Two-dimensional (2-D) echocardiographic measurement of the left atrium (LA) has the potential to be more accurate than the standard M-mode method, because the LA body can be measured. We evaluated a 2-D method for measuring LA and aorta (AO) in a right parasternal short-axis view and compared it to the M-mode method. An index for LA size (LA/AO) was calculated in 166 cavalier King Charles spaniels, 56 normal and 110 dogs with mitral regurgitation (MR) of varying degrees secondary to chronic valvular disease. In normal dogs, the AO-2-D and LA/AO-2-D did not correlate to body weight (BW) or BW2; whereas, all M-mode values and the LA-2-D were significantly (p < .05) related to both BW parameters. In normal dogs, there was no difference between M-mode and 2-D indices. For all dogs (normal and dogs with MR) there was an 11% bias between the M-mode and 2-D index with the LA/AO-2-D being higher than the LA/AO-M. The association between the mean and the difference of the indices demonstrated a quadratic relationship. Dogs with a mean LA/AO of 2.0-2.5 showed the largest difference between the two indices. Small values for the 2-D coefficients of variation for respiration and stage of diastole were found; 3.4 and 3.1%, respectively. The 2-D index is more sensitive to LA enlargement than the M-mode index.

Chromothripsis represents a novel phenomenon in the structural variation landscape of cancer genomes. Here, we analyze the genomes of ten patients with congenital disease who were preselected to carry complex chromosomal rearrangements with more than two breakpoints. The rearrangements displayed unanticipated complexity resembling chromothripsis. We find that eight of them contain hallmarks of multiple clustered double-stranded DNA breaks (DSBs) on one or more chromosomes. In addition, nucleotide resolution analysis of 98 breakpoint junctions indicates that break repair involves nonhomologous or microhomology-mediated end joining. We observed that these eight rearrangements are balanced or contain sporadic deletions ranging in size between a few hundred base pairs and several megabases. The two remaining complex rearrangements did not display signs of DSBs and contain duplications, indicative of rearrangement processes involving template switching. Our work provides detailed insight into the characteristics of chromothripsis and supports a role for clustered DSBs driving some constitutional chromothripsis rearrangements.

We evaluated the long-term effect of early angiotensin-converting enzyme (ACE) inhibition (enalapril maleate) as monotherapy to postpone or prevent congestive heart failure (CHF) in asymptomatic dogs with mitral regurgitation (MR) attributable to myxomatous valvular disease (MVD) in a prospective, randomized, double-blinded, placebo-controlled multicenter trial involving 14 centers in Scandinavia. Two hundred twenty-nine Cavalier King Charles (CKC) Spaniels with MR attributable to MVD but no signs of CHF were randomly allocated to treatment with enalapril 0.25-0.5 mg daily (n 116) or to placebo groups (n 113). Each dog was evaluated by physical examination, electrocardiography, and thoracic radiography at entry and every 12 months (30 days). The number of dogs developing heart failure was similar in the treatment and placebo groups (n 50 [43%] and n 48 [42%], respectively; P .99). The estimated means, adjusted for censored observations, for the period from initiation of therapy to heart failure were 1,150 50 days for dogs in the treatment group and 1,130 50 days for dogs in the placebo group (P .85). When absence or presence of cardiomegaly at the entrance of the trial was considered, there were still no differences between the treatment and placebo groups (P .98 and .51, respectively). Multivariate analysis showed that enalapril had no significant effect on the time from initiation of therapy to heart failure (P .86). Long-term treatment with enalapril in asymptomatic dogs with MVD and MR did not delay the onset of heart failure regardless of whether or not cardiomegaly was present at initiation of the study.

Facioscapulohumeral dystrophy (FSHD) is associated with somatic chromatin relaxation of the D4Z4 repeat array and derepression of the D4Z4-encoded DUX4 retrogene coding for a germline transcription factor. Somatic DUX4 derepression is caused either by a 1-10 unit repeat-array contraction (FSHD1) or by mutations in SMCHD1, which encodes a chromatin repressor that binds to D4Z4 (FSHD2). Here, we show that heterozygous mutations in DNA methyltransferase 3B (DNMT3B) are a likely cause of D4Z4 derepression associated with low levels of DUX4 expression from the D4Z4 repeat and increased penetrance of FSHD. Recessive mutations in DNMT3B were previously shown to cause immunodeficiency, centromeric instability, and facial anomalies (ICF) syndrome. This study suggests that transcription of DUX4 in somatic cells is modified by variations in its epigenetic state and provides a basis for understanding the reduced penetrance of FSHD within families.

Abstract. Th e pr ognostic vari ables of 223 consecutively sam pled sponta neous mammar y tum ors from fem ale dogs were studied. Th ese vari abl es included flow cyto metric DNA analysis and cell proliferat ion mea sur ed as cells in S-ph ase rate eva luated fro m D NA histogram s. Th e dogs were surgically treat ed , in mos t cases wit h unilat eral mastectom y (all mam mary glands), and 202 of th e 223 dogs were stud ied tem porally following surgery. Univa riate analysis with correction for age indi cated that the variables of lymph nod e metastasis, elevated S-phas e rat e, presen ce of a sarcoma, DNA aneuploidy, and ulcerati on and infiltrative growth int o und erl ying tissue had a statistically significant negat ive influence on th e sur vival rates of dogs with a d iagnosed malignant tum or. Simi lar results were obtained from tests on all dogs, but tumo r size and its relat ive hazard increase d with increasing size of the tumors, regard less of whet her total or d isease-specific mort alit y was cons ide red. Using mul tiva riate-analysiscon du cted Co x's proportion al hazard s mod el, elevated S-phase rate, increased age, and presence of a sarco ma remained statistically significant risk factor s. The prognostic value of DNA ploid y and lymph node status varied dependi ng on cho ice of end point. T he study of tum or growth patt ern and tum or size pro vided no prognostic in for mati on in the m ulti var iate analysis. Flow eytometrie cell ana lysis, incl ud ing S-phase rate and D NA ploid y, is of va lue in pred icting the prognosis of canine ma m ma ry tum ors and can be used as a new pro gnostic tool to improve the preoperative dia gnostics o f can ine mamm ary tumors.Key words: D NA ploidy; dogs; mammary tumor; multivariate statistical ana lysis; S-phase rate.Canine mammary tumors with apparent signs ofmalignancy, such as pronounced infiltr ative growth involving several mammary gland s, ede ma, ulcerated skin, and lymph node metastases, do not present an y diagno stic problems for experienced clinicians. However, becaus e man y canine mammar y tumors are not at an ad vanced stage of development when first detected by owners or clini cian s, th e current or pot ent ial biologic beha vior (hyperpl asia, benign proliferation , malignant tr ansformation) of these tumors is difficult to predict clinically. Becau se sma ll tumor s ha ve clinical characteristics th at are difficult to int erpret, bett er diagnostic tools are needed. A preoperat ive diagnosis th at includes tumor type and/o r prognostic information on th e tumor increases the possibility of adequate treatment. Cytologic diagnostics have been used for th at purpose. ' Progn ostic factors of canine mammary tum or s used in univariate anal yses include th e tumor type, th e growth/ stage, and th e size.4.5.8.,o.I,.2°The prognostic va lue of lymph node status, as determined by hist opathologic exa mination, is equivo cal.v-! '-" Th e valu e of additional information abo ut cell morphology ob-20 tain ed using flow cytom etr ic DNA analysi...

Six hunting dogs were investigated after showing signs of diffuse back pain. In three of the dogs, prodromal signs included coughing. Swelling in the dorsal lumbar region was noted in four of the dogs, but in two there was no visible or palpable swelling. Initial radiographs of the lumbar region were normal in two of the dogs and showed mild to moderate ventral periosteal reactions in the L1 to L4 region in the remaining four. On ultrasonography and magnetic resonance imaging, changes were seen in the sublumbar muscles (e.g., abnormal echogenicity and increased signal intensity) in five dogs examined. Exploratory surgery revealed plant material foreign bodies in the sublumbar muscles in the L1 to L4 region in five of the six dogs. The concurrent infections were caused predominantly by anaerobic bacteria common to the mucous membranes of the oropharyngeal and respiratory tracts. All dogs recovered, with restored hunting ability. The mean follow-up period was five years (range 1.3 to 7.8 years). It is proposed that the plant parts were inhaled, and then migrated along either diaphragmatic crus to lodge in the sublumbar muscles.

Heart rate variability was measured in 81 Cavalier King Charles spaniels to investigate if it could be used to evaluate the severity of mitral regurgitation and to predict decompensation. Heart rate variability was assessed by the natural logarithm of the variance of the R-R intervals for 20 consecutive beats obtained from electrocardiographic recordings. Twenty-two of the dogs were clinically normal and 59 had mitral regurgitation caused by chronic valvular disease. The severity of mitral regurgitation was evaluated by echocardiography and thoracic radiography. Heart rate variability was found to be reduced (P < 0.001) among dogs with severe left atrial and ventricular dilatation and clinical signs of congestion. No significant differences in heart rate variability were found among normal dogs, dogs with only cardiac murmur, and dogs with echoradiographic evidence of slight to moderate left atrial and ventricular dilatation. Overall, an association was found between heart rate variability and left atrial to aortic root ration and left ventricular end diastolic diameters (r = 0.72 and 0.64, respectively, P < 0.001), as well as heart and respiratory rate (r = 0.80 and 0.69, respectively, P < 0.001). Multiregression analysis showed that, in order of importance, heart rate, left atrial diameter and respiratory rate had significant effects on heart rate variability. Among these parameters, heart rate variability and left atrial diameter were found to be most efficient in separating decompensated dogs from compensated. It is concluded that heart rate variability may provide the clinician with valuable information when assessing the severity of mitral regurgitation caused by chronic valvular disease.

The vertebral heart size (VHS) method by Buchanan is based on anatomic landmarks. A potential source of variation among observers is differences in the selection of measurement points. The objective was to test variability between observers with different levels of training in thoracic radiology and small animal clinical practice. Fifty sets of thoracic radiographs of cavalier King Charles spaniels, were divided into five groups; (Normal) normal cardiopulmonary structures, (I) slight cardiomegaly, (II) moderate cardiomegaly, (II +) moderate cardiomegaly with congestive heart failure, and (III +) severe cardiomegaly with congestive heart failure. Cardiomegaly was confirmed by echocardiography to be caused by mitral regurgitation because of myxomatous mitral valve disease. Sixteen observers representing four levels of experience (four observers/level) evaluated the radiographs; (1) European Diplomates in Veterinary Diagnostic Imaging, (2) Experienced small animal clinicians, (3) Trainees in small animal clinical practice (4) Veterinary students. Almost identical mean VHS values were found among the four experience levels for each of the five groups of radiographs with a low coefficient of variation, range 1.5-3.2%. Mean difference among the 16 observers was 1.05 +/- 0.32 vertebrae (v). Mean difference among individuals in each observer group was approximately 0.5 v for all but the groups of trainees were the difference was 0.6-0.9 v. The conclusion is that VHS method for heart size is independent of observer experience but dependent of individual observers selection of reference points and transformation of long and short axis dimensions into VHS units.