@article{levine_birkenheuer_brooks_nordone_bellinger_jones_fischer_oglesbee_frey_brinson_et al._2014, title={A novel canine model of immune thrombocytopenia: has immune thrombocytopenia (ITP) gone to the dogs?}, volume={167}, ISSN={0007-1048}, url={http://dx.doi.org/10.1111/bjh.13005}, DOI={10.1111/bjh.13005}, abstractNote={Summary}, number={1}, journal={British Journal of Haematology}, publisher={Wiley}, author={LeVine, Dana N. and Birkenheuer, Adam J. and Brooks, Marjory B. and Nordone, Shila K. and Bellinger, Dwight A. and Jones, Sam L. and Fischer, Thomas H. and Oglesbee, Stephen E. and Frey, Kahlina and Brinson, Nicole S. and et al.}, year={2014}, month={Jul}, pages={110–120} }
 @article{papich_levine_gookin_davidson_stagner_hayes_2013, title={Ronidazole pharmacokinetics in cats following delivery of a delayed-release guar gum formulation}, volume={36}, ISSN={["1365-2885"]}, DOI={10.1111/jvp.12019}, abstractNote={Ronidazole (RDZ) is the only known effective treatment for feline diarrhea caused by Tritrichomonas foetus. This study aimed to develop guar gum‐coated colon‐targeted tablets of RDZ and to determine the pharmacokinetics of this delayed‐release formulation in cats. Guar gum‐coated tablets were administered orally once to five healthy cats (mean dose 32.3 mg/kg). The tablets were then administered once daily for 5 days to four cats (mean dose 34.5 mg/kg), and absorption studies repeated on day 5. Plasma was collected and analyzed for RDZ concentration, and pharmacokinetic noncompartmental and deconvolution analysis were performed on the data. There was negligible RDZ release until after 6 h, and a delayed peak plasma concentration (mean Cmax 28.9 μg/mL) at approximately 14.5 h, which coincides with colonic arrival in cats. Maximum input rate (mg/kg per hour) occurred between 6 and 16 h. This delayed release of ronidazole from guar gum‐coated tablets indicates that release of RDZ may be delayed to deliver the medication to a targeted area of the intestine. Repeated dosing with guar gum tablets to steady‐state did not inhibit drug bioavailability or alter the pharmacokinetics. Such targeted RDZ drug delivery may provide improved efficacy and reduce adverse effects in cats.}, number={4}, journal={JOURNAL OF VETERINARY PHARMACOLOGY AND THERAPEUTICS}, author={Papich, M. G. and LeVine, D. N. and Gookin, J. L. and Davidson, G. S. and Stagner, W. C. and Hayes, R. B.}, year={2013}, month={Aug}, pages={399–407} }
 @article{levine_papich_gookin_davidson_davis_hayes_2011, title={Ronidazole pharmacokinetics after intravenous and oral immediate-release capsule administration in healthy cats}, volume={13}, ISSN={["1532-2750"]}, DOI={10.1016/j.jfms.2010.12.001}, abstractNote={Ronidazole (RDZ) is an effective treatment for feline Tritrichomonas foetus infection, but has produced neurotoxicity in some cats. An understanding of the disposition of RDZ in cats is needed in order to make precise dosing recommendations. Single-dose pharmacokinetics of intravenous (IV) RDZ and immediate-release RDZ capsules were evaluated. A single dose of IV RDZ (mean 9.2 mg/kg) and a 95 mg immediate-release RDZ capsule (mean 28.2 mg/kg) were administered to six healthy cats in a randomized crossover design. Plasma samples were collected for 48 h and assayed for RDZ using high pressure liquid chromatography (HPLC). Systemic absorption of oral RDZ was rapid and complete, with detection in the plasma of all cats by 10 min after dosing and a bioavailability of 99.64 (±16.54)%. The clearance of RDZ following IV administration was 0.82 (±0.07) ml/kg/min. The terminal half-life was 9.80 (±0.35) and 10.50 (±0.82) h after IV and oral administration, respectively, with drug detectable in all cats 48 h after both administrations. The high oral bioavailability of RDZ and slow elimination may predispose cats to neurotoxicity with twice-daily administration. Less frequent administration should be considered for further study of effective treatment of T foetus-infected cats.}, number={4}, journal={JOURNAL OF FELINE MEDICINE AND SURGERY}, author={LeVine, Dana N. and Papich, Mark G. and Gookin, Jody L. and Davidson, Gigi S. and Davis, Jennifer L. and Hayes, Rebecca B.}, year={2011}, month={Apr}, pages={244–250} }
 @article{levine_zhang_harris_vaden_2010, title={The use of pooled vs serial urine samples to measure urine protein:creatinine ratios}, volume={39}, ISSN={["0275-6382"]}, DOI={10.1111/j.1939-165x.2009.00167.x}, abstractNote={Background:  Evaluation of serial urine protein:creatinine (UPC) ratios is important in prognosticating chronic kidney disease and monitoring response to therapeutic interventions. Owing to random biologic variation in dogs with stable glomerular proteinuria, multiple determinations of UPC ratios often are recommended to reliably assess urine protein loss. This can be cost‐prohibitive.}, number={1}, journal={VETERINARY CLINICAL PATHOLOGY}, author={LeVine, Dana N. and Zhang, Daowen and Harris, Tonya and Vaden, Shelly L.}, year={2010}, month={Mar}, pages={53–56} }
 @article{levine_zhou_ghiloni_fields_birkenheuer_gookin_roberston_malloy_feldman_2009, title={Hereditary 1,25-Dihydroxyvitamin D-Resistant Rickets in a Pomeranian Dog Caused by a Novel Mutation in the Vitamin D Receptor Gene}, volume={23}, ISSN={["1939-1676"]}, DOI={10.1111/j.1939-1676.2009.0405.x}, abstractNote={Hypocalcemic rickets encompasses a group of disorders in which intestinal absorption of calcium is insufficient to meet the calcium demands of a growing skeleton. Causes include dietary calcium deficiency and insufficient intestinal absorption of calcium caused by vitamin D deficiency or decreased vitamin D activity. Hereditary disorders of vitamin D documented in humans include vitamin D-dependent rickets type I (VDDR-I), in which there is a deficiency of the renal enzyme (1α-hydroxylase) that converts 25-hydroxyvitamin D3 to the active hormone 1α,25-dihydroxyvitamin D3 (1,25(OH)2D3 or calcitriol) and vitamin D-dependent rickets type II (VDDR-II) in which there is end-organ resistance to the active hormone. The latter is usually secondary to defects in the vitamin D receptor (VDR). VDDR-II is currently more commonly termed hereditary vitamin D-resistant rickets (HVDRR). We describe a case of rickets in a juvenile dog that led us to investigate potential hereditary vitamin D disorders and resulted in the documentation of HVDRR in a dog. The disease is characterized by hypocalcemia, secondary hyperparathyroidism, hypomineralization of bones, rickets, and in some cases, alopecia. An intact female Pomeranian dog was initially evaluated by one of the authors at 2 months of age for nonpruritic alopecia of the head and rear limbs. The remainder of the dog's physical examination at that time was unremarkable. A skin scraping was negative. The dog and her half-sibling (same sire, different dam) had been obtained from a breeder a few days before examination. The half-sibling was the same age as the affected dog, and was normal in appearance. Both dogs were eating a commercial puppy food. At 4 months of age, the affected dog appeared to tire easily when playing. On physical examination, there was lateral bowing of the antebrachium of both forelimbs and palpable thickening of the distal radii. The alopecia had become more generalized and remained nonpruritic (Fig 1). A serum biochemistry profile revealed marked hypocalcemia (total calcium 5.5 mg/dL; reference range 8.9–11.4 mg/dL) with a normal albumin concentration, hyperphosphatemia (phosphate 7.3 mg/dL; reference range 2.5–6 mg/dL), and increased alkaline phosphatase (ALP) (829 U/L; reference range 5–131 U/L). Blood urea nitrogen (BUN) and creatinine, complete blood count, and serum thyroxine (total thyroxine 2.7 μg/dL; reference range 1.0–4.0 μg/dL) were all within normal limits. Photograph of the affected dog at 3 months of age demonstrating the remarkable alopecia. The photograph shows partial alopecia on the ventral chest, in the perineal area, and on the caudo-medial aspect of thighs. In the areas where hair is present, it is thin, likely because of a decreased amount of secondary hairs. The normal half-sibling is pictured to the right for comparison. The dog was reevaluated at 5 months of age for intermittent lameness while playing. Although her alopecia was resolving, her abnormal forelimb conformation persisted. Radiographs showed widening and abnormal lucency (decreased mineralization) of the distal radial and ulnar physes, with sclerosis and widening of the adjacent epiphyses and metaphyses (Fig 2A and B). Persistent hypocalcemia (total calcium 5.7 mg/dL) and low-ionized calcium (0.66 mmol/L; reference range 1.24–1.43 mmol/L) were documented, along with hyperparathyroidism (intact parathyroid hormone [PTH] 739 pg/mL; reference range 27–155 pg/mL).a Pre- and postprandial serum concentrations of bile acids were within reference range. On the basis of hypocalcemia, hyperparathyroidism, and the skeletal abnormalities, a provisional diagnosis was a vitamin D-dependent form of rickets. Treatment with oral calcium supplementation (calcium carbonateb 29 mg/kg PO q24h) and 1,25(OH)2D3c (43 ng/kg PO q24h) was initiated. Lateral (A) and dorsopalmar (B) radiographs of the right carpus acquired at 5 months of age before initiation of treatment. There is widening and increased lucency of the distal radial and ulnar physes with irregular (frayed) metaphyseal margins and flaring of the adjacent epiphyses and metaphyses. Lateral (C) and dorsopalmar (D) radiographs of the right carpus acquired at 8.5 months of age, 3.5 months after initiation of treatment. The distal antebrachial physes appear more normal in width, opacity, and margination. Evidence of distal metaphyseal remodeling is present. Total serum calcium concentrations were persistently low (ranging from 4.9 to 6.2 mg/dL) despite consistent increases in oral calcium and 1,25(OH)2D3 supplementation to doses well above standard recommendations (25–50 mg/kg/d of calcium carbonate and 20–30 ng/kg/d 1,25(OH)2D3)1 (Table 1). At 7 months of age, the dog had a generalized seizure that was controlled by administration of diazepam. At the time of the seizure, total serum calcium concentration was 5.7 mg/dL (reference range 7.9–12 mg/dL).d The dog was referred to the Internal Medicine Service of North Carolina State University, College of Veterinary Medicine (NCSU CVM) for further evaluation. On examination, the dog was bright and alert and interactive. Her conformation was unusual, with the forelimbs being shorter than the hind limbs, and slightly bowed laterally. Despite prior resolution of the alopecia, the affected dog's coat was of poorer quality than that of her half-sibling. The remainder of the physical examination was unremarkable. A serum biochemistry profile confirmed persistent hypocalcemia (6.3 mg/dL; reference range 9.2–11.6 mg/dL), with normal serum phosphorous concentration (5.7 mg/dL; 2–6.7 mg/dL) and renal values (BUN and creatinine). There was high PTH (91 pmol/L; 3–17 pmol/L),e increased ALP (486 U/L; 14–120 U/L), low 25-hydroxyvitamin D (43 nmol/L; 60–215 nmol/L),e and low-ionized calcium (0.94 mmol/L; 1.25–1.45 mmol/L)e concentration in serum. Rickets due to vitamin D resistance was suspected because of the lack of response to high-dose therapy with 1,25(OH)2D3. Since the dog did not respond to oral calcium supplementation, calcium (12.5 mg/kg SQ q24h)f was administered parenterally. 1,25(OH)2D3 therapy (75 ng/kg PO q24h) was continued. At 8 months of age, while still receiving 1,25(OH)2D3, serum 1,25(OH)2D3 concentrationg was measured to definitively differentiate between vitamin D deficiency and the two types of vitamin D-dependent rickets, type-I and type-II (HVDRR). The dog's serum 1,25(OH)2D3 concentration was over 20-fold greater than the upper end of the reference range (1,017 pb/mL; 25–50 pg/mL) despite persistent hypocalcemia (total calcium 5.4 mg/dL; 8.9–11.4 mg/dL). The increased concentration of 1,25 (OH)2D3 was consistent with a diagnosis of HVDRR. In this case, even though the dog was being supplemented with 1,25(OH)2D3, HVDRR was considered likely because high-circulating concentrations of 1,25(OH)2D3 were ineffective in raising serum calcium concentrations, confirming 1,25(OH)2D3 resistance. Oral calcium carbonate therapy was reinitiated at this time (75 mg/kg PO q24h) in addition to the 1,25(OH)2D3 supplementation and daily SQ calcium injections. At 8.5 months of age, the dog became acutely paraplegic in the hind limbs and depressed. The dog was evaluated by her local veterinarian, where total calcium concentration was determined to be 4.0 mg/dL (reference range 7.9–12 mg/dL). The veterinarian administered calcium IM (25 mg/kg IM once)f and referred the dog to the Emergency Service at NCSU. On examination, the dog was opisthotonic and tetanic, stuporous, weak, and believed to be having frequent focal seizures. Ionized calcium was 0.61 mmol/L (reference range 1.11–1.40 mmol/L). Calcium gluconate (100 mg/kg IV once)h was administered slowly, followed by a continuous rate infusion of calcium (10 mg/kg/h IV).h The dog continued to have seizure-like activity and muscle tetany, despite normalization of serum-ionized calcium (0.91 mmol/L) and a normal ECG. Tetany and seizure activity were controlled with midazolami (0.5 mg/kg IV once, then 0.3 mg/kg/h IV). After initial stabilization, a neurologic examination revealed signs attributable to diffuse forebrain disease (variably obtunded to stuporous, intermittent lateral strabismus in both eyes, bilateral miotic pupils, and reduced nasal sensation bilaterally) and hind limb paresis (exaggerated pelvic limb segmental spinal reflexes, absent deep pain in both pelvic limbs and the tail). The forebrain signs were attributed to hypocalcemia exacerbated by potential cerebral edema. The pelvic limb paresis suggested a T3–L3 spinal lesion. Pain management was instituted with fentanyl (2 mcg/kg IV PRN).j Spinal radiographs were suggestive of a compression fracture of the vertebral body of T11, although a congenital deformity could not be ruled out (Fig 3A). Computed tomography confirmed the fracture of T11 and showed accompanying spinal cord compression. Flaring of the ribs at the costochondral junctions (so-called rachitic rosary in people) was also readily apparent on radiographs (Fig 3B). Radiographs of the distal radial and ulnar growth plates, however, showed progressive improvement in mineralization compared with the images taken at 5 months of age (Fig 2C and D). Radiographs at 8.5 months, 3.5 months after initiation of treatment. (A) Lateral radiograph of the spine at the thoracolumbar junction. There is generalized osteopenia, the T11 vertebral body is wedged shaped, and there is concavity of the ventral margin of the vertebral body. These changes are highly suggestive of a pathologic compression fracture, although a preexisting vertebral body anomaly could not be ruled out. (B) Lateral radiograph of the costochondral junctions. The junctions are “flared” and moderately sclerotic. This radiographic finding is frequently present in human patients with rickets, and is commonly called a rachitic rosary, because the lesions palpate like beads on a rosary. Given the severity of the dog's spinal injury (functionally complete), the chance of recovery was very low and would have been compromised by the difficulty in surgical repair of osteopenic bones. As a result, the dog was euthanized. Gross postmortem evaluation revealed signs of rickets with diffusely enlarged costochrondral junctions (beading), a fracture callus on the left eight rib, and displacement of the T11 vertebra. Microscopically, failure of endochondral ossification with retained cartilage cores was noted in several locations (ribs, radius, nasal turbinates). A compression fracture of T11 with subluxation was confirmed. In the region of T11, locally extensive, severe myelomalacia, and fibrinoid vasculitis of the spinal cord were seen. The brain was normal, suggesting that severe hypocalcemia was the cause for the dog's forebrain signs. The parathyroid was diffusely hyperplastic and hypertrophied, consistent with the persistently increased PTH levels. HVDRR in humans is almost always due to mutations in the VDR.2 For this reason, before euthanasia, blood samples were drawn from both the affected dog and the normal half-sibling for genomic sequence analysis of the VDR gene. With owner consent, immediately before euthanasia, the affected dog was anesthetized with propofolk to obtain skin biopsies from her ventral abdomen from which fibroblast cultures were derived. These cultures were subsequently used for analysis of VDR expression and as a source of RNA for VDR sequence analysis. The fibroblasts were grown in minimal essential media containing 10% calf seruml and maintained in an atmosphere of 95% air, 5% CO2 at 37°C. Genomic DNA was isolated from blood using a commercial kit.m Primers were designed based on the DNA sequence of Canis lupus familiaris VDR obtained from GenBank® (accession number NC_006609, Gene ID: 486588) (Table 2). Exons 2–9 of the VDR gene from the affected dog and half-sibling were amplified by PCR and directly sequenced at the Stanford University protein and nucleic acid facility. A unique single base deletion (guanine) was identified at the exon 4-intron junction (Fig 4A) in the affected dog's genomic DNA. The sequence of the exon 4-intron junction of the half-sibling was homozygous for the wild-type sequence (Fig 4B). DNA sequence of exon 4 of the VDR gene in the dog. (A) Genomic DNA sequence of the affected dog's VDR gene. A unique 1 bp (G) deletion was identified in the exon 4-intron junction (B) DNA sequence of the half-sibling's VDR gene. (C) Sequence of the affected dog's VDR cDNA. Deletion of a single guanine nucleotide base was identified in the dog's VDR cDNA resulting in a frameshift that introduced a downstream premature termination codon. The premature stop codon is predicted to be at codon 216, which is 232 amino acids upstream of the normal stop codon. The translated amino acid sequence is shown above the nucleotide sequence. The normal amino acid sequence and that of the affected dog diverge after amino acid R175. From the sequence in GenBank®, the normal VDR exon4-intron sequence is AGG|gtacgtggcc (exon 4 sequence in capitals and intron sequence in lower case with bolded letters indicating splicing recognition sequence). The deletion of a single guanine base in the GG|g triplet would generate the sequence AG|gtacgtggcc and leave the 5′-splice site intact. On the other hand, deletion of guanine in the coding sequence would cause a frameshift in exon 5. In order to document this frameshift, RNA was isolated from the dog's cultured fibroblasts. The RNA was reverse transcribedn and amplifiedo by PCR using gene specific primers (forward primer 5′-ctgcggcccaagctgtcgga and reverse primer 5′-ttggatgctgtaactgaccag). The VDR cDNA products were purifiedp and directly sequenced. As shown in Fig 4C, the single guanine nucleotide deletion in the VDR cDNA led to a frameshift that caused the amino acid sequence to diverge after R175. (It should be noted that the canine R175 corresponds to R154 in humans, because the canine VDR sequence is 21 amino acids longer at the N-terminus compared with the human sequence.) An additional 41 amino acids were in frame before a downstream termination signal occurred. The mutation deleted 273 amino acids of the VDR ligand-binding domain (LBD) and was expected to abolish 1,25(OH)2D3 binding. Although we were able to amplify the VDR cDNA from the dog's cells, the mutant VDR mRNA transcript may be subjected to nonsense-mediated mRNA decay and the affected dog may not express any VDR. To determine whether the mutation abolished 1,25(OH)2D3 binding, we examined [3H]1,25(OH)2D3 binding in the dog's fibroblasts compared with normal human fibroblasts. Cell extracts were incubated with 1 nM [3H]1,25(OH)2D3 (specific activity 158 Ci/mmol) with or without 250-fold excess of radioinert 1,25(OH)2D3 as described previously.3 Hydroxylapatite was used to separate bound and free hormone. Protein concentrations were determined by the Bradford method.4 No detectable binding was observed in extracts from the dog's cells. This report describes a VDR gene mutation resulting in HVDRR in a dog. The molecular basis for HVDRR was attributed to a 1 bp deletion in exon 4 that caused a frameshift and introduced a premature stop in exon 5. We expect that this mutation would lead to the affected dog's failure to respond to 1,25(OH)2D3 in one of 2 ways: either the mutation truncated a major portion of the LBD, leading to the inability of the dog's VDR to bind 1,25(OH)2D3, or the mRNA was subjected to nonsense-mediated degradation and this dog had a complete failure of VDR expression. The absence of 1,25(OH)2D3 binding in the dog fibroblast binding assay confirms that the affected dog's cells lack a VDR capable of responding to 1,25(OH)2D3, although it does not differentiate between these two causes of defective VDR binding. Over 100 human cases of HVDRR have been reported.2 In children, HVDRR is characterized by hypocalcemia, secondary hyperparathyroidism, and severe rickets.5,6 The disease is almost always because of mutations in the VDR, with many different mutations identified, including mutations in the LBD and in the DNA-binding domain.5,6 The VDR mutations result in end-organ resistance to 1,25(OH)2D3.2 Resistance leads to defective intestinal calcium absorption, hypocalcemia, and secondary hyperparathyroidism, which in turn causes failure of bone mineral deposition, especially failure of calcium deposition.5,7 As a result, metaphyseal cartilage accumulates, but cannot be properly mineralized and rickets results.7 A syndrome that is similar to HVDRR has been described in cats,7–9 although a genetic mutation in the VDR was not established in any of these animals. These case reports suggest that cats fare relatively well once they reach the end of their growth period, with the exception of one cat, which died suddenly at 13 months of age, and another that was euthanized at 9 years of age for hip pain from osteoarthritis.7–9 Inadequate dietary intake of vitamin D resulting in nutritional secondary hyperparathyroidism has been reported previously in dogs,10 but could be readily ruled out in this case because the dog failed to respond to high concentrations of calcitriol. VDDR-I has been reported in a Saint Bernard dog and a domestic short hair cat.11,12 In the dog reported here, clinical signs of early onset rickets, laboratory findings of hypocalcemia, secondary hyperparathyroidism, and markedly increased serum 1,25(OH)2D3 levels, and radiographic findings of abnormally wide growth plates are all consistent with those reported in people with HVDRR. The dog's poor response to therapy appears to be closely aligned with the human condition in how challenging it is to maintain normal calcium levels and adequate bone mineralization without functional VDRs. Most mutations in people result in a defective VDR that can no longer respond to even high doses of 1,25(OH)2D3. Some children can be treated by high doses of 1,25(OH)2D3 that overcome the defect in binding affinity for 1,25(OH)2D3, however, treatment usually requires high doses of IV calcium administered daily over many months to eventually correct the hypocalcemia, suppress the secondary hyperparathyroidism, and heal the rachitic bone abnormalities.13,14 IV calcium infusions bypass the intestinal calcium absorption defect caused by the disease. After the total body calcium deficit is restored to normal, some children can be transitioned to high doses of oral calcium to maintain their improved metabolic state and prevent rickets from recurring. It is possible that aggressive initial management of this dog with oral calcium therapy and injectable calcium supplementation may have improved the outcome in this case. Based on the VDR LBD mutation in this dog, she could not have responded to even high concentrations of calcitriol. Evidence that the calcium treatment regime used in this case had some efficacy was shown by the increase in bone mineralization seen in her appendicular skeletal radiographs from 5 to 8.5 months of age (Fig 2). Alternatively, an even more aggressive initial approach with vascular access port placement15 and daily IV calcium supplementation (with concurrent ECG monitoring) could have been undertaken as it is in human patients.16 This approach would be technically challenging, would likely be associated with port infections, and would require significant owner commitment. It is noteworthy that the alopecia observed in this dog is also present in many children with HVDDR.5,6 It is proposed that the product of the hairless gene (HR) acts as a corepressor of the VDR, and that the HR and the unliganded VDR are involved in regulation of the hair cycle.17–22 The details of the mechanism of alopecia in HVDDR remain unknown. Large cystic follicles filled with keratin were seen in this dog on postmortem evaluation along with thin epithelium, and reduced number and size of adnexal structures such as sebaceous and apocrine glands. The dog's secondary hair follicles were smaller than normal. In people with HVDRR, the hair follicles may appear normal on microscopic examination, but hair shafts are absent.5 It is interesting that the alopecia had resolved at the time of the dog's death, yet obvious dermal changes were still microscopically present. In contrast to this dog, alopecia persists in human patients with HVDRR that undergo successful therapy or that show spontaneous improvement in calcium homeostasis.5 In humans, all cases VDR mutations causing premature termination codons have life-long alopecia, even if medical treatment improves the hypocalcemia and rickets. We have no explanation for the improvement of the alopecia in this dog. Dogs may potentially have a compensatory mechanism in the hair cycle lacked by humans that can replace the absent VDR function. In humans, patients with alopecia generally have more severe resistance to 1,25(OH)2D3 than those without alopecia, which would correlate with the severity of this dog's disease.23 HVDRR is an autosomal recessive genetic disorder in humans.5 Unfortunately, the breeder of this dog was not interested in progenitor testing to help establish the pattern of heredity in this family. aAntech Diagnostics, Lake Success, NY bRoxane Laboratories Inc, Columbus, OH cCalcitriol, 100 ng/mL Fixed Oil Solution, compounded, Health Park Pharmacy, Raleigh, NC dIdexx VetTest 8008 Chemistry Analyzer, Idexx Laboratories, Westbrook, ME eDiagnostic Center for Population and Animal Health, Michigan State University, Lansing, MI fCalcium glycerophosphate and calcium lactate, Calphosan, Glenwood, Englewood, NJ gHeartland Assays, Ames, IA hCalcium gluconate 10%, AAP Pharmaceuticals LLC, Schaumburg, IL iMidazolam, Bedford Laboratories, Bedford, OH jFentanyl, Hospira, Lake Forest, IL kPropofol, Teva Pharmaceuticals, North Wales, PA lHyclone, Logan, UT mQIAamp DNA blood mini kit, Qiagen, Valencia, CA nSuperscript first strand CDNA synthesis kit, Invitrogen, Carlsbad, CA oTAQ DNA polymerase, New England Biolabs, Ipswich, MA pQIAquick PCR purification kit This work was supported by NIH grant DK42482 (to DF) and NCSU CVM teaching initiative funds (to DNL).}, number={6}, journal={JOURNAL OF VETERINARY INTERNAL MEDICINE}, author={LeVine, D. N. and Zhou, Y. and Ghiloni, R. J. and Fields, E. L. and Birkenheuer, A. J. and Gookin, J. L. and Roberston, I. D. and Malloy, P. J. and Feldman, D.}, year={2009}, pages={1278–1283} }
 @article{adamson_kaufmann_levine_millis_marcellin-little_2005, title={Assistive devices, orthotics, and prosthetics}, volume={35}, ISSN={["0195-5616"]}, DOI={10.1016/j.cvsm.2005.08.009}, abstractNote={Deciding on which supportive device, orthotic, or prosthetic is best suited for a given patient is a complex process involving many different factors. The ability to manage biomechanical abnormalities successfully may be enhanced by an understanding of the properties of the various materials that comprise these devices, their effect on functional performance, and other associated patient factors. Veterinary health care providers are faced with the challenge of effectively addressing the physiologic and fiscal needs of the patient in a rapidly changing patient care environment.}, number={6}, journal={VETERINARY CLINICS OF NORTH AMERICA-SMALL ANIMAL PRACTICE}, author={Adamson, C and Kaufmann, M and Levine, D and Millis, DL and Marcellin-Little, DJ}, year={2005}, month={Nov}, pages={1441-+} }
 @article{levine_millis_marcellin-little_2005, title={Introduction to veterinary physical rehabilitation}, volume={35}, ISSN={["1878-1306"]}, DOI={10.1016/j.cvsm.2005.07.002}, abstractNote={Physical therapy is a profession with an established scientific basis in human beings and companion animals. It has a large number of clinical applications in the restoration, maintenance, and promotion of optimal physical function. In providing physical therapy, the goal is to restore, maintain, and promote optimal function, optimal fitness, wellness, and quality of life as they relate to movement disorders and health. A major emphasis is to prevent or minimize the onset, clinical signs, and progression of impairments, functional limitations, and disabilities that may result from diseases, disorders, conditions, and injuries.}, number={6}, journal={VETERINARY CLINICS OF NORTH AMERICA-SMALL ANIMAL PRACTICE}, author={Levine, D and Millis, DL and Marcellin-Little, DJ}, year={2005}, month={Nov}, pages={1247-+} }
 @article{saunders_walker_levine_2005, title={Joint mobilization}, volume={35}, ISSN={["1878-1306"]}, DOI={10.1016/j.cvsm.2005.07.003}, abstractNote={Therapeutic touch has been used in human beings to soothe aches and pains. Most dogs also seem to enjoy being touched. Manual therapy techniques are skilled hand movements intended to improve tissue extensibility; increase range of motion; induce relaxation; mobilize or manipulate soft tissue and joints; modulate pain; and reduce soft tissue swelling, inflammation, or restriction. The intent of this article is to provide an overview of the principles of manual therapy, followed by selected treatment techniques for the hip, stifle, elbow, shoulder, carpus.and thoracic and lumbar spine. The techniques of G.D. Maitland, an Australian physical therapist who developed a clinically based approach in the 1960s and 1970s, are emphasized.}, number={6}, journal={VETERINARY CLINICS OF NORTH AMERICA-SMALL ANIMAL PRACTICE}, author={Saunders, DG and Walker, JR and Levine, D}, year={2005}, month={Nov}, pages={1287-+} }
 @article{steiss_levine_2005, title={Physical agent modalities}, volume={35}, number={6}, journal={Veterinary Clinics of North America. Small Animal Practice}, author={Steiss, J. E. and Levine, D.}, year={2005}, pages={1317-} }
 @article{marcellin-little_levine_taylor_2005, title={Rehabilitation and conditioning of sporting dogs}, volume={35}, ISSN={["1878-1306"]}, DOI={10.1016/j.cvsm.2005.08.002}, abstractNote={Owners and trainers exercise sporting dogs to increase their fitness and optimize their conditioning and performance. Training is designed to in-crease strength, endurance, and agility and is sport-specific. Sporting dogs are susceptible to specific musculoskeletal injuries. The rehabilitation of sporting dogs after these injuries follows specific principles during the acute, subacute, and reconditioning periods.}, number={6}, journal={VETERINARY CLINICS OF NORTH AMERICA-SMALL ANIMAL PRACTICE}, author={Marcellin-Little, DJ and Levine, D and Taylor, R}, year={2005}, month={Nov}, pages={1427-+} }
 @article{levine_millis_marcellin-little_taylor_2005, title={Rehabilitation and physical therapy - Preface}, volume={35}, ISSN={["1878-1306"]}, DOI={10.1016/j.cvsm.2005.09.016}, abstractNote={R ehabilitation and physical therapy for humans is a well-known discipline, and its positive effects have been well documented. Historically, little attention has been given to veterinary patients needing these services. Rehabilitation and physical therapy in veterinary medicine, however, is rapidly becoming a recognized discipline and is being sought after as a service by veterinary professionals and owners. There is a tremendous interest on the part of veterinary caregivers to investigate and provide rehabilitation and therapy following injury, surgery, and illness. Techniques used in human physical therapy are being adapted for use in small animal patients, and their effectiveness is being studied. The intent of this issue is to present a practical approach to rehabilitation of small animals as well as the science and research behind it. After an article introducing the principles of rehabilitation, the biomechanics of physical therapy, manual therapy, physical modalities, and emerging modalities are presented. Information on rehabilitation and physical therapy of specific patients follows, including sporting dogs, orthopedic, neurologic, and medically compromised patients and patients that have wounds. The issue concludes with an article on the logistics of companion animal rehabilitation in small animal practice. We would like to thank the authors who have contributed their time, expertise, and experience to this issue. Particular credit goes to John Vassallo}, number={6}, journal={VETERINARY CLINICS OF NORTH AMERICA-SMALL ANIMAL PRACTICE}, author={Levine, D and Millis, DL and Marcellin-Little, DJ and Taylor, R}, year={2005}, month={Nov}, pages={XIII-XIV} }