Liver-Specific Commd1 Knockout Mice Are Susceptible to Hepatic Copper Accumulation

Canine copper toxicosis is an autosomal recessive disorder characterized by hepatic copper accumulation resulting in liver fibrosis and eventually cirrhosis. We have identified COMMD1 as the gene underlying copper toxicosis in Bedlington terriers. Although recent studies suggest that COMMD1 regulates hepatic copper export via an interaction with the Wilson disease protein ATP7B, its importance in hepatic copper homeostasis is ill-defined. In this study, we aimed to assess the effect of Commd1 deficiency on hepatic copper metabolism in mice. Liver-specific Commd1 knockout mice (Commd1Δhep) were generated and fed either a standard or a copper-enriched diet. Copper homeostasis and liver function were determined in Commd1Δhep mice by biochemical and histological analyses, and compared to wild-type littermates. Commd1Δhep mice were viable and did not develop an overt phenotype. At six weeks, the liver copper contents was increased up to a 3-fold upon Commd1 deficiency, but declined with age to concentrations similar to those seen in controls. Interestingly, Commd1Δhep mice fed a copper-enriched diet progressively accumulated copper in the liver up to a 20-fold increase compared to controls. These copper levels did not result in significant induction of the copper-responsive genes metallothionein I and II, neither was there evidence of biochemical liver injury nor overt liver pathology. The biosynthesis of ceruloplasmin was clearly augmented with age in Commd1Δhep mice. Although COMMD1 expression is associated with changes in ATP7B protein stability, no clear correlation between Atp7b levels and copper accumulation in Commd1Δhep mice could be detected. Despite the absence of hepatocellular toxicity in Commd1Δhep mice, the changes in liver copper displayed several parallels with copper toxicosis in Bedlington terriers. Thus, these results provide the first genetic evidence for COMMD1 to play an essential role in hepatic copper homeostasis and present a valuable mouse model for further understanding of the molecular mechanisms underlying hepatic copper homeostasis

Study protocol subacromial impingement syndrome: the identification of pathophysiologic mechanisms (SISTIM)

<p>Abstract</p> <p>Background</p> <p>The Subacromial Impingement Syndrome (SIS) is the most common diagnosed disorder of the shoulder in primary health care, but its aetiology is unclear. Conservative treatment regimes focus at reduction of subacromial inflammatory reactions or pathologic scapulohumeral motion patterns (<it>intrinsic </it>aetiology). Long-lasting symptoms are often treated with surgery, which is focused at enlarging the subacromial space by resection of the anterior part of the acromion (based on <it>extrinsic </it>aetiology). Despite that acromionplasty is in the top-10 of orthopaedic surgical procedures, there is no consensus on its indications and reported results are variable (successful in 48-90%). We hypothesize that the aetiology of SIS, i.e. an increase in subacromial pressure or decrease of subacromial space, is multi-factorial. SIS can be the consequence of pathologic scapulohumeral motion patterns leading to humerus cranialisation, anatomical variations of the scapula and the humerus (e.g. hooked acromion), a subacromial inflammatory reaction (e.g. due to overuse or micro-trauma), or adjoining pathology (e.g. osteoarthritis in the acromion-clavicular-joint with subacromial osteophytes).</p> <p>We believe patients should be treated according to their predominant etiological mechanism(s). Therefore, the objective of our study is to identify and discriminate etiological mechanisms occurring in SIS patients, in order to develop tailored diagnostic and therapeutic strategies.</p> <p>Methods</p> <p>In this cross-sectional descriptive study, applied clinical and experimental methods to identify intrinsic and extrinsic etiologic mechanisms comprise: MRI-arthrography (eligibility criteria, cuff status, 3D-segmented bony contours); 3D-motion tracking (scapulohumeral rhythm, arm range of motion, dynamic subacromial volume assessment by combining the 3D bony contours and 3D-kinematics); EMG (adductor co-activation) and dynamometry instrumented shoulder radiographs during arm tasks (force and muscle activation controlled acromiohumeral translation assessments); Clinical phenotyping (Constant Score, DASH, WORC, and SF-36 scores).</p> <p>Discussion</p> <p>By relating anatomic properties, kinematics and muscle dynamics to subacromial volume, we expect to identify one or more predominant pathophysiological mechanisms in every SIS patient. These differences in underlying mechanisms are a reflection of the variations in symptoms, clinical scores and outcomes reported in literature. More insight in these mechanisms is necessary in order to optimize future diagnostic and treatment strategies for patients with SIS symptoms.</p> <p>Trial registration</p> <p>Dutch Trial Registry (Nederlands Trial Register) <a href="http://www.trialregister.nl/trialreg/admin/rctview.asp?TC=2283">NTR2283</a>.</p

Ion homeostasis in the Chloroplast

peer reviewedThe chloroplast is an organelle of high demand for macro- and micro-nutrient ions, which are required for the maintenance of the photosynthetic process. To avoid deficiency while preventing excess, homeostasis mechanisms must be tightly regulated. Here, we describe the needs for nutrient ions in the chloroplast and briefly highlight their functions in the chloroplastidial metabolism. We further discuss the impact of nutrient deficiency on chloroplasts and the acclimation mechanisms that evolved to preserve the photosynthetic apparatus. We finally present what is known about import and export mechanisms for these ions. Whenever possible, a comparison between cyanobacteria, algae and plants is provided to add an evolutionary perspective to the description of ion homeostasis mechanisms in photosynthesis

Rotator cuff interval reconstruction

Five pairs of cadaveric shoulders underwent posterior and anterior drawer and inferior sulcus tests in five progressive conditions: intact, vented, following opening of the rotator cuff interval, reconstruction of the interval, and transfer of the coracoacromial ligament. The surgical treatments-vented, open rotator cuff interval, reconstruction, and coracoacromial ligament transfer-had an effect compared to the intact shoulders on the inferior stiffness (P=.00002) and on the anteroposterior stiffness (P=.00031). The difference between the stiffness of the reconstructed rotator cuff interval compared to the coracoacromial ligament transfer was significant for loading in the AP direction (P=.006) and for loading in the inferior direction (P=.005)

Application of a multistate model to estimate culvert effects on movement of small fishes

While it is widely acknowledged that culverted road-stream crossings may impede fish passage, effects of culverts on movement of nongame and small-bodied fishes have not been extensively studied and studies generally have not accounted for spatial variation in capture probabilities. We estimated probabilities for upstream and downstream movement of small (30-120 mm standard length) benthic and water column fishes across stream reaches with and without culverts at four road-stream crossings over a 4-6-week period. Movement and reach-specific capture probabilities were estimated using multistate capture-recapture models. Although none of the culverts were complete barriers to passage, only a bottomless-box culvert appeared to permit unrestricted upstream and downstream movements by benthic fishes based on model estimates of movement probabilities. At two box culverts that were perched above the water surface at base flow, observed movements were limited to water column fishes and to intervals when runoff from storm events raised water levels above the perched level. Only a single fish was observed to move through a partially embedded pipe culvert. Estimates for probabilities of movement over distances equal to at least the length of one culvert were low (e.g., generally ≤0.03, estimated for 1-2-week intervals) and had wide 95% confidence intervals as a consequence of few observed movements to nonadjacent reaches. Estimates of capture probabilities varied among reaches by a factor of 2 to over 10, illustrating the importance of accounting for spatially variable capture rates when estimating movement probabilities with capture-recapture data. Longer-term studies are needed to evaluate temporal variability in stream fish passage at culverts (e.g., in relation to streamflow variability) and to thereby better quantify the degree of population fragmentation caused by road-stream crossings with culverts