Maduramicin Rapidly Eliminates Malaria Parasites and Potentiates the Gametocytocidal Activity of the Pyrazoleamide PA21A050

New strategies targeting Plasmodium falciparum gametocytes, the sexual-stage parasites that are responsible for malaria transmission, are needed to eradicate this disease. Most commonly used antimalarials are ineffective against P. falciparum gametocytes, allowing patients to continue to be infectious for over a week after asexual parasite clearance. A recent screen for gametocytocidal compounds demonstrated that the carboxylic polyether ionophore maduramicin is active at low nanomolar concentrations against P. falciparum sexual stages. In this study, we showed that maduramicin has an EC₅₀ (effective concentration that inhibits the signal by 50%) of 14.8 nM against late-stage gametocytes and significantly blocks in vivo transmission in a mouse model of malaria transmission. In contrast to other reported gametocytocidal agents, maduramicin acts rapidly in vitro, eliminating gametocytes and asexual schizonts in less than 12 h without affecting uninfected red blood cells (RBCs). Ring stage parasites are cleared by 24 h. Within an hour of drug treatment, 40% of the normally crescent-shaped gametocytes round up and become spherical. The number of round gametocytes increases to >60% by 2 h, even before a change in membrane potential as monitored by MitoProbe DiIC1 (5) is detectable. Maduramicin is not preferentially taken up by gametocyte-infected RBCs compared to uninfected RBCs, suggesting that gametocytes are more sensitive to alterations in cation concentration than RBCs. Moreover, the addition of 15.6 nM maduramicin enhanced the gametocytocidal activity of the pyrazoleamide PA21A050, which is a promising new antimalarial candidate associated with an increase in intracellular Na⁺ concentration that is proposed to be due to inhibition of PfATP4, a putative Na⁺ pump. These results underscore the importance of cation homeostasis in sexual as well as asexual intraerythrocytic-stage P. falciparum parasites and the potential of targeting this pathway for drug development.     

The impact of underweight and obesity on outcomes in anticoagulated patients with atrial fibrillation: A systematic review and meta‐analysis on the obesity paradox

Although obesity is associated with the development and progression of atrial fibrillation (AF), an obesity paradox may be present, illustrated by seemingly protective effects of obesity on AF‐related outcomes. Body mass index (BMI) has an impact on outcomes in AF patients using oral anticoagulants. After searching Medline and Embase, meta‐analysis of results of four randomized and five observational studies demonstrated significantly lower risks of stroke or systemic embolism (RR 0.80, 95%CI [0.73–0.87]; RR 0.63, 95%CI [0.57–0.70]; and RR 0.42, 95%CI [0.31–0.57], respectively) and all‐cause mortality (RR 0.73, 95%CI [0.64–0.83]; RR 0.61, 95%CI [0.52–0.71]; and RR 0.56, 95%CI [0.47–0.66], respectively) in overweight, obese and morbidly obese anticoagulated AF patients (BMI 25 to <30, ≥30 and ≥40 kg/m², respectively) compared to normal BMI anticoagulated AF patients (BMI 18.5 to <25 kg/m²). In contrast, thromboembolic (RR 1.92, 95%CI [1.28–2.90]) and mortality (RR 3.57, 95%CI [2.50–5.11]) risks were significantly increased in underweight anticoagulated AF patients (BMI <18.5 kg/m²). In overweight and obese anticoagulated AF patients, the risks of major bleeding (RR 0.86, 95%CI [0.76–0.99]; and RR 0.88, 95%CI [0.79–0.98], respectively) and intracranial bleeding (RR 0.75, 95%CI [0.58–0.97]; and RR 0.57, 95%CI [0.40–0.80], respectively) were also significantly lower compared to normal BMI patients, while similar risks were observed in underweight and morbidly obese patients. This meta‐analysis demonstrated lower thromboembolic and mortality risks with increasing BMI. However, as this paradox was driven by results from randomized studies, while observational studies rendered more conflicting results, these seemingly protective effects should still be interpreted with caution.     

Synthesis and Gas‐Transport Properties of Metathesis Polytricyclononenes Bearing Three Me3Si Groups per Monomer Unit

A new metathesis polynorbornene containing three SiMe₃ groups per monomer unit directly connected to the norbornene moiety via Si? C bonds is synthesized. The ring‐opening metathesis polymerization of sterically hindered 3,3,4‐tris(trimethylsilyl)tricyclononene‐7 is successfully conducted in yields 80–85% in the presence of first generation Grubbs catalyst. The corresponding polymer is obtained with molecular weight M_w up to 5.4 × 10⁵ Da. It is an amorphous glassy (T_g = 200 °C) polymer with high thermal stability. Gas permeability and diffusivity coefficients are studied for a range of gases (He, H₂, O₂, N₂, CO₂, CH₄). This polymer containing three SiMe₃ groups per monomer unit turns out to be more permeable (P(O₂) = 125 Barrer) than similar polymers with one or two SiMe₃ groups per monomer unit (P(O₂) = 30–50 Barrer). Wide angle X‐ray diffraction, positron annihilating lifetime spectroscopy, as well as Brunauer–Emmett–Teller investigations are also performed and discussed.

     

Survey of large protein complexes in D. vulgaris reveals great structural diversity

An unbiased survey has been made of the stable, most abundant multi-protein complexes in Desulfovibrio vulgaris Hildenborough (DvH) that are larger than Mr ≈ 400 k. The quaternary structures for 8 of the 16 complexes purified during this work were determined by single-particle reconstruction of negatively stained specimens, a success rate ≈10 times greater than that of previous “proteomic” screens. In addition, the subunit compositions and stoichiometries of the remaining complexes were determined by biochemical methods. Our data show that the structures of only two of these large complexes, out of the 13 in this set that have recognizable functions, can be modeled with confidence based on the structures of known homologs. These results indicate that there is significantly greater variability in the way that homologous prokaryotic macromolecular complexes are assembled than has generally been appreciated. As a consequence, we suggest that relying solely on previously determined quaternary structures for homologous proteins may not be sufficient to properly understand their role in another cell of interest.     

Effect of linoleic acid metabolites on Na(+)/K(+) pump current in N20.1 oligodendrocytes: role of membrane fluidity

Metabolic derivatives of linoleic acid, both monoepoxides and diols, have been reported to be toxic in humans and multiple animal tissue preparations. A previous electrophysiological study has shown these compounds produce multiple effects on the electrical activity of rat ventricular myocytes. The hydrophobic nature of these compounds suggests the possibility that these effects may be due to nonspecific lipid interactions, i.e., changes in membrane fluidity. This study investigates membrane fluidity as a possible mechanism by which linoleic acid metabolites inhibit Na(+)/K(+) pump current (I(p)). This study showed that positional isomers 9,10- and 12,13-epoxy-octadecenoic acid (EOA) and 9,10- and 12,13-dihydroxy-OA (DHOA) inhibit I(p) in a dose-dependent manner in N20.1 mouse oligodendrocytes, with greater inhibition produced by EOAs. These compounds, at 10 microM, inhibited I(p) by 4.7 +/- 1.6, 18.2 +/- 0.5, 11.7 +/- 0.5, and 25.1 +/- 0.9% for 12,13-DHOA, 9,10-DHOA, 12,13-EOA, and 9,10-EOA, respectively, in oligodendrocytes. Fluorescence recovery after photobleaching measurements showed that both DHOA isomers produced a 7-8% increase in diffusion coefficient of the probe at 10 microM, whereas the diffusion coefficient was decreased by 5 and 13% by 9,10-EOA and 12,13-EOA, respectively. There was no apparent correlation between membrane fluidity and inhibition of I(p) by these four linoleic acid metabolites. These results indicate that membrane fluidity alone cannot explain the effects of these compounds on I(p) and suggest that they have a specific interaction with the Na(+)/K(+) pump.     

Motor control and cerebral hemispheric specialization in highly qualified judo wrestlers

With the purpose of investigating motor and cognitive lateralization profiles associated with long-term motor training, we investigated differences in hemispheric specialization between proficient judo sportsmen and controls through the assessment of a number of handedness and footedness items including postural preferences as well as dichotic listening and lateralized visual field tests. Our data show that: (1) the different handedness and footedness items did differently relate to each other within the athlete and control groups as revealed by a principle component analysis (PCA); (2) stand side correlated differently to these motor profile factors in athletes and controls; (3) athletes preferred more frequently to perform certain movements with the left hand than controls, although overall right-handed; (4) this was especially true for athletes which proved to be most proficient/skilled; and (5) in a lateralized verbal listening task and a lateralized visual field task athletes revealed enhanced right-hemispheric involvement relative to controls. Our results suggest that during motor and postural skill acquisitions (long-term judo training) lateral preferences are modified, probably due to neuroplasticity. Moreover, the present findings support the multidimensional view of handedness by Steenhuis and Bryden [Cortex 25 (1989) 289] and the notion of a right-hemispheric "praxis system" involved in skilled action routines within peripersonal space [Brain and Cognition 23 (1993) 181].     

Parental and self-report of sleep in children with attention-deficit/hyperactivity disorder

OBJECTIVE: To determine the prevalence of parent-reported and self-reported sleep disturbances in a sample of school-aged children with attention-deficit/ hyperactivity disorder (ADHD). DESIGN: Cross-sectional survey questionnaire. SETTING: A multidisciplinary ADHD evaluation clinic in a children's teaching hospital (ADHD sample) and 3 elementary schools in southern New England (control sample). PARTICIPANTS: Forty-six unmedicated, school-aged children (mean age, 89.4 +/- 18.7 months; 74% male) diagnosed as having ADHD by Diagnostic and Statistical Manual of Mental Disorders, Fourth Edition, criteria who had been screened for marked symptoms of sleep-disordered breathing, and 46 normal control children (mean age, 86.5 +/- 16.9 months; 70% male). INTERVENTION: None. MAIN OUTCOME MEASURE: Sleep habits and sleep disturbances reported by parents and children. RESULTS: Children with ADHD had significantly higher (more sleep-disturbed) scores on all sleep subscales of the Children's Sleep Habits Questionnaire (parent measure) than did controls; average sleep duration as reported by parents was also significantly shorter in the ADHD group. Children with ADHD also reported their own sleep to be more disturbed than controls did on the Sleep Self-report, particularly on items relating to bedtime struggles (P range, .05-.001). There was a much higher correlation between parent and child sleep report items for the children with ADHD (mean correlation, 0.55) than for the control children. CONCLUSIONS: Sleep disturbances, particularly at bedtime, are frequently reported by both parents and children with ADHD. Children undergoing evaluation for ADHD should be routinely screened for sleep disturbances, especially symptoms of sleep-disordered breathing. The causes of sleep-onset delay in children with ADHD should be considered in designing intervention strategies for children with difficulty falling and staying asleep.     

Coronary venous blood flow in patients with acute myocardial infarction

In 94 patients with large myocardial infarction, their coronary venous blood flow was studied in the acute period of the disease by continuous coronary sinus thermodilution. No relationship was established between the coronary venous blood flow and the duration of coronary heart disease. The patients with anterior myocardial infarction had a significantly less blood flow in the vena cordis magna than those with posterolateral infarction. No correlation was found between the blood flow and precordial mapping parameters. Thus, continuous coronary sinus thermodilution cannot be used for indirect identification of the site of myocardial infarction and for prediction of its progression severity.