Effect of intravenous nitroglycerin on lipid peroxidation after thrombolytic therapy for acute myocardial infarction

Free oxygen radicals are produced after coronary artery occlusion and reperfusion. Polyunsaturated fatty acids are oxidized by free radicals to lipid peroxides. Measurements of plasma malondialdehyde (MDA) formed by the breakdown of lipid peroxides are often used as markers of lipid peroxidation. The effect of intravenous nitroglycerin on plasma MDA levels was studied in 43 patients who received thrombolytic therapy for acute myocardial infarction. Plasma MDA levels in patients were elevated on admission to the hospital compared with healthy controls, and normalized within 48 hours. A greater increase in plasma MDA concentrations after thrombolysis was found in patients with noninvasive signs of reperfusion than in patients judged to have a persistent occlusion. In the 23 patients receiving immediate intravenous nitroglycerin infusion, plasma MDA levels did not change from baseline to 90 minutes (0.92 ± 0.22 and 0.92 ± 0.23 μmol/L, p = 0.99), whereas a significant increase was found in the 20 control patients who did not receive nitroglycerin (from 0.83 ± 0.22 to 1.01 ± 0.30 μmol/L, p = 0.0004) (p = 0.036 for the difference between groups). Successful reperfusion after thrombolytic therapy entails increased lipid peroxidation. Intravenous nitroglycerin reduces lipid peroxidation during myocardial ischemia and reperfusion.     

In Vitro Activity of wALADin Benzimidazoles against Different Life Cycle Stages of Plasmodium Parasites

wALADin1 benzimidazoles are specific inhibitors of δ-aminolevulinic acid dehydratase from Wolbachia endobacteria of filarial nematodes. We report that wALADin1 and two derivatives killed blood stage Plasmodium falciparum in vitro (50% inhibitory concentrations, 39, 7.7, and 12.8 μM, respectively). One of these derivatives inhibited gliding motility of Plasmodium berghei ANKA infectious sporozoites with nanomolar affinity and blocked invasion into hepatocytes but did not affect intrahepatocytic replication. Hence, wALADin1 benzimidazoles are tools to study gliding motility and potential antiplasmodial drug candidates.     

Direct observation of prefreezing at the interface melt–solid in polymer crystallization

Crystallization is almost always initiated at an interface to a solid. This observation is classically explained by the assumption of a reduced barrier for crystal nucleation at the interface. However, an interface can also induce crystallization by prefreezing (i.e., the formation of a crystalline layer that is already stable above the bulk melting temperature). We present an atomic force microscopy (AFM)-based in situ observation of a prefreezing process at the interface of a polymeric model system and a crystalline solid. Explicitly, we show an interfacial ordered layer that forms well above the bulk melting temperature with thickness that increases on approaching melt–solid coexistence. Below the melting temperature, the ordered layer initiates crystal growth into the bulk, leading to an oriented, homogeneous semicrystalline structure.The fundamental process of crystallization from the liquid or gaseous state is of importance in many areas of condensed matter physics and materials science. In practice, crystallization is, in most cases, initiated at an interface to a solid. Crystal growth on solid substrates from the gaseous state has been studied in depth, and detailed understanding of different growth modes as well as interfacial thermodynamics has been achieved (1–3). Much less experimental data are available for crystallization occurring at the interface from the solid to the melt. Generally, crystallization can be initiated at the solid–melt interface by two processes: heterogeneous nucleation or formation of a crystalline wetting layer (so-called prefreezing) (4–6). In terms of thermodynamics, these processes are very different. Whereas nucleation takes place under nonequilibrium conditions at finite supercooling below the melting temperature T_m of the bulk material, the formation of a wetting layer is an equilibrium phenomenon taking place above T_m (4). It is often assumed that heterogeneous nucleation is the more relevant process (7), but in simulations, nucleation as well as prefreezing have been shown to occur (4, 8). Prefreezing is expected for strongly attractive surfaces or epitaxial systems for which the lattices of the substrate and the crystallizing materials match well (9–12). In the case of polymers, prefreezing can also manifest itself in the conformational degrees of freedom, leading to an interfacial layer with nematic order, which was recently shown in simulations (13). Because of the difficult accessibility of the buried interface between a melt and a solid, direct observation of crystallization of molecular systems at the interface is lacking, and there is only limited, indirect evidence that, in some cases, prefreezing at the solid interface exists (e.g., for the growth of aluminum crystals on TiB₂ particles) (14, 15). Recently, it has been suggested that prefreezing also plays a role during epitaxial crystallization in some polymeric systems (16). It is well-known, however, that one or sometimes several ordered layers of organic molecules can form on suitable substrates at temperatures above the bulk melting point, which was observed for, for example, alkanes or similar molecules on graphite by scanning tunneling microscopy (17), atomic force microscopy (AFM) (18–20), or scattering methods (21, 22; review in ref. 23). A related but more special phenomenon is surface freezing of liquids (22). In some liquids, an ordered monolayer forms at the free surface in a finite temperature range above the bulk melting temperature [e.g., alkanes (24), alkylated side chain polymers (25), and AuSi alloys (26)]. It is an open question, however, which exact role all of these structures play for the initiation of crystal growth (27) and in most cases, the temperature range around melt–solid coexistence, where crystallization starts has not been studied in detail. Only for colloidal model systems has crystallization by prefreezing been directly observed (28) and studied in simulations (8, 10, 11).We here present direct AFM observations of an ordered wetting layer at the interface to a solid close to coexistence of the solid and the liquid phases of a polymeric model system. We show evidence for a temperature-dependent thickness of the wetting layer and its disappearance at a prewetting transition at finite superheating above T_m. Our observations are in line with a divergence of the layer thickness at the bulk melting temperature as expected for complete wetting. Below T_m, crystal growth into the film is initiated by the interfacial layer.     

Biomarkers for Type 2 Diabetes and Impaired Fasting Glucose Using a Nontargeted Metabolomics Approach

Using a nontargeted metabolomics approach of 447 fasting plasma metabolites, we searched for novel molecular markers that arise before and after hyperglycemia in a large population-based cohort of 2,204 females (115 type 2 diabetic [T2D] case subjects, 192 individuals with impaired fasting glucose [IFG], and 1,897 control subjects) from TwinsUK. Forty-two metabolites from three major fuel sources (carbohydrates, lipids, and proteins) were found to significantly correlate with T2D after adjusting for multiple testing; of these, 22 were previously reported as associated with T2D or insulin resistance. Fourteen metabolites were found to be associated with IFG. Among the metabolites identified, the branched-chain keto-acid metabolite 3-methyl-2-oxovalerate was the strongest predictive biomarker for IFG after glucose (odds ratio [OR] 1.65 [95% CI 1.39–1.95], P = 8.46 × 10⁻⁹) and was moderately heritable (h² = 0.20). The association was replicated in an independent population (n = 720, OR 1.68 [ 1.34–2.11], P = 6.52 × 10⁻⁶) and validated in 189 twins with urine metabolomics taken at the same time as plasma (OR 1.87 [1.27–2.75], P = 1 × 10⁻³). Results confirm an important role for catabolism of branched-chain amino acids in T2D and IFG. In conclusion, this T2D-IFG biomarker study has surveyed the broadest panel of nontargeted metabolites to date, revealing both novel and known associated metabolites and providing potential novel targets for clinical prediction and a deeper understanding of causal mechanisms.Currently, stratification of individuals at risk for type 2 diabetes (T2D) within the general population is based on well-established factors such as age, BMI, and fasting glucose (1). Although these factors contribute considerably to disease risk, they may not identify at-risk individuals before the disease process is well under way.Recently, a number of studies have found several metabolites to be correlated with insulin resistance and T2D (2–6), and T2D-associated metabolic profiles have been identified 10–15 years before the diagnosis/onset of the disease (7–9). To help preventive strategies, and maximize the potential for existing effective interventions, it is important to characterize the molecular changes that take place in the development of T2D.We aim to understand other biochemical changes, in addition to hyperglycemia, that take place at the onset of T2D using the largest metabolomic screening approach to date. We assessed >400 metabolites to determine which metabolomic profiles are correlated with T2D and impaired fasting glucose (IFG) in a large cohort of females from TwinsUK with independent replication.     

Signalling pathways identified in salivary glands from primary Sjögren’s syndrome patients reveal enhanced adipose tissue development

A characteristic feature of primary Sjögren’s syndrome (pSS) is the destruction of salivary and lacrimal glands mediated by mononuclear cell infiltration. Adipocytes can also occupy a large portion of the salivary gland (SG) tissue area, although little is known about their significance in pSS. We have previously investigated adipose tissue infiltration in SG biopsies from pSS patients and non-SS sicca controls. Our findings indicated the distinct incidence of adipose tissue replacement in pSS patients, where adipocytes were detected in interleukin (IL) 6 rich regions. We now aimed to examine the development of adipocytes in the SG microenvironment, and delineate their possible involvement in immune reactions. A microarray analysis was performed on SG from 6 pSS patients and 6 non-SS controls, where the expression levels of genes involved in adipose tissue development, inflammatory responses, and lymphoma development were assessed. Real-time PCR was carried out on SG from 14 pSS patients and 15 non-SS controls to account for IL6, IL10, and IL17 mRNA levels. Immunohistochemical staining of frozen SG tissue using IL17 was also conducted. Our results indicate signalling pathways identified in SG of pSS patients displayed genes leading to prominent adipose tissue development and reduced mitochondrial fatty acid beta-oxidation (ARID5B, OXCT1, BDH1, SOX8, HMGCS2, FTO, ECHS1, PCCA, ACADL and ACADVL), inflammatory responses (IL1R1, IL7R, IL10RA, IL15, IL18RAP, CCL2, CCL5, CCL22, CXCR6, CD14, and CD48), and lymphoma development via JAK-STAT signalling (STAT2, TYK2, EBI3, FAS, TNFRSF1B, MAP3K8, HMOX1, LTB, TNF, STAT1, and BAK1). Genes involved in interferon production and signalling were also detected (IRF1, IRF9, and IRF7), in addition to IL6, IL10, and IL17. Higher mRNA levels of IL6, IL17 and IL10 were observed in the SG of pSS patients compared to controls. Moreover, IL17 positive cells were detected mostly interstitially in the SG and around adipocytes, also within the focal infiltrates. In conclusion, adipocyte development seems to be more prominent in the SG of pSS patients, where adipose tissue replacement is also evident. Whether this is due to disease progression, or the repair process, remains to be investigated. Detection of IL17 positive adipocytes in the target organ suggests their involvement in immune reactions.     

Bioavailability of metals to the amphipod Monoporeia affinis: interactions with authigenic sulfides in urban brackish-water and freshwater sediments

Could reduced eutrophication be a potential environmental threat because of increased mobility and bioavailability of trace metals? This question was addressed by oxygenating intact sediment cores, varying in redox potential and salinity, in a test system containing the amphipod Monoporeia affinis. Results show a low mobility of metals during oxygenation, and despite high concentrations of metals in sediments, only Pb showed a notable degree of bioaccumulation. Cadmium was bioaccumulated particularly in freshwater sediment, and body burden of Cd was related to salinity, porewater, and sediment concentrations. Despite high sediment and porewater concentrations of Cu and Zn, no relationship was recorded to body burden. For three of four tested metals, Cd, Pb, and Zn, metals in sediment were more important for body burdens in amphipods as compared to metals in porewater. Food, rather than interstitial water, therefore seems to be the main route of metal contaminants to these amphipods. Furthermore, this observed low release of metals from sediments and low body burden significance of porewater metals indicate that ameliorated oxygen conditions in contaminated sediments may be regarded as a minor environmental threat for one of the most important Baltic benthic organisms.     

No increase of plasma malondialdehyde after primary coronary angioplasty for acute myocardial infarction

OBJECTIVE: Free radicals formed after coronary artery occlusion and reperfusion are assumed to produce myocardial stunning and possibly other forms of reperfusion injury as well. Malondialdehyde (MDA) is an end product in the lipid peroxidation chain reaction and is frequently used as a marker for free oxygen radical production. Increased levels of plasma MDA have been found following successful thrombolytic therapy. The aim of this study was to investigate whether plasma MDA levels also increase after successful primary percutaneous transluminal coronary angioplasty (PTCA) in acute myocardial infarction (AMI). DESIGN: In 23 patients with AMI, treated with primary PTCA, plasma MDA was analysed using a high-performance liquid chromatography method (HPLC). The results obtained with this method were compared with those obtained with a fluorimetric assay of thiobarbituric acid reactive substances (TBARS). This assay measures MDA but with a lower specificity. RESULTS: We found a significant decrease of plasma MDA from baseline 0.99 to 0.87 micro mol/l at 30 min and to 0.90 micro mol/l at 90 min following the primary PTCA (p = 0.048 and 0.014, respectively). No significant changes in TBARS method levels were observed. CONCLUSION: Instead of the expected increase in MDA following reperfusion we found a significant decrease. The results from measurements of MDA and TBARS were significantly incompatible. The results raise serious doubts as to the usefulness of increased plasma levels of MDA as a marker of oxidative stress caused by coronary reperfusion in patients treated with angioplasty.