Tolerability and pharmacokinetic profile of a novel benzene-poly-carboxylic acids complex with cis-diammineplatinum (II) dichloride in dogs with malignant mammary tumours.

The pharmacokinetic profile, tolerability and efficacy of benzene-poly-carboxylic acids complex with cis-diammineplatinum (II) dichloride (BP-C1) were studied in dogs with mammary cancer. A three-level response surface pathway designed trial was performed on seven dogs. At each level BP-C1 was administered subcutaneously daily for 7 days followed by a 7-day rest period in a dose escalating manner. Adverse events according to VCOG-CTCAE, performance status and tumour progression were recorded. The pharmacokinetic profile followed a two-compartment model with rapid absorption, short distribution, and a slow elimination phase. The overall elimination half-life was 125 h. The maximum tolerated dose of BP-C1 was estimated to be above 0.46 mg kg-1 . A significant reduction in VCOG-CTCAE toxicity which correlated negatively with increasing dose was found. The dogs' general performance status remained unchanged. No decrease in total tumour burden was found, although temporary tumour reduction was seen in some target tumours.

Breed differences in the proportional morbidity of testicular tumours and distribution of histopathologic types in a population-based canine cancer registry.

Histologically verified tumours submitted to the Norwegian Canine Cancer Register from 1990 to 1998 were studied (n=14,401). The proportion of testicular tumours (n=345) was 2.4%, and the breakdown of histological tumour diagnoses is presented. The frequency of the most common histopathological types was 33% interstitial (Leydig), 26.4% Sertoli and 33.9% seminomas/germ cell tumours. The average age at diagnosis was 10 years, but was significantly lower for Sertoli cell tumours (8.6 years) than for the other tumour types. Following a histopathological re-evaluation, 22.5% of the original tumor diagnoses were modified. Proportional morbidity ratios were calculated and individuals from the breeds Shetland sheepdog and Collie were five times more likely to have testicular tumours than the overall average for the registry. Breed differences in the distribution of histopathologic types were observed. Shetland sheepdog and Collie were most commonly diagnosed with Sertoli cell tumours, while all tumours from Norwegian elkhound in this material were seminomas.

Inflammatory response to therapeutic gold bead implantation in canine hip joint osteoarthritis.

Inflammatory changes associated with periarticular pure gold bead implants were studied in dogs involved in a clinical trial investigating motor dysfunction and chronic pain owing to hip joint dysplasia and osteoarthritis. Gold beads were percutaneously implanted via a needle into different locations surrounding the greater trochanter of the femur. Nine dogs with implants were necropsied. In all examined animals, characteristic histologic lesions were observed in the tissue surrounding the gold implants--namely, a fibrous capsule composed of concentric fibroblasts intermixed with a variable number of inflammatory cells and a paucicellular innermost layer of collagen with a few fibrocyte-like cells in empty lacunae. Lymphocytes dominated the inflammatory infiltrate, with rarely observed macrophages present in close proximity to the implant site. No giant cells were observed. Immunohistochemistry showed mixed populations of lymphocytes, both CD3 positive (T cells) and CD79a positive (B cells), which in some cases formed lymphoid follicles. Diffuse inflammatory changes were present to a minor extent in the perimysium and surrounding fascia. The inflammation observed in dogs is similar to that observed with gold implants in humans. It is possible that the clinically beneficial effect of gold beads for chronic osteoarthritis depends on sustained localized inflammation with localized release of soluble mediators. The encapsulation of the implant by a paucicellular and poorly vascularized fibrous capsule may help prevent an exaggerated inflammatory reaction by sequestering the gold bead from the surrounding tissue.

Risk factors affecting metaphyseal irregularities in the radius and ulna of growing Newfoundland dogs.

The main objective of this study was to study risk factors affecting metaphyseal irregularities (MI) in the distal radius and ulna of growing Newfoundland dogs. Risk factors studied included the genetic effects, effects of litters, BW, circumferences of the distal radius and ulna (CDRU), and total serum alkaline phosphatase (ALP) concentrations. The study included 118 Newfoundland dogs (60 females, 58 males), derived from 32 litters. Body weight, separated on sex and MI, was fitted to the Gompertz function. Occurrence of MI differed significantly between sexes, with 55% of males and 35% of females affected (P = 0.03). Growth curves for the 2 groups of dogs, with and without MI, diverged after 60 to 70 d, and dogs with irregularities were heavier at maturity than dogs of the same sex without irregularities. In univariate analysis, the litter effect was a significant predictor of MI, explaining 32% of total variability of the MI incidence, but the genetic effects were not significant. However, the latter were significant in bivariate analysis of MI and BW. In the bivariate analysis, the effects of litter on MI and BW were significantly correlated at all observational points except at birth, 180 d, and 536 d. Total ALP concentrations decreased with increasing age, and differences between groups diminished with increasing age, indicating a negative effect of total ALP on MI. Correlation between MI and total ALP concentrations of litters was estimated in a bivariate analysis. This correlation was significant and ranged between -0.34 and -0.62. Similarly, the genetic relationship between total ALP and MI from 120 d of age onward varied between -0.31 to -0.60. However, correlations were only significant at 356 d of age (genetic correlation = 0.60; P = 0.01). The mean CDRU increased from 90 d of age toward a peak at 180 d. Thereafter, CDRU declined and stabilized at about 1 yr of age. The mean CDRU between the groups of dogs with and without MI diverged most at 90 d of age, then was nearly stable until 180 d and gradually declined until 356 d, when the CDRU began to equalize. Metaphyseal irregularities and CDRU levels of litter were significantly correlated. Litter effect was a significant predictor of MI. The effects of litters and the genetic effects on BW and MI were correlated at most phases of the growth of the dog. Similar, but lower, correlations were found for CDRU and MI, and total ALP and MI.

A longitudinal study on growth and growth variables in dogs of four large breeds raised in domestic environments.

The main objective of this study was to describe the growth patterns of 4 large dog breeds [Newfoundland (NF), Labrador retriever (LR), Leonberger (LEO), and Irish wolfhound (IW)] raised in domestic environments and concomitant changes in 2 growth-related clinical variables: total serum alkaline phosphatase (ALP) and the circumference of the distal radius and ulna (CDRU). The second objective was to investigate whether these measurements were affected by a range of independent variables like age, sex, litter number, and birth weight. Seven hundred dogs were included in the study, and BW data, separated by breed and sex, were fitted to the Gompertz function. Birth weight, adjusted for litter number, differed significantly between sexes for 3 breeds (LEO, P = 0.004; NF, P = 0.02; LR, P = 0.009) and approached significance for IW (P = 0.07). Estimated mean BW increased rapidly during the first 100 d after birth in all 4 breeds, then plateaued, with maturity being reached between 351 (female LR) and 413 d (male NF). Estimated mature BW ranged from 30.8 kg for the female LR up to 65.7 kg for the male IW. Weight gain, as expressed by the derivative of the Gompertz function, reached its peak in the smallest breed (LR) at the youngest age, 89 d for the females and 95 d for males. Log-transformed BW was significantly related to age, breed, and sex, and the age x sex and age x breed interactions. Within breeds, age, birth weight, and litter number had a significant effect on log-transformed BW. The estimated average CDRU increased from 90 d of age toward a peak at 180 d. Thereafter, CDRU declined and stabilized at about 1 yr of age. The estimated total ALP concentrations decreased from 90 to 360 d of age, after which they stabilized, at mean concentrations varying among breeds from 98 to 131 IU/L. Maximum least squares mean total ALP concentrations were found at 3 mo of age in all breeds, with the greatest least squares mean concentration in the IW breed (713 IU/L). In a mixed model analysis of the complete data set, total ALP was affected (P < 0.001) by age, breed, and the interaction of age x breed. This study described the main factors influencing growth and provided reference data for other studies, including those related to nutrition and disorders of growth.

Double-blind, placebo-controlled trial of the pain-relieving effects of the implantation of gold beads into dogs with hip dysplasia.

Seventy-eight dogs with pain due to hip dysplasia were studied in a controlled, double-blind clinical trial to evaluate gold bead implantation as a pain-relieving treatment. The dogs were randomly assigned to two groups, 36 in the gold implantation group and 42 in the placebo group. Both groups were treated equally regarding anaesthesia, hair clipping and penetration of the skin with the same type of needle. The gold implantation group had small pieces of 24 carat gold inserted through needles at five different acupuncture points and the placebo group had the skin penetrated at five non-acupuncture points so as to avoid any possible effect of stimulating the acupuncture points. A certified veterinary acupuncturist marked the points, and two surgeons performed the implantations according to a randomisation code made in advance. After 14 days, three months and six months, the owners assessed the overall effect of the treatments by answering a questionnaire, and the same veterinarian examined each dog and evaluated its degree of lameness by examining videotaped footage of it walking and trotting. The treatment was blinded for both the owners and the veterinarian. There were significantly greater improvements in mobility and greater reductions in the signs of pain in the dogs treated with gold implantation than in the placebo group. The veterinarian's and the owners' assessments corresponded well.

Stratification, blinding and placebo effect in a randomized, double blind placebo-controlled clinical trial of gold bead implantation in dogs with hip dysplasia.

UNLABELLED: The purpose of this study was to investigate the need for and choice of stratification factors, and the effects of blinding and placebo in a clinical experiment. Eighty dogs with canine hip dysplasia (CHD) were included in a randomized, placebo-controlled and double blind clinical trial with stratified parallel group design, in which body weight and degree of CHD were used as stratification factors. Thirty-eight dogs were allocated to gold bead implantation and 42 to placebo. After six months, 33 of the 42 placebo-treated dogs received gold bead implantation in an open study lasting a further 18 months. The main outcome variable in the study was change in pain signs of CHD as assessed by the owner. No significant difference in the main outcome variable, regardless of the treatment given, could be detected in the two chosen stratification factors. The only factor to influence the main outcome variable significantly was age. The blinding procedure used in the study, in which 60% of the owners correctly guessed the treatment given, was found sufficient. Of those who guessed the treatment erroneously, 88% believed the treatment given was gold bead implantation. The treatment efficacy after six months in the blinded treatment group was found to be significantly larger compared to the efficacy obtained in the open study. A significant placebo effect was therefore detected. CONCLUSION AND CLINICAL RELEVANCE: The age of the dogs influenced the outcome of the CHD treatment, and is recommended as a stratification factor. A significant placebo effect has to be expected and an optimal blinding procedure is necessary in similar clinical studies.

Shortened duration of untreated first episode of psychosis: changes in patient characteristics at treatment.

OBJECTIVE: This study examined whether duration of untreated psychosis can be shortened in patients with first episodes of DSM-IV schizophrenia spectrum disorders and whether shorted duration alters patient appearance at treatment. METHOD: Two study groups were ascertained in the same Norwegian health care sector: one from 1993-1994 with usual detection methods and one from 1997-1998 with early detection strategies that included education about psychosis. RESULTS: Patients with early detection had a shorter median duration of untreated psychosis by 21.5 weeks than patients with usual detection. The number with psychosis was greater in the early detection group; the number with schizophrenia was less. Early detection patients had more substance abuse and were younger, better adjusted premorbidly, and less ill. CONCLUSIONS: Early detection can shorten duration of untreated psychosis and help more patients when they are less severely ill. Given the devastation of psychosis, this is a significant treatment advance.

Adult-onset alcohol consumption induces osteopenia in female rats.

BACKGROUND: Alcohol is a known risk factor for osteopenia and fracture in humans, and its effects on the skeleton have been studied extensively in animal models. Almost all studies of rats, however, have begun rats on alcohol diets while the animals were young and still growing. The purpose of the current study was to examine the effects of alcohol consumption on rats that began drinking alcohol as adults, so that the confounding effects of growth might be minimized. METHODS: Nine-month-old female Sprague-Dawley rats were studied for two durations (8 and 14 weeks). The following diet groups were used for both durations: alcohol (n = 7), in which rats were fed a liquid diet containing ethanol (8.1% v/v; Lieber-DeCarli method); pair-fed (n = 7), in which rats were fed a caloric-equivalent liquid diet matched to the alcohol-fed animals; and pellet (n = 6), in which rats consumed standard rat chow and water. A cessation protocol was also used in which alcohol- and pair-fed groups were fed liquid diets for 8 weeks and then given pellet chow and water for 6 weeks, with pair feeding maintained during the cessation period. RESULTS: Only minor effects developed in the rats in the 8-week group, but after 14 weeks, the cancellous bone of the proximal tibia was severely osteopenic in the alcohol-fed animals. The bone volume and trabecular number were both significantly lower in the alcohol-fed animals than in the pair-fed and pellet-fed control animals and also lower than in the alcohol-fed animals in the 8-week group. Mechanical properties of the cancellous bone in the distal femur also were significantly diminished in the 14-week alcohol-fed group. Composition and mechanical properties of the cortical bone in the femur diaphysis were largely unaffected, but the yield stress was significantly lower in the 14-week alcohol-fed group than in the 8-week alcohol-fed group. No significant effects were found in the cessation groups with regard to almost all parameters measured. CONCLUSIONS: Our study results demonstrate that chronic adult-onset alcohol consumption leads to significantly diminished cancellous bone properties and that these effects depend on the duration of alcohol use.

Calculation of urinary enzyme excretion, with renal structure and function in dogs with pyometra.

The urinary enzyme markers of renal damage, alkaline phosphatase (AP), gamma-glutamyl transferase (GGT) and N-acetyl-beta-glucosaminidase (NAG), glomerular filtration rate (GFR) and renal biopsies were studied to evaluate renal status in dogs with pyometra. After ovariohysterectomy, urinary enzymes were measured daily for 12 days in 55 dogs, and again at a later follow-up visit. Thirteen dogs had high levels of at least one enzyme at initial presentation. Seventeen dogs had a transient increase in urinary enzyme values between one and five days after surgery. Enzyme values usually declined to low activities within 12 post-operative days. Renal biopsies demonstrated tubular abnormalities in many dogs. Mean GFR was 2.4 and 2.0 ml min(-1) kg(-1), respectively on day 1 post-operatively and at the follow-up visit 1-4 months later. High urinary enzyme values often reflected extensive lesions in renal proximal tubular cells and sometimes reduced GFR.

Population-based incidence of mammary tumours in some dog breeds.

Data from two population-based studies in four Norwegian counties were used to calculate the crude incidence of mammary tumours, and the age- and breed-specific incidence of mammary tumours in female dogs of three different breeds. The largest study comprised 14401 histologically verified tumour cases from four counties covered by the Norwegian Canine Cancer Register. The registry covers about 25% of the total Norwegian dog population. The second study was a census in Norway that was sent to all owners of the following breeds: boxers, bichon frisé and Bernese mountain dogs, to estimate the age distribution of the female dog population at risk of developing mammary tumours. The crude incidence of malignant mammary tumours in female dogs of any breed was 53.3%. The highest relative risk ratio of mammary tumours was found in boxers, cocker spaniels, English springer spaniels and dachshunds. The mean age of histologically diagnosed mammary tumours was 7.9 years in boxers and 7.8 years in springer spaniels, compared with 8.8 years in all other breeds. In the four Norwegian counties from 1992 to 1997, the population-based incidence rates (for all ages) of malignant mammary tumours per 1000 female dogs per year were 35.47 in boxers, 3.87 in Bernese mountain dogs and 17.69 in bichon frisé. Mammary cancer is the most common tumour in female dogs in Norway, and represents a population of almost entirely reproductively intact females. The age-specific incidence rates for mammary cancer vary considerably among the three breeds that were studied in detail.

Renal microcystic tubular lesions in two 1Year-old dogs - an early sign of hereditary renal cystadenocarcinoma?

As a part of a study of early renal changes in renal cystadenocarcinoma (RC), a 5-year-old German shepherd dog and two 1-year-old German shepherd mixed-breed dogs were examined. All three animals had bilateral, microscopic renal cysts, and the 5-year-old dog also had RC. Microscopical examination showed papillary hyperplastic tubular epithelial cells lining the inner wall of the renal cysts in all dogs. These cells showed strong reactivity with a monoclonal antibody against a broad-spectrum type of cytokeratin. The dam of the young dogs had suffered from autosomal dominant inherited RC and nodular dermatofibrosis (ND) syndrome. It is likely that the microscopic renal cystic lesions seen in the young dogs represented an early renal change in the RC/ND syndrome. This suggests that the diagnosis of RC can be made on suspected carriers by microscopical examination of renal biopsies as early as 1 year of age, i.e., before the dogs are used for breeding.

Premorbid functioning versus duration of untreated psychosis in 1 year outcome in first-episode psychosis.

OBJECTIVE: This study examines 1year outcome in patients having first-episode non-affective psychosis, with emphasis on Duration of Untreated Psychosis (DUP) and premorbid functioning, in order to clarify how these factors interact. METHOD: Forty-three consecutively admitted patients were all rated on the Positive and Negative Syndrome Scale (PANSS) and the Global Assessment of Functioning Scale (GAF), both upon hospitalization and at 1year follow-up. In addition, premorbid functioning, DUP, duration of hospitalization, and social functioning were rated. RESULTS: Fifty-six per cent were in remission, 18% suffered multiple relapses and 26% were continuously psychotic at 1 year follow-up. Both poor premorbid functioning and long DUP are significantly correlated with more negative symptoms and poorer global functioning at follow-up. Long DUP is also significantly correlated with more positive symptoms. Even when we control for other factors, including premorbid functioning and gender, DUP is a strong predictor of outcome. To a limited degree premorbid functioning and DUP interact, but DUP has an independent influence on outcome. CONCLUSIONS: these findings strengthen the rationale for establishing health service programs for early detection and treatment of first-onset psychosis

Genetic mapping of a naturally occurring hereditary renal cancer syndrome in dogs.

Canine hereditary multifocal renal cystadenocarcinoma and nodular dermatofibrosis (RCND) is a rare, naturally occurring inherited cancer syndrome observed in dogs. Genetic linkage analysis of an RCND-informative pedigree has identified a linkage group flanking RCND (CHP14-C05.377-C05.414-FH2383-C05. 771-[RCND-CPH18]-C02608-GLUT4-TP53-ZuBe Ca6-AHT141-FH2140-FH2594) thus localizing the disease to a small region of canine chromosome 5. The closest marker, C02608, is linked to RCND with a recombination fraction (theta) of 0.016, supported by a logarithm of odds score of 16.7. C02608 and the adjacent linked markers map to a region of the canine genome corresponding to portions of human chromosomes 1p and 17p. A combination of linkage analysis and direct sequencing eliminate several likely candidate genes, including tuberous sclerosis 1 and 2 genes (TSC1 and TSC2) and the tumor suppressor gene TP53. These data suggest that RCND may be caused by a previously unidentified tumor suppressor gene and highlight the potential for canine genetics in the study of human disease predisposition.

Chromosomal assignment of canine TSC2, PKD1 and CLN3 genes by radiation hybrid- and linkage analyses.

The canine tuberous sclerosis 2 (TSC2) gene has been mapped to canine chromosome 6 using a canine whole genome radiation hybrid panel. There is close linkage between canine TSC2 and the polycystic kidney disease 1 gene (PKD1), as has been observed in humans and other mammalian species. The gene responsible for the human juvenile form of neuronal ceroid lipofuscinosis (CLN3), maps close to TSC2 and PKD1 in humans, and is also syntenic in the dog. We further demonstrate linkage to a group of polymorphic markers assigned to canine chromosome 6 (CFA6).

The relationship between some plasma clearance methods for estimation of glomerular filtration rate in dogs with pyometra.

The purpose of the present study was to compare different pharmacokinetic models for estimation of glomerular filtration rate (GFR) in 50 dogs with pyometra. GFR was estimated by plasma clearance (CLplasma) of iohexol by four 1-compartment methods (CL1c), a 2-compartment method (CL2c), and the trapezoidal method (CLtr). Regression analysis was performed to establish correction formulas for prediction of CLtr from the CL1c values and to find optimal times of sampling. Standardization of clearance values to body weight (kg), body surface area (m2) and extracellular fluid volume (ECFV) was compared by ranking of values. CLtr and CL2c values were similar, whereas CL1c overestimated CLtr. CLtr could be predicted from 2 samples at 2 and 3 hours after injection, using the formula CLtr = 4.52 + 0.84CL1c - 0.00080(CL1c)2 (R2 = .97). Similar relationships were found when sampling at 2 and 4 hours or at 2, 3 and 4 hours after injection, whereas predictions from the 3- and 4-hour estimates were not optimal (R2 = .79). The 2-sample methods for calculating GFR/ECFV generally produced unreliable predictions of the complete curve GFR/ECFV values. For some dogs, the choice of standardization procedure substantially changed the apparent level of renal function relative to other dogs in the study. We conclude that by applying an appropriate correction formula, GFR may be estimated using 2 blood samples at 2 and 3, or 2 and 4 hours after injection of iohexol when renal function is normal or moderately reduced. The method of standardizing the analysis with respect to body size may influence interpretation of the results substantially.

Internal radionuclide therapy of primary osteosarcoma in dogs, using 153Sm-ethylene-diamino-tetramethylene-phosphonate (EDTMP).

Fifteen dogs were referred because of a spontaneous bone tumor, lameness, and local pain. The osteosarcoma diagnosis was established by clinical examination, X-ray, bone scintigraphy, and histological examination of biopsy material. The tumors were located in the extremities (n = 12), scapula (n = 1), maxilla (n = 1), and the frontal bone (n = 1). The dogs were given one to four i.v. injections of 153Sm-labeled ethylene-diamino-tetramethylene-phosphonate (153Sm-EDTMP; 36-57 MBq/kg body weight). Three dogs had surgery in addition to the radionuclide treatment. Platelet and WBC counts showed a moderate and transient decrease. No other toxicity was observed. Average tumor doses after a single injection were approximately 20 Gy, considerably higher in some areas because of inhomogeneous uptake. Macroscopically distant metastases were detected in seven dogs at autopsy. One dog died from an intercurrent disease, free of cancer, 5 months after the radionuclide treatment. None of the dogs was cured. The median and mean survival times from the first treatment to death or euthanasia were 150 and 252 days, respectively. Nine of the dogs had obvious pain relief, and five of them seemed pain-free: one for 20 months and one for 48 months. It is concluded that high tumor doses may be deposited in dog osteosarcomas by 153Sm-EDTMP, and the ratio between tumor dose and the dose to surrounding tissues is favorable. The treatment gives pain relief and in some cases tumor growth delay. In combination with surgery, 153Sm-EDTMP may prolong life significantly and possibly cure the disease because the development of metastases are seemingly postponed. No serious side effects were observed.

Pharmacokinetic aspects of measurement of glomerular filtration rate in the dog: a review.

Glomerular filtration rate (GFR) is estimated by means of clearance, defined as the volume of plasma that has been cleared of a particular substance per unit time. Glomerular filtration rate may be estimated by measuring the renal clearance of a filtration marker using data from both urine and plasma or by plasma clearance using only plasma data. Several alternative pharmacokinetic models are used for the calculation of clearance using various filtration markers with slightly different pharmacokinetic properties. The purpose of this article is to discuss how the choice of marker and pharmacokinetic model may influence estimated GFR values and to elucidate commonly used methods and reported GFR values in the dog.

Genetic markers linked to neuronal ceroid lipofuscinosis in English setter dogs.

The neuronal ceroid lipofuscinoses (NCL) are a group of fatal autosomal recessive neurodegenerative diseases occurring in human and some domesticated animal species. A canine form of the disease (CNCL) has been extensively studied in a Norwegian colony of inbred English setters since 1960. A resource family developed for genetic mapping and comprising 170 individuals was typed for 103 genetic markers. Linkage analysis showed three genetic markers to be linked to the disease locus with the closest marker at a distance of about 3 CM. Two other loci were linked with these markers making a linkage group of five genetic markers. The linkage group spanned a distance of 54 CM. Two genes for human forms of the disease, CLN2 and CLN3, have been identified and mapped to human chromosome 11p15 and 16p12, respectively. The present study did not indicate any linkage between CNCL and the canine CLN3 homologue or to homologues of markers for genes that map close to human CLN2.