Laurent Blond

Dose response of bone-targeted enzyme replacement for murine hypophosphatasia

Hypophosphatasia (HPP) features rickets or osteomalacia from tissue-nonspecific alkaline phosphatase (TNSALP) deficiency due to deactivating mutations within the ALPL gene. Enzyme replacement therapy with a bone-targeted, recombinant TNSALP (sALP-FcD(10), renamed ENB-0040) prevents manifestations of HPP when initiated at birth in TNSALP knockout (Akp2(-/-)) mice. Here, we evaluated the dose-response relationship of ENB-0040 to various phenotypic traits of Akp2(-/-) mice receiving daily subcutaneous (SC) injections of ENB-0040 from birth at 0.5, 2.0, or 8.2mg/kg for 43days. Radiographs, μCT, and histomorphometric analyses documented better bone mineralization with increasing doses of ENB-0040. We found a clear, positive correlation between ENB-0040 dose and prevention of mineralization defects of the feet, rib cage, lower limbs, and jaw bones. According to a dose-response model, the ED(80) (the dose that prevents bone defects in 80% of mice) was 3.2, 2.8 and 2.9mg/kg/day for these sites, respectively. Long bones seemed to respond to lower daily doses of ENB-0040. There was also a positive relationship between ENB-0040 dose and survival. Median survival, body weight, and bone length all improved with increasing doses of ENB-0040. Urinary PP(i) concentrations remained elevated in all treatment groups, indicating that while this parameter is a good biochemical marker for diagnosing HPP in patients, it may not be a good follow up marker for evaluating response to treatment when administering bone-targeted TNSALP to mice. These dose-response relationships strongly support the pharmacological efficacy of ENB-0040 for HPP, and provide the experimental basis for the therapeutic range of ENB-0040 chosen for clinical trials.

Comparison of sonographic features of benign and neoplastic deep lymph nodes in dogs.

The differentiation of benign vs. neoplastic lymph nodes impacts patient management. Specific sonographic features are typically considered when assessing lymph nodes in dogs. However, the usefulness of these criteria in distinguishing benign vs. malignant lymph nodes remains largely unknown, especially for deep lymph nodes. Our aim was to compare sonographic features in benign and neoplastic deep lymph nodes with the hope of identifying predictive criteria. Thirty-one deep lymph nodes (16 mesenteric, 10 medial iliac, three hepatic, one sternal, and one cranial mediastinal) in 31 dogs were examined prospectively with B-mode and Color flow Doppler. Lymph nodes were aspirated using ultrasound-guidance and final diagnosis were established based on cytologic and/or histopathologic interpretation. Prevalence of each sonographic feature and combinations of two features was calculated for each group and compared using a χ(2) -test or Students t-test for unequal variances. Ten lymph nodes were benign (hyperplastic and/or inflammatory) and 21 were neoplastic. All were hypoechoic, except for one neoplastic lymph node. Maximal short-axis diameter (P=0.0006) and long-axis diameter (P=0.01), and SA/LA ratio (P=0.008) were increased significantly for neoplastic (2.8, 5.5 cm, and 0.50, respectively) vs. benign (1.2, 3.8 cm, and 0.34, respectively) lymph nodes. The prevalence of other features was similar between groups. Doppler evaluation was possible in 77% of lymph nodes, but there was no significant difference between groups. When any two ultrasound features were combined, the only difference between benign and neoplastic lymph nodes was for the combination of contour regularity and appearance of the perinodal fat (P=0.03).

A COMPARISON OF COMPUTED TOMOGRAPHY, COMPUTED RADIOGRAPHY, AND FILM‐SCREEN RADIOGRAPHY FOR THE DETECTION OF CANINE PULMONARY NODULES

Computed tomography (CT) has become more widely available and computed radiography (CR) has replaced film-screen radiography for canine thoracic imaging in many veterinary practices. There are limited data comparing these modalities in a veterinary clinical setting to detect pulmonary nodules. We compared CT, CR, and film-screen radiography for detecting the presence, number, and characteristics of pulmonary nodules in dogs. Observer performance for a variety of experience levels was also evaluated. Twenty-one client-owned dogs with a primary neoplastic process underwent CT and CR; nine also received film-screen radiographs. Positive/negative classification by consensus agreed between the three modalities in 8/9 dogs and between CR and CT in the remaining 12. CT detected the greatest (P = 0.002) total number of nodules and no difference was seen between CR and films. The greatest number of nodules was seen in the right middle and both caudal regions, but only using CT (P < 0.0001). Significantly smaller nodules were detected with CT (P = 0.0007) and no difference in minimum size was detected between CR and films. Observer accuracy was high for all modalities; particularly for CT (90.5-100%) and for the senior radiologist (90.5-100%). CT was also characterized by the least interobserver variability. Although CT, CR, and film-screen performed similarly in determining the presence or absence of pulmonary nodules, a greater number of smaller nodules was detected with CT, and CT was associated with greater diagnostic confidence and observer accuracy and agreement.

Ultrasonography of the bovine respiratory system and its practical application.

Ultrasonography of the respiratory system is a noninvasive and readily available tool that allows an accurate evaluation of the pleura and some superficial lung lesions. It can aid clinicians in the diagnosis and treatment of various thoracic conditions that affect cattle.

Basis of Ultrasound Imaging and the Main Artifacts in Bovine Medicine

Ultrasound imaging is a noninvasive and readily available diagnostic modality that meets increasing applications in bovine medicine. This article presents the basis of physical principles of this imaging modality based on the interaction of ultrasound with the tissues, different modes of examination, and ways to obtain good quality images. The main artifacts that may be encountered during ultrasound imaging are also described. Finally, Doppler ultrasound is briefly explained. This article aims to help practitioners perform an optimal ultrasonographic examination.

Computed tomography and magnetic resonance imaging in the study of joint development in the equine pelvic limb.

Osteochondrosis dissecans (OCD) is a focal failure of endochondral ossification of the epiphysis characterized by the presence of cartilage flaps and osteochondral fragments. The objective of this study was to image epiphyseal development in the equine pelvic limb to determine whether there was a variation in site maturation that could be a predisposing factor for OCD. Pelvic limbs (fetuses and foals) were studied post-mortem. The epiphyses of the distal femur, tibia and talus were scanned with computed tomography (CT) and 1.5T magnetic resonance imaging (MRI) to investigate the degree and pattern of ossification, the regularity of the ossification front and cartilage percentage (articular epiphyseal cartilage thickness as a percentage of total epiphyseal diameter) at predetermined sites. The secondary ossification centers (SOCs) were first identified in the femoral epiphyses at 7months, and both tibia and talus at 8months of gestation (MOG). At ⩾8 MOG the cartilage percentage was higher at the majority of OCD-susceptible sites when compared to control sites. At 8-9 MOG the lateral trochlear ridge of the femur, medial malleolus of the tibia (MM), cranial part of the distal intermediate ridge of the tibia (DIRT(Cr)), all OCD susceptible sites, had the greatest cartilage percentage compared to all other sites assessed. Post-partum, the cartilage percentage of the MM and DIRT(Cr), common sites of OCD, remained high. CT and MRI images illustrate equine epiphyseal development and provide additional evidence that greater cartilage thickness at specific joint sites could play a role in the development of OCD.

Comparison of Computed Tomography and Routine Radiography of the Tympanic Bullae in the Diagnosis of Otitis Media in the Calf

BACKGROUND Otitis media is difficult to diagnose antemortem. Case reports have described computed tomography (CT) in the diagnosis, but not all cases were confirmed. HYPOTHESIS CT is a sensitive and specific imaging modality of the tympanic bullae and can be used as the gold standard for the diagnosis of otitis media. ANIMALS Sixteen Holstein calves 5-7 weeks of age were included. METHODS Prospective study. All calves were sedated with i.v. xylazine (0.05-0.15 mg/kg) for routine radiography (3 views) and CT of the tympanic bullae followed by necropsy. RESULTS Based upon necropsy findings, 10 of 16 calves were affected with otitis media, 4 unilaterally and 6 bilaterally. Imaging changes associated with otitis media included increased soft tissue opacity within the bulla, thickening of the bulla wall, enlarged bulla, and osteolysis of the bulla wall and trabeculations. The most frequent radiographic changes were lysis of trabeculations and increased soft tissue opacity, which were present in 56.3% of affected bullae. On CT, increased soft tissue opacity within the bulla was present in 93.8% of affected bullae. Sensitivity of radiography and CT was 68.8 and 93.8% and specificity was 50 and 100%, respectively. The κ value between radiography and CT with necropsy diagnosis was 0.19 for radiography, indicating poor agreement, and 0.94 for CT, indicating excellent agreement. CONCLUSION CT is more specific, more sensitive, and easier to interpret than radiography and can be used as the gold standard in the diagnosis of otitis media in the calf.

Imaging of primary bone tumors in veterinary medicine: Which differences?

Veterinary medicine is most often a mysterious world for the human doctors. However, animals are important for human medicine thanks to the numerous biological similarities. Primary bone tumors are not uncommon in veterinary medicine and especially in small domestic animals as dogs and cats. As in human medicine, osteosarcoma is the most common one and especially in the long bones extremities. In the malignant bone tumor family, chondrosarcoma, fibrosarcoma and hemangiosarcoma are following. Benign bone tumors as osteoma, osteochondroma and bone cysts do exist but are rare and of little clinical significance. Diagnostic modalities used depend widely on the owner willing to treat his animal. Radiographs and bone biopsy are the standard to make a diagnosis but CT, nuclear medicine and MRI are more an more used. As amputation is treatment number one in appendicular bone tumor in veterinary medicine, this explains on the one hand why more recent imaging modalities are not always necessary and on the other hand, that prognostic on large animals is so poor that it is not much studied. Chemotherapy is sometimes associated with the surgery procedure, depending on the aggressivity of the tumor. Although, the strakes differs a lot between veterinary and human medicine, biological behavior are almost the same and should led to a beneficial team work between all.

EFFECT OF ACQUISITION TIME AND CHEMICAL FAT SUPPRESSION ON MENINGEAL ENHANCEMENT ON MR IMAGING IN DOGS

Our purpose was to characterize meningeal gadolinium enhancement on magnetic resonance (MR) imaging in dogs with inflammatory and neoplastic diseases, and to assess interobserver variability and the impact of delayed acquisition and chemical fat saturation on its conspicuity. Transverse T1-weighted FLAIR images were acquired prior to, and immediately following gadolinium injection (T0), and at 5 (T5) and 15-20 min delay (TD), with and without fat suppression, in 155 consecutive dogs imaged for suspected brain disease. The agreement on meningeal enhancement was globally substantial (kappa = 0.61) and the likelihood of obtaining a definite diagnosis was significantly increased with the use of fat suppression (P < or = 0.004). Meningeal enhancement was judged definitively present by consensus in 46 of 155 (30%) dogs. Of these, meningeal enhancement was characterized qualitatively and quantitatively in 30 dogs with a clinical diagnosis (18 inflammatory, 11 neoplastic, 1 infarct), and image sequences were compared. Meningeal enhancement was more often diffuse and leptomeningeal in animals with inflammation versus neoplasia (50% vs. 42%, and 69% vs. 48%, respectively), but significant associations were not found. Meningeal thickness and contrast ratio were higher with neoplasia (P < or = 0.02), but results did not vary significantly between series for either group. Yet, images with fat suppression were most useful 50% of the time for definite diagnosis and/or characterization of meningeal enhancement. While delayed image acquisition following gadolinium injection does not improve characterization of meningeal enhancement in dogs, fat suppression is beneficial qualitatively.

Effects of observer on the diagnostic accuracy of low-field MRI for detecting canine meniscal tears.

Low-field MRI (lfMRI) has become increasingly accepted as a method for diagnosing canine meniscal tears in clinical practice. However, observer effects on diagnostic accuracy have not been previously reported. In this study, 50 consecutive stifle joints with clinical and radiologic evidence of cranial cruciate ligament insufficiency were investigated by lfMRI and arthroscopy. Fifteen observers who had varying levels of experience and who were unaware of arthroscopic findings independently reviewed lfMRI studies and recorded whether lateral and medial meniscal tears were present. Diagnostic accuracy (sensitivity, specificity, positive (PPV) and negative predictive value (NPV)) was determined for each observer and median values were calculated for all observers, using arthroscopy as the reference standard. Interrater agreement was determined based on intraclass correlation coefficient (ICC) analysis. Observer level of experience was compared with diagnostic sensitivity and specificity using correlation analysis. Based on pooled data for all observers, median sensitivity, specificity, PPV, and NPV for lfMRI diagnosis of lateral meniscal tears were 0.00, 0.94, 0.05, and 0.94, respectively. Median sensitivity, specificity, PPV, and NPV for medial meniscal tears were 0.74, 0.89, 0.83, and 0.79, respectively. Interrater agreement for all menisci was fair (0.51). Menisci were less consistently scored as having no tears (ICC = 0.13) than those scored as having tears (ICC = 0.50). No significant correlations between observer experience and diagnostic sensitivity/specificity were identified. Findings indicated that the accuracy of lfMRI for diagnosing canine meniscal tears was poor to fair and observer-dependent. Future studies are needed to develop standardized and widely accepted lfMRI criteria for diagnosing meniscal tears.