An integrated care pathway for menorrhagia across the primary–secondary interface : patients' experience, clinical outcomes, and service utilisation

Background: ‘‘Referral’’ characterises a significant area of interaction between primary and secondary care. Despite advantages, it can be inflexible, and may lead to duplication. Objective: To examine the outcomes of an integrated model that lends weight to general practitioner (GP)-led evidence based care. Design: A prospective, non-random comparison of two services: women attending the new (Bridges) pathway compared with those attending a consultant-led one-stop menstrual clinic (OSMC). Patients’ views were examined using patient career diaries, health and clinical outcomes, and resource utilisation. Follow-up was for 8 months. Setting: A large teaching hospital and general practices within one primary care trust (PCT). Results: Between March 2002 and June 2004, 99 women in the Bridges pathway were compared with 94 women referred to the OSMC by GPs from non-participating PCTs. The patient career diary demonstrated a significant improvement in the Bridges group for patient information, fitting in at the point of arrangements made for the patient to attend hospital (ease of access) (p,0.001), choice of doctor (p = 0.020), waiting time for an appointment (p,0.001), and less ‘‘limbo’’ (patient experience of non-coordination between primary and secondary care) (p,0.001). At 8 months there were no significant differences between the two groups in surgical and medical treatment rates or in the use of GP clinic appointments. Significantly fewer (traditional) hospital outpatient appointments were made in the Bridges group than in the OSMC group (p,0.001). Conclusion: A general practice-led model of integrated care can significantly reduce outpatient attendance while improving patient experience, and maintaining the quality of care

Osmotic Water Transport with Glucose in GLUT2 and SGLT

Carrier-mediated water cotransport is currently a favored explanation for water movement against an osmotic gradient. The vestibule within the central pore of Na+-dependent cotransporters or GLUT2 provides the necessary precondition for an osmotic mechanism, explaining this phenomenon without carriers. Simulating equilibrative glucose inflow via the narrow external orifice of GLUT2 raises vestibular tonicity relative to the external solution. Vestibular hypertonicity causes osmotic water inflow, which raises vestibular hydrostatic pressure and forces water, salt, and glucose into the outer cytosolic layer via its wide endofacial exit. Glucose uptake via GLUT2 also raises oocyte tonicity. Glucose exit from preloaded cells depletes the vestibule of glucose, making it hypotonic and thereby inducing water efflux. Inhibiting glucose exit with phloretin reestablishes vestibular hypertonicity, as it reequilibrates with the cytosolic glucose and net water inflow recommences. Simulated Na+-glucose cotransport demonstrates that active glucose accumulation within the vestibule generates water flows simultaneously with the onset of glucose flow and before any flow external to the transporter caused by hypertonicity in the outer cytosolic layers. The molar ratio of water/glucose flow is seen now to relate to the ratio of hydraulic and glucose permeability rather than to water storage capacity of putative water carriers

Understanding Conformational Dynamics of Complex Lipid Mixtures Relevant to Biology

This is a perspective article entitled “Frontiers in computational biophysics: understanding conformational dynamics of complex lipid mixtures relevant to biology” which is following a CECAM meeting with the same name.Fil: Friedman, Ran. Linnæus University; ArgentinaFil: Khalid, Syma. University of Southampton; Reino UnidoFil: Aponte Santamaría, Camilo. Ruprecht-Karls-Universität Heidelberg; Alemania. Universidad de los Andes; ColombiaFil: Arutyunova, Elena. University of Alberta; CanadáFil: Becker, Marlon. Westfälische Wilhelms Universität; AlemaniaFil: Boyd, Kevin J.. University of Connecticut; Estados UnidosFil: Christensen, Mikkel. University Aarhus; DinamarcaFil: Coimbra, João T. S.. Universidad de Porto; PortugalFil: Concilio, Simona. Universita di Salerno; ItaliaFil: Daday, Csaba. Heidelberg Institute for Theoretical Studies; AlemaniaFil: Eerden, Floris J. van. University of Groningen; Países BajosFil: Fernandes, Pedro A.. Universidad de Porto; PortugalFil: Gräter, Frauke. Heidelberg University; Alemania. Heidelberg Institute for Theoretical Studies; AlemaniaFil: Hakobyan, Davit. Westfälische Wilhelms Universität; AlemaniaFil: Heuer, Andreas. Westfälische Wilhelms Universität; AlemaniaFil: Karathanou, Konstantina. Freie Universität Berlin; AlemaniaFil: Keller, Fabian. Westfälische Wilhelms Universität; AlemaniaFil: Lemieux, M. Joanne. University of Alberta; CanadáFil: Marrink, Siewert J.. University of Groningen; Países BajosFil: May, Eric R.. University of Connecticut; Estados UnidosFil: Mazumdar, Antara. University of Groningen; Países BajosFil: Naftalin, Richard. Colegio Universitario de Londres; Reino UnidoFil: Pickholz, Mónica Andrea. Consejo Nacional de Investigaciones Científicas y Técnicas. Oficina de Coordinación Administrativa Ciudad Universitaria. Instituto de Física de Buenos Aires. Universidad de Buenos Aires. Facultad de Ciencias Exactas y Naturales. Instituto de Física de Buenos Aires; ArgentinaFil: Piotto, Stefano. Universita di Salerno; ItaliaFil: Pohl, Peter. Johannes Kepler University; AustriaFil: Quinn, Peter. Colegio Universitario de Londres; Reino UnidoFil: Ramos, Maria J.. Universidad de Porto; PortugalFil: Schiøtt, Birgit. University Aarhus; DinamarcaFil: Sengupta, Durba. National Chemical Laboratory India; IndiaFil: Sessa, Lucia. Universita di Salerno; ItaliaFil: Vanni, Stefano. University Of Fribourg;Fil: Zeppelin, Talia. University Aarhus; DinamarcaFil: Zoni, Valeria. University of Fribourg; SuizaFil: Bondar, Ana-Nicoleta. Freie Universität Berlin; AlemaniaFil: Domene, Carmen. University of Oxford; Reino Unido. University of Bath; Reino Unid

Reptation-Induced Coalescence of Tunnels and Cavities in Escherichia Coli XylE Transporter Conformers Accounts for Facilitated Diffusion

Structural changes and xylose docking to eight conformers of Escherichia Coli XylE, a xylose transporter similar to mammalian passive glucose transporters GLUTs, have been examined. Xylose docks to inward and outward facing conformers at a high affinity central site (K(i) 4–20 µM), previously identified by crystallography and additionally consistently docks to lower affinity sites in the external and internal vestibules (K(i) 12–50 µM). All these sites lie within intramolecular tunnels and cavities. Several local regions in the central transmembrane zone have large positional divergences of both skeleton carbon Cα positions and side chains. One such in TM 10 is the destabilizing sequence G388-P389-V390-C391 with an average RMSD (4.5 ± 0.4 Å). Interchange between conformer poses results in coalescence of tunnels with adjacent cavities, thereby producing a transitory channel spanning the entire transporter. A fully open channel exists in one inward-facing apo-conformer, (PDB 4ja4c) as demonstrated by several different tunnel-finding algorithms. The conformer interchanges produce a gated network within a branched central channel that permits staged ligand diffusion across the transporter during the open gate periods. Simulation of this model demonstrates that small-scale conformational changes required for sequentially opening gate with frequencies in the ns-μs time domain accommodate diffusive ligand flow between adjacent sites with association–dissociation rates in the μs-ms domain without imposing delays. This current model helps to unify the apparently opposing concepts of alternate access and multisite models of ligand transport. ELECTRONIC SUPPLEMENTARY MATERIAL: The online version of this article (doi:10.1007/s00232-014-9711-7) contains supplementary material, which is available to authorized users

Does apical membrane GLUT2 have a role in intestinal glucose uptake? [v1; ref status: indexed, http://f1000r.es/4w6]

It has been proposed that the non-saturable component of intestinal glucose absorption, apparent following prolonged exposure to high intraluminal glucose concentrations, is mediated via the low affinity glucose and fructose transporter, GLUT2, upregulated within the small intestinal apical border. The evidence that the non-saturable transport component is mediated via an apical membrane sugar transporter is that it is inhibited by phloretin, after exposure to phloridzin. Since the other apical membrane sugar transporter, GLUT5, is insensitive to inhibition by either cytochalasin B, or phloretin, GLUT2 was deduced to be the low affinity sugar transport route. As in its uninhibited state, polarized intestinal glucose absorption depends both on coupled entry of glucose and sodium across the brush border membrane and on the enterocyte cytosolic glucose concentration exceeding that in both luminal and submucosal interstitial fluids, upregulation of GLUT2 within the intestinal brush border will usually stimulate downhill glucose reflux to the intestinal lumen from the enterocytes; thereby reducing, rather than enhancing net glucose absorption across the luminal surface. These states are simulated with a computer model generating solutions to the differential equations for glucose, Na and water flows between luminal, cell, interstitial and capillary compartments. The model demonstrates that uphill glucose transport via SGLT1 into enterocytes, when short-circuited by any passive glucose carrier in the apical membrane, such as GLUT2, will reduce transcellular glucose absorption and thereby lead to increased paracellular flow. The model also illustrates that apical GLUT2 may usefully act as an osmoregulator to prevent excessive enterocyte volume change with altered luminal glucose concentrations

A computer model simulating human glucose absorption and metabolism in health and metabolic disease states

A computer model designed to simulate integrated glucose-dependent changes in splanchnic blood flow with small intestinal glucose absorption, hormonal and incretin circulation and hepatic and systemic metabolism in health and metabolic diseases e.g. non-alcoholic fatty liver disease, (NAFLD), non-alcoholic steatohepatitis, (NASH) and type 2 diabetes mellitus, (T2DM) demonstrates how when glucagon-like peptide-1, (GLP-1) is synchronously released into the splanchnic blood during intestinal glucose absorption, it stimulates superior mesenteric arterial (SMA) blood flow and by increasing passive intestinal glucose absorption, harmonizes absorption with its distribution and metabolism. GLP-1 also synergises insulin-dependent net hepatic glucose uptake (NHGU). When GLP-1 secretion is deficient post-prandial SMA blood flow is not increased and as NHGU is also reduced, hyperglycaemia follows. Portal venous glucose concentration is also raised, thereby retarding the passive component of intestinal glucose absorption.   Increased pre-hepatic sinusoidal resistance combined with portal hypertension leading to opening of intrahepatic portosystemic collateral vessels are NASH-related mechanical defects that alter the balance between splanchnic and systemic distributions of glucose, hormones and incretins.The model reveals the latent contribution of portosystemic shunting in development of metabolic disease. This diverts splanchnic blood content away from the hepatic sinuses to the systemic circulation, particularly during the glucose absorptive phase of digestion, resulting in inappropriate increases in insulin-dependent systemic glucose metabolism.  This hastens onset of hypoglycaemia and thence hyperglucagonaemia. The model reveals that low rates of GLP-1 secretion, frequently associated with T2DM and NASH, may be also be caused by splanchnic hypoglycaemia, rather than to intrinsic loss of incretin secretory capacity. These findings may have therapeutic implications on GLP-1 agonist or glucagon antagonist usage

Multiple Interactions of Glucose with the Extra-Membranous Loops of GLUT1 Aid Transport

Molecular dynamics simulations amounting to ≈8 μs demonstrate that the glucose transporter GLUT1 undergoes structural fluctuations mediated by the fluidity of the lipid bilayer and the proximity to glucose. The fluctuations of GLUT1 increase as the glucose concentration is raised. These fluctuations are more pronounced when the lipid bilayer is in the fluid compared to the gel phase. Glucose interactions are confined to the extra-membranous residues when the lipid is in the gel phase but diffuses into the transmembrane regions in the fluid phase. Proximity of glucose to GLUT1 causes asynchronous expansions of key bottlenecks at the internal and external openings of the central pore. This is accomplished only by small conformational changes at the single residue level that lower the resistance to glucose movements, thereby permitting unsteered glucose and water movements along the entire length of the pore. When glucose is near salt bridges located at the external and internal openings of the central pore, the distance separating the polar amino acid residues guarding these apertures tends to increase in both fluid and gel phases. It is evident that the multiplicity of glucose interactions, obtained with high concentrations, amplifies the structural fluctuations in GLUT1. The findings that most of the salt bridges and the bottlenecks appear to be operated by glucose proximity suggest that the main triggers to activation of transport are located within the solvent accessible linker regions in the extramembranous zones.</p