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William R Widmer

Publications and source records attributed to William R Widmer.

11 recordsLinked to original sources
PubMed2006

Folate-targeted immunotherapy effectively treats established adjuvant and collagen-induced arthritis.

Activated macrophages express a cell surface receptor for the vitamin folic acid. Because this receptor is inaccessible or not measurably expressed on other normal cells, folic acid has been recently exploited to selectively deliver attached radio-emitters to sites of activated macrophage accumulation, allowing scintigraphic imaging of inflamed joints and organs of arthritic rats. We demonstrate here that folate-linked haptens can also be targeted to activated macrophages, decorating their cell surfaces with highly immunogenic molecules. Under conditions in which the rodent has already been immunized against keyhole limpet hemocyanine-(fluorescein isothiocyanate) FITC, activated macrophages are eliminated. Administration of folate-FITC conjugates to rodents with experimental arthritis attenuates (a) systemic and peri-articular inflammation, (b) bone and cartilage degradation, and (c) arthritis-related body weight loss. Treatment with folate-hapten conjugates is comparable to methotrexate, etanercept, anakinra, and celecoxib at alleviating the symptoms of arthritis. We conclude that reduction of activated macrophages by folate-targeted immunotherapy can ameliorate the symptoms of arthritis in two rodent models of the disease.

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PubMed2005

Detection of synovial macrophages in the joint capsule of dogs with naturally occurring rupture of the cranial cruciate ligament.

OBJECTIVE: To test the hypotheses that the densities of macrophages in the synovial membranes and capsules of stifle joints in dogs with ruptured cranial cruciate ligaments are greater than those of normal joints and that those densities in affected joints are positively correlated with the chronicity and severity of the disease. ANIMALS: 17 dogs with naturally occurring rupture of the cranial cruciate ligament and 5 healthy control dogs. PROCEDURE: All dogs underwent orthopedic and radiographic evaluations. In affected dogs, duration of clinical signs was used as an indicator of disease chronicity and the severity of osteoarthritis in the stifle joint was determined radiographically. Joint capsule specimens were evaluated histologically; macrophages, interleukin-6, and tumor necrosis factor-alpha were identified by use of immunocytochemical techniques. RESULTS: Compared with unaffected joints, macrophage density was increased in all affected joints. Duration of disease was significantly associated with radiographic severity of osteoarthritis and synovial macrophage density. Synovial macrophage density was significantly associated with severity of osteoarthritis and with the presence of interleukin-6 and tumor necrosis factor-a. CONCLUSIONS AND CLINICAL RELEVANCE: Results suggest that synovial macrophages may be involved in the development of pathologic changes (including osteophyte formation) in the stifle joints of dogs with osteoarthritis secondary to rupture of the cranial cruciate ligament. Determination of the importance of synovial macrophages in the development of changes in osteoarthritic joints may result in new treatment strategies that involve elimination of the deleterious effects of those cells.

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PubMed2004

A preliminary study of intravenous surfactants in paraplegic dogs: polymer therapy in canine clinical SCI.

Hydrophilic polymers, both surfactants and triblock polymers, are known to seal defects in cell membranes. In previous experiments using laboratory animals, we have exploited this capability using polyethylene glycol (PEG) to repair spinal axons after severe, standardized spinal cord injury (SCI) in guinea pigs. Similar studies were conducted using a related co-polymer Poloxamer 188 (P 188). Here we carried out initial investigations of an intravenous application of PEG or P 188 (3500 Daltons, 30% w/w in saline; 2 mL/kg I.V. and 2 mL/kg body weight or 300 mL P 188 per kg, respectively) to neurologically complete cases of paraplegia in dogs. Our aim was to first determine if this is a clinically safe procedure in cases of severe naturally occurring SCI in dogs. Secondarily, we wanted to obtain preliminary evidence if this therapy could be of clinical benefit when compared to a larger number of similar, but historical, control cases. Strict entry criteria permitted recruitment of only neurologically complete paraplegic dogs into this study. Animals were treated by a combination of conventional and experimental techniques within approximately 72 h of admission for spinal trauma secondary to acute, explosive disk herniation. Outcome measures consisted of measurements of voluntary ambulation, deep and superficial pain perception, conscious proprioception in hindlimbs, and evoked potentials (somatosensory evoked potentials [SSEP]). We determined that polymer injection is a safe adjunct to the conventional management of severe neurological injury in dogs. We did not observe any unacceptable clinical response to polymer injection; there were no deaths, nor any other problem arising from, or associated with, the procedures. Outcome measures over the 6-8-week trial were improved by polymer injection when compared to historical cases. This recovery was unexpectedly rapid compared to these comparator groups. The results of this pilot trial provides evidence consistent with the notion that the injection of inorganic polymers in acute neurotrauma may be a simple and useful intervention during the acute phase of the injury.

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PubMed2003

Lightning injury in an outdoor swine herd.

Three pigs, weighing 63 kg-70 kg each, from a group of 8 pigs in an outdoor pen that was struck by lightning were necropsied. All 3 pigs presented with hind limb paralysis. The only lesions identified were multiple fractures of the last (seventh) lumbar vertebral body and first sacral vertebral segment, with dorsal displacement of the sacrum and transection of the distal spinal cord and spinal nerves. Hemorrhages extended from the fracture sites into muscles immediately surrounding the lumbosacral junction and retroperitoneally into the pelvic cavity. These hemorrhages were not clearly visible until the pelvic region was dissected. Lesions commonly found in human lightning-strike victims were not present in these pigs. Because vertebral fractures may be the only lesions and may be grossly subtle in heavily muscled pigs, careful pelvic and vertebral dissection is recommended in cases of suspected lightning strike and electrocution.

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PubMed2002

Evaluation of treatment with doxorubicin and piroxicam or doxorubicin alone for multicentric lymphoma in dogs.

OBJECTIVE: To evaluate the antitumor and toxic effects of treatment with doxorubicin combined with piroxicam or doxorubicin alone for multicentric lymphoma in dogs. DESIGN: Nonrandomized clinical trial. ANIMALS: 75 dogs with multicentric lymphoma. PROCEDURE: 33 dogs were treated with doxorubicin (30 mg/m2, IV, q 21 d, for 3 doses) and piroxicam (0.3 mg/kg [0.14 mg/lb], PO, q 24 h); results were compared with a historical control group of 42 dogs treated with doxorubicin (30 mg/M2, IV, q 21 d, for 3 doses) alone. Results-The percentages of dogs that had remission with doxorubicin-piroxicam treatment (79%) or doxorubicin treatment alone (74%) were not significantly different. Median duration of first remission was 130 days with doxorubicin-piroxicam and 147 days with doxorubicin alone; these values were not significantly different. Severe toxicosis was observed in 22% of dogs treated with doxorubicin-piroxicam and 17% of dogs treated with doxorubicin alone. CONCLUSIONS AND CLINICAL RELEVANCE: Both treatment protocols were efficacious and well tolerated. The doxorubicin-piroxicam treatment was no more effective regarding response rate, remission duration, or survival duration, compared with the control group treated with doxorubicin alone.

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PubMed2002

Effects of the cyclooxygenase inhibitor, piroxicam, on tumor response, apoptosis, and angiogenesis in a canine model of human invasive urinary bladder cancer.

The mechanisms by which cyclooxygenase inhibitors exert antitumor effects are not completely defined but are postulated to involve antiangiogenic effects and induction of apoptosis. In this study, we determined the effects of the cox inhibitor, piroxicam, on tumor response, apoptotic index, proliferative index, cyclooxygenase-2 expression, prostaglandin E(2) concentration, tumor microvessel density, and urine basic fibroblast growth factor and vascular endothelial growth factor concentrations in pet dogs with naturally occurring invasive transitional cell carcinoma of the urinary bladder. Piroxicam caused reduction in tumor volume in 12 of 18 dogs, and this was strongly associated with induction of apoptosis (Fisher's exact test P < 0.015) and reduction in urine basic fibroblast growth factor concentration.

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PubMed2002

Folate-targeted imaging of activated macrophages in rats with adjuvant-induced arthritis.

OBJECTIVE: To determine whether overexpression of the high-affinity folate receptor (FR) on activated macrophages can be exploited to selectively target imaging agents to sites of inflammation in rats with adjuvant-induced arthritis (AIA). METHODS: Folic acid was conjugated to a (99m)Tc chelator (the complex termed EC20), and its distribution was visualized using gamma scintigraphy in healthy rats, rats with AIA, and arthritic rats that had been depleted of macrophages. To confirm that uptake was mediated by the FR, excess folic acid competition studies were conducted, and tissue FR levels were quantitated using a radioligand binding assay. Flow cytometry was also used to investigate uptake of folate conjugates into macrophages of both arthritic and healthy rats. RESULTS: EC20 concentrated in the arthritic extremities of diseased rats but not in the extremities of healthy rats. The intensity of images of affected tissues was greatly reduced in the presence of excess competing folic acid. The livers and spleens of arthritic animals also showed enhanced uptake of EC20 and increased levels of FR. Depletion of macrophages from arthritic animals reduced tissue FR content and concomitantly abolished uptake of EC20. In addition, macrophages isolated from livers of rats with AIA exhibited a significantly higher binding capacity for folate conjugates than did macrophages obtained from healthy rats. CONCLUSION: Although EC20 is currently undergoing clinical evaluation for use in the imaging of ovarian carcinomas, the present results suggest that it may also be useful for assaying the participation of activated macrophages in inflammatory processes such as rheumatoid arthritis.

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PubMedDate not supplied

Canine transitional cell carcinoma.

Transitional cell carcinoma (TCC) of the urinary bladder, the most common malignancy of the urinary tract in dogs, is challenging to both diagnose and treat effectively. The prevalence of this disease may be increasing. The etiology of canine TCC is likely multifactorial. Epidemiological studies of TCC in the dog have revealed a number of risk factors, including breed and female gender, as well as environmental factors, such as insecticide exposure. This tumor is difficult to remove surgically and responds poorly to chemotherapy. The efficacy of radiotherapy and other treatment modalities needs further investigation. Cyclooxygenase-inhibiting drugs have some activity against TCC, and studies to further define these effects are ongoing. Use of the tumor/node/ metastasis (TNM) classification scheme for bladder cancer has allowed for the identification of prognostic factors. Urinary tract obstruction and metastatic disease remain challenges to treat. Work with canine TCC has demonstrated how closely this disease resembles human invasive urinary bladder cancer. Therefore, future research has the potential to benefit both dogs and humans with TCC.

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