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Abstract: Objective: The indications for aortic root replacement in acute type A dissection are unclear. We reviewed the immediate and long-term outcome of consecutive patients in a series in which a low-threshold policy of composite aortic root replacement had evolved. Methods: From a prospectively compiled aortic surgery database, we identified 162 patients who had either supracoronary interposition grafting, Group A (n=89), or composite root replacement, Group B (n=73) for acute type A dissection. Patients receiving total arch replacements were excluded. Operative and clinical details were analyzed and patient survival was compared to an age and gender matched census cohort. Need for reoperation on the proximal or distal aorta was also noted. Follow-up totaled 795.5 patient-years. Results: Hospital mortality rates were identical in both groups (12.3%: 11 deaths in group A; 9 in group B). Chronic pulmonary disease, diabetes, malperfusion, hemodynamic compromise and aortic root dilatation were independent risk factors for hospital death. Actuarial survival estimates at 1, 5 and 10 years were 79% (71–88%), 64% (53–75%), and 55% (41–68%) for group A, and 79% (70–86%), 73% (62–83%), and 65% (52–78%) for group B (P=0.48). Age and operative patency of the ascending false lumen were independent risk factors for death after hospital discharge. Proximal aortic reoperation was required for four patients in group A and none in group B (P=0.085). Conclusion: A strategy of replacement rather than repair of the dissected aortic root for specific indications in type A dissection yielded high survival and low proximal reoperation rates. These results support an aggressive policy of composite root replacement in acute type A dissection. [Copyright &y& Elsevier]

Due to a high unresponsiveness to chemotherapy, biofilm formation is an important medical problem that frequently occurs during infection with many bacterial pathogens. In this study, the marine sponge-derived natural compounds 4,6-dibromo-2-(2′,4′-dibromophenoxy)phenol and 3,4,6-tribromo-2-(2′,4′-dibromophenoxy)phenol were found to exhibit broad antibacterial activity against medically relevant gram-positive and gram-negative pathogens. The compounds were not only bactericidal against both replicating and stationary phase–persistent planktonic cells of methicillin-resistant Staphylococcus aureus (MRSA) and Pseudomonas aeruginosa; they also killed biofilm-incorporated cells of both species while not affecting biofilm structural integrity. Moreover, these compounds were active against carbapenemase-producing Enterobacter sp. This simultaneous activity of compounds against different growth forms of both gram-positive and gram-negative bacteria is rare. Genome sequencing of spontaneous resistant mutants and proteome analysis suggest that resistance is mediated by downregulation of the bacterial EIIBC phosphotransferase components scrA and mtlA in MRSA likely leading to a lower uptake of the molecules. Due to their only moderate cytotoxicity against human cell lines, phenoxyphenols provide an interesting new scaffold for development of antimicrobial agents with activity against planktonic cells, persisters and biofilm-incoporated cells of ESKAPE pathogens. Key points: • Brominated phenoxyphenols kill actively replicating and biofilm-incorporated bacteria. • Phosphotransferase systems mediate uptake of brominated phenoxyphenols. • Downregulation of phosphotransferase systems mediate resistance. [ABSTRACT FROM AUTHOR]

OBJECTIVE To investigate metabolite concentrations of the brains of dogs with intracranial neoplasia or noninfectious meningoencephalitis by use of short echo time, single voxel proton magnetic resonance spectroscopy ('H MRS) at 3.0T. ANIMALS 29 dogs with intracranial lesions (14 wiuS neoplasia [3 oligodendromas. 3 glioblastomas multiformes, 3 astrocytomas, 2 lymphomas, and 3 meningiomas] and 15 is with noninfectious meningoencephalitis) and 10 healthy control dogs. PROCEDURES Short echo time, single voxel 1H-MRS at 3.0 T was performed on neoplastic and noninfectious inflammatory intracranial lesions identified with conventional MRI. Metabolites of interest included N-acetyl aspartate (NAA), total choline, creatine, myoinositol, the glutamine-glutamate complex (Glx), glutathione, taurine, lactate, and lipids. Data were analyzed with postprocessing fitting algorithm software. Metabolite concentrations relative to brain water content were calculated and compared with results for the healthy control dogs, which had been previously evaluated with the same 1H MRS technique. RESULTS NAA, creatine, and Glx concentrations were reduced in the brains of dogs with neoplasia and noninfectious meningoencephalitis, whereas choline concentration was increased. Concentrations of dieso metabolites differed significantly between dogs with neoplasia and dogs with noninfectious meningoencephalitis. Concentrations of NAA. creatine, and Glx were significantly lower in dogs with neoplasia, whereas the concentration of choline was significantly higher in dogs with neoplasia. Lipids were predominantly found in dogs with high-grade intra-axial neoplasia, meningioma, and necrotizing meningoencephalitis. A high concentration of taurine was found in 10 of 15 dogs with noninfectious meningoencephalitis. CONCLUSIONSAND CLINICAL RELEVANCE 1H MRS provided additional metabolic information about intracranial neoplasia and noninfectious meningoencephalitis in dogs. [ABSTRACT FROM AUTHOR]

Background: Tauopathies are a group of neurodegenerative disorders with accumulation of three-repeat (3R) or four-repeat (4R) Tau. While 3R tau is found in Pick's disease and Alzheimer's disease (AD), 4R tau is more abundant in corticobasal degeneration, progressive supranuclear palsy, and AD. We have previously shown that Cerebrolysin™ (CBL), a neuropeptide mixture with neurotrophic effects, ameliorates the pathology in amyloid precursor protein transgenic (tg) mouse model of AD and 4R tau, however it is unclear if CBL ameliorates the deficits and neuropathology in the mouse model of Pick's disease over expressing 3R tau. Results: Mice expressing 3R tau (L266V and G272V mutations) under the mThy-1 promoter were treated with CBL in two separate groups, the first was 3 months old (treated for 3 months, IP) and the second was 6 months old (treated for 3 months, IP) at the start of the treatment. We found that although the levels of total 3R tau were unchanged, CBL reduced the levels of hyper-phosphorylated tau in both groups of mice. This was accompanied by reduced neurodegenerative pathology in the neocortex and hippocampus in both groups and by improvements in the behavioral deficits in the nest-building test and water maze in the 3-6 month group. Conclusion: Taken together these results support the notion that CBL may be beneficial in other taupathy models by reducing the levels of aberrantly phosphorylated tau. [ABSTRACT FROM AUTHOR]

BACKGROUND: Exposure to excessive levels of manganese (Mn) is known to induce psychiatric and motor disorders, including parkinsonian symptoms. Therefore, finding a reliable means for early detection of Mn neurotoxicity is desirable. OBJECTIVES: Our goal was to determine whether in vivo brain levels of γ-aminobutyric acid (GABA), N.-acetylaspartate (NAA), and other brain metabolites in male smelters were altered as a consequence of Mn exposure. METHODS: We used T1-weighted magnetic resonance imaging (MRI) to visualize Mn deposition in the brain. Magnetic resonance spectroscopy (MRS) was used to quantify concentrations of NAA, glutamate, and other brain metabolites in globus pallidus, putamen, thalamus, and frontal cortex from a well-established cohort of 10 male Mn-exposed smelters and 10 male age-matched control subjects. We used the MEGA-PRESS MRS sequence to determine GABA levels in a region encompassing the thalamus and adjacent parts of the basal ganglia [GABA-VOI (volume of interest)]. RESULTS: Seven of 10 exposed subjects showed clear T1-hyperintense signals in the globus pallidus indicating Mn accumulation. We found a significant increase (82%; p = 0.014) in the ratio of GABA to total creatine (GABA/tCr) in the GABA-VOI of Mn-exposed subjects, as well as a distinct decrease (9%; p = 0.04) of NAA/tCr in frontal cortex that strongly correlated with cumulative Mn exposure (R = -0.93; p < 0.001). CONCLUSIONS: We demonstrated elevated GABA levels in the thalamus and adjacent basal ganglia and decreased NAA levels in the frontal cortex, indicating neuronal dysfunction in a brain area not primarily targeted by Mn. Therefore, the noninvasive in vivo MRS measurement of GABA and NAA may prove to be a powerful tool for detecting presymptomatic effects of Mn neurotoxicity. [ABSTRACT FROM AUTHOR]

A Correction to this paper has been published: https://doi.org/10.1007/s00253-021-11409-5 [ABSTRACT FROM AUTHOR]

Thia analogs of fosmidomycin are potent inhibitors of the non-mevalonate isoprenoid biosynthesis enzyme 1-deoxy- d -xylulose 5-phosphate reductoisomerase (IspC, Dxr) of Plasmodium falciparum. Several new thioethers displayed antiplasmodial in vitro activity in the low nanomolar range, without apparent cytotoxic effects in HeLa cells. The (S) - (+) - enantiomer of a typical representative selectively inhibited IspC and the growth of P. falciparum in continuous culture. The inhibitor was stable at pH 7.6 and room temperature, and no racemization was observed under these conditions during a period of up to two days. Oxidation of selected thioethers to sulfones reduced antiplasmodial activity and the inhibitory activity against Escherichia coli , Mycobacterium tuberculosis and P. falciparum IspC orthologs. Image 1 • Synthesis of novel α-phenyl-substituted β-thia-isosteric fosmidomycin analogs. • The new inhibitors exert nanomolar activity against P. falciparum and E. coli IspC. • Compounds 5e-j showed potent antiplasmodial activity against P. falciparum. • The 5a (S)-(+)-enantiomer showed higher antiplasmodial activity than the racemate. [ABSTRACT FROM AUTHOR]

Main Conclusion: The biochemical characterization of glycolate oxidase in Ricinus communis hints to different physiological functions of the enzyme depending on the organ in which it is active. Enzymatic activities of the photorespiratory pathway are not restricted to green tissues but are present also in heterotrophic organs. High glycolate oxidase (GOX) activity was detected in the endosperm of Ricinus communis. Phylogenetic analysis of the Ricinus L-2-hydroxy acid oxidase (Rc(L)-2-HAOX) family indicated that Rc(L)-2-HAOX1 to Rc(L)-2-HAOX3 cluster with the group containing streptophyte long-chain 2-hydroxy acid oxidases, whereas Rc(L)-2-HAOX4 clusters with the group containing streptophyte GOX. Rc(L)-2-HAOX4 is the closest relative to the photorespiratory GOX genes of Arabidopsis. We obtained Rc(L)-2-HAOX4 as a recombinant protein and analyze its kinetic properties in comparison to the Arabidopsis photorespiratory GOX. We also analyzed the expression of all Rc(L)-2-HAOXs and conducted metabolite profiling of different Ricinus organs. Phylogenetic analysis indicates that Rc(L)-2-HAOX4 is the only GOX encoded in the Ricinus genome (RcGOX). RcGOX has properties resembling those of the photorespiratory GOX of Arabidopsis. We found that glycolate, the substrate of GOX, is highly abundant in non-green tissues, such as roots, embryo of germinating seeds and dry seeds. We propose that RcGOX fulfills different physiological functions depending on the organ in which it is active. In autotrophic organs it oxidizes glycolate into glyoxylate as part of the photorespiratory pathway. In fast growing heterotrophic organs, it is most probably involved in the production of serine to feed the folate pathway for special demands of those tissues.

Chemical investigation of secondary metabolites from the endophytic fungus Pseudopestalotiopsis theae led to the isolation of eighteen new polyketide derivatives, pestalotheols I-Q ( 1 - 9 ) and cytosporins O-W ( 15 - 23 ), together with eight known analogs ( 10 - 14 and 24 - 26 ). The structures of the new compounds were elucidated by HRMS and 1D and 2D NMR data, as well as by comparison with literature data. Modified Mosher's method was applied to determine the absolute configuration of some compounds. Compound 23 showed significant cytotoxicity against the mouse lymphoma cell line L5178Y with an IC 50 value of 3.0 μM. Furthermore, compounds 22 and 23 showed moderate antibacterial activity against drug-resistant Acinetobacter baumannii (ATCC BAA-1605) in combination with sublethal colistin concentrations.

Didymellanosine (1), the first analogue of the decahydrofluorene-class of natural products bearing a 13-membered macrocyclic alkaloid conjugated with adenosine, and a new benzolactone derivative, ascolactone C (4) along with eight known compounds (2, 3, 5-10), were isolated from a solid rice fermentation of the endophytic fungus Didymella sp. IEA-3B.1 derived from the host plant Terminalia catappa . In addition, ascochitamine (11) was obtained when (NH 4 ) 2 SO 4 was added to rice medium and is reported here for the first time as a natural product. Didymellanosine (1) displayed strong activity against the murine lymphoma cell line L5178Y, Burkitt's lymphoma B cells (Ramos) and adult lymphoblastic leukemia T cells (Jurkat J16), with IC 50 values of 2.0, 3.3 and 4.4 µM, respectively. When subjected to a NFκB inhibition assay, didymellanosine (1) moderately blocked NFκB activation in the triple-negative breast cancer cell line MDA-MB 231. In an antimicrobial assay, ascomylactam C (3) was the most active compound when tested against a panel of Gram-positive bacteria including drug-resistant strains with MICs of 3.1-6.3 µM, while 1 revealed weaker activity. Interestingly, both compounds were also found active against Gram-negative Acinetobacter baumannii with MICs of 3.1 µM, in the presence of a sublethal concentration (0.1 µM) of colistin., Competing Interests: There are no conflicts to declare., (This journal is © The Royal Society of Chemistry.)

Xanthoangelol is a geranylated chalcone isolated from fruits of Amorpha fructicosa that exhibits antibacterial effects at low micromolar concentration against Gram-positive bacterial pathogens such as methicillin-resistant Staphylococcus aureus (MRSA), Enterococcus faecium and Enterococcus faecalis. We demonstrate that Xanthoangelol treatment of Gram-positive bacteria affects bacterial membrane integrity and leads to a leakage of intracellular metabolites. This correlates with a rapid collapse of the membrane potential and results in a fast and strong bactericidal effect. Proteomic profiling of Xanthoangelol-treated cells revealed signatures of cell wall and/or membrane damage and oxidative stress. Xanthoangelol specifically disturbs the membrane of Gram-positive bacteria potentially by forming pores resulting in cell lysis. In contrast, Xanthoangelol treatment of human cells showed only mildly hemolytic and cytotoxic effects at higher concentrations. Therefore, geranylated chalcones such as Xanthoangelol are promising lead structures for new antimicrobials against drug-resistant gram-positive pathogens., (Copyright © 2019 Elsevier Ltd. All rights reserved.)

The objective of the present study was to describe two non-invasive methods for fat quantification in normal canine liver by using magnetic resonance imaging (MRI) and spectroscopy. Eleven adult beagle dogs were anesthetized and underwent magnetic resonance examination of the cranial abdomen by performing morphologic, modified Dixon (mDixon) dual gradient echo sequence, and proton magnetic resonance spectroscopy ( 1 H MRS) imaging. In addition, ultrasonographic liver examination was performed, fine-needle liver aspirates and liver biopsies were obtained, and hepatic triglyceride content was assayed. Ultrasonographic, cytologic, and histologic examination results were unremarkable in all cases. The median hepatic fat fraction calculated was 2.1% (range, 1.3%-5.5%) using mDixon, 0.3% (range, 0.1%-1.0%) using 1 H MRS, and 1.6% (range 1.0%-2.5%) based on triglyceride content. The hepatic fat fractions calculated using mDixon and 1 H MRS imaging were highly correlated to that based on triglyceride content. A weak correlation between mDixon and 1 H MRS imaging was detected. The results show that hepatic fat content can be estimated using non-invasive techniques (mDixon or 1 H MRS) in healthy dogs. Further studies are warranted to evaluate the use of these techniques in dogs with varying hepatic fat content and different hepatic disorders.

The rise of multidrug resistance in bacteria rendering pathogens unresponsive to many clinical drugs is widely acknowledged and considered a critical global healthcare issue. There is broad consensus that novel antibacterial chemotherapeutic options are extremely urgently needed. However, the development pipeline of new antibacterial drug lead structures is poorly filled and not commensurate with the scale of the problem since the pharmaceutical industry has shown reduced interest in antibiotic development in the past decades due to high economic risks and low profit expectations. Therefore, academic research institutions have a special responsibility in finding novel treatment options for the future. In this mini review, we want to provide a broad overview of the different approaches and concepts that are currently pursued in this research field.

Background and aims In an effort to characterize the effects of Cerebrolysin for treatment of stroke that are essential for successful clinical translation, we have demonstrated that Cerebrolysin dose dependently enhanced neurological functional recovery in experimental stroke. Here, we conduct a prospective, randomized, placebo-controlled, blinded study to examine the therapeutic window of Cerebrolysin treatment of rats subjected to embolic stroke. Methods Male Wistar rats age 3-4 months (n = 100) were subjected to embolic middle cerebral artery occlusion. Animals were randomized to receive saline or Cerebrolysin daily for 10 consecutive days starting 4, 24, 48, and 72 h after middle cerebral artery occlusion. Neurological outcome was measured weekly with a battery of behavioral tests (adhesive removal test, modified neurological severity score (mNSS), and foot-fault test). Global test was employed to assess Cerebrolysin effect on neurological recovery with estimation of mean difference between Cerebrolysin and control-treated groups and its 95% confidence interval in the intent-to-treat population, where a negative value of the mean difference and 95% confidence interval < 0 indicated a significant treatment effect. All rats were sacrificed 28 days after middle cerebral artery occlusion and infarct volume was measured. Results Cerebrolysin treatment initiated within 48 h after middle cerebral artery occlusion onset significantly improved functional outcome; mean differences and 95% confidence interval were -11.6 (-17.7, -5.4) at 4 h, -7.1 (-13.5, -0.8) at 24 h, -8.4 (-14.2, -8.6) at 48 h, and -4.9 (-11.4, 1.5) at 72 h. There were no differences on infarct volume and mortality rate among groups. Conclusions With a clinically relevant rigorous experimental design, our data demonstrate that Cerebrolysin treatment effectively improves stroke recovery when administered up to 48 h after middle cerebral artery occlusion.

Abnormal accumulation and propagation of the neuronal protein α-synuclein has been hypothesized to underlie the pathogenesis of Parkinson's disease, dementia with Lewy bodies and multiple system atrophy. Here we report a de novo-developed compound (NPT100-18A) that reduces α-synuclein toxicity through a novel mechanism that involves displacing α-synuclein from the membrane. This compound interacts with a domain in the C-terminus of α-synuclein. The E83R mutation reduces the compound interaction with the 80-90 amino acid region of α-synuclein and prevents the effects of NPT100-18A. In vitro studies showed that NPT100-18A reduced the formation of wild-type α-synuclein oligomers in membranes, reduced the neuronal accumulation of α-synuclein, and decreased markers of cell toxicity. In vivo studies were conducted in three different α-synuclein transgenic rodent models. Treatment with NPT100-18A ameliorated motor deficits in mThy1 wild-type α-synuclein transgenic mice in a dose-dependent manner at two independent institutions. Neuropathological examination showed that NPT100-18A decreased the accumulation of proteinase K-resistant α-synuclein aggregates in the CNS and was accompanied by the normalization of neuronal and inflammatory markers. These results were confirmed in a mutant line of α-synuclein transgenic mice that is prone to generate oligomers. In vivo imaging studies of α-synuclein-GFP transgenic mice using two-photon microscopy showed that NPT100-18A reduced the cortical synaptic accumulation of α-synuclein within 1 h post-administration. Taken together, these studies support the notion that altering the interaction of α-synuclein with the membrane might be a feasible therapeutic approach for developing new disease-modifying treatments of Parkinson's disease and other synucleinopathies., (© The Author (2016). Published by Oxford University Press on behalf of the Guarantors of Brain. All rights reserved. For Permissions, please email: journals.permissions@oup.com.)