We report the design, synthesis and testing of a series of novel bisphosphonates, pyridinium-1-yl-hydroxy-bisphosphonates, based on the results of comparative molecular similarity indices analysis and pharmacophore modeling studies of farnesyl diphosphate synthase (FPPS) inhibition, human Vgamma2Vdelta2 T cell activation and bone resorption inhibition. The most potent molecules have high activity against an expressed FPPS from Leishmania major, in Dictyostelium discoideum growth inhibition, in gammadelta T cell activation and in an in vitro bone resorption assay. As such, they represent useful new leads for the discovery of new bone resorption, antiinfective and anticancer drugs.

BackgroundIdiopathic pulmonary fibrosis (IPF) is a devastating interstitial pneumonia causing a loss of respiratory surface area due to a proliferative fibrotic response involving hyperplastic, hypertrophic, and metaplastic epithelium, cystic honeycomb change, septal expansion, and variable inflammation. Wnt (wingless) signaling glycoproteins are known to be involved in lung development and tissue repair, and are up-regulated in patients with IPF. Based on previous qRT-PCR data showing increased Wnt7B in lungs of IPF patients, a systematic, quantitative examination of its tissue site distribution was undertaken.MethodsTissue samples from the Lung Tissue Research Consortium (LTRC) of 39 patients diagnosed with mild to severe IPF/usual interstitial pneumonia (UIP) and 19 normal patients were examined for the immunolocalization of Wnt7B.ResultsIn normal lung, moderate Wnt7B reactivity was confined to airway epithelium, smooth muscle of airways and vasculature, and macrophages. IPF lung showed strong Wnt7B reactivity in fibroblastic foci, dysplastic airway and alveolar epithelium, and in highly discrete subepithelial, basement membrane-associated regions. All reactive sites were sized and counted relative to specific microscopic regions. Those in the subepithelial sites were found in significantly greater numbers and larger relative area compared with the others. No reactive sites were present in normal patient controls.ConclusionsThe results demonstrate Wnt7B to be expressed at high concentrations in regions of active hyperplasia, metaplasia, and fibrotic change in IPF patients. In this context and its previously established biologic activities, Wnt7B would be expected to be of potential importance in the pathogenesis of IPF.

Ten normal, non-asthmatic subjects performed an 18 min graduated exercise test on a static exercise bicycle on 3 separate days. They received either no medication, or propranolol 80 mg orally 2 h before, or ipratropium bromide 0.216 mg by inhalation 30 min before, the start of exercise. With no medication, transpulmonary index (TPI), a measure of airway resistance, fell linearly during exercise from a resting value of 0.269 +/- 0.024 to 0.170 +/- 0.014 kPa X 1(-1) X s by the end of exercise. This returned to baseline between 2 and 4 min after stopping exercise. Propranolol elevated baseline TPI slightly from 0.270 +/- 0.024 to 0.294 +/- 0.024 before exercise and during exercise this fell linearly to 0.185 +/- 0.016 kPa X 1(-1) X s. The fall in TPI during exercise after propranolol was not significantly different from the fall seen with no medication. Six minutes after exercise stopped TPI rose to 0.336 +/- 0.035 kPa X 1(-1) X s after propranolol. All values for TPI from 4 min to 16 min after exercise were significantly higher after propranolol than the corresponding values found after no medication (P less than 0.05). Ipratropium bromide decreased baseline TPI from 0.264 +/- 0.024 to 0.163 +/- 0.013 kPa X 1(-1) X s (P less than 0.001) and this did not change significantly further either during or after exercise. Normal subjects show considerable airway dilatation during exercise and this appears to result from inhibition of resting vagal tone. The sympathetic system does not appear to mediate the airway dilatation during exercise, but it may be important in protecting against post-exercise bronchoconstriction.

Medical therapy for pythiosis is hampered by a lack of efficacious drugs. The present report describes a case of canine gastrointestinal pythiosis in which lesions were resolved through the administration of itraconazole, terbinafine, and the agricultural fungicide mefenoxam. No substantial adverse effects occurred in association with administration of the latter compound. Additional studies are needed to evaluate the pharmacokinetics of mefenoxam and to further assess its tolerability and potential efficacy for the treatment of pythiosis in dogs.

Metallosis is the accumulation of metallic debris in soft tissues resulting from wear following total joint replacement. A dog was evaluated for lameness 4 years after total hip arthroplasty using a titanium alloy and cobalt chromium total hip system. Radiographs revealed severe acetabular component wear, implant-bone interface deterioration, and peri-acetabular osteolysis. During surgical revision, black periarticular tissue surrounded the implants. Histologically, there was fibrosis and granulomatous inflammation with abundant, intra- and extracellular, black, granular material and smaller amounts of clear punctate to acicular material. Laser capture microdissection followed by x-ray fluorescence microscopy indicated the material contained large amounts of titanium with smaller amounts of vanadium, cobalt, and chromium, confirming the diagnosis of metallosis. The clear material was birefringent under cross-polarized light, stained positive with Oil-Red-O, and thus was consistent with polyethylene. Metallosis exhibits characteristic gross and histologic lesions and is a differential diagnosis for aseptic loosening of hip implants.

Case series summaryThis case series documents ultrasonographic and clinicopathologic features of four cats with marked segmental dilatations of the common bile duct (CBD). All cats had additional ultrasonographic changes to the hepatobiliary system, including hepatomegaly, tubular to saccular intra/extrahepatic biliary duct dilatation and biliary debris accumulation. Based on all available data the presence of extrahepatic biliary duct obstruction (EHBDO) was ruled out in 3/4 cases and was equivocal in one case. One cat underwent re-routing surgery to address the CBD dilatation after multiple recurrent infections, one cat was euthanized and had a post-mortem examination and two cats were medically managed with antibiotics, liver protectants, gastroprotectants and cholerectics.Relevance and novel informationThe ultrasonographic features of the CBD in this population of cats were supportive of choledochal cysts (CCs). The maximal diameter of the CBD dilatations exceeded 5 mm in all cases, a sign that has been previously reported to be consistent with EHBDO. In our study, dilatations were segmental rather than diffuse. Given the high morbidity and mortality associated with hepatobiliary surgery in cats, segmental dilatation of the CBD should not prompt emergency surgery. Some cats may respond to medical management. Careful planning for cyst resection was beneficial in one cat. Evaluation of CC morphology (eg, size, location, concurrent intrahepatic anomalies) may assist in selecting cats that could benefit from surgical intervention.

A 12-year-old male neutered Bichon Frise presented to the Emergency Department for stupor and bradycardia after ingestion of chocolate covered 450 mg (90 mg/kg) tetrahydrocannabinol. The patient was hospitalized for supportive care, IV fluid therapy and monitoring in the intensive care unit. During hospitalization the patient became comatose and bradypneic. Treatment with intravenous lipid emulsion (ILE) therapy was instituted to accelerate toxin elimination, reduce the risk of complications related to progressive obtundation and shorten hospitalization time. Five hours after infusion, the patient developed severe respiratory distress and was ultimately euthanized. Post-mortem histologic evaluation of lung revealed severe pulmonary edema consistent with acute respiratory distress syndrome. There are infrequent reports of adverse effects associated with ILE therapy for toxicosis in veterinary medicine despite reports of complications such as acute respiratory distress syndrome in human literature. The purpose of this report is to describe the potential for a severe adverse event after treatment of a toxicosis with ILE therapy.

A Miniature Pinscher developed acute blindness and behavioral changes. On magnetic resonance imaging (MRI), there were multiple small intra-axial cystic lesions, and primary differential diagnoses included primary or metastatic neoplasia and neurocysticercosis. These cystic lesions were subsequently diagnosed histopathologically as disseminated choroid plexus carcinoma. This is only the second documented description of this diagnosis in a dog, but both patients had very similar MRI findings. This patient adds to the literature about the MRI characteristics of choroid plexus tumors and indicates that choroid plexus tumor should be considered as a possible cause of small multifocal intra-axial cystic brain lesions in dogs, regardless of whether a primary intraventricular lesion is visible.