A systematic survey of loss-of-function variants in human protein-coding genes

Genome-sequencing studies indicate that all humans carry many genetic variants predicted to cause loss of function (LoF) of protein-coding genes, suggesting unexpected redundancy in the human genome. Here we apply stringent filters to 2951 putative LoF variants obtained from 185 human genomes to determine their true prevalence and properties. We estimate that human genomes typically contain ~100 genuine LoF variants with ~20 genes completely inactivated. We identify rare and likely deleterious LoF alleles, including 26 known and 21 predicted severe disease-causing variants, as well as common LoF variants in nonessential genes. We describe functional and evolutionary differences between LoF-tolerant and recessive disease genes and a method for using these differences to prioritize candidate genes found in clinical sequencing studies.     

Detection of Aphanomyces invadans and epizootic ulcerative syndrome in the Murray‐Darling drainage

Epizootic ulcerative syndrome was diagnosed, and the presence of Aphanomyces invadans confirmed, from an outbreak of clinical disease in wild‐caught bony bream (Nematalosa erebi) from the Darling River near Bourke, in New South Wales, Australia, during 2008. This confirms a significant extension of the agent beyond its historical range.     

Radiographic findings of the medial humeral epicondyle in 200 canine elbow joints

Objectives: To determine the frequency and radiographic aspect of medial humeral epicondylar lesions as a primary or concomitant finding and to evaluate the association with osteoarthritis. Methods: Medical records of dogs diagnosed with elbow lameness were reviewed. Inclusion criteria for this study were a complete clinical examination, a complete set of digital radiographs and a final diagnosis made by computed tomography or magnetic resonance imaging and arthroscopy. Changes of the medial humeral epicondyle were recorded and correlated with the radiographic osteoarthritis and final diagnosis. Results: Eighty of the 200 elbows showed changes of the medial humeral epicondyle. In 12 of these 80 elbows, changes of the medial epicondyle were the only findings within the joint, and these elbows were diagnosed with primary flexor enthesopathy. In the remaining 68 elbows, other concomitant elbow pathologies were found. In those cases of concomitant epicondylar changes, high grades of osteoarthritis were recorded, while most elbows with primary flexor enthesopathy showed a low grade of osteoarthritis. Clinical significance: Changes of the medial humeral epicondyle are often considered clinically unimportant and are regarded as an expression of osteoarthritis. This study showed the relatively frequent presence of epicondylar changes of which the majority were considered concomitant to a primary elbow problem. If changes of the medial humeral epicondyle are the only pathologic finding (primary flexor enthesopathy) they should be considered as the cause of lameness and not as a sign of osteoarthritis.     

Ultrasonographic appearance of bony abnormalities at the dorsal aspect of the fetlock joint in geriatric cadaver horses

This article describes the ultrasonographic (US) appearance of bony abnormalities on the dorsal aspect of the third metacarpal/metatarsal bone of the equine fetlock in cadavers with radiographic signs of osteoarthrosis. After US, computed tomography was undertaken to better characterise the lesions. Twelve fetlock joints were collected and all had more than one bone abnormality on US. Normal subchondral bone appeared on US as a well-defined and regular hyperechoic line with distal acoustic shadowing. Bone abnormalities detected on US included (1) gaps in the proximal subchondral bone filled with material of heterogeneous echogenicity, (2) bone fragments represented as small straight smoothly delineated hyperechoic lines with distal shadowing located superficial to the surface of the adjacent bone, (3) proximal new bone formation visible as mild to severe cortical protrusions, (4) marginal osteophytoses seen as an elevation of the hyperechoic surface of the subchondral bone at the edges of the joint surfaces, (5) indentations in subchondral bone seen as a concave deviation of the hyperechoic line without interruption, (6) focal or diffuse irregularities of the subchondral bone seen as disruptions of the normal smooth bony contours, and (7) focal hyperechoic spikes originating from the subchondral plate and invading the articular cartilage. These findings are discussed.     

RADIOGRAPHIC FEATURES OF PRIMARY AND CONCOMITANT FLEXOR ENTHESOPATHY IN THE CANINE ELBOW

Primary flexor enthesopathy is a recently recognized elbow disorder and should be considered in the differential diagnosis of elbow lameness. For treatment planning purposes, it is important to make a distinction between primary and concomitant forms of the disease. The purpose of this prospective study was to compare radiographic findings for dogs with primary flexor enthesopathy (n = 17), concomitant flexor enthesopathy (n = 24), elbow dysplasia (n = 13), and normal dogs (n = 7). All dogs underwent a complete radiographic examination and each radiographic image was evaluated for the presence or absence of following characteristics: irregular medial humeral epicondyle, spur and calcified body. Additionally, the presence or absence of other elbow disorders (medial coronoid process disease, osteochondritis dissecans, ununited anconeal process, incongruity, subtrochlear sclerosis, and osteoarthritis) was recorded. Radiographic characteristics of flexor enthesopathy were found in 86% of painful joints in the primary flexor enthesopathy group and in 100% of painful joints in the concomitant flexor enthesopathy group. Radiographic characteristics of flexor enthesopathy were not found in sound elbow and elbow dysplasia groups. Frequencies and details of individual radiographic characteristics did not differ between primary and concomitant flexor enthesopathy groups. Findings support the use of radiography as a first screening method for detection of flexor enthesopathy, but not as a technique for distinguishing primary vs. concomitant forms.     

The Histological Appearance of the Proximal Aspect of the Dorsal Condylar Sagittal Ridge of the Third Metacarpal and Metatarsal Bone in Young Warmblood Horses: Normal Appearance and Correlation with Detected Radiographic Variations

The objective of this study is to describe the normal histological appearance of the dorsoproximal aspect of the sagittal ridge of the third metacarpal/metatarsal bone in young Warmblood horses, and to compare it to the different radiographic variations (irregular, indentation, lucency, notch) described at this level. A total of 25 metacarpo/metatarsophalangeal joints of 12 Warmblood horses were used. Five samples of each radiographically described group were selected for histological processing. Each category was compared with the normal control group. Each group showed a bone cortex, covered by hyaline cartilage and longitudinally aligned collagen fibres covered by loosely organized connective tissue proximally. The normal and irregular group showed a smooth bone cortex. In the indentation and lucency group, a depression in the cortex was detected. The notch group presented an expansion of the cortex. The collagen fibres and connective tissue were located in the depression in the indentation group whereas the location varied in the lucency and notch group. The radiologic detected differences are translated into detectable histological differences. Further research is warranted to determine whether these variations are developmental or congenital and to evaluate their potential influence on the joint function during hyperextension.     

Palatal erosion and oronasal fistulation following covered nasopharyngeal stent placement in two dogs

Treatment options for dogs with nasopharyngeal stenosis include fluoroscopic placement of metallic stents. Reported complications include entrapment of hair and food, obstruction and persistent nasal discharge. Two toy breed dogs were examined for persistent nasal discharge and halitosis at 4 and 20 months after placement of permanent metallic stents for acquired nasopharyngeal stenosis. Full thickness defects were found in the palate of both dogs, with extensive communication between the mouth and the nasal passages. Portions of the metal stent were observed within the lesion in both patients. Additional treatment was declined by the owner of one dog; the stent was removed through the fistula in the other dog. Palatal erosion with secondary oronasal fistulation is a potential complication of nasopharyngeal stent placement in dogs.