Prognostic value of preoperative dynamic contrast-enhanced MRI perfusion parameters for high-grade glioma patients

Introduction

The prognostic value of the dynamic contrast-enhanced (DCE) MRI perfusion and its histogram analysis-derived metrics is not well established for high-grade glioma (HGG) patients. The aim of this prospective study was to investigate DCE perfusion transfer coefficient (K^trans), vascular plasma volume fraction (v_p), extracellular volume fraction (v_e), reverse transfer constant (k_ep), and initial area under gadolinium concentration time curve (IAUGC) as predictors of progression-free (PFS) and overall survival (OS) in HGG patients.

Methods

Sixty-nine patients with suspected anaplastic astrocytoma or glioblastoma underwent preoperative DCE-MRI scans. DCE perfusion whole tumor region histogram parameters, clinical details, and PFS and OS data were obtained. Univariate, multivariate, and Kaplan–Meier survival analyses were conducted. Receiver operating characteristic (ROC) curve analysis was employed to identify perfusion parameters with the best differentiation performance.

Results

On univariate analysis, v_e and skewness of v_p had significant negative impacts, while k_ep had significant positive impact on OS (P < 0.05). v_e was also a negative predictor of PFS (P < 0.05). Patients with lower v_e and IAUGC had longer median PFS and OS on Kaplan–Meier analysis (P < 0.05). K^trans and v_e could also differentiate grade III from IV gliomas (area under the curve 0.819 and 0.791, respectively).

Conclusions

High v_e is a consistent predictor of worse PFS and OS in HGG glioma patients. v_p skewness and k_ep are also predictive for OS. K^trans and v_e demonstrated the best diagnostic performance for differentiating grade III from IV gliomas.

     

The missing enzymatic link in syntrophic methane formation from fatty acids

The microbial production of methane from organic matter is an essential process in the global carbon cycle and an important source of renewable energy. It involves the syntrophic interaction between methanogenic archaea and bacteria that convert primary fermentation products such as fatty acids to the methanogenic substrates acetate, H₂, CO₂, or formate. While the concept of syntrophic methane formation was developed half a century ago, the highly endergonic reduction of CO₂ to methane by electrons derived from β-oxidation of saturated fatty acids has remained hypothetical. Here, we studied a previously noncharacterized membrane-bound oxidoreductase (EMO) from Syntrophus aciditrophicus containing two heme b cofactors and 8-methylmenaquinone as key redox components of the redox loop–driven reduction of CO₂ by acyl–coenzyme A (CoA). Using solubilized EMO and proteoliposomes, we reconstituted the entire electron transfer chain from acyl-CoA to CO₂ and identified the transfer from a high- to a low-potential heme b with perfectly adjusted midpoint potentials as key steps in syntrophic fatty acid oxidation. The results close our gap of knowledge in the conversion of biomass into methane and identify EMOs as key players of β-oxidation in (methyl)menaquinone-containing organisms.

The microbial conversion of natural polymers into methane plays an important role in the global carbon cycle and accounts for more than one-half of all methane produced on Earth per year (1, 2). Methane is formed in anoxic environments, including marine and freshwater sediments, but also in biogas reactors of wastewater treatment plants and other engineered systems. A complex syntrophic association between fermenting bacteria and methanogenic archaea is involved in the degradation of biomass to CH₄ and CO₂. Primary fermenting bacteria hydrolyze complex polymers into monomers and degrade them mainly into short chain fatty acids (scFA) and alcohols. Secondary fermenting bacteria then oxidize these products to the methanogenic substrates acetate, H₂, CO₂, and formate that are finally converted into methane by hydrogenotrophic or acetotrophic archaea (Fig. 1A) (3). The reduction of CO₂ to CH₄ depends on interspecies electron transfer from secondary fermenting bacteria to methanogenic archaea usually via the diffusible low-potential carriers formate and/or H₂ (3–5) or, as recently proposed, directly via nanowires (6).Open in a separate windowFig. 1.Syntrophic degradation of organic matter to methane. (A) Major metabolic processes involving primary fermenters, secondary fermenters, and methanogenic archaea (for simpler presentation, acetogenic conversion of monomers is not depicted here). (B) Model for syntrophic β-oxidation of butyrate to two acetates coupled to the reduction of protons or CO₂. The enzyme mediating electron transfer from reduced ETF to FDH has not been studied before and was assigned to noncharacterized DUF224 based on omics-based predictions.The oxidation of scFA to acetate coupled to the reduction of H⁺ or CO₂ is endergonic under standard conditions (+48 kJ/mol butyrate) but becomes clearly exergonic at an H₂ partial pressure below 10 Pa (3, 7). On the other side, the H₂ threshold partial pressure of hydrogenotrophic methanogenesis is around 8 Pa corresponding to E′(2H⁺/H₂) ∼ −290 mV or around 10 µM formate, resulting in similar values for the CO₂/formate redox couple (2). The syntrophic oxidation of the scFA model compound butyrate to acetate is accomplished by gram-positive Firmicutes (model organism Syntrophomonas wolfei) or gram-negative Deltaproteobacteria (model organism Syntrophus aciditrophicus) (3, 4, 7). It proceeds via two unequal β-oxidation steps (SI Appendix, Fig. 1) (8, 9): 1) Butyryl-CoA is oxidized to crotonyl-CoA by an acyl-CoA dehydrogenase (DH) (E°′ ∼ −10 mV) (10) with an electron-transferring flavoprotein (ETF) serving as electron acceptor, and 2) the 3-hydroxybutyryl-CoA formed by crotonase is subsequently oxidized to acetoacetyl-CoA by 3-hydroxybutyryl-CoA DH (ΔE°′ = −250 mV) (11) using NAD⁺ as acceptor. The reduction of H⁺ or CO₂ by the NADH formed is feasible under syntrophic conditions, whereas butyryl-CoA oxidation coupled to H⁺ or CO₂ reduction has to overcome a gap of ΔE ∼ −280 mV, giving ΔG°′ ∼ +54 kJ ⋅ mol^–1 (3–5). Considering that only one ATP is gained via substrate-level phosphorylation, the energy metabolism of syntrophic butyrate oxidation has remained enigmatic.Omics-based studies have led to the proposal of models for energy coupling processes during syntrophic scFA oxidation (12–16). The redox loop model is based on the identification of a putative membrane-bound gene product (DUF224) (14–16). It proposes that electrons are transferred from acyl-CoA via ETF, DUF224, and menaquinone (MK) to a membrane-bound formate dehydrogenase (FDH) or hydrogenase driven by the translocation of protons to the cytoplasm, resulting in two energetically unequal half reactions:Acyl-CoA + MK →Enoyl-CoA + MKH2 ΔG°’ = +12.5 kJ mol–1CO2+ MKH2→Formate + H++ MKΔG’ = +41.5 kJ mol–1.In agreement, a protonophore inhibited formation of H₂ from butyrate in whole-cell suspension of S. wolfei (17), and MK was reported in S. wolfei and S. aciditrophicus (12, 17). In an alternative model, an electron-confurcating ETF couples endergonic reduction of NAD⁺ by ETF_red to the exergonic reduction of NAD⁺ by reduced ferredoxin (Fd_red^–) (18). The NADH formed then may serve as an electron donor for a cytoplasmic FDH. Biochemical evidence for either of the two models is lacking.Here, we study the missing membrane components that link fatty acid oxidation to CO₂ reduction during syntrophic methane production. We provide biochemical evidence that a membrane-bound diheme oxidoreductase and a modified methylmenaquinone with perfectly adjusted redox potentials are the key players of this process. We further propose that related enzymes play a previously overlooked role in the lipid catabolism of the majority of microorganisms.     

Antioxidant and scavenging capacity of Anacamptis pyrimidalis L. – Pyrimidal Orchid from Vojvodina

In the present study we investigated the antioxidative properties of flowers and aboveground part of Anacamptis pyrimidalis L. from Vojvodina. Activities of antioxidant enzymes (superoxide dismutase, catalase, peroxidase, and glutathione peroxidase), quantities of malonyldialdehyde, superoxide and hydroxyl radicals and reduced glutathione and also the contents of chlorophylls a and b, carotenoids and soluble proteins were determined. Lipofuscin ‘plant age pigments’, total antioxidant capacity and scavenging activity were also determined. Our results indicated that the aboveground part of the plant exhibited higher antioxidant activity due to low MDA and lipofuscin pigment accumulation (2.82 nmol/mg protein; 92.90%), higher scavenging activity (54.16%) and antioxidant capacity (432.00 μmol Fe²⁺/dm³). Copyright © 2009 John Wiley & Sons, Ltd.     

Aetiological diagnostics of acute bacterial meningitis in children

Aetiology of bacterial meningitis (BM) can be confirmed by various microbiological methods. The aim of this study was to assess the role of microbiological methods used for confirmation of BM in children and determine the influence of the aetiological agent, patient age and antibacterial treatment on study results. Over a 5-y period (1998-2002) BM was diagnosed in 90 children at Vilnius University Centre for Paediatrics. Aetiology was confirmed by cerebrospinal fluid (CSF) and blood culture, microscopic CSF smear examination, CSF and blood latex agglutination test. CSF and blood cultures were positive in 53% and 39% of cases, respectively. Microscopic CSF smear examination was positive for 57% of the specimens. CSF latex agglutination was positive in 64% and blood in 47% of cases. Causative agent and received antibiotic therapy prior to investigation of obtained material affected some final microbiological results. However, no influence of patient age was found. Microbiological confirmation was achieved in 59% of cases using CSF and/or blood culture and in 78% of cases using all available methods in practice. The most common pathogens of bacterial meningitis were H. influenzae type b, N. meningitidis and S. pneumoniae.     

Is There Material Loss at the Backside Taper in Modular CoCr Acetabular Liners?

BackgroundMetal wear and corrosion products generated by hip replacements have been linked to adverse local tissue reactions. Recent investigations of the stem/head taper junction have identified this modular interface as another possible source of metal debris; however, little is known regarding other modular metallic interfaces, their ability to produce metal debris, and possibly to provide insight in the mechanisms that produce metal debris.Questions/purposesWe asked three questions: (1) can we develop a reliable method to estimate volumetric material loss from the backside taper of modular metal-on-metal liners, (2) do backside tapers of modular metal-on-metal liners show a quantifiable volumetric material loss, and, if so, (3) how do regions of quantitatively identified material loss correspond to visual and microscopic investigations of surface damage?MethodsTwenty-one cobalt-chromium (CoCr) liners of one design and manufacturer were collected through an institutional review board-approved retrieval program. All liners were collected during revision surgeries, where the primary revision reason was loosening (n = 11). A roundness machine measured 144 axial profiles equally spaced about the circumference of the taper region near the rim to estimate volume and depth of material loss. Sensitivity and repeatability analyses were performed. Additionally, visual and scanning electron microscopy investigations were done for three liners.ResultsOur measurement method was found to be reproducible. The sensitivity (how dependent measurement results are on experimental parameters) and repeatability (how consistent results are between measurements) analyses confirmed that component alignment had no apparent effect (weak correlation, R² = 0.04) on estimated volumetric material loss calculations. Liners were shown to have a quantifiable material loss (maximum = 1.7 mm³). Visual investigations of the liner surface could identify pristine surfaces as as-manufactured regions, but could misidentify discoloration as a possible region of material loss. Scanning electron microscopy more accurately distinguished between as-manufactured and damaged regions of the taper.ConclusionsThe roundness machine has been used to develop a repeatable method for characterizing material loss; future work comparing a gravimetric standard with estimations of material loss determined from the roundness machine may show the accuracy and effectiveness of this method. Liners show rates of material loss that compare with those reported for other taper junctions. Visual inspection alone may misidentify as-manufactured regions as regions of material loss.

Clinical relevance

This study identifies the acetabular liner/shell interface in modular metal-on-metal devices as a potential source of metal wear or corrosion products. The relation between metal debris and clinical performance, regardless of the type of bearing couple, is a concern for clinicians. Therefore, it is important to characterize every type of modular junction to understand the quantity, location, and mechanism(s) of material loss.     

Effectiveness of Non-Primary Care-Based Smoking Cessation Interventions for Adults with Diabetes: A Systematic Literature Review

Diabetes is a chronic disease that affects over 25 million adults, many of whom are smokers. The negative health impact of diabetes and comorbid smoking is significant and requires comprehensive interdisciplinary management. The National Diabetes Education Program has identified specific providers, known as PPOD, who include pharmacists, podiatrists, optometrists, and dentists, as key individuals to improve diabetes-related clinical outcomes. These providers are encouraged to work together through interdisciplinary collaboration and to implement evidence-based strategies as outlined in the PPOD toolkit. The toolkit encourages healthcare providers to ask, advise, and assist patients in their efforts to engage in risk reduction and healthy behaviors, including smoking cessation as an important risk factor. While individual PPOD providers have demonstrated effective smoking cessation interventions in adults with other acute and chronic systemic diseases, they lack specific application and focus on adults with diabetes. This literature review examines the current role of PPOD providers in smoking cessation interventions delivered to adults with diabetes.