Patterns of metastatic progression and association with clinical outcomes in canine osteosarcoma: A necropsy study of 83 dogs.

Osteosarcoma is a highly metastatic primary bone tumour that occurs spontaneously in both pet dogs and humans. Patterns of metastasis to organs beyond the most common site (lung) are poorly characterised and it is unknown whether specific associations between patterns of metastatic progression and patient features exist. This retrospective study characterised the necropsy findings of 83 dogs receiving standardised therapy and clinical monitoring in a prospective clinical trial setting to document patterns of metastasis and correlate outcomes with these patterns and other patient and tumour-specific factors. A total of 20 different sites of metastasis were documented, with lung as the most common site, followed by bone, kidney, liver, and heart. Two distinct clusters of dogs were identified based on patterns of metastasis. There was no significant association between site of enrollment, trial arm, sex, serum alkaline phosphatase (ALP) activity, or tumour location and clinical outcomes. A second cancer type was identified at necropsy in 10 dogs (10/83; 12%). These data showcase the extensive nature of osteosarcoma metastasis beyond the lung and provide a benchmark for clinical monitoring of the disease. Further, this study provides insight into transcriptional features of primary tumours that may relate to a propensity for osteosarcoma metastasis to specific organs and tissues.

Role of obesity, metabolic variables, and diabetes in HIV-associated neurocognitive disorder.

OBJECTIVE: To evaluate relationships between HIV-associated neurocognitive disorder and metabolic variables in a subgroup of HIV+ participants examined in a prospective, observational, multicenter cohort study. METHODS: In a cross-sectional substudy of the CNS HIV Anti-Retroviral Therapy Effects Research (CHARTER) cohort, 130 HIV+ participants provided fasting blood samples. Neurocognitive impairment (NCI) was defined by performance on neuropsychological tests adjusting for age, education, gender, and race/ethnicity. Global ratings and global deficit scores were determined. Demographics, biomarkers of HIV disease, metabolic variables, combination antiretroviral therapy (CART) history, other drug exposures, and self-reported diabetes were examined in multivariate models predicting NCI. Separate models were used for body mass index (BMI) alone (n = 90) and BMI and waist circumference (WC) together (n = 55). RESULTS: NCI (global impairment rating ≥5) was diagnosed in 40%. In univariate analyses, age, longer duration of HIV infection, obesity, and WC, but not BMI, were associated with NCI. Self-reported diabetes was associated with NCI in the substudy and in those >55 in the entire CHARTER cohort. Multivariate logistic regression analyses demonstrated that central obesity (as measured by WC) increased the risk of NCI and that greater body mass may be protective if the deleterious effect of central obesity is accounted for. CONCLUSIONS: As in HIV-uninfected persons, central obesity, but not more generalized increases in body mass (BMI), was associated with a higher prevalence of NCI in HIV+ persons. Diabetes appeared to be associated with NCI only in older patients. Avoidance of antiretroviral drugs that induce central obesity might protect from or help to reverse neurocognitive impairment in HIV-infected persons.

Electron beam quality control using an amorphous silicon EPID.

An amorphous silicon EPID has been investigated to determine whether it is capable of quality control constancy measurements for linear accelerator electron beams. The EPID grayscale response was found to be extremely linear with dose over a wide dose range and, more specifically, for exposures of 95-100 MU. Small discrepancies of up to 0.8% in linearity were found at 6 MeV (8-15 MeV showed better agreement). The shape of the beam profile was found to be significantly altered by scatter in air over the approximately 60 cm gap between the end of the applicator and the EPID. Nevertheless, relative changes in EPID-measured profile flatness and symmetry were linearly related to changes in these parameters at 95 cm focus to surface distance (FSD) measured using a 2D diode array. Similar results were obtained at 90 degrees and 270 degrees gantry angles. Six months of daily images were acquired and analyzed to determine whether the device is suitable as a constancy checker. EPID output measurements agreed well with daily ion chamber measurements, with a 0.8% standard deviation in the difference between the two measurement sets. When compared to weekly parallel plate chamber measurements, this figure dropped to 0.5%. A Monte Carlo (MC) model of the EPID was created and demonstrated excellent agreement between MC-calculated profiles in water and the EPID at 95 and 157 cm FSD. Good agreement was also found with measured EPID profiles, demonstrating that the EPID provides an accurate measurement of electron profiles. The EPID was thus shown to be an effective method for performing electron beam daily constancy checks.

Association of a null allele of SPRN with variant Creutzfeldt-Jakob disease.

BACKGROUND: No susceptibility genes have been identified in human prion disase, apart from the prion protein gene (PRNP). The gene SPRN, encodes Shadoo (Sho, shadow of prion protein) which has protein homology and possible functional links with the prion protein. METHODS: A genetic screen was carried out of the open reading frame of SPRN by direct sequencing in 522 patients with prion disease, including 107 with variant Creutzfeldt-Jakob disease (vCJD), and 861 healthy controls. RESULTS: A common coding variant of SPRN, two further single nucleotide polymorphisms (SNPs) and three rare insertion or deletion variants were found. A single base-pair insertion at codon 46, predicted to cause a frameshift and potentially a novel protein, was found in two patients with vCJD but not in controls (p = 0.01). Two linked SNPs, one in intron 1 and the other a missense variant at codon 7, were associated with risk of sporadic CJD (p = 0.009). CONCLUSION: These data justify the functional genetic characterisation of SPRN and support the involvement of Shadoo in prion pathobiology.

Impact of long-term treatment with neurotoxic dideoxynucleoside antiretrovirals: implications for clinical care in resource-limited settings.

OBJECTIVES: A minority of HIV-infected patients taking an antiretroviral (ARV) regimen containing dideoxynucleosides (d-drugs) such as stavudine (d4T) and didanosine (DDI) experiences dose-limiting neuropathic pain and paraesthesias, usually within weeks of starting these drugs. Because d-drugs are among the few affordable options available in developing countries, continuing d-drug therapy would be a desirable strategy for many HIV-infected individuals. Therefore, we evaluated the safety of continuing d-drug therapy. METHODS: In a US cohort, we compared the rates of worsening neuropathic symptoms and signs in HIV-infected individuals on stable ARV regimens that did (n=252) or did not (n=250) include d-drugs. Rates of worsening were compared using proportional hazards model and the log-rank test. RESULTS: The risk ratios (RR) were not significantly larger for worsening neuropathy signs [0.94; 95% confidence interval (CI) 0.84-1.07] or symptoms (0.99; 95% CI 0.88-1.14) in patients taking d-drugs continuously compared to those not taking d-drugs. CONCLUSIONS: Continued d-drug exposure among patients tolerating an initial trial did not increase the risk of worsening neuropathy compared to non-d-drug-containing regimens. If applicable in developing countries, these findings suggest that in most patients d-drugs can be continued safely in the long term without increasing the risk of worsening neuropathy.

Intracranial empyema: literature review and two novel cases in cats.

OBJECTIVES: To review the literature on intracranial empyema and report two new cases in cats. METHODS: Literature review and case reports. RESULTS: Intracranial empyema has been rarely reported in small animals. In two novel cases in cats, the route of infection was postulated to be local extension from a retrobulbar abscess of odontogenic origin in one case and direct inoculation from a penetrating bite wound to the skull, confirmed at post-mortem examination, in the other. On magnetic resonance imaging of the first case, there was a contrast-enhancing large extra-axial fluid collection overlying the right cerebral hemisphere, consistent with subdural empyema. Infection was caused by an Actinomyces spp. This is the first report of successful treatment of intracranial empyema by craniotomy, drainage and antibiotics. CLINICAL SIGNIFICANCE: Intracranial empyema is a neurosurgical emergency. Favourable outcomes may be achieved with surgical decompression, antimicrobial therapy and intensive care.

Familial prion disease in a Hungarian family with a novel 144-base pair insertion in the prion protein gene.

About 15% of human prion diseases are inherited, and are associated with point or insertional mutations of the prion protein gene (PRNP). Four families with six octapeptide repeat insertions (OPRI) in the PRNP gene have been described in the literature so far. Here we report two cases in a Hungarian family with a new six OPRI (R1R2R2R3R2R3gR3R2R2R3R4) in the PRNP gene. The clinical features (progressive ataxia, dementia and anosmia), the age of onset and the duration of disease were almost identical. In addition to the cerebellar and parahippocampal pathological changes already described, we also found deposits of pathological prion protein in the olfactory system.

A presenilin 1 R278I mutation presenting with language impairment.

Presenilin (PSEN)1 mutations are responsible for many cases of autosomal dominant Alzheimer disease (AD), although the clinical spectrum has not been fully defined. The authors describe two members of a kindred with a novel PSEN1 mutation (R278I) presenting with language impairment and relative preservation of memory. Screening for PSEN1 mutations may be appropriate in cases of familial dementia even where the clinical phenotype is not typical of AD.

Early onset familial Alzheimer's disease: Mutation frequency in 31 families.

BACKGROUND: Three causative genes have been identified for autosomal dominant AD. OBJECTIVE: To determine the proportion of patients with early onset AD with a positive family history accounted for by mutations in these genes. METHODS: A mutational analysis of the amyloid precursor protein (APP), presenilin 1 (PSEN1), and presenilin 2 (PSEN2) genes was performed in 31 probands with probable or definite AD from UK families with an age at onset (AAO) <61 years. RESULTS: The mean AAO was 46.9 years (median 45 years; range 33 to 60 years). The majority of patients (23 of 31; 74%) fulfilled recognized criteria for autosomal dominant inheritance. In 17 (55%) probands the authors identified eight novel PSEN1 sequence variants and eight recognized pathogenic mutations. In 4 (13%) probands the authors identified one novel APP sequence variant (H677R) and two recognized mutations. Thus in this series 21 of 31 (68%) probands were associated with a sequence variant in APP or PSEN1. Nine of the 11 (82%) probands with neuropathologically confirmed AD who additionally fulfilled recognized criteria for autosomal dominant inheritance were associated with a sequence variant in APP or PSEN1. The 10 patients in whom the authors were unable to identify a mutation in APP, PSEN1, or PSEN2 were older than the probands with sequence variants (55.4 vs 44.7 years: p = 0.001). CONCLUSIONS: Sequence variants in APP and PSEN1 accounted for the majority of neuropathologically confirmed autosomal dominant early onset AD; no mutations in PSEN2 were detected. There may be a further genetic factor involved in the etiology of autosomal dominant early onset AD.

Skin-fold advancement flaps for closing large proximal limb and trunk defects in dogs and cats.

OBJECTIVE: To describe the use of skin-fold advancement flaps for covering large skin defects in dogs and cats. STUDY DESIGN: Clinical study. ANIMALS: Eight client-owned animals: 6 dogs and 2 cats. METHODS: Six dogs and 2 cats underwent reconstruction of soft-tissue wounds resulting from traumatic, neoplastic, or infectious lesions. Skin-fold flaps were created by division of the medial and lateral attachment to the proximal limb or the dorsal and ventral attachment to the trunk, enabling closure of adjacent defects on the trunk or proximal limb, respectively. RESULTS: Skin-fold flaps proved effective for closing defects in all animals. Necrosis of a portion of the flap occurred in 2 dogs due to technical errors, but the resultant defects remained amenable to primary closure. All wounds ultimately healed primarily, without major complications. CONCLUSION AND CLINICAL RELEVANCE: The skin-fold advancement flap is a versatile technique that lends itself to use in a variety of locations, depending on which attachments are divided. The clinical results are comparable with those reported for axial pattern and subdermal plexus flaps.

Two-octapeptide repeat deletion of prion protein associated with rapidly progressive dementia.

Insertions of integral numbers of an octapeptide repeat in the prion protein gene are pathogenic mutations associated with inherited prion diseases. Conversely, deletions of a single octapeptide repeat are found as normal polymorphisms in many populations and do not predispose individuals to prion disease. The authors report a two-octapeptide repeat deletion in an elderly woman with a rapidly progressive dementia consistent with Creutzfeldt-Jakob disease. This mutation was absent from more than 3,000 individuals and may be causally related to prion disease and represent a novel disease mechanism.

Identification of multiple quantitative trait loci linked to prion disease incubation period in mice.

Polymorphisms in the prion protein gene are known to affect prion disease incubation times and susceptibility in humans and mice. However, studies with inbred lines of mice show that large differences in incubation times occur even with the same amino acid sequence of the prion protein, suggesting that other genes may contribute to the observed variation. To identify these loci we analyzed 1,009 animals from an F2 intercross between two strains of mice, CAST/Ei and NZW/OlaHSd, with significantly different incubation periods when challenged with RML scrapie prions. Interval mapping identified three highly significantly linked regions on chromosomes 2, 11, and 12; composite interval mapping suggests that each of these regions includes multiple linked quantitative trait loci. Suggestive evidence for linkage was obtained on chromosomes 6 and 7. The sequence conservation between the mouse and human genome suggests that identification of mouse prion susceptibility alleles may have direct relevance to understanding human susceptibility to bovine spongiform encephalopathy (BSE) infection, as well as identifying key factors in the molecular pathways of prion pathogenesis. However, the demonstration of other major genetic effects on incubation period suggests the need for extreme caution in interpreting estimates of variant Creutzfeldt-Jakob disease epidemic size utilizing existing epidemiological models.

Intraoperative hemorrhage during patent ductus arteriosus ligation in dogs.

OBJECTIVE: To determine the prevalence of intraoperative hemorrhage in a consecutive series of dogs undergoing patent ductus arteriosus (PDA) ligation at a veterinary teaching hospital, and to describe strategies to reduce the risk of ductus perforation and deal with hemorrhage when it occurs. STUDY DESIGN: Retrospective clinical study. ANIMALS: Sixty-four dogs. METHODS: The records of all dogs undergoing PDA ligation at the University Veterinary Center, Sydney between May 1989 and February 1998 were reviewed and the prevalence and nature of complications identified. RESULTS: Serious hemorrhage occurred in 4 of 64 dogs (6.25%) that underwent PDA ligation. In all cases, hemorrhage resulted from perforation of the craniomedial aspect of the ductus while attempting to expose the tips of the dissecting forceps. Hemorrhage was controlled in 3 dogs by clamping the main pulmonary artery, digital compression of the descending aorta, and completion of ductus ligation during an approximately 5-minute period of circulatory arrest. The remaining dog exsanguinated during an unsuccessful attempt to locate, clamp, and ligate the bleeding point. The mortality rate for PDA ligation was I of 64 dogs (1.6 %). CONCLUSIONS: The technique described in this report permits simple ligation of a range of different ductus morphologies in dogs of varying breeds, weights, and ages. In the event of serious hemorrhage, prompt ventricular outflow occlusion and ductus ligation followed by rapid whole blood transfusion is life saving in most cases.

Clinical factors associated with focal infiltrates in wheezing infants and toddlers.

It can be challenging to determine which findings are associated with focal infiltrates in young wheezing children. A prospective study of wheezing children < or = 18 months of age revealed focal infiltrates on chest radiograph in 23%. By use of multivariate analysis, findings significantly associated with focal infiltrates included grunting (OR 4.1, 95% CI, 2.0, 8.6) and oxygen saturation < or = 93% (OR 2.2, 95% CI, 1.1, 4.8); with a sensitivity and specificity of 12.5% and 97%, respectively. Variables not associated with focal infiltrates included first-time wheezing, fever, and tachypnea. The combination of grunting and oxygen saturation < or = 93% is highly specific and can be used to help diagnose pneumonia in wheezing infants and toddlers.

Perirenal pseudocysts in 26 cats.

OBJECTIVE: To evaluate clinical features, anatomical location, nature of pseudocyst fluid, results of surgical treatment and links with underlying renal disease in cats with perirenal pseudocysts. DESIGN: A retrospective study of 26 affected cats, including 8 treated surgically. RESULTS: Nineteen (73%) affected cats were male. The median age was 11 years. Most presented for abdominal enlargement and had varying degrees of renal dysfunction on presentation. Thirteen cats (50%) had bilateral pseudocysts. The pseudocyst fluid was a transudate or modified transudate in all cases. All surgically treated cats had subcapsular perirenal pseudocysts. Associated renal lesions were identified in all cats that had renal biopsies or detailed ultrasonographic examinations. Surgery relieved clinical signs but did not stop progression of renal disease. Cats survived a median of 9 months after surgery and survival was correlated statistically to degree of azotaemia at presentation. Percutaneous drainage of pseudocysts was ineffective in controlling long-term fluid accumulation. CONCLUSIONS: Subcapsular perirenal pseudocysts are formed in cats by accumulation of transudate between the capsule and parenchyma of the kidney as a result of underlying parenchymal disease. Pseudocyst formation can occur at variable stages of renal dysfunction. Resection of the pseudocyst wall is usually effective in eliminating signs but does not stop progression of renal disease. The prognosis for cats with pseudocyst formation is related to the degree of renal dysfunction at time of diagnosis.

Genealogies of mouse inbred strains.

The mouse is a prime organism of choice for modelling human disease. Over 450 inbred strains of mice have been described, providing a wealth of different genotypes and phenotypes for genetic and other studies. As new strains are generated and others become extinct, it is useful to review periodically what strains are available and how they are related to each other, particularly in the light of available DNA polymorphism data from microsatellite and other markers. We describe the origins and relationships of inbred mouse strains, 90 years after the generation of the first inbred strain. Given the large collection of inbred strains available, and that published information on these strains is incomplete, we propose that all genealogical and genetic data on inbred strains be submitted to a common electronic database to ensure this valuable information resource is preserved and used efficiently.

Benign masses in the pericardium of two dogs.

Two miniature Schnauzer dogs were treated for pericardial masses. In one dog the mass consisted of necrotic fat that was attached to the apex of the pericardium by a pedicle. No obvious communication with the abdomen was present. The second dog had a peritoneopericardial hernia associated with a chronic cystic haematoma. In each case the mass was presumed to have arisen following congenital displacement of the omentum into the pericardium. The pericardial mass was removed and subtotal pericardectomy performed in both dogs. Recovery was complete in each case.