The Carboxy-Terminal Modulator Protein (CTMP) Regulates Mitochondrial Dynamics

Background: Mitochondria are central to the metabolism of cells and participate in many regulatory and signaling events. They are looked upon as dynamic tubular networks. We showed recently that the Carboxy-Terminal Modulator Protein (CTMP) is a mitochondrial protein that may be released into the cytosol under apoptotic conditions.

Prospective Evaluation of Clinical and Ultrasound Findings in Ankle Disease in Juvenile Idiopathic Arthritis: Importance of Ankle Ultrasound

Objective. To prospectively compare clinical examination of the ankle structures with ultrasound (US) findings. Methods. In 42 children with juvenile idiopathic arthritis (JIA; 25 girls, 17 boys, mean age 11.3 yrs, range 2.3–22.3 yrs), a total of 61 swollen/painful ankles were assessed clinically and ultrasonographically. Accurate clinical examination of the entire ankle joint was performed, focusing especially on 3 regions — tibiotalar joint and medial and lateral tendons. Clinical and US findings were both scored 0–3 (normal-severe). Results. US demonstrated no signs of tibiotalar joint effusion in 14 out of 43 ankles considered clinically involved. For the medial tendons, US showed tenosynovitis in 13 ankles out of 31 thought to be clinically normal; and for the lateral tendons, of the 19 deemed to be clinically involved, less than 50% had involvement on US. Very poor agreement was observed comparing the clinical and US scores for the 3 regions: tibiotalar joint, kappa = 0.3; medial tendons, kappa = 0.24; lateral tendons, kappa = 0.25. With regard to other ankle structures, only 39% of the subtalar (talocalcaneal) joints considered clinically involved were deemed abnormal on US. Finally, of the 10 ankles with talonavicular US effusion, only 2 were considered clinically involved. Conclusion. Using US findings as the “gold standard,” clinical examination of the ankle in children with JIA was found to be inadequate in identifying the structures involved. US assessment prior to any glucocorticoid injection should be considered to improve the outcome. A prospective study comparing the outcome following clinical- versus US-guided ankle joint injection should be undertaken, to confirm our findings.

Residual stress due to curing can initiate damage in porous bone cement: experimental and theoretical evidence

Residual stress due to shrinkage of polymethylmethacrylate bone cement after polymerisation is possibly one factor capable of initiating cracks in the mantle of cemented hip replacements. No relationship between residual stress and observed cracking of cement has yet been demonstrated. To investigate if any relationship exists, a physical model has been developed which allows direct observation of damage in the cement layer on the femoral side of total hip replacement. The model contains medial and lateral cement layers between a bony surface and a metal stem; the tubular nature of the cement mantle is ignored. Five specimens were prepared and examined for cracking using manual tracing of stained cracks, observed by transmission microscopy: cracks were located and measured using image analysis. A mathematical approach for the prediction of residual stress due to shrinkage was developed which uses the thermal history of the material to predict when stress-locking occurs, and estimates subsequent thermal stress. The residual stress distribution of the cement layer in the physical model was then calculated using finite element analysis. Results show maximum tensile stresses normal to the observed crack directions, suggesting a link between residual stress and preload cracking. The residual stress predicted depends strongly on the definition of the reference temperature for stress-locking. The highest residual stresses (4-7 MPa) are predicted for shrinkage from maximum temperature, in this case, magnitudes are sufficiently high to initiate cracks when the influence of stress raisers such as pores or interdigitation at the bone/cement interface are taken into account (up to 24 MPa when calculating stress around a pore according to the method of Harrigan and Harris (J. Biomech. 24(11) (1991) 1047-1058)). We conclude that the damage accumulation failure scenario begins before weight-bearing due to cracking induced by residual stress around pores or stress raisers. (C) 2002 Elsevier Science Ltd. All rights reserved.

Pull-out behaviour of axially loaded basalt fibre reinforced polymer (BFRP) rods bonded parallel to the grain of glulam elements

Synopsis: Bonded-in rod timber joints off er several advantages over conventional types of joint, including high local force transfer, very stiff connections, and improved ?re and aesthetic properties since the connection is completely hidden in the insulating timber members. More recently, the use of ?bre reinforced polymer (FRP) as a connecting rod, alternative to steel rods, in bonded-in rod connections for timber structures has been investigated. However, the investigation into the behaviour of such joints is limited, in particular, connections involving basalt ?bre reinforced polymers (BFRP) bars - which is the primary focus of this research. This paper presents an experimental programme conducted to investigate the behaviour of bonded-in BFRP bars loaded parallel to the grain of glulam members. Tensile pull-out tests were conducted to examine the effect of bonded length and bond stress-slip on the structural capacity of the connection. An analytical design expression for predicting pull-out capacity is proposed and the results have been compared with some established design equations. It was found that pull-out load increased approximately linearly with the bonded length, up to maximum which occurred at a bonded length of 15 times the hole diameter, and did not increase beyond this bonded length. The most signi?cant failure modes were failure at the timber/adhesive interface followed by pullout of the BFRP rod. Increased bonded lengths resulted in higher bond slip values compared to lower equivalent bonded lengths. The proposed design model gave the best predictions of pull-out capacity compared with other existing models.

Stiffness prediction for bolted moment-connections between cold-formed steel members

The authors have recently described a cold-formed steel portal framing system in which simple bolted moment-connections, formed through brackets, were used for the eaves and apex joints. Such connections, however, cannot be considered as rigid because of localised in-plane elongation of the bolt-holes caused by bearing against the bolt-shanks. To therefore predict the initial stiffness of such connections, it is necessary to know the initial bolt-hole elongation stiffness k(b). In this paper, a finite element-solid idealisation of a bolted lap joint in shear will be described that can be used to determine k(b); the results obtained are validated against experimental data. A beam idealisation of a cold-formed steel bolted moment-connection is then described, in which spring elements are used to idealise the rotational flexibility of the bolt-groups resulting from bolt-hole elongation: Using the value of k(b) in the beam idealisation, the deflections predicted are shown to be similar to those measured experimentally in laboratory tests conducted on the apex joint of a cold-formed steel portal frame. (C) 2003 Elsevier Ltd. All rights reserved.

Ultimate strength of bolted moment-connections between cold-formed steel members

The behaviour and design of bolted moment-connections between cold-formed steel members, formed by using brackets bolted to the webs of the section, is considered. The particular problem of the moment-capacity of such joints being lower than that of the cold-formed steel sections being connected because of web buckling, caused by the concentration of load transfer from the bolts, is addressed. In this paper, a combination of laboratory tests and finite element analyses is used to investigate this mode of failure. It is demonstrated that there is good agreement between the measured ultimate moment-capacity and that predicted by using the finite element method. A parametric study conducted using the finite element model shows that the moment-capacity of a practical size joint can be up to 20% lower than that of the cold-formed steel sections being connected. Web buckling so-caused must therefore be considered in the design of such connections. (C) 2003 Elsevier Ltd. All rights reserved.

Finite element idealization of a cold-formed steel portal frame

A simple linear beam idealization of a cold-formed steel portal frame is presented in which beam elements are used to idealize the column and rafter members, and rotational spring elements are used to represent the rotational flexibility of the joints. In addition, the beam idealization takes into account the finite connection length of the joints. Deflections predicted using the beam idealization are shown to be comparable to deflections obtained from both a linear finite element shell idealization and full-scale laboratory tests. Using the beam idealization, deflections under rafter load are divided into three components: Deflection due to flexure of the column and rafter members, deflection due to bolt-hole elongation, and deflection due to in-plane bracket deformation. Of these deflection components, the deflection due to bolt-hole elongation is the most significant and cannot, therefore, be ignored. Using the beam idealization, engineers can analyze and design cold-formed steel portal frames, including making appropriate allowances for connection effects, without the need to resort to expensive finite element shell analysis.

Effects of elevated temperatures on bolted moment-connections between cold-formed steel members

Experimental investigations at ambient temperature into the behaviour of bolted moment-connections between cold-formed steel members have previously been described. Full-scale joint tests have demonstrated that the channel-sections being connected are susceptible to premature failure, the result of web buckling caused by the concentration of load transfer from the bolts. The results of tests on bolted lap joints have been used to propose design recommendations for the shear strength in bearing of the bolt-hole. For both types of test, the results of non-linear elasto-plastic finite element analyses have been shown to have good agreement. No consideration, however, has been given to the behaviour of such connections at elevated temperatures. This paper describes non-linear elasto-plastic finite element parametric studies into the effects of elevated temperatures on bolted moment-connections between cold-formed steel members. Two issues at elevated temperatures are investigated:

IHG-1 amplifies TGF-beta1 signaling and is increased in renal fibrosis

Induced in high glucose-1 (IHG-1) is an evolutionarily conserved gene transcript upregulated by high extracellular glucose concentrations, but its function is unknown. Here, it is reported that the abundance of IHG-1 mRNA is nearly 10-fold higher in microdissected, tubule-rich renal biopsies from patients with diabetic nephropathy compared with control subjects. In the diabetic nephropathy specimens, in situ hybridization localized IHG-1 to tubular epithelial cells along with TGF-beta1 and activated Smad3, suggesting a possible role in the development of tubulointerstitial fibrosis. Supporting this possibility, IHG-1 mRNA and protein expression also increased with unilateral ureteral obstruction. In the HK-2 proximal tubule cell line, overexpression of IHG-1 increased TGF-beta1-stimulated expression of connective tissue growth factor and fibronectin. IHG-1 was found to amplify TGF-beta1-mediated transcriptional activity by increasing and prolonging phosphorylation of Smad3. Conversely, inhibition of endogenous IHG-1 with small interference RNA suppressed transcriptional responses to TGF-beta1. In summary, IHG-1, which increases in diabetic nephropathy, may enhance the actions of TGF-beta1 and contribute to the development of tubulointerstitial fibrosis.

The effect of hypobaric hypoxia on misonidazole binding in normal and tumour-bearing mice

The effect of hypobaric hypoxia on the in vivo binding of misonidazole was investigated in normal mice and mice bearing T50/80 or CA NT mammary carcinomas. After the intraperitoneal injection of radiolabelled misonidazole, mice were randomised to breathe either room air or air at 0.5 atmospheres. The distribution of misonidazole in liver, kidney, heart, spleen and tumour tissue, 24 h later, was studied by scintillation counting and by autoradiography. Significantly higher misonidazole binding occurred in the livers (x2.5), kidneys (x2.4), spleens (x2.9) and hearts (x1.8) of hypoxic mice compared to controls. Hypobaric hypoxia was associated with a greater than four-fold increase in misonidazole binding within T50/80 tumours. However, significantly higher binding was not demonstrated within CA NT tumours after exposure of tumour-bearing animals to hypoxic conditions. In autoradiographs of hypoxic liver, labelling was intense in regions near to hepatic veins but sparse in areas surrounding portal tracts. This pattern was striking and consistent. In hypoxic kidney, labelling was most intense over tubular cells, less intense over glomeruli and sparse in the renal medulla. It is likely that the hepatic and renal cortical distributions of misonidazole binding reflect local oxygen gradients.

Influence of progressive renal dysfunction in chronic heart failure

Chronic heart failure (CHF) is often associated with impaired renal function due to hypoperfusion. Such patients are very sensitive to changes in renal perfusion pressure, and may develop acute tubular necrosis if the pressure falls too far. The situation is complicated by the use of diuretics, ACE inhibitors and spironolactone, all of which may affect renal function and potassium balance. Chronic renal failure (CRF) may also be associated with fluid overload. Anaemia and hypertension in CRF contribute to the development of left ventricular hypertrophy (LVH), which carries a poor prognosis, so correction of these factors is important.

Genetic renal abnormalities

Inherited disorders of renal structure and function are relatively common causes of end-stage renal disease requiring renal replacement therapy. A family history of haematuria, urinary tract infection or renal failure can alert the clinician to the possible diagnosis of underlying renal genetic abnormalities. In practice, the commonest inherited renal disorder is autosomal dominant polycystic kidney disease (ADPKD), characterized by multiple kidney cysts associated with hypertension and renal failure. Insights into the cell biology of ADPKD are informing new therapeutic approaches to limit cyst growth and prevent progressive renal failure. Non-visible haematuria is a clinical finding that presents a diagnostic challenge because it has so many possible causes. Mutations in the genes encoding collagen proteins within the glomerular basement membrane (GBM) can disrupt its normal barrier function. Thin basement membrane nephropathy, caused by GBM collagen gene mutations, is a relatively common cause of familial haematuria that normally has a good long-term prognosis. Alport syndrome is a rare and genetically heterogeneous condition leading to renal failure in men inheriting the X-linked gene defect. Single-gene defects may cause diverse renal tubular disorders, such as predisposition to renal calculi, diabetes insipidus, renal tubular acidosis or hypertension with associated electrolyte imbalance. Gene mutations responsible for familial renal cancer syndromes, such as tuberous sclerosis complex and von Hippel–Lindau disease, have also been identified

Vitamin D binding protein isoforms as candidate predictors of disease extension in childhood arthritis

Introduction: Juvenile idiopathic arthritis (JIA) comprises a poorly understood group of chronic autoimmune diseases with variable clinical outcomes. We investigated whether the synovial fluid (SF) proteome could distinguish a subset of patients in whom disease extends to affect a large number of joints.

Methods: SF samples from 57 patients were obtained around time of initial diagnosis of JIA, labeled with Cy dyes and separated by two-dimensional electrophoresis. Multivariate analyses were used to isolate a panel of proteins which distinguish patient subgroups. Proteins were identified using MALDI-TOF mass spectrometry with expression verified by immunochemical methods. Protein glycosylation status was confirmed by hydrophilic interaction liquid chromatography.

Results: A truncated isoform of vitamin D binding protein (VDBP) is present at significantly reduced levels in the SF of oligoarticular patients at risk of disease extension, relative to other subgroups (p < 0.05). Furthermore, sialylated forms of immunopurified synovial VDBP were significantly reduced in extended oligoarticular patients (p < 0.005).

Conclusion: Reduced conversion of VDBP to a macrophage activation factor may be used to stratify patients to determine risk of disease extension in JIA patients.

An Experimental and Numerical Study of the Static and Fatigue Performance of a Composite Adhesive Repair

Experimental static and fatigue tension-tension tests were carried out on 5HS/RTM6 composite intact coupons and coupons incorporating adhesively-bonded (FM300-2) stepped flush joints. The results show that the adhesive joint, which is widely used in repairs, significantly reduces the static strength as well as the fatigue life of the composite. Both, the static and the fatigue failure of the ‘repaired’ coupons occur at the adhesive joint and involve crack initiation and propagation. The latter is modelled using interface finite elements based on the decohezive zone approach. The material degradation in the interface constitutive law is described by a damage variable, which can evolve due to the applied loads as well as the number of fatigue cycles. The fatigue formulation, based on a published model, is adapted to fit the framework of the pseudotransient formulation that is used as a numerical tool to overcome convergence difficulties. The fatigue model requires three material parameters. Numerical tests show that a single set of these parameters can be used to recover, very accurately, the experimental S-N relationship. Sensitivity studies show that the results are not mesh dependent.

Pull-out behaviour of axially loaded Basalt Fibre Reinforced Polymer (BFRP) rods bonded perpendicular to the grain of glulam elements

The behaviour of Basalt Fibre Reinforced Polymer (BFRP) loaded perpendicular to glulam timber elements was investigated. It was found that pull-out load increased approximately linearly with the bonded length up to maximum which occurred at a bonded length of 250 mm (~15 times the hole diameter) and did not increase beyond this bonded length. Failure mode of the samples was mostly shear fracture which was located at the cylindrical zone at the timber/adhesive interface. Increased bonded lengths resulted in corresponding decrease in interfacial bond stress. At 250 mm bonded length, the pull-out capacity of the proposed design model was about 2% lower than that of the tests. The results also showed that the bond stress of the theoretical model (at the ascending and descending branches) of the stress–slip curve was approximately 5–10% of that of the experiment.