Hydrogen Peroxide Disproportionation Activity Is Sensitive to Pyridine Substitutions on Manganese Catalysts Derived from 12-Membered Tetra-Aza Macrocyclic Ligands.

The abundance of manganese in nature and versatility to access different oxidation states have made manganese complexes attractive as catalysts for oxidation reactions in both biology and industry. Macrocyclic ligands offer the advantage of substantially controlling the reactivity of the manganese center through electronic tuning and steric constraint. Inspired by the manganese catalase enzyme, a biological catalyst for the disproportionation of H2O2 into water and O2, the work herein employs 12-membered tetra-aza macrocyclic ligands to study how the inclusion of and substitution to the pyridine ring on the macrocyclic ligand scaffold impacts the reactivity of the manganese complex as a H2O2 disproportionation catalyst. Synthesis and isolation of the manganese complexes was validated by characterization using UV-vis spectroscopy, SC-XRD, and cyclic voltammetry. Potentiometric titrations were used to study the ligand basicity as well as the thermodynamic equilibrium with Mn(II). Manganese complexes were also produced in situ and characterized using electrochemistry for comparison to the isolated species. Results from these studies and H2O2 reactivity showed a remarkable difference among the ligands studied, revealing instead a distinction in the reactivity regarding the number of pyridine rings within the scaffold. Moreover, electron-donating groups on the 4-position of the pyridine ring enhanced the reactivity of the manganese center for H2O2 disproportionation, demonstrating a handle for control of oxidation reactions using the pyridinophane macrocycle.

Increased Efficiency of a Functional SOD Mimic Achieved with Pyridine Modification on a Pyclen-Based Copper(II) Complex.

A series of Cu(II) complexes with the formula [CuRPyN3]2+ varying in substitution on the pyridine ring were investigated as superoxide dismutase (SOD) mimics to identify the most efficient reaction rates produced by a synthetic, water-soluble copper-based SOD mimic reported to date. The resulting Cu(II) complexes were characterized by X-ray diffraction analysis, UV-visible spectroscopy, cyclic voltammetry, and metal-binding (log ß) affinities. Unique to this approach, the modifications to the pyridine ring of the PyN3 parent system tune the redox potential while exhibiting high binding stabilities without changing the coordination environment of the metal complex within the PyN3 family of ligands. We were able to adjust in parallel the binding stability and the SOD activity without compromising on either through simple modification of the pyridine ring on the ligand system. This goldilocks effect of high metal stabilities and high SOD activity reveals the potential of this system to be explored in therapeutics. These results serve as a guide for factors that can be modified in metal complexes using pyridine substitutions for PyN3, which can be incorporated into a range of applications moving forward.

Pyridine modifications regulate the electronics and reactivity of Fe-pyridinophane complexes.

12-Membered pyridinophanes are the focus of many studies as biological mimics, chelators, and catalytic precursors. Therefore, the desire to tune the reactivity of pyridinophanes to better control the applications of derivative metal complexes has inspired many structure-activity relationship studies. However, the separation of structural versus electronic changes imparted by ligand modification has made these structure-activity relationship studies of transition metal catalysts challenging to define. In this work we show that 4-substitution of the pyridine ring in 12-membered tetra-aza pyridinophanes successfully provides a regulatory handle on the electronic properties of the metal center and, therefore, the catalytic C-C coupling activity of the respective iron complexes. The C-C coupling reaction catalyzed by Fe(L1-L6) provides a range of yields (32-58%) that directly correlate with iron redox potentials (ΔE1/2 = 152 mV) and metal binding constants (Δlog ß = 3.45), while the geometry of the complexes was virtually indistinguishable. These are the first results to definitively show the redox potential and metal binding as independent properties from the coordination chemistry in one ligand series. Adjustments to these chemical properties were then shown to provide a regulatory handle for the C-C coupling reactivity tuned via pyridine substitution in pyridinophanes.

Manganese (III/IV) µ-Oxo Dimers and Manganese (III) Monomers with Tetraaza Macrocyclic Ligands and Historically Relevant Open-Chain Ligands.

The oxygen-evolving complex (OEC) located in photosystem II (PSII) of green plants is one of the best-known examples of a manganese-containing enzyme in nature, but it is also used in a range of other biological processes. OEC models incorporate two multi-dentate nitrogen-containing ligands coordinated to a bis-µ-oxo Mn(III,IV) core. Open-chain ligands were the initial scaffold used for biomimetic studies, but their macrocyclic counterparts have proven to be particularly appropriate due to their enhanced stability. Dimer and monomer complexes with such ligands have shown to be useful for a wide range of applications, which will be reviewed herein. The purpose of this review is to state with some clarity the different spectroscopic and structural characteristics of the Mn complexes formed with tetraaza macrocyclic ligands both in solution and solid-state that allow the reader to successfully identified the species involved when dealing with similar complexes of Mn.

Manganese Complex of a Rigidified 15-Membered Macrocycle: A Comprehensive Study.

Owing to the increasing importance of manganese(II) complexes in the field of magnetic resonance imaging (MRI), large efforts have been devoted to find an appropriate ligand for Mn(II) ion encapsulation by providing balance between the seemingly contradictory requirements (i.e., thermodynamic stability and kinetic inertness vs low ligand denticity enabling water molecule(s) to be coordinated in its metal center). Among these ligands, a large number of pyridine or pyridol based open-chain and macrocyclic chelators have been investigated so far. As a next step in the development of these chelators, 15-pyN3O2Ph and its transition metal complexes were synthesized and characterized using established methods. The 15-pyN3O2Ph ligand incorporates both pyridine and ortho-phenylene units to decrease ligand flexibility. The thermodynamic properties, protonation and stability constants, were determined using pH-potentiometry; the solid-state structures of two protonation states of the free ligand and its manganese complex were obtained by single crystal X-ray diffractometry. The results show a seven-coordinate metal center with two water molecules in the first coordination sphere. The longitudinal relaxivity of [Mn(15-pyN3O2Ph)]2+ was found to be 5.16 mM-1 s-1 at 0.49 T (298 K). Furthermore, the r2p value of 11.72 mM-1 s-1 (0.49 T), which is doubled at 1.41 T field, suggests that design of this Mn(II) complex does achieve some characteristics required for contrast imaging. In addition, 17O NMR measurements were performed in order to access the microscopic parameters governing this key feature (e.g., water exchange rate). Finally, manganese complexes of ligands with analogous polyaza macrocyclic scaffold have been investigated as low molecular weight Mn(CAT) mimics. Here, we report the H2O2 disproportionation study of [Mn(15-pyN3O2Ph)]2+ to demonstrate the versatility of this ligand scaffold as well.

Hydrogen Peroxide Disproportionation with Manganese Macrocyclic Complexes of Cyclen and Pyclen.

The catalase family of enzymes, which include a variety with a binuclear manganese active site, mitigate the risk from reactive oxygen species by facilitating the disproportionation of hydrogen peroxide into molecular oxygen and water. In this work, hydrogen peroxide disproportionation using complexes formed between manganese and cyclen or pyclen were investigated due to the spectroscopic similarities with the native MnCAT enzyme. Potentiometric titrations were used to construct speciation diagrams that identify the manganese complex compositions at different pH values. Each complex behaves as a functional mimic of catalase enzymes. UV-visible spectroscopic investigations of the H2O2 decomposition reaction yielded information about the structure of the initial catalyst and intermediates that include monomeric and dimeric species. The results indicate that rigidity imparted by the pyridine ring of pyclen is a key factor in increased TON and TOF values measured compared to cyclen.

Risk Analysis Based on the Timing of Tracheostomy Procedures in Patients with Spinal Cord Injury Requiring Cervical Spine Surgery.

OBJECTIVE: To determine the optimal moment to perform tracheostomy in a patient requiring anterior cervical fixation. METHODS: A retrospective observational study conducted over an 18-year period included 56 patients who had been admitted to the intensive care unit with acute spinal cord injury and underwent tracheostomy and surgical fixation. The sample was divided into 2 groups: at-risk group (31 patients who had undergone tracheostomy before cervical surgery or <4 days after surgery) and not-at-risk group (25 patients who had undergone tracheostomy >4 days after fixation surgery). Descriptive and comparative studies were carried out. Overall trend of the collected data was analyzed using cubic splines (graphic methods). RESULTS: The only infectious complications diagnosed as related to the surgical procedure were infection of the surgical wound in 2 patients in the not-at-risk group (12%) and deep tissue infection in 1 patient in the at-risk group (3.2%). During the study period, we identified a tendency toward performance of early tracheostomies. CONCLUSIONS: Our results suggest that the presence of a tracheostomy stoma before or immediately after surgery is associated with a low risk of infection of the cervical surgical wound in instrumented spinal fusion.

Low-level Chronic Lead Exposure Impairs Neural Control of Blood Pressure and Heart Rate in Rats.

Lead (Pb) induces adverse effects when it chronically accumulates in the body, including effects on the nervous and cardiovascular systems. Wistar rats were exposed to lead acetate for 30 days (first dose 4 µg/100 g followed by 0.05 µg/100 g/day, i.m.) to investigate the cardiovascular system impact on the autonomic control. The femoral artery and vein were catheterised to perform hemodynamic evaluations in awake rats: heart rate variability (HRV), baroreflex sensitivity, cardiopulmonary reflex and hemodynamic responses to vagal and sympathetic pharmacological blockade. Rats exposed to Pb exhibited a higher blood pressure and reduced HRV in the time domain when compared to the saline-injected group. Spectral analysis of the HRV in the frequency-domain showed an augmented low-frequency component of the spectrum. Methylatropine and atenolol administration suggest increased sympathetic tone and reduced vagal tone on the control of heart rate. Chronic Pb exposure decreased the sensitivity of the baroreflex without significantly changing the cardiopulmonary reflex. This study demonstrated for the first time in an animal model of a controlled, low-dose chronic lead exposure that cardiovascular changes, such as arterial hypertension, are accompanied by impaired autonomic control of the cardiovascular system, as characterised by reduced baroreflex sensitivity and a sympathovagal imbalance.

Low-level lead exposure changes endothelial modulation in rat resistance pulmonary arteries.

Lead exposure induces hypertension and endothelial dysfunction. However, the effects on the pulmonary vasculature have not been explored. In this study, rats exposed to lead acetate for seven days (4µg/100g on the 1st day and 0.05µg/100g/day i.m. subsequently) had lead blood level of 3.9±0.7µg/dL and increased right ventricular pressures. There was an increased Pb deposition and superoxide anions production in the pulmonary arteries, associated with reduced vasoconstriction but unchanged endothelium-dependent vasodilatation to acetylcholine (ACh). In both groups, inhibition of the nitric oxide (NO) synthase with L-NAME blocked the response to ACh, while indomethacin (cycloxygenase inhibitor) had no effect. Incubation with nonspecific potassium channel blocker (tetraethylammonium) reduced the ACh-induced vasodilatation only in the Pb group. Apamin (SKCa channel blocker) and 4-aminopyridine (Kv channel blocker), but not iberiotoxin (BKCa channel blocker), also inhibited this response in the Pb group. The vasodilatation to exogenous NO was reduced by Pb, while relaxation to the cGMP analogue was similar between groups. Concordantly, the protein level of soluble guanylate cyclase (sGC) was reduced. In conclusion, short-term and low-level exposure to Pb changes pulmonary haemodynamic and increases oxidative stress. The pulmonary vasculature exhibited increased hyperpolarization by the Kv and SKCa channels, probably as a compensatory mechanism to the decreased responsiveness to NO.

Maternal protein restriction compromises myocardial contractility in the young adult rat by changing proteins involved in calcium handling.

Maternal protein restriction (MPR) during pregnancy is associated with increased cardiovascular risk in the offspring in adulthood. In this study we evaluated the cardiac function of young male rats born from mothers subjected to MPR during pregnancy, focusing on the myocardial mechanics and calcium-handling proteins. After weaning, rats received normal diet until 3 mo old, when the following parameters were assessed: arterial and left ventricular hemodynamics and in vitro cardiac contractility in isolated papillary muscles. The body weight was lower and arterial pressure higher in the MPR group compared with young adult offspring of female rats that received standard diet (controls); and left ventricle time derivatives increased in the MPR group. The force developed by the cardiac muscle was similar; but time to peak and relaxation time were longer, and the derivatives of force were depressed in the MPR. In addition, MPR group exhibited decreased post-pause potentiation of force, suggesting reduced reuptake function of the sarcoplasmic reticulum. Corroborating, the myocardial content of SERCA-2a and phosphorylated PLB-Ser16/total PLB ratio was decreased and sodium-calcium exchanger was increased in the MPR group. The contraction dependent on transsarcolemmal influx of calcium was higher in MPR if compared with the control group. In summary, young rats born from mothers subjected to protein restriction during pregnancy exhibit changes in the myocardial mechanics with altered expression of calcium-handling proteins, reinforcing the hypothesis that maternal malnutrition is related to increased cardiovascular risk in the offspring, not only for hypertension, but also cardiac dysfunction.

Predicting mortality in burn patients with bacteraemia.

OBJECTIVE: To determine factors associated with mortality in burn patients with bacteraemia. BACKGROUND: Previous studies have shown the negative impact of bacteraemia on the prognosis of burn patients, but only a few of these have analysed variables intervening in the clinical progress of these patients. METHODS: A retrospective study of adult burn patients (n = 73) with bacteraemia (103 episodes) in a Burns Unit during the 2000-2013 period. The study collected demographic variables, and comorbidity, injury-related and clinical data related to bacteraemia. Variables related to hospital mortality were analysed using a multiple logistic regression model. RESULTS: The cumulative incidence of bacteraemia was 4.4 episodes/100 patients. The mean age was 53.3 ± 19.2 years (65.8 % male). The median total body surface area (TBSA) was 35 %, while 50.7 % of the population had inhalation syndrome. The mean SOFA score at the onset of bacteraemia was 2.7 ± 3.8. The most common pathogen was Pseudomonas aeruginosa (17.5 %). The mortality rate was 24.7 %. The variables that were significantly associated with mortality were age (OR = 1.13), TBSA (OR = 1.05), SOFA score at the onset of bacteraemia (OR = 1.53) and recurrent bacteraemia (OR = 41.6). CONCLUSION: In addition to conventional risk factors, recurrence and organ dysfunction at the onset of bacteraemia are also associated with mortality, while the pathogen involved is not a prognostic factor.

Tracheostomy in the management of patients with thermal injuries.

OBJECTIVE: To assess the use and clinical impact of tracheostomy in burn patients. SUMMARY BACKGROUND DATA: The role of tracheostomy in the management of burn patients is controversial, with only a few recent studies conducted in this population. METHODS: Retrospective study of all adult burn patients who underwent a tracheostomy in a Burns Unit between 1995 and 2013. These were compared with a control group (1:1) who underwent orotracheal intubation. Hospital records were reviewed to obtain demographic and clinical information, including those related to respiratory support and tracheostomy. The McNemar's Chi-square and Signed-Rank Tests were used to study differences in morbimortality between both groups. RESULTS: A total of n = 20 patients underwent tracheostomy (0.9% of admissions, 56.0 ± 19.5 years, 60.0% women). The most common indication was long-term ventilation (75%), 24.6 ± 19.7 days after admission. Thirteen patients were successfully decannulated with a fatal complication observed in one case. Patients in the tracheostomy group were found to require longer-term mechanical ventilation (43.2 vs. 20.4 days; P = 0.004), with no differences in respiratory infection rates (30.0% vs. 31.6%; P = 0.687) or mortality (30.0% vs. 42.1%; P = 0.500). Ventilator weaning times (15.7 vs. 3.3 days; P = 0.001) and hospital stays (99.1 vs. 53.1 days; P = 0.030) were longer in the tracheostomy group, with no differences in duration of sedation. CONCLUSIONS: Tracheostomy may be a safe procedure in burn patients and is not associated with higher rates of mortality or respiratory infection. Tracheostomy patients showed longer mechanical ventilation times and higher morbidity, probably not attributable to tracheostomy.

Aeromonas y meningitis: una presentación infrecuente / No disponible

El hábitat natural del género Aeromonas es el medio acuático. Describimos el caso de un varón que sufre traumatismo craneoencefálico grave y presenta en su evolución meningitis por A. hydrophila (AU)

[Aeromonas and meningitis: An unusual presentation]. / Aeromonas y meningitis: una presentación infrecuente.

The natural habitat of the genus Aeromonas is an aquatic environment. We describe the case of a patient suffering severe traumatic brain injury and meningitis by A. hydrophyla.

Postpartum amaurosis in a woman with severe preeclampsia.

The maternal and perinatal fetal prognosis of preeclampsia depends on the gestational age of the fetus at onset, the severity of the disease, the quality of care, and the presence of pre-existent medical conditions. One of the uncommon effects of severe preeclampsia on the eye is sudden loss of vision. The present case report is of a woman with severe preeclampsia exacerbated by delivery that coursed with difficult-to-control arterial hypertension and reversible cortical amaurosis without impaired consciousness or seizures.