essential. In this study, we compared the histopathology, the number of each epithelial cell in the jejunum and colon, and the expression patterns of some molecular markers between healthy and WMS-affected marmosets. Atrophy of villi in the jejunum and mononuclear cell infiltration in the lamina propria were observed in the intestinal tract of WMS-affected marmosets. Although the numbers of transient amplifying cells and tuft cells were increased, the number of goblet cells was obviously decreased in the jejunum and colon of WMS-affected marmosets compared to healthy marmosets. In addition, the number of enterocytes in the jejunum was decreased in WMS animals. There was no apparent difference in the numbers of stem cells, enteroendocrine cells, or Paneth cells. The expression of β-catenin and Tcf7l2 was increased in WMS, and the co-existence of β-catenin and Tcf7l2/Cyclin D1 was observed around the crypts in WMS-affected marmosets. These findings suggest that cell proliferation continues, but cell differentiation is halted in the intestinal tract due to the enhanced β-catenin/Tcf7l2/Cyclin D1signaling pathway in WMS, which results in malfunction of the villus and mucosa.