Patients with AP often develop prediabetes and/or DM after discharge from hospital, and have a greater than twofold increased risk of DM over 5 years. Further studies are warranted to determine the optimal strategy for its detection and whether the risk of developing DM after AP can be reduced.
Available evidence showed increased risk of poor graft outcome in moderate-severe steatotic livers. A large prospective multi-centred trial will be required to identify the true risks of steatotic livers. Consistent definition of primary non-function/impaired primary function and description of type of steatosis is also required.
Aims/hypothesis Cu(II)-selective chelation with trientine ameliorates cardiovascular and renal disease in a model of diabetes in rats. Here, we tested the hypothesis that Cu(II)-selective chelation might improve left ventricular hypertrophy (LVH) in type 2 diabetic patients. Methods We performed a 12 month randomised placebocontrolled study of the effects of treatment with the Cu (II)-selective chelator trientine (triethylenetetramine dihydrochloride, 600 mg given orally twice daily) on LVH in diabetic patients (n=15/group at baseline) in an outpatient setting wherein participants, caregivers and those assessing outcomes were blinded to group assignment. Using MRI, we measured left ventricular variables at baseline, and at months 6 and 12. The change from baseline in left ventricular mass indexed to body surface area (LVM bsa ) was the primary endpoint variable.Results Diabetic patients had LVH with preserved ejection fraction at baseline. Trientine treatment decreased LVM bsa by 5.0± 7.2 g/m 2 (mean ±SD) at month 6 (when 14 trientine-treated and 14 placebo-treated participants were analysed; p=0.0056 compared with placebo) and by 10.6± 7.6 g/m 2 at month 12 (when nine trientine-treated and 13 placebo-treated participants were analysed; p=0.0088), whereas LVM bsa was unchanged by placebo treatment. In a multiple-regression model that explained~75% of variation (R 2 =0.748, p=0.001), cumulative urinary Cu excretion over 12 months was positively associated with trientine-evoked decreases in LVM bsa . Conclusions/interpretation Cu(II)-selective chelation merits further exploration as a potential pharmacotherapy for diabetic heart disease.
BackgroundVenous leg ulcers can be very hard to heal and represent a significant medical need with no effective therapeutic treatment currently available.Principal FindingsIn wound edge biopsies from human venous leg ulcers we found a striking upregulation of dermal N-cadherin, Zonula Occludens-1 and the gap junction protein Connexin43 (Cx43) compared to intact skin, and in stark contrast to the down-regulation of Cx43 expression seen in acute, healing wounds. We targeted the expression of these proteins in 3T3 fibroblasts to evaluate their role in venous leg ulcers healing. Knockdown of Cx43 and N-cadherin, but not Zonula Occludens-1, accelerated cell migration in a scratch wound-healing assay. Reducing Cx43 increased Golgi reorientation, whilst decreasing cell adhesion and proliferation. Furthermore, Connexin43 and N-cadherin knockdown led to profound effects on fibroblast cytoskeletal dynamics after scratch-wounding. The cells exhibited longer lamelipodial protrusions lacking the F-actin belt seen at the leading edge in wounded control cells. This phenotype was accompanied by augmented activation of Rac-1 and RhoA GTPases, as revealed by Förster Resonance Energy Transfer and pull down experiments.ConclusionsCx43 and N-cadherin are potential therapeutic targets in the promotion of healing of venous leg ulcers, by acting at least in part through distinct contributions of cell adhesion, migration, proliferation and cytoskeletal dynamics.
Understanding of the microvasculature has previously been limited by the lack of methods capable of capturing and modelling complete vascular networks. We used novel imaging and computational techniques to establish the topology of the entire blood vessel network of a murine lymph node, combining 63706 confocal images at 2 μm pixel resolution to cover a volume of 3.88 mm3. Detailed measurements including the distribution of vessel diameters, branch counts, and identification of voids were subsequently re-visualised in 3D revealing regional specialisation within the network. By focussing on critical immune microenvironments we quantified differences in their vascular topology. We further developed a morphology-based approach to identify High Endothelial Venules, key sites for lymphocyte extravasation. These data represent a comprehensive and continuous blood vessel network of an entire organ and provide benchmark measurements that will inform modelling of blood vessel networks as well as enable comparison of vascular topology in different organs.
BACKGROUND AND PURPOSE Amylin (Amy) is an important glucoregulatory peptide and AMY receptors are clinical targets for diabetes and obesity. Human (h) AMY receptor subtypes are complexes of the calcitonin (CT) receptor with receptor activity‐modifying proteins (RAMPs); their rodent counterparts have not been characterized. To allow identification of the most clinically relevant receptor subtype, the elucidation of rat (r) AMY receptor pharmacology is necessary. EXPERIMENTAL APPROACH Receptors were transiently transfected into COS‐7 cells and cAMP responses measured in response to different agonists, with or without antagonists. Competition binding experiments were performed to determine rAmy affinity. KEY RESULTS rCT was the most potent agonist of rCT(a) receptors, whereas rAmy was most potent at rAMY1(a) and rAMY3(a) receptors. rAmy bound to these receptors with high affinity. Rat α‐calcitonin gene‐related peptide (CGRP) was equipotent to rAmy at both AMY receptors. Rat adrenomedullin (AM) and rAM2/intermedin activated all three receptors but were most effective at rAMY3(a). AC187, AC413 and sCT8‐32 were potent antagonists at all three receptors. rαCGRP8‐37 displayed selectivity for rAMY receptors over rCT(a) receptors. rAMY8‐37 was a weak antagonist but was more effective at rAMY1(a) than rAMY3(a). CONCLUSIONS AND IMPLICATIONS AMY receptors were generated by co‐expression of rCT(a) with rRAMP1 or 3, forming rAMY1(a) and rAMY3(a) receptors, respectively. CGRP was more potent at rAMY than at hAMY receptors. No antagonist tested was able to differentiate the rAMY receptor subtypes. The data emphasize the need for and provide a useful resource for developing new CT or AMY receptor ligands as pharmacological tools or potential clinical candidates. LINKED ARTICLES This article is part of a themed section on Secretin Family (Class B) G Protein‐Coupled Receptors. To view the other articles in this section visit http://dx.doi.org/10.1111/bph.2012.166.issue-1
The thoracic duct (TD) transports ingested fat, drains lymph from the gastrointestinal vascular bed, and delivers the lymph to central veins in the neck. Preliminary evidence suggests that diversion of TD lymph may mitigate the severity of end-organ dysfunction in critical illness. Variations in the anatomy of the TD may determine whether reliable and safe cannulation of the duct, a necessary step for diversion, is possible. A systematic review was undertaken using the Google Scholar, MEDLINE, PubMed, and Scopus databases until 31st March, 2013. Both English and non-English articles were searched for, and surgical, cadaveric, and radiologic studies were included. Fifty-seven articles from the past 102 years were retrieved. There are significant variations in the anatomy of the TD in terms of its formation at the cisterna chyli, its course through the thorax, and its termination in the venous system. The most common site of termination is at the internal jugular vein (46%), followed by the jugulosubclavian angle (32%), and the subclavian vein (18%). An improved understanding of the anatomy of the TD would help surgeons to avoid inadvertent injury and potentially afford new opportunities for diagnosis and intervention in patients with critical illness.
Renal lymphatics are abundant in the cortex of the normal kidney but have been largely neglected in discussions around renal diseases. They originate in the substance of the renal lobule as blind-ended initial capillaries, and can either follow the main arteries and veins toward the hilum, or penetrate the capsule to join capsular lymphatics. There are no valves present in interlobular lymphatics, which allows lymph formed in the cortex to exit the kidney in either direction. There are very few lymphatics present in the medulla. Lymph is formed from interstitial fluid in the cortex, and is largely composed of capillary filtrate, but also contains fluid reabsorbed from the tubules. The two main factors that contribute to renal lymph formation are interstitial fluid volume and intra-renal venous pressure. Renal lymphatic dysfunction, defined as a failure of renal lymphatics to adequately drain interstitial fluid, can occur by several mechanisms. Renal lymphatic inflow may be overwhelmed in the setting of raised venous pressure (e.g., cardiac failure) or increased capillary permeability (e.g., systemic inflammatory response syndrome). Similarly, renal lymphatic outflow, at the level of the terminal thoracic duct, may be impaired by raised central venous pressures. Renal lymphatic dysfunction, from any cause, results in renal interstitial edema. Beyond a certain point of edema, intra-renal collecting lymphatics may collapse, further impairing lymphatic drainage. Additionally, in an edematous, tense kidney, lymphatic vessels exiting the kidney via the capsule may become blocked at the exit point. The reciprocal negative influences between renal lymphatic dysfunction and renal interstitial edema are expected to decrease renal function due to pressure changes within the encapsulated kidney, and this mechanism may be important in several common renal conditions.
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