The discovery and implementation of antibiotics in the early twentieth century transformed human health and wellbeing. Chemical synthesis enabled the development of the first antibacterial substances, organoarsenicals and sulfa drugs, but these were soon outshone by a host of more powerful and vastly more complex antibiotics from nature: penicillin, streptomycin, tetracycline, and erythromycin, among others. These primary defences are now significantly less effective as an unavoidable consequence of rapid evolution of resistance within pathogenic bacteria, made worse by widespread misuse of antibiotics. For decades medicinal chemists replenished the arsenal of antibiotics by semisynthetic and to a lesser degree fully synthetic routes, but economic factors have led to a subsidence of this effort, which places society on the precipice of a disaster. We believe that the strategic application of modern chemical synthesis to antibacterial drug discovery must play a critical role if a crisis of global proportions is to be averted.

Diffusion- and perfusion-weighted magnetic resonance imaging provides important pathophysiological information in acute brain ischemia. We performed a prospective study in 19 sub-6-hour stroke patients using serial diffusion- and perfusion-weighted imaging before intravenous thrombolysis, with repeat studies, both subacutely and at outcome. For comparison of ischemic lesion evolution and clinical outcome, we used a historical control group of 21 sub-6-hour ischemic stroke patients studied serially with diffusion- and perfusion-weighted imaging. The two groups were well matched for the baseline National Institutes of Health Stroke Scale and magnetic resonance parameters. Perfusion-weighted imaging-diffusion-weighted imaging mismatch was present in 16 of 19 patients treated with tissue plasminogen activator, and 16 of 21 controls. Perfusion-weighted imaging-diffusion-weighted imaging mismatch patients treated with tissue plaminogen activator had higher recanalization rates and enhanced reperfusion at day 3 (81% vs 47% in controls), and a greater proportion of severely hypoperfused acute mismatch tissue not progressing to infarction (82% vs -25% in controls). Despite similar baseline diffusion-weighted imaging lesions, infarct expansion was less in the recombinant tissue plaminogen activator group (14cm(3) vs 56cm(3) in controls). The positive effect of thrombolysis on lesion growth in mismatch patients translated into a greater improvement in baseline to outcome National Institutes of Health Stroke Scale in the group treated with recombinant tissue plaminogen activator, and a significantly larger proportion of patients treated with recombinant tissue plaminogen activator having a clinically meaningful improvement in National Institutes of Health Stroke Scale of > or = 7 points. The natural evolution of acute perfusion-weighted imaging-diffusion-weighted imaging mismatch tissue may be altered by thrombolysis, with improved stroke outcome. This has implications for the use of diffusion- and perfusion-weighted imaging in selecting and monitoring patients for thrombolytic therapy.

The chemical modification of structurally complex fermentation products, a process known as semisynthesis, has been an important tool in the discovery and manufacture of antibiotics for the treatment of various infectious diseases. However, many of the therapeutics obtained in this way are no longer effective, because bacterial resistance to these compounds has developed. Here we present a practical, fully synthetic route to macrolide antibiotics by the convergent assembly of simple chemical building blocks, enabling the synthesis of diverse structures not accessible by traditional semisynthetic approaches. More than 300 new macrolide antibiotic candidates, as well as the clinical candidate solithromycin, have been synthesized using our convergent approach. Evaluation of these compounds against a panel of pathogenic bacteria revealed that the majority of these structures had antibiotic activity, some efficacious against strains resistant to macrolides in current use. The chemistry we describe here provides a platform for the discovery of new macrolide antibiotics and may also serve as the basis for their manufacture.

Background and Purpose-Knowledge of the topographic distribution of infarcts of the middle cerebral artery (MCA) may give insight into the limits of the arterial territory and infarct mechanism and may influence the decision to use thrombolytic therapy. We describe the creation of a digital atlas of MCA (DA-MCA) infarction associated with MCA branch and trunk occlusion using magnetic resonance (MR) techniques. Methods-Hemispheric infarcts, with evidence of MCA trunk or branch occlusion, were manually segmented into binary images, linearly registered into a common stereotaxic coordinate space, and averaged to yield the probability of involvement by infarction at each voxel. Comparisons were made with existing maps of the MCA territory. Results-Twenty-eight patients with median age of 74 years (range, 26 to 87 years) were studied. On the DA-MCA, the highest frequency of infarction was within the striatocapsular region, centrum semiovale, and the insula. The mean and maximal MCA infarct volumes were 195.5 cm 3 and 366.3 cm 3 , respectively. Comparison with published maps showed that the most common difference from the DA-MCA was in the superomedial extent of the MCA territory. Some maps showed the MCA territory reaching the interhemispheric fissure, whereas in the DA-MCA it did not. There was a lower variability in the anterior boundary of the MCA territory compared with its posterior counterpart. Conclusion-We

ω-Pentadecalactone (PDL) was copolymerized with lactones of varying sizes (6-, 7-, 9-, and 13-membered rings) in order to characterize the properties of PDL copolymers throughout the lactone range for copolymerizations catalyzed by magnesium 2,6-di-tertbutyl-4-methylphenoxide (Mg(BHT) 2 (THF) 2 ). Kinetics of the copolymerization reactions were studied using quantitative 13 C NMR spectroscopy, which revealed that the polymerization of the smaller, strained lactone monomer occurred rapidly before the incorporation of PDL into the polymer. Furthermore, all polymers were randomly sequenced as a consequence of transesterification side reactions that occurred throughout polymerization. The copolymers were all shown to cocrystallize to produce polymers with melting and crystallization temperatures that displayed a linear relationship with respect to monomer ratio. Differences in degradation behavior of the smaller lactones enabled the synthesis of PDL copolymer materials that displayed independently controllable thermal and degradation properties.

Phenol has been used as an additive to enhance the rate of SET‐LRP in toluene at ambient temperature. A direct relationship between reaction time and amount of phenol added has been found with the optimum amount being ∼ 20 equiv. of phenol with respect to initiator. Polymerization of methyl acrylate (MA) has been carried out in the presence of varying amounts of phenol and the rate of polymerization depends on the concentration of phenol relative to initiator. With a 20‐fold excess 93% conversion is observed after 218 min (PDI = 1.06, Mn = 11,500 g mol−1) when compared with 80% conversion with a 5‐fold excess (PDI = 1.21, Mn = 5310 g mol−1). When nonsterically hindered phenols are employed in a 20 molar excess with respect to the initiator the polymerizations have good linear first‐order kinetics and give polymers with PDI between 1.06 and 1.16. When a highly hindered phenol is employed there is a significant induction period prior to polymerization taking place which is similar to when using no phenol. Less hindered phenols accelerated the polymerization when compared with polymerizations with no added phenol. Increasing steric hindrance at the OH prevents this coordination which indicates that the role of phenol is different with either copper(0) or copper(I). Aliphatic and aromatic esters and amides were used successfully as initiators giving polymers with Mn close to that predicted at ∼ 10,000 g mol−1 and PDI typically less than 1.10. An induction period is observed in most cases which can be removed by a pre‐equilibrium step before the addition of monomer. This results in excellent first‐order kinetics being observed in the polymerization of MA in toluene solution (50 vol %). Here Cu(0) (powder)/Me6‐TREN with 20 equiv. of phenol and all of the reactants, except the monomer, were added to the reaction flask and stirred for 45 min at 25 °C. The structure of the polymer is shown by MALDI TOF MS to contain bromide chain ends derived from the alkyl bromide initiator. The retention of this end group is consistent with living radical polymerization. © 2008 Wiley Periodicals, Inc. J Polym Sci Part A: Polym Chem 46: 7376–7385, 2008

In ischaemic stroke, expansion of the infarct core occurs at the expense of surrounding hypoxic, metabolically compromised tissue over a period of 24 h or more in a considerable proportion of patients. It is uncertain whether hypoxic tissue observed at later times after stroke onset retains the potential for survival or whether such survival has an impact on functional outcome. These factors may determine the effectiveness of therapeutic strategies aimed at salvaging this tissue. We tested the hypotheses that metabolically compromised hypoxic tissue observed within 48 h after onset of ischaemic stroke retains the potential for spontaneous survival and that the impact of such survival on functional outcome is time dependent. Consecutive patients presenting within 48 h of ischaemic stroke were studied with [(18)F]fluoromisonidazole, a ligand binding to hypoxic but viable tissue, and PET. Subjects were grouped into two time epochs, 12 h, based on the interval from stroke onset to the time of tracer injection, and had infarct volumes measured on CT/MRI at 7 days (n = 60). The total ischaemic volume (TIV) and the proportion of the TIV that spontaneously survived (surviving hypoxic volume ratio, SHVR) were defined from the co-registered CT/MRI images. These volumetric measures were correlated with neurological outcome assessed at day 7-10 by percentage change in the National Institutes of Health Stroke Scale (DeltaNIHSS), and at 3 months by Barthel Index (BI) and modified Rankin Score (mRS). Of 66 patients investigated, hypoxic tissue occurred in 33 and outcome data was available in 27. Hypoxic tissue constituted >20% of the TIV in 60% of studies 12 h. The spontaneously surviving proportion of the TIV (median 6.9%) or hypoxic tissue (median 45.9%) was not significantly different in patient subgroups studied 12 h after stroke onset. Spontaneous survival of hypoxic tissue (surviving hypoxic volume ratio) was associated with improved neurological outcome in both time epochs: 12 h, DeltaNIHSS (r = 0.59, P < 0.01) and day 90 mRS (r = -0.46, P < 0.05). The finding that similar proportions of hypoxic tissue survived spontaneously within each time epoch suggests that its fate is not predetermined. The favourable neurological outcome associated with spontaneous survival of hypoxic tissue, even 12-48 h after stroke onset, suggests that the volume of hypoxic tissue that progressed to infarction may represent a valuable target for therapeutic intervention.

The ‘immortal’ ring-opening polymerization (iROP) of pentadecalactone (PDL), catalysed by magnesium 2,6-di-tert-butyl-4-methylphenoxide (Mg(BHT)2(THF)2) under non-inert conditions is reported for the first time.