Serum Inflammatory Markers and Preeclampsia in Type 1 Diabetes:A prospective study

OBJECTIVE Inflammation and endothelial dysfunction have been associated with the immunobiology of preeclampsia (PE), a significant cause of adverse pregnancy outcomes. The prevalence of PE is elevated several fold in the presence of maternal type 1 diabetes mellitus (T1DM). Although cross-sectional studies of pregnancies among women without diabetes have shown altered inflammatory markers in the presence of PE, longitudinal studies of diabetic women are lacking. In maternal serum samples, we examined the temporal associations of markers of inflammation with the subsequent development of PE in women with T1DM. RESEARCH DESIGN AND METHODS We conducted longitudinal analyses of serum C-reactive protein (CRP), adhesion molecules, and cytokines during the first (mean ± SD, 12.2 ± 1.9 weeks), second (21.6 ± 1.5 weeks), and third (31.5 ± 1.7 weeks) trimesters of pregnancy (visits 1-3, respectively). All study visits took place before the onset of PE. Covariates were BMI, HbA1c, age of onset, duration of diabetes, and mean arterial pressure. RESULTS In women with T1DM who developed PE versus those who remained normotensive, CRP tended to be higher at visits 1 (P = 0.07) and 2 (P = 0.06) and was significantly higher at visit 3 (P <0.05); soluble E-selectin and interferon-?-inducible protein-10 (IP-10) were significantly higher at visit 3; interleukin-1 receptor antagonist (IL-1ra) and eotaxin were higher and lower, respectively, at visit 2 (all P <0.05). These conclusions persisted following adjustment for covariates. CONCLUSIONS In pregnant women with T1DM, elevated CRP, soluble E-selectin, IL-1ra, and IP-10 and lower eotaxin were associated with subsequent PE. The role of inflammatory factors as markers and potential mechanisms of the high prevalence of PE in T1DM merits further investigation.

Intensive diabetes therapy and glomerular filtration rate in type 1 diabetes

An impaired glomerular filtration rate (GFR) leads to end-stage renal disease and increases the risks of cardiovascular disease and death. Persons with type 1 diabetes are at high risk for kidney disease, but there are no interventions that have been proved to prevent impairment of the GFR in this population.

Long-term renal outcomes of patients with type 1 diabetes mellitus and microalbuminuria:an analysis of the Diabetes Control and Complications Trial/Epidemiology of Diabetes Interventions and Complications cohort

Microalbuminuria is a common diagnosis in the clinical care of patients with type 1 diabetes mellitus. Long-term outcomes after the development of microalbuminuria are variable.

Intraretinal Leakage and Oxidation of LDL in Diabetic Retinopathy

Purpose: The pathogenesis of diabetic retinopathy (DR) is not fully understood. Clinical studies suggest that dyslipidemia is associated with the initiation and progression of DR. However, no direct evidence supports this theory.

Methods: Immunostaining of apolipoprotein B100 (ApoB100, a marker of low-density lipoprotein [LDL]), macrophages, and oxidized LDL was performed in retinal sections from four different groups of subjects: nondiabetic, type 2 diabetic without clinical retinopathy, diabetic with moderate nonproliferative diabetic retinopathy (NPDR), and diabetic with proliferative diabetic retinopathy (PDR). Apoptosis was characterized using the TUNEL assay. In addition, in cell culture studies using in vitro-modi?ed LDL, the induction of apoptosis by heavily oxidized-glycated LDL (HOG-LDL) in human retinal capillary
pericytes (HRCPs) was assessed.

Results: Intraretinal immuno?uorescence of ApoB100 increased with the severity of DR. Macrophages were prominent only in sections from diabetic patients with PDR. Merged images revealed that ApoB100 partially colocalized with macrophages. Intraretinal oxidized LDL was absent in nondiabetic subjects but present in all three diabetic groups, increasing with the severity of DR. TUNEL-positive cells were present in retinas from diabetic subjects but absent in those from nondiabetic subjects. In cell culture, HOG-LDL induced the activation of caspase, mitochondrial dysfunction, and apoptosis in
HRCPs.

Conclusions: These ?ndings suggest a potentially important role for extravasated, modi?ed LDL in promoting DR by promoting apoptotic pericyte loss.

Apolipoprotein C-III protein concentrations and gene polymorphisms in type 1 diabetes:associations with lipoprotein subclasses

Serum apolipoprotein C-III (apoCIII) concentration and apoCIII gene polymorphisms have been shown to be a risk factor for cardiovascular disease; however, the underlying mechanisms remain unclear. In addition, no studies have been performed that address these issues in type 1 diabetes. The current study investigated apoCIII protein and apoCIII gene variation in a normotriglyceridemic (82 +/- 57 mg/dL) population of patients with type 1 diabetes, the Diabetes Control and Complications Trial/Epidemiology of Diabetes Intervention and Complications (DCCT/EDIC) cohort. Blood samples were obtained in 409 patients after an overnight fast. Serum apoCIII concentration was highly correlated with multiple changes in lipids and lipoproteins that resulted in an adverse cardiovascular disease risk profile. Higher apoCIII concentrations were associated (P <.0001) with increased triglycerides (r = 0.78), total (r = 0.61) and low-density lipoprotein (LDL) (r = 0.40) cholesterol, apoA-I (r = 0.26), and apoB (r = 0.50), and these relationships persisted after controlling for age, gender, body mass index (BMI), and hemoglobin A1c (HbA1c). Nuclear magnetic resonance (NMR) lipoprotein subclass analyses demonstrated that apoCIII was correlated with an increase in very-low-density lipoprotein (VLDL) subclasses (P = .0001). There also was a highly significant positive relationship between serum apoCIII concentration and the LDL particle concentration in both men (r = 0.49, P = .001) and women (r = 0.40, P = .001), and a highly significant negative relationship between serum apoCIII levels and average LDL particle size in both men (r = -0.37, P = .001) and women (r = -0.22, P = .001) due primarily to an augmentation in the small L1 subclass (r = 0.42, P = .0001). Neither the T(-455) --> C polymorphism affecting an insulin response element in the apoCIII gene promoter nor a SacI polymorphism in the 3'UTR were associated with any alterations in circulating apoCIII concentrations, serum lipids, apolipoprotein concentrations, lipoprotein composition, or parameters measured by NMR lipoprotein subclass analyses. In summary, elevated apoCIII concentration was associated with risk factors for cardiovascular disease in normolipidemic type 1 diabetic patients through associated changes in lipoprotein subfraction distributions, which were independent of apoCIII genotype.

Immune complexes containing modified lipoproteins are related to the progression of internal carotid intima-media thickness in patients with type 1 diabetes

Modified lipoproteins induce autoimmune responses including the synthesis of autoantibodies with pro-inflammatory characteristics. Circulating modified lipoprotein autoantibodies combine with circulating antigens and form immune complexes (IC). We now report the results of a study investigating the role of circulating IC containing modified lipoproteins in the progression of carotid intima-media thickness (IMT) in patients enrolled in the Epidemiology of Diabetes Interventions and Complications (EDIC) Trial, a follow-up study of the Diabetes Control and Complications Trial (DCCT). This cohort includes 1229 patients with type 1 diabetes in whom B-mode ultrasonography of internal and common carotid arteries was performed in 1994-1996 and in 1998-2000. Conventional CHD risk factors, antibodies against modified forms of LDL and modified lipoprotein IC were determined in 1050 of these patients from blood collected in 1996-1998. Cholesterol and apolipoprotein B content of IC (surrogate markers of modified ApoB-rich lipoproteins) were significantly higher in patients who showed progression of the internal carotid IMT than in those showing no progression, regression or mild progression. Multivariate linear and logistic regression modeling using conventional and non-conventional risk factors showed that the cholesterol content of IC was a significant positive predictor of internal carotid IMT progression. In conclusion these data demonstrate that increased levels of modified ApoB-rich IC are associated with increased progression of internal carotid IMT in the DCCT/EDIC cohort of type 1 diabetes.

Evaluation of an algorithm to guide patients with type 1 diabetes treated with continuous subcutaneous insulin infusion on how to respond to real-time continuous glucose levels:A randomized controlled trial

OBJECTIVE - To evaluate an algorithm guiding responses of continuous subcutaneous insulin infusion (CSII)-treated type 1 diabetic patients using real-time continuous glucose monitoring (RT-CGM). RESEARCH DESIGN AND METHODS - Sixty CSII-treated type 1 diabetic participants (aged 13-70 years, including adult and adolescent subgroups, with A1C =9.5%) were randomized in age-, sex-, and A1C-matched pairs. Phase 1 was an open 16-week multicenter randomized controlled trial. Group A was treated with CSII/RT-CGM with the algorithm, and group B was treated with CSII/RT-CGM without the algorithm. The primary outcome was the difference in time in target (4-10 mmol/l) glucose range on 6-day masked CGM. Secondary outcomes were differences in A1C, low (=3.9 mmol/l) glucose CGM time, and glycemic variability. Phase 2 was the week 16-32 follow-up. Group A was returned to usual care, and group B was provided with the algorithm. Glycemia parameters were as above. Comparisons were made between baseline and 16 weeks and 32 weeks. RESULTS - In phase 1, after withdrawals 29 of 30 subjects were left in group A and 28 of 30 subjects were left in group B. The change in target glucose time did not differ between groups. A1C fell (mean 7.9% [95% CI 7.7-8.2to 7.6% [7.2-8.0]; P <0.03) in group A but not in group B (7.8% [7.5-8.1] to 7.7 [7.3-8.0]; NS) with no difference between groups. More subjects in group A achieved A1C =7% than those in group B (2 of 29 to 14 of 29 vs. 4 of 28 to 7 of 28; P = 0.015). In phase 2, one participant was lost from each group. In group A, A1C returned to baseline with RT-CGM discontinuation but did not change in group B, who continued RT-CGM with addition of the algorithm. CONCLUSIONS - Early but not late algorithm provision to type 1 diabetic patients using CSII/RT-CGM did not increase the target glucose time but increased achievement of A1C =7%. Upon RT-CGM cessation, A1C returned to baseline. © 2010 by the American Diabetes Association.

Studies of alpha-adrenoceptor antagonists on sympathetic mydriasis in rabbits

This study was undertaken to identify the alpha-adrenergic receptor type responsible for sympathetically evoked mydriasis in pentobarbital-anesthetized rabbits. Frequency-response curves of pupillary dilation were generated by stimulation of the preganglionic cervical sympathetic nerve (1-64 Hz). Evoked mydriatic responses were inhibited by systemic administration of nonselective alpha-adrenergic antagonists, phentolamine (0.3-10 mg/kg) and phenoxybenzamine (0.03-0.3 mg/kg), as well as the selective alpha(1)-adrenergic antagonist, prazosin (0.1-1 mg/kg). The alpha(2)-adrenergic antagonist, RS 79948 (0.3 mg/kg, i.v.) was without inhibitory effect, but potentiated the mydriatic response. In addition, the selective alpha(1A)-adrenoceptor antagonist, 5-methylurapidil (0.1-1 mg/kg, i.v.), antagonized the elicited mydriasis in a dose-dependent fashion. Unlike previous observations that prazosin does not block the adrenoceptor in rabbit iris dilator muscle, our results suggest that prazosin is effective in inhibiting neuronally elicited mydriasis in this species, and that alpha(1A)-adrenoceptors appear to mediate the response.

The effect of helium accretion efficiency on rates of Type Ia supernovae: Double detonations in accreting binaries

he double-detonation explosion scenario of Type Ia supernovae (SNe Ia) has gained increased support from the SN Ia community as a viable progenitor model, making it a promising candidate alongside the well-known single degenerate and double degenerate scenarios. We present delay times of double-detonation SNe, in which a sub-Chandrasekhar mass carbon–oxygen white dwarf (WD) accretes non-dynamically from a helium-rich companion. One of the main uncertainties in quantifying SN rates from double detonations is the (assumed) retention efficiency of He-rich matter. Therefore, we implement a new prescription for the treatment of accretion/accumulation of He-rich matter on WDs. In addition, we test how the results change depending on which criteria are assumed to lead to a detonation in the helium shell. In comparing the results to our standard case (Ruiter et al.), we find that regardless of the adopted He accretion prescription, the SN rates are reduced by only ∼25 per cent if low-mass He shells (≲0.05 M⊙) are sufficient to trigger the detonations. If more massive (0.1 M⊙) shells are needed, the rates decrease by 85 per cent and the delay time distribution is significantly changed in the new accretion model – only SNe with prompt (<500 Myr) delay times are produced. Since theoretical arguments favour low-mass He shells for normal double-detonation SNe, we conclude that the rates from double detonations are likely to be high, and should not critically depend on the adopted prescription for accretion of He.

One-pot two-step mechanochemical synthesis: ligand and complex preparation without isolating intermediates

Although the use of ball milling to induce reactions between solids (mechanochemical synthesis) can provide lower-waste routes to chemical products by avoiding solvent during the reaction, there are further potential advantages in using one-pot multistep syntheses to avoid the use of bulk solvents for the purification of intermediates. We report here two-step syntheses involving formation of salen-type ligands from diamines and hydroxyaldehydes followed directly by reactions with metal salts to provide the corresponding metal complexes. Five salen-type ligands 2,2'-[1,2-ethanediylbis[(E)-nitrilomethylidyne]] bisphenol, ` salenH2', 1; 2,2'-[(+/-)-1,2-cyclohexanediylbis-[(E)-nitrilomethylidyne]] bis-phenol, 2; 2,2'-[1,2-phenylenebis( nitrilomethylidyne)]-bis-phenol, ` salphenH2' 3; 2-[[(2-aminophenyl) imino] methyl]-phenol, 4; 2,2'-[(+/-)-1,2-cyclohexanediylbis[(E)-nitrilomethylidyne]]-bis[4,6-bis(1,1-dimethylethyl)]-phenol, ` Jacobsen ligand', 5) were found to form readily in a shaker-type ball mill at 0.5 to 3 g scale from their corresponding diamine and aldehyde precursors. Although in some cases both starting materials were liquids, ball milling was still necessary to drive those reactions to completion because precipitation of the product and or intermediates rapidly gave in thick pastes which could not be stirred conventionally. The only ligand which required the addition of solvent was the Jacobsen ligand 5 which required 1.75 mol equivalents of methanol to go to completion. Ligands 1-5 were thus obtained directly in 30-60 minutes in their hydrated forms, due to the presence of water by-product, as free-flowing yellow powders which could be dried by heating to give analytically pure products. The one-armed salphen ligand 4 could also be obtained selectively by changing the reaction stoichiometry to 1 : 1. SalenH(2) 1 was explored for the onepot two-step synthesis of metal complexes. In particular, after in situ formation of the ligand by ball milling, metal salts (ZnO, Ni(OAc)2 center dot 4H(2)O or Cu(OAc)(2)center dot H2O) were added directly to the jar and milling continued for a further 30 minutes. Small amounts of methanol (0.4-1.1 mol equivalents) were needed for these reactions to run to completion. The corresponding metal complexes [M(salen)] (M = Zn, 6; Ni, 7; or Cu, 8) were thus obtained quantitatively after 30 minutes in hydrated form, and could be heated briefly to give analytically pure dehydrated products. The all-at-once ` tandem' synthesis of [Zn(salen)] 6 was also explored by milling ZnO, ethylene diamine and salicylaldehyde together in the appropriate mole ratio for 60 minutes. This approach also gave the target complex selectively with no solvent needing to be added. Overall, these syntheses were found to be highly efficient in terms of time and the in avoidance of bulk solvent both during the reaction and for the isolation of intermediates. The work demonstrates the applicability of mechanochemical synthesis to one-pot multi-step strategies.

Self-cleaning perovskite type catalysts for the dry reforming of methane

Gas-to-liquid processes are generally used to convert natural gas or other gaseous hydrocarbons into liquid fuels via an intermediate syngas stream. This includes the production of liquid fuels from biomass-derived sources such as biogas. For example, the dry reforming of methane is done by reacting CH4 and CO2, the two main components of natural biogas, into more valuable products, i.e., CO and H2. Nickel containing perovskite type catalysts can promote this reaction, yielding good conversions and selectivities; however, they are prone to coke laydown under certain operating conditions. We investigated the addition of high oxygen mobility dopants such as CeO2, ZrO2, or YSZ to reduce carbon laydown, particularly using reaction conditions that normally result in rapid coking. While doping with YSZ, YDC, GDC, and SDC did not result in any improvement, we show that a Ni perovskite catalyst (Na0.5La0.5Ni0.3Al0.7O2.5) doped with 80.9 ZrO2 15.2 CeO2 gave the lowest amount of carbon formation at 800 °C and activity was maintained over the operating time.