Low-dose xenogeneic mesenchymal stem cells target canine osteoarthritis through systemic immunomodulation and homing.

BACKGROUND: As current therapies for canine osteoarthritis (OA) provide mainly symptomatic improvement and fail to address the complex pathology of the disease, mesenchymal stem cells (MSCs) offer a promising biological approach to address both aspects of OA through their immunomodulatory properties. METHODS: This study aimed to investigate the safety and efficacy of xenogeneic MSCs in dogs with OA at different dose levels after intravenous injection. OA was surgically induced in the right stifle joint. Thirty-two male and female dogs were divided into three treatment groups and a control group. Regular general physical examinations; lameness, joint, radiographic, and animal caretaker assessments; pressure plate analyses; and blood analyses were performed over 42 days. At study end, joint tissues were evaluated regarding gross pathology, histopathology, and immunohistochemistry. In a follow-up study, the biodistribution of intravenously injected 99mTc-labeled equine peripheral blood-derived MSCs was evaluated over 24h in three dogs after the cruciate ligament section. RESULTS: The dose determination study showed the systemic administration of ePB-MSCs in a canine OA model resulted in an analgesic, anti-inflammatory, and joint tissue protective effect associated with improved clinical signs and improved cartilage structure, as well as a good safety profile. Furthermore, a clear dose effect was found with 0.3 × 106 ePB-MSCs as the most effective dose. In addition, this treatment was demonstrated to home specifically towards the injury zone in a biodistribution study. CONCLUSION: This model-based study is the first to confirm the efficacy and safety of systemically administered xenogeneic MSCs in dogs with OA. The systemic administration of a low dose of xenogeneic MSCs could offer a widely accessible, safe, and efficacious treatment to address the complex pathology of canine OA and potentially slow down the disease progression by its joint tissue protective effect.

Comparison of cystocentesis versus home sampling to determine urinary protein: Creatinine ratio and urine specific gravity in cats.

BACKGROUND: Urinalysis is necessary for the diagnostic evaluation of chronic kidney disease in cats. Performing cystocentesis is not always feasible, but data comparing urine obtained by cystocentesis in the clinic with voided samples collected at home are lacking in cats. OBJECTIVES: To compare urinary protein:creatinine ratio (UPC) and urine specific gravity (USG) and to detect clinically relevant changes in proteinuria substage or urine concentration between urine collected at home and in-clinic by cystocentesis in cats. ANIMALS: Ninety-two healthy and diseased client-owned cats. METHODS: Prospective study. Owners collected voided urine at home and within 1 to 15 hours, cystocentesis was performed in the clinic. RESULTS: In a subset of motivated owners, 55% succeeded in collecting urine at home. Overall, UPC was higher (mean ±SD difference = 0.09 ±0.22; P < .001) and USG was lower (mean ±SD difference = -0.006 ±0.009; P < .001) in cystocentesis samples than in voided urine. Substantial agreement existed between sampling methods for UPC (weighted к = 0.68) and USG (к = 0.64) categories. A different proteinuria substage (UPC < 0.2, 0.2-0.4, >0.4) was present in paired urine samples from 28% of cats. In 18% of cats, urine concentrating ability (USG < or ≥1.035) differed between both samples. CONCLUSIONS AND CLINICAL IMPORTANCE: Home sampling of urine is a valid alternative to cystocentesis in cats. However, because clinically relevant differences in UPC and USG were present in 28% and 18% of cats, respectively, by the same collection method for monitoring each cat is advised.

Intravenous Injection of Equine Mesenchymal Stem Cells in Dogs with Articular Pain and Lameness: A Feasibility Study.

Osteoarthritis is a frequently occurring joint disorder in veterinary practice. Current treatments are focused on pain and inflammation; however, these are not able to reverse the pathological condition. Mesenchymal stem cells (MSCs) could provide an interesting alternative because of their immunomodulatory properties. The objective of this study was to evaluate the potential of a single intravenous (IV) injection of xenogeneic equine peripheral blood-derived MSCs (epbMSCs) as treatment for articular pain and lameness. Patients with chronic articular pain were injected intravenously with epbMSCs. They were evaluated at three time points (baseline and two follow-ups) by a veterinarian based on an orthopedic joint assessment and an owner canine brief pain inventory scoring. Thirty-five dogs were included in the safety and efficacy evaluation of the study. Results showed that the epbMSC therapy was well tolerated, with no treatment-related adverse events and no increase in articular heat or pain. A significant improvement in lameness, range of motion, joint effusion, pain severity, and interference scores was found 6 weeks post-treatment compared with baseline. This study demonstrates that future research on IV administration of epbMSCs is warranted to further explore its possible beneficial effects in dogs with chronic articular pain and lameness. Clinical Trial gov ID: EC_2018_002.

B-Mode and Contrast-Enhanced Ultrasonography Aspects of Benign and Malignant Superficial Neoplasms in Dogs: A Preliminary Study.

Contrast-enhanced ultrasonography (CEUS) is considered a promising technique for differentiation of benign and malignant tumors in humans. However, few studies have assessed superficial neoplasms in dogs by means of CEUS. The aim of this study was to identify ultrasonographic criteria evaluated by B-mode ultrasound (US) and CEUS that may be used to distinguish benign and malignant superficial neoplasms in dogs. A total of 63 superficial neoplasms from 59 dogs were evaluated using B-mode US and CEUS prior to histopathologic examination. Qualitative and quantitative parameters were compared between benign and malignant neoplasms by Fischer's exact test or fixed effects model. With B-mode US, a significant difference was found for border definition, echogenicity and echotexture. With CEUS, a significant difference was found for the enhancement pattern at wash-in and the wash-out area under the curve at the center of the neoplasm. Malignant neoplasms had on average a lower regional blood volume during the wash-out phase compared to benign neoplasms. Despite these significant differences, there was a considerable overlap in B-mode and CEUS parameters between benign and malignant neoplasms. In conclusion, B-mode US and CEUS might contribute to malignancy prediction; however, based on individual ultrasonographic parameters, they seem unable to replace cytology or histopathology.

Prevalence, risk factors and zoonotic potential of intestinal parasites in dogs from four locations in Morocco.

Dogs can harbor various intestinal parasites that have serious clinical, economic, and zoonotic impact. In Morocco, the epidemiological status of those parasites is largely unknown. This study aimed to obtain data on the prevalence of intestinal parasites in various Moroccan dog populations, to identify associated risk factors, to evaluate people's knowledge regarding zoonotic parasites and to estimate the risk of human infection. A total of 291 fecal samples were analyzed using a 33% Zinc Sulphate (ZnSO4) centrifugal flotation and a sheather's sugar simple flotation techniques. In addition, 100 dog owners were asked to fill out a questionnaire about their knowledge regarding canine zoonotic intestinal parasites. Overall, 58% of sampled dogs were positive for at least one parasite species. Ancylostoma/Uncinaria spp. (31.9%), Toxascaris leonina (27.4%), Toxocara canis (27.1%), Cystoisospora spp. (13.4%) and Giardia spp. (7.2%) were the most frequently isolated parasites. The overall prevalence was associated with the dogs' activity, and feces consistency. More specifically, the prevalence of Ancylostoma/Uncinaria spp., Toxascaris leonina and Cystoisospora spp. was associated with dogs' activity and feces consistency and, additionally with age for Cystoisosporaspp.Toxocara canis prevalence was associated with age and feces consistency, while Giardia spp. prevalence was associated with dogs' activity. A weak awareness among dog owners regarding the zoonotic potential of canine intestinal parasites was noticed (33%) especially when their knowledge was compared to another endemic zoonotic disease, i.e. rabies (85%). Furthermore, the rate of respecting the vaccination protocol (82%) was significantly higher than the rate of respecting the deworming protocol (47%). We conclude that intestinal parasites, including the zoonotic ones, were highly prevalent in the dogs sampled in this study whereas people's knowledge about those parasites was very limited. These findings suggest that the risk of human infection is very likely, which highlights the need for effective control programs and health education.

Computed tomographic examination of the articular process joints of the cervical spine in warmblood horses: 86 cases (2015-2017).

OBJECTIVE: To describe articular process joints (APJs) of the cervical spine in horses on the basis of CT and to determine whether abnormalities were associated with clinical signs. ANIMALS: 86 client-owned warmblood horses. PROCEDURES: Horses that underwent CT of the cervical spine between January 2015 and January 2017 were eligible for study inclusion. Medical records were reviewed for age, body weight, breed, sex, history, clinical signs, and CT findings. Horses were divided into 3 case groups and 1 control group on the basis of clinical signs. RESULTS: 70 warmblood horses were cases, and 16 were controls. Abnormalities were more frequent from C5 through T1 and were severe in only horses from the case group. Narrowing of the intervertebral foramen was common in horses in the case group (85.7%), often owing to enlarged, misshaped articular processes, followed by degenerative changes, periarticular osteolysis, cyst-like lesions, and fragmentation. High articular process-to-vertebral body (C6) ratio (APBR) and high-grade narrowing of the intervertebral foramen and periarticular osteolysis were noted for horses with forelimb lameness or signs of cervical pain or stiffness. No association was identified between APBR and age or sex. An APBR > 1.5 was found in only horses in the case group, and 32.3% of APJs with APBRs > 1.5 did not have any degenerative changes and periarticular osteolysis. CONCLUSIONS AND CLINICAL RELEVANCE: CT was useful to identify abnormalities of the APJs of the cervical spine. An association existed between CT findings and clinical signs. The APJs can be enlarged without concurrent degenerative changes.

Repeated intra-articular administration of equine allogeneic peripheral blood-derived mesenchymal stem cells does not induce a cellular and humoral immune response in horses.

OBJECTIVE: The use of mesenchymal stem cells (MSCs) for the treatment of equine joint disease is widely investigated because of their regenerative and immunomodulatory potential. Allogeneic MSCs provide a promising alternative to autologous MSCs, since the former are immediately available and enable a thorough donor screening. However, questions have been raised concerning the immunogenic potential of allogeneic MSCs, especially after repeated administration. METHODS: Current retrospective study assessed the cellular and humoral immunogenicity of ten jumping and dressage horses with naturally occurring degenerative joint disease which were treated 3 times intra-articularly with a 1 mL stem cell suspension containing 1.4-2.5 million chondrogenic induced equine allogeneic peripheral blood-derived MSCs (ciMSCs) combined with 1 mL equine allogeneic plasma. Stem cells from 2 donor horses were used. Horses were clinically evaluated for joint effusion, presence of pain to palpation and skin surface temperature at the local injection site, joint range of motion, occurrence of adverse events and the presence of ectopic tissue. The cellular immune response was analyzed using a modified mixed lymphocyte reaction and the humoral immune response was investigated using a flow cytometric crossmatch assay by which the presence of alloantibodies against the ciMSCs was evaluated. Presence of anti-bovine serum albumin antibodies was detected via ELISA. RESULTS: Clinical evaluation of the horses revealed no serious adverse effects or suspected adverse drug reactions and no ectopic tissue formation at the local injection site or in other areas of the body. Generally, repeated administration led to a decrease of horses with joint effusion of the affected joint. Pain to palpation, skin surface temperature and joint range of motion did not increase or even decreased after treatment administration. Allogeneic ciMSCs did not induce a cellular immune response and no alloantibodies were detected in the recipients' serum, regardless the presence of BSA antibodies in 70 % of the horses. CONCLUSION: Repeated intra-articular injections with allogeneic equine ciMSCs did not elicit clinically relevant adverse events. Furthermore, current study indicates the absence of a cellular or a humoral immune response following repeated intra-articular injections.

Scintigraphic tracking of 99mTechnetium-labelled equine peripheral blood-derived mesenchymal stem cells after intravenous, intramuscular, and subcutaneous injection in healthy dogs.

BACKGROUND: Mesenchymal stem cell treatments in dogs have been investigated as a potential innovative alternative to current conventional therapies for a variety of conditions. So far, the precise mode of action of the MSCs has yet to be determined. The aim of this study was to gain more insights into the pharmacokinetics of MSCs by evaluating their biodistribution in healthy dogs after different injection routes. METHODS: Three different studies were performed in healthy dogs to evaluate the biodistribution pattern of radiolabelled equine peripheral blood-derived mesenchymal stem cells following intravenous, intramuscular and subcutaneous administration in comparison with free 99mTechnetium. The labelling of the equine peripheral blood-derived mesenchymal stem cells was performed using stannous chloride as a reducing agent. Whole-body scans were obtained using a gamma camera during a 24-h follow-up. RESULTS: The labelling efficiency ranged between 59.58 and 83.82%. Free 99mTechnetium accumulation was predominantly observed in the stomach, thyroid, bladder and salivary glands, while following intravenous injection, the 99mTechnetium-labelled equine peripheral blood-derived mesenchymal stem cells majorly accumulated in the liver throughout the follow-up period. After intramuscular and subcutaneous injection, the injected dose percentage remained very high at the injection site. CONCLUSIONS: A distinct difference was noted in the biodistribution pattern of the radiolabelled equine peripheral blood-derived mesenchymal stem cells compared to free 99mTechnetium indicating equine peripheral blood-derived mesenchymal stem cells have a specific pharmacokinetic pattern after systemic administration in healthy dogs. Furthermore, the biodistribution pattern of the used xenogeneic equine peripheral blood-derived mesenchymal stem cells appeared to be different from previously reported experiments using different sources of mesenchymal stem cells.

Liver-type fatty acid-binding protein and neutrophil gelatinase-associated lipocalin in cats with chronic kidney disease and hyperthyroidism.

BACKGROUND: Liver-type fatty acid-binding protein (L-FABP) and neutrophil gelatinase-associated lipocalin (NGAL) are candidate biomarkers for the detection of early chronic kidney disease (CKD) in cats. OBJECTIVE: To evaluate urinary and serum L-FABP and NGAL concentrations in CKD cats and in hyperthyroid cats before and after radioiodine (131 I) treatment. ANIMALS: Nine CKD cats, 45 healthy cats and hyperthyroid cats at 3 time points including before (T0, n = 49), 1 month (T1, n = 49), and 11 to 29 months after (T2, n = 26) 131 I treatment. METHODS: Cross-sectional and longitudinal study. Serum L-FABP (sL-FABP), serum NGAL (sNGAL), urinary L-FABP (uL-FABP), and urinary NGAL (uNGAL) were compared between the 3 groups and between hyperthyroid cats before and after treatment. Data are reported as median (min-max). RESULTS: CKD cats had significantly higher sL-FABP (13.50 [3.40-75.60] ng/ml) and uL-FABP/Cr (4.90 [0.97-2139.44] µg/g) than healthy cats (4.25 [1.34-23.25] ng/ml; P = .01 and 0.46 [0.18-9.13] µg/g; P < .001, respectively). Hyperthyroid cats at T0 had significantly higher uL-FABP/Cr (0.94 [0.15-896.00] µg/g) than healthy cats (P < .001), thereafter uL-FABP/Cr significantly decreased at T2 (0.54 [0.10-76.41] µg/g, P = .002). For the detection of CKD, uL-FABP/Cr had 100% (95% confidence interval [CI], 66.4-100.0) sensitivity and 93.2% (95% CI, 81.3-98.6) specificity. There were no significant differences in sNGAL and uNGAL/Cr between the 3 groups. CONCLUSIONS AND CLINICAL IMPORTANCE: L-FABP, but not NGAL, is a potential biomarker for the detection of early CKD in cats. Utility of uL-FABP to predict azotemia after treatment in hyperthyroid cats remains unknown.

Planar and single-photon emission computed tomography imaging in dogs with thyroid tumors: 68 cases.

BACKGROUND: Information on scintigraphy findings in dogs with thyroid neoplasia is scarce. The use of single-photon emission computed tomography (SPECT) could improve detection of metastatic disease. HYPOTHESIS/OBJECTIVES: To describe planar and SPECT imaging findings in dogs with thyroid tumors, and to compare SPECT and thoracic radiography for metastasis detection. ANIMALS: Sixty-eight dogs with thyroid neoplasia. METHODS: Retrospective study, search of medical records for dogs with thyroid neoplasia (2008-2018). RESULTS: Thyroid scintigraphy was available from 68 dogs, of which 6 presented after surgical resection. Radionuclide uptake was increased in 56% of dogs, decreased in 24%, and comparable to that of the salivary glands in 13%. The remainder had multiple masses with variable uptake. A homogeneous uptake pattern was present in 16% and a heterogeneous uptake pattern in 73%. In 11% (all dogs with multiple masses), various uptake patterns were present. Thyroid tumors were well delineated in 55%. There was a significant association between hormone status and uptake pattern (P = .009), with a heterogeneous uptake pattern in the majority of euthyroid dogs, and hormone status and tumor circumscription (P = .003), with well-circumscribed margins in the majority of hypothyroid and hyperthyroid dogs. Thoracic SPECT imaging was available in 39 dogs and identified metastatic lesions in 15 dogs. Thoracic radiographs were performed in 14 of these dogs, and detected metastases in 3 dogs. CONCLUSIONS AND CLINICAL IMPORTANCE: SPECT imaging is a viable imaging technique to screen for thoracic metastasis and wider use of SPECT imaging is recommended in dogs with thyroid neoplasia.

The socio-economic burden of cystic echinococcosis in Morocco: A combination of estimation method.

Cystic echinococcosis (CE) is a major zoonosis in Morocco despite the launch of a national control programme in 2005. As its economic consequences have not been studied yet in Morocco, this study estimated CE impact in terms of monetary losses, disability-adjusted life years (DALY), and DALY for zoonotic diseases (zDALY) in the entire country and in specific regions for the 2011 to 2014 period. The direct monetary losses were related to organ seizure from infected animal in slaughterhouses, and to healthcare expenses as well as lost wages for infected humans. Animal production losses concerned milk yield, fertility, carcass weight, and wool production. Losses due to human infection were also composed of disability and productivity losses at work. Monte Carlo simulations were used to estimate monetary losses and zDALY values. Nationwide, the estimated DALY was 0.5 years per 100,000 persons per year, and the zDALY was 55 years per 100,000 persons per year. Total yearly losses were estimated at 73 million USD (54-92 million USD). However, losses differed significantly among regions. Most of the economic losses consisted of unperceived consequences, i.e. decreased animal production and reduced productivity of asymptomatic individuals. Future studies should determine the socioeconomic and epidemiological factors underlying the differences in economic losses among regions to develop better adapted control programmes.

Safety and immunomodulatory properties of equine peripheral blood-derived mesenchymal stem cells in healthy cats.

OBJECTIVE: Due to the immunomodulatory properties of mesenchymal stem cells (MSCs) through stimulation of endogenous immune cells by paracrine signals and cell contact, they have been proposed as alternative treatment option for many inflammatory and immune-mediated diseases in veterinary medicine. However, the long-term cultivation possibilities of feline MSCs are currently compromised due to a restricted proliferation capacity. Therefore, the xenogeneic use of equine peripheral blood-derived MSCs (ePB-MSCs) would present an interesting alternative thanks to their superior cultivation properties. To the authors' knowledge, there are currently no safety reports concerning the xenogeneic use of ePB-MSCs in cats. Therefore, the overall goal of this preliminary study was to investigate if ePB-MSCs can safely be administered in healthy cats and by extension evaluating their immunogenic and immunomodulatory properties. METHODS: Ten healthy cats were intravenously (i.v.) injected with 3 × 105 ePB-MSCs at three time points (T0, T1, T2). All cats were daily inspected by the caretaker and underwent a physical examination with hematological and biochemical analysis at day 0 (T0), week 2 (T1), week 4 (T2) and week 6 (T3) by a veterinarian. Furthermore, a modified mixed lymphocyte reaction (MLR) was performed at T0 and T3 for each cat in order to evaluate immunogenic and immunomodulatory properties of the ePB-MSCs RESULTS: No adverse clinical effects could be detected following repeated i.v. administration of ePB-MSCs in all cats. Significant lower protein (T1: P-value = 0.002; T2: P-value > 0.001; T3: P-value = 0.004) and albumin levels (T1: P-value = 0.003; T2: P-value = 0.001) were seen after repeated administration of ePB-MSCs, compared to T0. However, all biochemical and hematological parameters stayed within clinical acceptance level. In addition, the repeated injections did not induce a cellular immune response before and after repeated ePB-MSCs administration. Furthermore, convincing immunomodulatory properties of ePB-MSCs on feline peripheral blood mononuclear cells were confirmed in the MLR-assay CONCLUSION: This preliminary study demonstrates that ePB-MSCs can safely be administered in healthy cats and provide a promising alternative for the treatment of various inflammatory diseases in cats.

Comparison of free thyroxine measurement by chemiluminescence and equilibrium dialysis following 131I therapy in hyperthyroid cats.

OBJECTIVES: The first objective was to assess correlation between free thyroxine (fT4) measurements by equilibrium dialysis (fT4ED; Antech Diagnostics) and a chemiluminescent enzyme immunoassay (fT4CEIA; IMMULITE 2000 Veterinary Free T4 [Siemens Healthcare Diagnostics Products]) in hyperthyroid, otherwise healthy, cats before (T0), and 1 month (T1) and 11-23 months (T2) after radioactive iodine (131I) therapy. The second objective was to determine correlation between thyroid status based on fT4 (by both techniques) and the gold standard, thyroid scintigraphy. METHODS: Thyroid status, including thyroid-stimulating hormone (TSH), total thyroxine (TT4) and fT4 serum concentrations, were assessed in 45 client-owned hyperthyroid cats before (T0), and 1 month (T1) and 11-23 months (T2) after 131I therapy. fT4 was determined by a chemiluminescent enzyme immunoassay (CEIA) and equilibrium dialysis (ED). Quantitative thyroid scintigraphy (with sodium 99m-Tc-pertechnetate) was performed at T2. RESULTS: Spearman correlation between fT4CEIA and fT4ED was 0.81, 0.88 and 0.79 at T0, T1 and T2, respectively. fT4CEIA was consistently lower than fT4ED, with a median difference of -5.4 pmol/l (P <0.001) and -4.9 pmol/l (P <0.0001) at T1 and T2, respectively. At T2, all cats were identified as euthyroid based on thyroid scintigraphy. None of the cats were identified as being hypothyroid, based on serum TT4 and TSH measurements. Nine of 22 (40.9%) cats had an fT4CEIA below the reference interval (RI) at T2, whereas only 2/22 (9.1%) cats had an fT4ED concentration below the RI at T2. CONCLUSIONS AND RELEVANCE: Good correlation exists between both assays at T1 and T2, but a significant systematic difference is noted at both time points. This could be an indication for reconsideration of the current RI, although further studies are warranted for assessing test accuracy (in otherwise healthy cats and cats with non-thyroidal illness). At this time, routine use of fT4CEIA after 131I therapy is not advised in feline patients.

Development of a dissolution method for lumefantrine and artemether in immediate release fixed dose artemether/lumefantrine tablets.

BACKGROUND: Dissolution of artemether (ART) and lumefantrine (LUM) active pharmaceutical ingredients (APIs) in fixed dose combination (FDC) ART/LUM tablets is one of the critical quality attributes. Thus, the verification of the release profile of ART and LUM from FDC ART/LUM tablets using a robust and discriminatory dissolution method is crucial. Therefore, the aim of this study was to develop and validate an appropriate dissolution method for quality control of FDC ART/LUM tablets. METHODS: The dissolution medium was selected based on saturation solubility data and sink conditions. The effect of agitation speed, pH and surfactant concentration on the release of ART and LUM was evaluated by employing a two-level factorial experiment. The resulting final method was validated for linearity, precision, robustness and API stability. In addition, the discriminatory power of the method was evaluated using expired and unexpired FDC ART/LUM products. RESULTS: A suitable dissolution profile of FDC ART/LUM tablets was obtained in 900 ml HCl (0.025 N, pH 1.6) with 1%Myrj 52 using paddle method at 100 rpm and 37 °C. ART and LUM were analysed using a HPLC method with UV detection at wavelengths of 210 and 335 nm, respectively. The results from the stability study showed that ART and LUM were sufficiently stable in HCl (0.025 N, pH 1.6) with 1%Myrj 52 at 37 °C. The method was linear (r2 = 0.999) over the concentration range of 6.25-100 µg/ml. The results for precision were within the acceptance limit (%RSD < 2). The percent relative standard deviation (< 2%) and statistically non-significant (p > 0.05) difference in release of ART and LUM observed between deliberately changed dissolution method settings (pH = 1.6 ± 0.2 or agitation speed = 100 ± 2) and optimized dissolution conditions revealed the robustness of the dissolution method. The method was capable to discriminate among different FDC ART/LUM products with different quality. CONCLUSIONS: The developed dissolution method is robust and discriminatory. It can be used in the quality evaluation of FDC ART/LUM tablets.

A Patient-Reported Outcomes Analysis Of Lanreotide In The Treatment Of NETs Patients With Carcinoid Syndrome: Evidence From The ELECT Trial.

PURPOSE: The purpose of this analysis of patient-reported outcomes from the ELECT (Evaluation of Lanreotide Depot/Autogel Efficacy and Safety as a Carcinoid Syndrome Treatment) trial (NCT00774930) was to explore the effect of lanreotide on symptoms of carcinoid syndrome. Specifically, this post hoc analysis was designed to identify the most important patient-reported outcomes for patients in ELECT. METHODS: The post hoc analysis of ELECT, a placebo-controlled study of lanreotide in patients with neuroendocrine tumors, evaluated patient-reported outcomes during the double-blind phase of the trial, specifically daily diarrhea and flushing symptoms, octreotide rescue use, and the EORTC QLQ-C30 and QLQ-GINET21 questionnaires at baseline and week 12. Principal component (PC) analysis was applied on baseline data to identify independent variable clusters and clinically meaningful summary measures that highly correlated to these PCs. From those, the minimum clinical important differences were derived so to perform a responder analysis. RESULTS: The three largest PCs captured 42.9% of the variation among baseline variables. The C30 summary score (C30-SS), diarrhea burden, and flushing burden were highly correlated with PC1, PC2, and PC3, respectively. Lanreotide patients were more likely to experience an improvement on the C30-SS (risk ratio [RR] 2.42; P=0.023), diarrhea burden (RR 2.85; P=0.005), and flushing burden (RR 1.39; P=0.31) compared to placebo patients. Lanreotide-treated patients have a higher probability of being a responder on at least one of the three domains of C30-SS, diarrhea burden, or flushing burden compared to placebo patients (RR 1.48; P=0.06). CONCLUSION: The higher response rates in the diarrhea burden are consistent with the previously reported effects of lanreotide on octreotide rescue medication use, while the findings of a greater efficacy of lanreotide vs placebo in the quality-of-life domains represent a novel aspect in the benefits of lanreotide. TRIAL REGISTRATION: ClinicalTrials.gov identifier: NCT00774930.

Acaricidal activity of plant-derived essential oil components against Psoroptes ovis in vitro and in vivo.

BACKGROUND: Treatment of Psoroptes ovis in cattle is limited to topical acaricides or systemic treatment with macrocyclic lactones. Treatment failure of macrocyclic lactones has been reported. The aim of this study was to evaluate a potential alternative treatment against P. ovis. METHODS: The acaricidal activity against P. ovis of four plant-derived essential oil components, i.e. geraniol, eugenol, 1,8-cineol and carvacrol, was assessed in vitro and in vivo. In vitro contact, fumigation and residual bioassays were performed. In addition, 12 Belgium Blue cattle were artificially infested and treated topically once a week for three successive weeks with carvacrol in Tween-80 (treatment group) or with Tween-80 alone (control). The efficacy of carvacrol was determined by the reduction in lesion size and mite counts. Six additional animals were topically treated with carvacrol to assess local adverse reactions. RESULTS: Three components showed a concentration-dependent acaricidal activity in a contact assay, with LC50 of 0.56, 0.38 and 0.26% at 24 h for geraniol, eugenol, and carvacrol, respectively. However, 1,8-cineol showed no activity at any of the tested concentrations in a contact bioassay. In a fumigation bioassay, carvacrol killed all mites within 50 min after treatment, whereas geraniol, eugenol and 1,8-cineol needed 90 to 150 min. Following a 72 h incubation period in a residual bioassay, carvacrol killed all mites after 4 h of exposure to LC90, while geraniol and eugenol killed all mites only after 8 h exposure. Based on these results, carvacrol was further assessed in vivo. Mite counts in the treatment group were reduced by 98.5 ± 2.4% at 6 weeks post-treatment, while in the control group the mite population had increased. Topical application of carvacrol only caused mild and transient erythema 20 min after treatment. No other side effects were observed. CONCLUSIONS: Considering the strong acaricidal activity of carvacrol in vitro and in vivo and the mild and transient local side effects, carvacrol shows potential as an acaricidal agent in the treatment of P. ovis in cattle.

Evaluation of an osteochondral fragment-groove procedure for induction of metacarpophalangeal joint osteoarthritis in horses.

OBJECTIVE To evaluate lameness and morphological changes associated with an osteochondral fragment-groove procedure as a means of experimental induction of metacarpophalangeal (MCP) joint osteoarthritis within an 11-week period in horses. ANIMALS 6 nonlame adult warmbloods. PROCEDURES The right MCP joint of each horse underwent an osteochondral fragment-groove procedure (day 0). After 1 week of stall rest (ie, starting day 7), each horse was trained daily on a treadmill. Weekly, horses underwent visual and inertial sensor-based assessments of lameness. Both MCP joints were assessed radiographically on days 0 (before surgery), 1, 35, and 77. A synovial fluid sample was collected from the right MCP joint on days 0 (before surgery), 35, 36, 49, 63, and 77 for cytologic and biomarker analyses. On day 77, each horse was euthanized; both MCP joints were evaluated macroscopically and histologically. RESULTS Right forelimb lameness was detected visually and by the inertial sensor system when horses were moving on a straight line after distal forelimb flexion or circling left on days 14 to 77. Compared with presurgical values, synovial fluid interleukin-6, prostaglandin E2, hyaluronic acid, and interleukin-1 receptor antagonist protein concentrations were increased at 2 or 3 time points, whereas tumor necrosis factor-α and interleukin-10 concentrations were decreased at 1 time point. Gross examination of all right MCP joints revealed synovitis and wear lines; synovitis was confirmed histologically. CONCLUSIONS AND CLINICAL RELEVANCE Results indicated that a combined osteochondral fragment-groove procedure can be used to induce clinically and grossly observable early MCP joint osteoarthritis during an 11-week period in horses.

Assessment of symmetric dimethylarginine as a biomarker of renal function in hyperthyroid cats treated with radioiodine.

BACKGROUND: Measurement of serum creatinine (sCr) and urea nitrogen fail to detect decreased renal function in many hyperthyroid cats because of low muscle mass and glomerular hyperfiltration of affected cats. Serum symmetric dimethylarginine (sSDMA) is an earlier and more sensitive renal biomarker than sCr. OBJECTIVE: Evaluate sSDMA as a biomarker of renal function in hyperthyroid cats before (T0) and 1 month after (T1) radioiodine (131 I) treatment. ANIMALS: Forty-seven client-owned hyperthyroid nonazotemic cats were evaluated at T0 and T1. METHODS: A prospective study in which sCr and sSDMA concentrations were determined in 47 hyperthyroid cats at T0 and at T1. Glomerular filtration rate (GFR) was estimated at T0 and T1 in 10 of these 47 cats using plasma exogenous creatinine clearance test. RESULTS: Serum SDMA was elevated (>14 µg/dL) in 6 of 47 cats at T0 and normalized after treatment in 4 of those cats. All cats remained nonazotemic after treatment. In 10 cats in which GFR was measured, correlation between GFR and sSDMA was low and not significant (τb = -0.35, P = .17 at T0 and τb = -.22, P = .41 at T1), whereas correlation between GFR and sCr was moderate and significant (τb = -0.52, P < .05 at T0 and τb = -.53, P = <.05 at T1). CONCLUSIONS AND CLINICAL IMPORTANCE: Careful interpretation of mildly increased sSDMA with normal sCr in hyperthyroid cats is warranted as sSDMA values might normalize after resolution of hyperthyroidism in some cats. In this population of hyperthyroid cats, sSDMA was poorly correlated with GFR.

B-mode and contrast-enhanced ultrasonography of the mammary gland during the estrous cycle of dogs.

Pathology of the mammary gland is a common health issue in dogs and includes neoplasia, cysts, inflammation and infection. The use of the B-mode (US) and contrast-enhanced (CEUS) ultrasonography may aid in the diagnosis. Previous studies are currently lacking of the ultrasonic images of the mammary gland of healthy bitches in different stages of the estrous cycle and associated normal blood perfusion patterns. The purpose, therefore, was to describe the normal B-mode US and CEUS images of the mammary gland and inguinal lymph node, in six intact female beagles during five different stages of the estrous cycle (proestrus, estrus, early and late diestrus and anestrus). Within the same stage of the estrous cycle, the size (thickness) of the caudal mammary glands increased. During early and late diestrus, all mammary glands increased in thickness and had an increased heterogeneous B-mode ultrasonic appearance. The mammary glands had a heterogeneous, disorganized perfusion pattern when assessed using CEUS. For the cranial abdominal mammary gland, the area under the curve and the mean transit time increased between estrus and late diestrus and decreased between late diestrus and anestrus. For the inguinal mammary gland, only the time to peak was longer during the periods of anestrus compared to estrus whereas all the other contrast parameters did not change during the estrous cycle. In conclusion, hormonal influences cause major changes in the size, appearance and blood perfusion of mammary glands during the estrous cycle and should be considered when evaluating pathological changes of mammary glands.

Cardiorespiratory effects of a 7° reverse Trendelenburg position in anaesthetized horses: a randomized clinical trial.

OBJECTIVE: To evaluate the cardiorespiratory effects of a 7° reverse Trendelenburg position (RTP) in anaesthetized horses. STUDY DESIGN: Randomized, non-blinded clinical trial. ANIMALS: A total of 125 horses undergoing elective surgery in dorsal recumbency. METHODS: Horses were allocated to one of three weight classes and assigned to be positioned either on a horizontal table or on a table in 7° RTP, according to a randomized block design. In all horses, anaesthesia was maintained with isoflurane in oxygen and a constant rate infusion of romifidine. All horses were mechanically ventilated throughout anaesthesia, and routine cardiovascular monitoring and arterial blood gas analysis were performed at 15-minute intervals and relevant variables calculated. Data from the first 60 minutes of anaesthesia were compared between both positions using a mixed model analysis of variance. RESULTS: A significant interaction was found between position and weight class for the alveolar to arterial oxygen tension gradient and F-shunt: these variables were lower in RTP than in horizontal position in the two lowest weight classes and vice versa in the highest weight class. Arterial oxygen tension and oxygenation indices were significantly worse in the horses in the higher weight classes. CONCLUSIONS AND CLINICAL RELEVANCE: A 7° RTP did not result in clinically relevant changes in gas exchange or cardiovascular function. Horses with a higher body weight are at increased risk for hypoxaemia during anaesthesia in dorsal recumbency.