The effectiveness of case management for comorbid diabetes type 2 patients; the CasCo study. Design of a randomized controlled trial

BACKGROUND: More than half of the patients with type 2 diabetes (T2DM) patients are diagnosed with one or more comorbid disorders. They can participate in several single-disease oriented disease management programs, which may lead to fragmented care because these programs are not well prepared for coordinating care between programs. Comorbid patients are therefore at risk for suboptimal treatment, unsafe care, inefficient use of health care services and unnecessary costs. Case management is a possible model to counteract fragmented care for comorbid patients. It includes evidence-based optimal care, but is tailored to the individual patients' preferences.The objective of this study is to examine the effectiveness of a case management program, in addition to a diabetes management program, on the quality of care for comorbid T2DM patients. METHODS/DESIGN: The study is a randomized controlled trial among patients with T2DM and at least one comorbid chronic disease (N=230), who already participate in a diabetes management program. Randomization will take place at the level of the patients in general practices. Trained practice nurses (case managers) will apply a case management program in addition to the diabetes management program. The case management intervention is based on the Guided Care model and includes six elements; assessing health care needs, planning care, create access to other care providers and community resources, monitoring, coordinating care and recording of all relevant information. Patients in the control group will continue their participation in the diabetes management program and receive care-as-usual from their general practitioner and other care providers. DISCUSSION: We expect that the case management program, which includes better structured care based on scientific evidence and adjusted to the patients' needs and priorities, will improve the quality of care coordination from both the patients' and caregivers' perspective and will result in less consumption of health care services. TRIAL REGISTRATION: Netherlands Trial Register (NTR): NTR1847. (aut. ref.

Biochemical Similarities and Differences between the Catalytic [4Fe-4S] Cluster Containing Fumarases FumA and FumB from <em>Escherichia coli</em>

<div><h3>Background</h3><p>The highly homologous [4Fe-4S] containing fumarases FumA and FumB, sharing 90% amino acid sequence identity, from <em>Escherichia coli</em> are differentially regulated, which suggests a difference in their physiological function. The ratio of FumB over FumA expression levels increases by one to two orders of magnitude upon change from aerobic to anaerobic growth conditions.</p> <h3>Methodology/Principal Findings</h3><p>To understand this difference in terms of structure-function relations, catalytic and thermodynamic properties were determined for the two enzymes obtained from homologous overexpression systems. FumA and FumB are essentially identical in their Michaelis-Menten kinetics of the reversible fumarate to L-malate conversion; however, FumB has a significantly greater catalytic efficiency for the conversion of D-tartrate to oxaloacetate consistent with the requirement of the <em>fumB</em> gene for growth on D-tartrate. Reduction potentials of the [4Fe-4S]²⁺ Lewis acid active centre were determined in mediated bulk titrations in the presence of added substrate and were found to be approximately −290 mV for both FumA and FumB.</p> <h3>Conclusions/Significance</h3><p>This study contradicts previously published claims that FumA and FumB exhibit different catalytic preferences for the natural substrates L-malate and fumarate. FumA and FumB differ significantly only in the catalytic efficiency for the conversion of D-tartrate, a supposedly non-natural substrate. The reduction potential of the substrate-bound [4Fe-4S] active centre is, contrary to previously reported values, close to the cellular redox potential.</p> </div

Kinetic parameters of fumarase and tartrate dehydratase activity of FumA and FumB^a.

a<p>All values are corrected for Fe-S cluster content.</p>b<p><i>K_m</i> in mM.</p>c<p><i>V_max</i> in µmol product/minute/mg enzyme.</p>d<p><i>k_cat/K_m</i> in s⁻¹ M⁻¹.</p>e<p><i>K_eq</i> is the equilibrium constant for the hydration of fumarate as calculated using the Haldane relationship: <i>K_eq</i> = <i>(k_cat/K_M)_fumarate/(k_cat/K_M)_L-malate</i>.</p

EPR-monitored redox titration curves of FumA (•, red) and FumB (□, blue).

<p>The two points at low, undefined potential represent samples reduced with excess dithionite (10 mM). The solid lines represents fits to the Nernst equation: . Fit parameters for FumA: E_m = −300±6 mV; and for FumB: E_m = −283±9 mV.</p

Oxygen sensitivity of FumA (•, red) and FumB (□, blue).

<p>Fumarase activity was measured after air oxidation for 0, 0.5, 1 or 2 minutes. The residual activity was plotted as a percentage of the initial activity. The solid lines represent fits to the following equation:. The fit parameters were as follows, for FumA: <i>A</i> = 5±6%; <i>k_inact</i> = (1.8±0.5)·10² M⁻¹s⁻¹, for FumB: <i>A</i> = 6±6%; <i>k_inact</i> = (1.6±0.4)·10² M⁻¹s⁻¹.</p

Amino acid sequence alignment of <i>E. coli</i> FumA and FumB. FumA and FumB share 90% sequence identity and 95% sequence similarity.

<p>*Cysteine residues strictly conserved in multiple sequence alignment, using the ‘Cobalt’ program, from the 500 homologs exhibiting >72% sequence identity with <i>E. coli</i> FumA.</p

EPR spectra of FumA (red) and FumB (blue).

<p>a FumA [3Fe-4S]¹⁺ clusters; as isolated, not regenerated. b FumB [3Fe-4S]¹⁺ clusters; as isolated, not regenerated. c FumA [4Fe-4S]¹⁺ clusters; regenerated, reduced and in the presence of 5 mM fumarate. d FumB [4Fe-4S]¹⁺ clusters; regenerated, reduced and in the presence of 5 mM fumarate. The g-values are 2.032, 1.914 and 1.822 for FumA and 2.032, 1.916 and 1.821 for FumB. EPR parameters: microwave frequency a 9.630 GHz, b 9.631 GHz, c 9.407 GHz, d 9.631 GHz; microwave power a 8.0 mW, b 8.0 mW, c 20 mW, d 20 mW; modulation frequency 100 kHz; modulation amplitude a 0.63 mT, b 0.63 mT, c 1.25 mT, d 1.25 mT; temperature a 14.5 K, b 14.5 K, c 16K, d 14.5 K.</p

A physical complex of the Fanconi anemia proteins FANCG/XRCC9 and FANCA

Fanconi anemia (FA) is a recessively inherited disease characterized at the cellular level by spontaneous chromosomal instability and specific hypersensitivity to cross-linking agents. FA is genetically heterogeneous, comprising at least eight complementation groups (A-H). We report that the protein encoded by the gene mutated in complementation group G (FANCG) localizes to the cytoplasm and nucleus of the cell and assembles in a molecular complex with the FANCA protein, both in vivo and in vitro. Endogenous FANCA/FANCG complex was detected in both non-FA cells and in FA cells from groups D and E. By contrast, no complex was detected in specific cell lines belonging to groups A and G, whereas reduced levels were found in cells from groups B, C, F, and H. Wild-type levels of FANCA/FANCG complex were restored upon correction of the cellular phenotype by transfection or cell fusion experiments, suggesting that this complex is of functional significance in the FA pathway. These results indicate that the cellular FA phenotype can be connected to three biochemical subtypes based on the levels of FANCA/FANCG complex. Disruption of the complex may provide an experimental strategy for chemosensitization of neoplastic cells