Anesthetic management of parturients with Arnold Chiari malformation-I: a multicenter retrospective study.

BACKGROUND: Consensus regarding the safest mode of delivery and anesthetic management for parturients with Arnold Chiari malformation-I (ACM-I) remains controversial. This study assessed their anesthetic management and reported anesthetic complications during hospitalization for delivery. METHODS: This was a multicenter, retrospective, cohort study of patients with ACM-I undergoing vaginal or cesarean delivery. Data were obtained from the electronic databases of four United States academic institutions using International Classification of Diseases (ICD) codes from 2007-2017 at three sites and 2004-2017 at one site. The primary outcome was anesthetic complications. RESULTS: Data were analyzed for 185 deliveries in 148 patients. Diagnosis of ACM-I was made prior to delivery in 147 (80%) cases. Pre-delivery neurosurgical consultation for management of ACM-I was performed in 53 (36%) patients. Pre-existing symptoms were recorded for 89 (48%) of the deliveries. Vaginal deliveries occurred in 80 (43%) cases, and 62 women (78%) received neuraxial labor analgesia. Cesarean delivery was performed in 105 (57%) cases, of which 70 women (67%) had neuraxial anesthesia and 34 (32%) received general anesthesia. Post-dural puncture headache was reported in three (2%) patients who had neuraxial anesthesia, and in two (12%) patients with syringomyelia. There was one (3%) reported case of aspiration pneumonia with general anesthesia. CONCLUSIONS: The findings suggest that anesthetic complications occur infrequently in patients with ACM-I regardless of the anesthetic management. Although institutional preference in anesthetic and obstetric care appears to drive patient management, the findings suggest that an individualized approach has favorable outcomes in this population.

Repeated storage of respired carbon in the equatorial Pacific Ocean over the last three glacial cycles.

As the largest reservoir of carbon exchanging with the atmosphere on glacial-interglacial timescales, the deep ocean has been implicated as the likely location of carbon sequestration during Pleistocene glaciations. Despite strong theoretical underpinning for this expectation, radiocarbon data on watermass ventilation ages conflict, and proxy interpretations disagree about the depth, origin and even existence of the respired carbon pool. Because any change in the storage of respiratory carbon is accompanied by corresponding changes in dissolved oxygen concentrations, proxy data reflecting oxygenation are valuable in addressing these apparent inconsistencies. Here, we present a record of redox-sensitive uranium from the central equatorial Pacific Ocean to identify intervals associated with respiratory carbon storage over the past 350 kyr, providing evidence for repeated carbon storage over the last three glacial cycles. We also synthesise our data with previous work and propose an internally consistent picture of glacial carbon storage and equatorial Pacific Ocean watermass structure.

No iron fertilization in the equatorial Pacific Ocean during the last ice age.

The equatorial Pacific Ocean is one of the major high-nutrient, low-chlorophyll regions in the global ocean. In such regions, the consumption of the available macro-nutrients such as nitrate and phosphate is thought to be limited in part by the low abundance of the critical micro-nutrient iron. Greater atmospheric dust deposition could have fertilized the equatorial Pacific with iron during the last ice age--the Last Glacial Period (LGP)--but the effect of increased ice-age dust fluxes on primary productivity in the equatorial Pacific remains uncertain. Here we present meridional transects of dust (derived from the (232)Th proxy), phytoplankton productivity (using opal, (231)Pa/(230)Th and excess Ba), and the degree of nitrate consumption (using foraminifera-bound δ(15)N) from six cores in the central equatorial Pacific for the Holocene (0-10,000 years ago) and the LGP (17,000-27,000 years ago). We find that, although dust deposition in the central equatorial Pacific was two to three times greater in the LGP than in the Holocene, productivity was the same or lower, and the degree of nitrate consumption was the same. These biogeochemical findings suggest that the relatively greater ice-age dust fluxes were not large enough to provide substantial iron fertilization to the central equatorial Pacific. This may have been because the absolute rate of dust deposition in the LGP (although greater than the Holocene rate) was very low. The lower productivity coupled with unchanged nitrate consumption suggests that the subsurface major nutrient concentrations were lower in the central equatorial Pacific during the LGP. As these nutrients are today dominantly sourced from the Subantarctic Zone of the Southern Ocean, we propose that the central equatorial Pacific data are consistent with more nutrient consumption in the Subantarctic Zone, possibly owing to iron fertilization as a result of higher absolute dust fluxes in this region. Thus, ice-age iron fertilization in the Subantarctic Zone would have ultimately worked to lower, not raise, equatorial Pacific productivity.

Large deglacial shifts of the Pacific Intertropical Convergence Zone.

The position of the Intertropical Convergence Zone (ITCZ) is sensitive to changes in the balance of heat between the hemispheres which has fundamental implications for tropical hydrology and atmospheric circulation. Although the ITCZ is thought to experience the largest shifts in position during deglacial stadial events, the magnitude of shifts has proven difficult to reconstruct, in part because of a paucity of high-resolution records, particularly those including spatial components. Here we track the position of the ITCZ from 150 to 110 ka at three sites in the central equatorial Pacific at sub-millennial time resolution. Our results provide evidence of large, abrupt changes in tropical climate during the penultimate deglaciation, coincident with North Atlantic Heinrich Stadial 11 (∼136-129 ka). We identify this event both as a Northern Hemisphere increase in aeolian dust and as a shift in the mean position of the ITCZ a minimum of 4° southwards at 160° W.

How well can we quantify dust deposition to the ocean?

Deposition of continental mineral aerosols (dust) in the Eastern Tropical North Atlantic Ocean, between the coast of Africa and the Mid-Atlantic Ridge, was estimated using several strategies based on the measurement of aerosols, trace metals dissolved in seawater, particulate material filtered from the water column, particles collected by sediment traps and sediments. Most of the data used in this synthesis involve samples collected during US GEOTRACES expeditions in 2010 and 2011, although some results from the literature are also used. Dust deposition generated by a global model serves as a reference against which the results from each observational strategy are compared. Observation-based dust fluxes disagree with one another by as much as two orders of magnitude, although most of the methods produce results that are consistent with the reference model to within a factor of 5. The large range of estimates indicates that further work is needed to reduce uncertainties associated with each method before it can be applied routinely to map dust deposition to the ocean. Calculated dust deposition using observational strategies thought to have the smallest uncertainties is lower than the reference model by a factor of 2-5, suggesting that the model may overestimate dust deposition in our study area.This article is part of the themed issue 'Biological and climatic impacts of ocean trace element chemistry'.

Two modes of change in Southern Ocean productivity over the past million years.

Export of organic carbon from surface waters of the Antarctic Zone of the Southern Ocean decreased during the last ice age, coinciding with declining atmospheric carbon dioxide (CO(2)) concentrations, signaling reduced exchange of CO(2) between the ocean interior and the atmosphere. In contrast, in the Subantarctic Zone, export production increased into ice ages coinciding with rising dust fluxes, thus suggesting iron fertilization of subantarctic phytoplankton. Here, a new high-resolution productivity record from the Antarctic Zone is compiled with parallel subantarctic data over the past million years. Together, they fit the view that the combination of these two modes of Southern Ocean change determines the temporal structure of the glacial-interglacial atmospheric CO(2) record, including during the interval of "lukewarm" interglacials between 450 and 800 thousand years ago.

Inhibition of radical-induced DNA strand breaks by water-soluble constituents of coffee: phenolics and caffeine metabolites.

Epidemiological studies have associated coffee consumption with an inverse risk of developing Parkinson's disease, hepatocellular carcinoma and cirrhosis. The molecular mechanisms by which low concentrations of the constituents of coffee measured in human plasma can reduce the incidence of such diseases are not clear. Using an in vitro plasmid DNA system and radiolytically generated reactive oxygen species under constant radical scavenging conditions, we have shown that coffee chlorogenic acid, its derivatives and certain metabolites of caffeine reduce some of the free radical damage sustained to the DNA. A reduction in the amount of prompt DNA single-strand breaks (SSBs) was observed for all compounds whose radical one-electron reduction potential is < 1.0 V. However, except for chlorogenic acid, the compounds were found to be inactive in reducing the amount of radical damage to the DNA bases. These results support a limited antioxidant role for such compounds in their interaction with DNA radicals.

Comparative bioactivation of the novel anti-tuberculosis agent PA-824 in Mycobacteria and a subcellular fraction of human liver.

BACKGROUND AND PURPOSE: PA-824 is a 2-nitroimidazooxazine prodrug currently in Phase II clinical trial for tuberculosis therapy. It is bioactivated by a deazaflavin (F(420) )-dependent nitroreductase (Ddn) isolated from Mycobacterium tuberculosis to form a des-nitro metabolite. This releases toxic reactive nitrogen species which may be responsible for its anti-mycobacterial activity. There are no published reports of mammalian enzymes bioactivating this prodrug. We have investigated the metabolism of PA-824 following incubation with a subcellular fraction of human liver, in comparison with purified Ddn, M. tuberculosis and Mycobacterium smegmatis. EXPERIMENTAL APPROACH: PA-824 (250 µM) was incubated with the 9000 × g supernatant (S9) of human liver homogenates, purified Ddn, M. tuberculosis and M. smegmatis for metabolite identification by liquid chromatography mass spectrometry analysis. KEY RESULTS: PA-824 was metabolized to seven products by Ddn and M. tuberculosis, with the major metabolite being the des-nitro product. Six of these products, but not the des-nitro metabolite, were also detected in M. smegmatis. In contrast, only four of these metabolites were observed in human liver S9; M3, a reduction product previously proposed as an intermediate in the Ddn-catalyzed des-nitrification and radiolytic reduction of PA-824; two unidentified metabolites, M1 and M4, which were products of M3; and a haem-catalyzed product of imidazole ring hydration (M2). CONCLUSIONS AND IMPLICATIONS: PA-824 was metabolized by des-nitrification in Ddn and M. tuberculosis, but this does not occur in human liver S9 and M. smegmatis. Thus, PA-824 was selectively bioactivated in M. tuberculosis and there was no evidence for 'cross-activation' by human enzymes.

The last glacial termination.

A major puzzle of paleoclimatology is why, after a long interval of cooling climate, each late Quaternary ice age ended with a relatively short warming leg called a termination. We here offer a comprehensive hypothesis of how Earth emerged from the last global ice age. A prerequisite was the growth of very large Northern Hemisphere ice sheets, whose subsequent collapse created stadial conditions that disrupted global patterns of ocean and atmospheric circulation. The Southern Hemisphere westerlies shifted poleward during each northern stadial, producing pulses of ocean upwelling and warming that together accounted for much of the termination in the Southern Ocean and Antarctica. Rising atmospheric CO2 during southern upwelling pulses augmented warming during the last termination in both polar hemispheres.

Wind-driven upwelling in the Southern Ocean and the deglacial rise in atmospheric CO2.

Wind-driven upwelling in the ocean around Antarctica helps regulate the exchange of carbon dioxide (CO2) between the deep sea and the atmosphere, as well as the supply of dissolved silicon to the euphotic zone of the Southern Ocean. Diatom productivity south of the Antarctic Polar Front and the subsequent burial of biogenic opal in underlying sediments are limited by this silicon supply. We show that opal burial rates, and thus upwelling, were enhanced during the termination of the last ice age in each sector of the Southern Ocean. In the record with the greatest temporal resolution, we find evidence for two intervals of enhanced upwelling concurrent with the two intervals of rising atmospheric CO2 during deglaciation. These results directly link increased ventilation of deep water to the deglacial rise in atmospheric CO2.

Hypoxia-selective antitumor agents. 16. Nitroarylmethyl quaternary salts as bioreductive prodrugs of the alkylating agent mechlorethamine.

Nitrobenzyl quaternary salts of nitrogen mustards have been previously reported as hypoxia-selective cytotoxins. In this paper we describe the synthesis and evaluation of a series of heterocyclic analogues, including pyrrole, imidazole, thiophene, and pyrazole examples, chosen to cover a range of one-electron reduction potentials (from -277 to -511 mV) and substitution patterns. All quaternary salt compounds were less toxic in vitro than mechlorethamine, and all were more toxic under hypoxic than aerobic conditions, although the differentials were highly variable within the series. The most promising analogue, imidazole 2, demonstrated DNA cross-linking selectively in hypoxic RIF-1 cells, and was active in vivo in combination with radiation or cisplatin. However, 2 also produced unpredictable toxicity in vivo, suggestive of nonspecific nitrogen mustard release, and this has restricted further development of these compounds as hypoxia-selective cytotoxins.

Glacial surface temperatures of the southeast Atlantic Ocean.

A detailed record of sea surface temperature from sediments of the Cape Basin in the subtropical South Atlantic indicates a previously undocumented progression of marine climate change between 41 and 18 thousand years before the present (ky B.P.), during the last glacial period. Whereas marine records typically indicate a long-term cooling into the Last Glacial Maximum (around 21 ky B.P.) consistent with gradually increasing global ice volume, the Cape Basin record documents an interval of substantial temperate ocean warming from 41 to 25 ky B.P. The pattern is similar to that expected in response to changes in insolation owing to variations in Earth's tilt.

Green tea catechins partially protect DNA from (.)OH radical-induced strand breaks and base damage through fast chemical repair of DNA radicals.

The catechins, (-)-epicatechin (EC), (-)-epigallocatechin (EGC), (-)-epicatechin gallate (ECG) and (-)-epigallocatechin gallate (EGCG) are believed to be active constituents of green tea accounting for the reported chemoprevention of certain cancers. The molecular mechanisms by which the measured low concentrations (ca. micromolar) of catechins in humans can reduce the incidence of carcinogenesis is not clear. Using an in vitro plasmid DNA system and radiolytically generating reactive oxygen species (ROS) under constant scavenging conditions, we have shown that all four catechins, when present at low concentrations, ameliorate free radical damage sustained by DNA. A reduction in both prompt DNA single-strand breaks and residual damage to the DNA bases, detected by subsequent incubation with the DNA glycosylases formamidopyrimidine (FPG), endonuclease III (EndoIII) and 5' AP endonuclease exonuclease III (ExoIII), was observed. EGCG was found to be the most active of the catechins, with effects seen at micromolar concentrations. Combined fast-reaction chemistry studies support a mechanism of electron transfer (or H-atom transfer) from catechins to ROS-induced radical sites on the DNA. These results support an antioxidant role for catechins in their direct interaction with DNA radicals.

Coupled electron/proton transfer in complex flavoproteins: solvent kinetic isotope effect studies of electron transfer in xanthine oxidase and trimethylamine dehydrogenase.

A solvent kinetic isotope effect study of electron transfer in two complex flavoproteins, xanthine oxidase and trimethylamine dehydrogenase, has been undertaken. With xanthine oxidase, electron transfer from the molybdenum center to the proximal iron-sulfur center of the enzyme occurs with a modest solvent kinetic isotope effect of 2.2, indicating that electron transfer out of the molybdenum center is at least partially coupled to deprotonation of the Mo(V) donor. A Marcus-type analysis yields a decay factor, beta, of 1.4 A(-1), indicating that, although the pyranopterin cofactor of the molybdenum center forms a nearly contiguous covalent bridge from the molybdenum atom to the proximal iron-sulfur center of the enzyme, it affords no exceptionally effective mode of electron transfer between the two centers. For trimethylamine dehydrogenase, rates of electron equilibration between the flavin and iron-sulfur center of the one-electron reduced enzyme have been determined, complementing previous studies of electron transfer in the two-electron reduced form. The results indicate a substantial solvent kinetic isotope effect of 10 +/- 4, consistent with a model for electron transfer that involves discrete protonation/deprotonation and electron transfer steps. This contrasts to the behavior seen with xanthine oxidase, and the basis for this difference is discussed in the context of the structures for the two proteins and the ionization properties of their flavin sites. With xanthine oxidase, a rationale is presented as to why it is desirable in certain cases that the physical layout of redox-active sites not be uniformly increasing in reduction potential in the direction of physiological electron transfer.

Radiolytic studies of trimethylamine dehydrogenase. Spectral deconvolution of the neutral and anionic flavin semiquinone, and determination of rate constants for electron transfer in the one-electron reduced enzyme.

Trimethylamine dehydrogenase from the pseudomonad Methylophilus methylotrophus has been examined using the technique of pulse radiolysis to rapidly introduce a single reducing equivalent into the enzyme. Using enzyme that has had its iron-sulfur center rendered redox-inert by prior reaction with ferricenium hexafluorophosphate, we determined the spectral change associated with formation of both the anionic and neutral forms that were generated at high and low pH, respectively, of the unique 6-cysteinyl-FMN of the enzyme. With native enzyme, electron transfer was observed within the radiolytically generated one-electron reduced enzyme but only at low pH (6.0). The kinetics and thermodynamics of this electron transfer in one-electron reduced enzyme may be compared with that studied previously in the two-electron reduced enzyme. In contrast to previous studies with two-electron reduced enzyme in which a pK(a) of approximately 8 was determined for the flavin semiquinone, in the one-electron reduced enzyme the semiquinone was not substantially protonated even at pH 6. 0. These results indicate that reduction of the iron-sulfur center of the enzyme significantly decreases the pK(a) of the flavin semiquinone of the active site. This provides further evidence, in conjunction with the strong magnetic interaction known to exist between the centers in the two-electron reduced enzyme, that the two redox-active centers in trimethylamine dehydrogenase are in intimate contact with one another in the active site of the enzyme.

Reduction in free-radical-induced DNA strand breaks and base damage through fast chemical repair by flavonoids.

This paper provides evidence that dietary flavonoids can repair a range of oxidative radical damages on DNA, and thus give protection against radical-induced strand breaks and base alterations. We have irradiated dilute aqueous solutions of plasmid DNA in the absence and presence of flavonoids (F) in a "constant *OH radical scavenging environment", k of 1.5 x 10(7) s(-1) by decreasing the concentration of TRIS buffer in relation to the concentration of added flavonoids. We have shown that the flavonoids can reduce the incidence of single-strand breaks in double-stranded DNA as well as residual base damage (assayed as additional single-strand breaks upon post-irradiation incubation with endonucleases) with dose modification factors of up to 2.0+/-0.2 at [F] < 100 microM by a mechanism other than through direct scavenging of *OH radicals. Pulse radiolysis measurements support the mechanism of electron transfer or H* atom transfer from the flavonoids to free radical sites on DNA which result in the fast chemical repair of some of the oxidative damage on DNA resulting from *OH radical attack. These in vitro assays point to a possible additional role for antioxidants in reducing DNA damage.

Primary closure of infected diabetic foot wounds. A report of closed instillation in 30 cases.

Multiple surgical strategies are available for managing the infected diabetic foot at risk for amputation. The authors present their experience with the closed instillation system in the management of 30 such cases in 29 patients over a 5-year period. Data were collected from the hospital records of neuropathic patients presenting with deep-plantar-space infections or presumed acute osteomyelitis. All 29 patients were male; 57% had marginal or poor vascular supply, and 83% were nutritionally compromised or had proteinuria. At the conclusion of the study, 34% of the patients were dead, reflecting the severity of comorbid conditions found in this population. Despite the marginal healing capacity of these patients, the procedure had a 90% success rate, as defined by expeditious return to prior level of functioning and residential living situation without need for re-operation or higher-level amputation.

Protonation studies of reduced ruthenium(II) complexes with polypyridyl ligands.

The pKa values associated with protonation of the one-electron reduced forms of series of [L'2Ru(II)L]2+ complexes [L' = bidentate polypyridyl ligand; L = bidentate polypyridyl ligand with additional uncoordinated N atoms in the aromatic ring system: e.g., dpp = 2,3-bis(2-pyridyl)pyrazine, bpz = 2,2'-bipyrazine] were assessed using pulse radiolysis techniques by the measurement of spectral variations as a function of pH. A linear correlation was observed between pKa and E (RuL'2L2+/+) for complexes in which the protonatable ligand was at the same time the site of reduction. In complexes where one or more of the nonprotonatable ligands (L') had very low pi* energy levels [e.g. (CF3)4bpy], reduction occurs on a nonprotonatable ligand and a dramatic decrease in the pKa values was observed for the reduced species. In complexes where the energies of the protonatable and nonprotonatable ligands were comparable, the protonation behavior was consistent with some orbital mixing/ delocalization of the electronic charge.