Mutation of juxtamembrane tyrosine residue 1001 suppresses loss-of-function mutations of the met receptor in epithelial cells.

Signals transduced by the met tyrosine kinase, which is the receptor for scatter factor/hepatocyte growth factor, are of major importance for the regulation of epithelial cell motility, morphogenesis, and proliferation. We report here that different sets of tyrosine residues in the cytoplasmic domain of the met receptor affect signal transduction in epithelial cells in a positive or negative fashion: mutation of the C-terminal tyrosine residues 13-16 (Y1311, Y1347, Y1354, and Y1363) reduced or abolished ligand-induced cell motility and branching morphogenesis. In contrast, mutation of the juxtamembrane tyrosine residue 2 (Y1001) produced constitutively mobile, fibroblastoid cells. Furthermore, the gain-of-function mutation of tyrosine residue 2 suppressed the loss-of-function mutations of tyrosine residue 15 or 16. The opposite roles of the juxtamembrane and C-terminal tyrosine residues may explain the suggested dual function of the met receptor in both epithelial-mesenchymal interactions and tumor progression.

SCAPHOID AND LUNATE CARPAL MECHANICS OVER THE SPECTRUM OF HEALTHY FUNCTION

When ligaments within the wrist are damaged, the resulting loss in range of motion and grip strength can lead to reduced earning potential and restricted ability to perform important activities of daily living. Left untreated, ligament injuries ultimately lead to arthritis and chronic pain. Surgical repair can mitigate these issues but current procedures are often non-anatomic and unable to completely restore the wrist’s complex network of ligaments. An inability to quantitatively assess wrist function clinically, both before and after surgery, limits the ability to assess the response to clinical intervention. Previous work has shown that bones within the wrist move in a similar pattern across people, but these patterns remain challenging to predict and model. In an effort to quantify and further develop the understanding of normal carpal mechanics, we performed two studies using 3D in vivo carpal bone motion analysis techniques. For the first study, we measured wrist laxity and performed CT scans of the wrist to evaluate 3D carpal bone positions. We found that through mid-range radial-ulnar deviation range of motion the scaphoid and lunate primarily flexed and extended; however, there was a significant relationship between wrist laxity and row-column behaviour. We also found that there was a significant relationship between scaphoid flexion and active radial deviation range of motion. For the second study, an analysis was performed on a publicly available database. We evaluated scapholunate relative motion over a full range of wrist positions, and found that there was a significant amount of variation in the location and orientation of the rotation axis between the two bones. Together the findings from the two studies illustrate the complexity and subject specificity of normal carpal mechanics, and should provide insights that can guide the development of anatomical wrist ligament repair surgeries that restore normal function.

Lameness, metabolic and digestive disorders, and technical efficiency in Danish dairy herds: a stochastic frontier production function approach

The relationship between reported treatments of lameness, metabolic disorders (milk fever, ketosis), digestive disorders, and technical efficiency (TE) was investigated using neutral and non-neutral stochastic frontier analysis (SFA). TE is estimated relative to the stochastic frontier production function for a sample of 574 Danish dairy herds collected in 1997. Contrary to most published results, but in line with the expected negative impact of disorders on the average cow milk production, herds reporting higher frequencies of milk fever are less technically efficient. Unexpectedly, however, the opposite results were observed for lameness, ketosis, and digestive disorders. The non-neutral stochastic frontier indicated that the opposite results are due to the relative. high productivities of inputs. The productivity of the cows is also reflected by the direction of impact of herd management variables. Whereas efficient farms replace cows more frequently, enroll heifers in production at an earlier age, and have shorter calving intervals, they also report higher frequency of disorder treatments. The average estimated energy corrected milk loss per cow is 1036, 451 and 242 kg for low, medium and high efficient farms. The study demonstrates the benefit of the stochastic frontier production function involving the estimation of individual technical efficiencies to evaluate farm performance and investigate the source of inefficiency. (C) 2004 Elsevier B.V. All rights reserved.

Australian norms for a quantitative olfactory function test

Quantitative olfactory assessment is often neglected in clinical practice, although olfactory loss can assist diagnosis and leads to significant morbidity. The aim of this study was to develop normative data for the Australian population for the 'Sniffin' Sticks', an internationally established olfactory function test. As in other populations, Australian females performed better than males and both lost olfactory function with age. From the normative data, criterion test scores for males and females were established for clinical classifications ('normosmic', 'hyposmic', and 'anosmic'). These clinical classifications were assessed in Parkinson's patients: 81.1 % were anosmic or severely hyposmic and only 7.7% were normosmic. A new term ('prebyosmia') is introduced to describe age-related loss of olfactory capacity of unknown aetiology. With these norms, the Sniffin' Sticks can be used in the Australian population to compare an individual's olfactory function against the population of others of similar age and sex and to identify olfactory dysfunction. (C) 2003 Elsevier Ltd. All rights reserved.

Neonatal calyceal dilation and renal fibrosis resulting from loss of Adamts-1 in mouse kidney is due to a developmental dysgenesis

Background. A disintegrin and metalloproteinase with thrombospondin motifs 1, Adamts-1, is important for the development and function of the kidney. Mice lacking this protein present with renal lesions comprising enlarged calyces, and reduced cortex and medulla layers. Our current findings are consistent with the defect occurring due to a developmental dysgenesis. Methods. We generated Adamts-1 null mice, and further investigated their kidney phenotype in a time course study ranging from E18.5 to 12 months of age. Immunohistochemistry was used to assess the localization of type IV collagen, TGF-beta and F4/80-positive macrophages in the kidneys of Adcants-1 null mice compared to wild-type control animals. The expression of Adamts-1 mRNA was determined in metanephric kidney explants by in situ hybridization. Results. Adamts-1 null mice have a gross kidney defect. At day 18.5 of gestation, the Adcants-1 null kidney has a normal appearance but at birth when the kidney begins to function, the defect becomes evident. During development of the kidney Adamts-1 expression was specifically detected in the developing loops of Henle, as well as in the proximal and distal convoluted tubules. Expression was not detected in the ureter, ureteric bud or its derivatives as had been previously suggested. At 6 months and I year of age, the Adamts-1 null mice displayed interstitial fibrosis in the cortical and medullary regions of the kidney. At I year of age, the Adamts-1 null mice displayed mild interstitial matrix expansion associated with increased collagen type IV expression, without apparent tubular dilatation, compared to wild-type animals. Immunohistochemical analysis demonstrated TGF-beta protein localized to infiltrating macrophages and glomeruli of Adamts-1 null mice. Conclusions. Adamts-1 is required for the normal development of the kidney. The defect observed in its absence results from a dysgenic malformation affecting the medulla that becomes apparent at birth, once the kidneys start to function.

Mapping loss of heterozygosity in normal human breast cells from BRCA1/2 carriers

We have studied loss of heterozygosity at the BRCA1 and BRCA2 loci in 992 normal cell clones derived from topographically defined areas of normal tissue in four samples from BRCA1/BRCA2 mutation carriers. The frequency of loss of heterozygosity in the clones was low ( 1.01%), but it was found in all four samples, whether or not a tumour was present. Topographical mapping revealed that the genetic changes were clustered in some breast samples. Our study confirms the previous finding that a field of genetic instability can exist around a tumour, suggesting that sufficient tissue must be removed at surgery to avoid local recurrence. We also demonstrate that such a field of genetic change can exist in morphologically normal tissue before a tumour develops and, for the first time, we demonstrate that the field is of a size greater than one terminal duct-lobular unit. The genetic changes are not identical, however, which suggests that genetic instability in these regions may play an early role in tumour development. We also confirm and extend our original observation of loss of the wild-type BRCA1 allele in some clones, and loss of the mutant allele in others, demonstrating that loss of either allele is a stochastic event.

Normal ranges for automated analysis of global LV function using 2D Strain

Background: Automated measurement of LV function could extend the clinical utility of echo by less expert readers. We sought to define normal ranges of global 2D strain (2DS) and strain-rate (SR) in an international, multicenter study of healthy subjects, and to assess the determinants of variation. Methods: SR and 2DS were measured in 18 myocardial segts in both apical and short axis views of 227 normal subjects (38% men, 48±14y) with no cardiac history, risk factors or drug therapy. The association of age and resting hemodynamics with global strain indices was sought using multiple regression. Differences in variance were expressed as F values. Results: Baseline SBP was 127±18 mmHg, pulse was 76±13/min and ejection fraction 50±20%. Although global longitudinal strain was influenced by endsystolic volume (F=4.2, p