Single-shot liposomal bupivacaine in place of rectus sheath catheters to provide non-opiate analgesia after laparotomy: a quality improvement project to reduce the need for ongoing nursing input.

Opioid-sparing pain management is an integral component of enhanced recovery after colonic and rectal surgery. In our hospital, rectus sheath catheters (RSCs) are routinely placed during emergency laparotomy for colorectal procedures to allow a postoperative compartmental block of the surgical site with repeated doses of bupivacaine. However, RSCs require a significant amount of clinical nursing time to maintain and 'top-up'. We present a quality improvement project in which we administered single-shot liposomal bupivacaine (LB) intraoperatively as an alternative to bolus doses of conventional bupivacaine delivered through RSCs. Having thereby reduced the demands placed on nursing time through a reduction in the use of RSCs, we sought to establish whether there was any associated change in analgesic efficacy. Patient pain scores, use of patient-controlled analgesia (PCA) and length of stay following surgery were analysed before and after the introduction of LB. No disruption in these outcomes was identified using statistical process control analysis. A direct comparison of results for patients who received LB versus those who received bolus dosing of bupivacaine via RSCs found no significant differences, with a median total PCA dose of 270 mg oral morphine equivalents (OME) for patients who received LB versus 396 mg OME for patients who had RSCs (p=0.54). The median length of stay for patients who received LB was 15.5 days versus 16 days for those who had RSCs (p=0.87). We conclude that LB represents a viable alternative to boluses of conventional bupivacaine via RSCs in promoting enhanced recovery after emergency laparotomy and look to extend its use locally.

Observation of Enhanced Dissociative Photochemistry in the Non-Native Nucleobase 2-Thiouracil.

We present the first study to measure the dissociative photochemistry of 2-thiouracil (2-TU), an important nucleobase analogue with applications in molecular biology and pharmacology. Laser photodissociation spectroscopy is applied to the deprotonated and protonated forms of 2-TU, which are produced in the gas-phase using electrospray ionization mass spectrometry. Our results show that the deprotonated form of 2-thiouracil ([2-TU-H]-) decays predominantly by electron ejection and hence concomitant production of the [2-TU-H]· free-radical species, following photoexcitation across the UVA-UVC region. Thiocyanate (SCN-) and a m/z 93 fragment ion are also observed as photodecay products of [2-TU-H]- but at very low intensities. Photoexcitation of protonated 2-thiouracil ([2-TU·H]+) across the same UVA-UVC spectral region produces the m/z 96 cationic fragment as the major photofragment. This ion corresponds to ejection of an HS· radical from the precursor ion and is determined to be a product of direct excited state decay. Fragment ions associated with decay of the hot ground state (i.e., the ions we would expect to observe if 2-thiouracil was behaving like UV-dissipating uracil) are observed as much more minor products. This behaviour is consistent with enhanced intersystem crossing to triplet excited states compared to internal conversion back to the ground state. These are the first experiments to probe the effect of protonation/deprotonation on thionucleobase photochemistry, and hence explore the effect of pH at a molecular level on their photophysical properties.

Auto-titrating CPAP for the treatment of obstructive sleep apnea in children.

STUDY OBJECTIVES: In-laboratory titration polysomnography (PSG) is standard to determine optimal therapeutic continuous positive airway pressure (CPAP) in children with obstructive sleep apnea (OSA). The use of auto-titrating CPAP devices (autoCPAP) as an alternative to CPAP titration has not been well studied in children. We hypothesized that autoCPAP-derived pressures (PMEAN, PPEAKMEAN, P90) would be similar to titration PSG pressure (PPSG). METHODS: This is a retrospective study of children with OSAS initiated on autoCPAP between 2007 and 2017, who used autoCPAP for at least 2 h/night and who had adequate titration PSG were included in the analysis. AutoCPAP-derived pressures were obtained from use downloads and compared with PPSG. PPSG predictive factors were analyzed by median regression. Nonparametric methods were used for analysis. RESULTS: Of 110 children initiated on autoCPAP, 44 satisfied the inclusion criteria. Age (median (interquartile range)) was 13.01 (9.98-16.72) years, and 63.6% were obese. PPSG median (interquartile range) was 8 (7-11) cmH2O, mean autoCPAP-derived pressure (PMEAN) was 6.2 (5.6-7.6) cmH2O, peak mean pressure (PPEAKMEAN) was 9.4 (7.7-11.1) cmH2O, and average device pressure ≤ 90% of the time (P90) was 8.1 (7.2-9.7) cmH2O. AutoCPAP-derived pressures correlated with PPSG (P < .05). PMEAN was lower than the other 3 pressures (P < .0002). Median regression analysis demonstrated that after adjusting for patient characteristics such as age, sex, and obesity status, autoCPAP-derived pressures remained significant predictors of PPSG (P < .05). There were no significant interactions between these patient characteristics and autoCPAP-derived pressures. CONCLUSIONS: This study demonstrates that autoCPAP-derived pressures correlate with the titration PSG-derived pressures. These results indicate that autoCPAP can be used in the pediatric population and can determine pressures that are close to the titration pressures.

Mapping the intrinsic absorption properties and photodegradation pathways of the protonated and deprotonated forms of the sunscreen oxybenzone.

Sunscreens provide vital protection against the photodamaging effects of UV radiation, however, many fundamental questions remain about the detailed mechanisms by which they dissipate UV energy. One such issue is the extent to which the pH environment of an organic sunscreen molecule alters its effectiveness, both in terms of ability to absorb UV radiation, and also its potential to photodegrade. Here, we use gas-phase laser photodissociation spectroscopy for the first time to measure the intrinsic UVA-UVC absorption spectra and associated photodegradation products of protonated and deprotonated oxybenzone, away from the complications of bulk mixtures. Our results reveal that protonation state has a dramatic effect on the absorption and photodissociation properties of this sunscreen. While the UV absorption profile of oxybenzone is only modestly affected by protonation across the range from 400-216 nm, deprotonated oxybenzone displays a significantly modified absorption spectrum, with very low photoabsorption between 370-330 nm. Protonated oxybenzone primarily photofragments by rupture of the bonds on either side of the central carbonyl group, producing cationic fragments with m/z 151 and 105. Additional lower mass photofragments (e.g. m/z 95 and 77) are also observed. The production spectra for the photofragments from protonated oxybenzone fall into two distinct categories, which we discuss in the context of different excited state decay pathways. For deprotonated oxybenzone, the major photofragments observed are m/z 211 and 212, which are associated with the ejection of methane and the methyl free radical from the parent ion, respectively. Implications for the suitability of oxybenzone in its protonated and deprotonated forms as an optimum sunscreen molecule are discussed.

Observation of Near-Threshold Resonances in the Flavin Chromophore Anions Alloxazine and Lumichrome.

Lumichrome (LC) is the chromophore of the flavin family of photoactive biomolecules, where key biochemical activity involves interplay between redox and photophysical events. Questions remain about the relationship between the redox status of the ground and excited states and demand an improved understanding of the intrinsic photochemistry. Using anion photodissociation spectroscopy, we have measured the intrinsic electronic spectroscopy (564-220 nm) and accompanying photodegradation pathways of the deprotonated anionic form of LC. Experiments were also performed on alloxazine (AL), which is equivalent to LC minus two methyl groups. We observe a resonance state close to 3.8 eV for both anions for the first time, which we tentatively assign to dipole-bound excited states. For AL this state is sufficiently long-lived to facilitate dissociative electron attachment. Our results suggest that the presence of methyl group rotors at key positions along the molecular dipole may reduce the lifetime of the resonance state and hence provide a structural barrier to valence electron capture, and ensuing molecular dissociation.

Protomer-Dependent Electronic Spectroscopy and Photochemistry of the Model Flavin Chromophore Alloxazine.

Flavin chromophores play key roles in a wide range of photoactive proteins, but key questions exist in relation to their fundamental spectroscopic and photochemical properties. In this work, we report the first gas-phase spectroscopy study of protonated alloxazine (AL∙H⁺), a model flavin chromophore. Laser photodissociation is employed across a wide range (2.34⁻5.64 eV) to obtain the electronic spectrum and characterize the photofragmentation pathways. By comparison to TDDFT quantum chemical calculations, the spectrum is assigned to two AL∙H⁺ protomers; an N5 (dominant) and O4 (minor) form. The protomers have distinctly different spectral profiles in the region above 4.8 eV due to the presence of a strong electronic transition for the O4 protomer corresponding to an electron-density shift from the benzene to uracil moiety. AL∙H⁺ photoexcitation leads to fragmentation via loss of HCN and HNCO (along with small molecules such as CO2 and H2O), but the photofragmentation patterns differ dramatically from those observed upon collision excitation of the ground electronic state. This reveals that fragmentation is occurring during the excited state lifetime. Finally, our results show that the N5 protomer is associated primarily with HNCO loss while the O4 protomer is associated with HCN loss, indicating that the ring-opening dynamics are dependent on the location of protonation in the ground-state molecule.

Photoexcitation of iodide ion-pyrimidine clusters above the electron detachment threshold: Intracluster electron transfer versus nucleobase-centred excitations.

Laser photodissociation spectroscopy of the I-·thymine (I-·T) and I-·cytosine (I-·C) nucleobase clusters has been conducted for the first time across the regions above the electron detachment thresholds to explore the excited states and photodissociation channels. Although photodepletion is strong, only weak ionic photofragment signals are observed, indicating that the clusters decay predominantly by electron detachment. The photodepletion spectra of the I-·T and I-·C clusters display a prominent dipole-bound excited state (I) in the vicinity of the vertical detachment energy (∼4.0 eV). Like the previously studied I-·uracil (I-·U) cluster [W. L. Li et al., J. Chem. Phys. 145, 044319 (2016)], the I-·T cluster also displays a second excited state (II) centred at 4.8 eV, which we similarly assign to a π-π* nucleobase-localized transition. However, no distinct higher-energy absorption bands are evident in the spectra of the I-·C. Time-dependent density functional theory (TDDFT) calculations are presented, showing that while each of the I-·T and I-·U clusters displays a single dominant π-π* nucleobase-localized transition, the corresponding π-π* nucleobase transitions for I-·C are split across three separate weaker electronic excitations. I- and deprotonated nucleobase anion photofragments are observed upon photoexcitation of both I-·U and I-·T, with the action spectra showing bands (at 4.0 and 4.8 eV) for both the I- and deprotonated nucleobase anion production. The photofragmentation behaviour of the I-·C cluster is distinctive as its I- photofragment displays a relatively flat profile above the expected vertical detachment energy. We discuss the observed photofragmentation profiles of the I-·pyrimidine clusters, in the context of the previous time-resolved measurements, and conclude that the observed photoexcitations are primarily consistent with intracluster electron transfer dominating in the near-threshold region, while nucleobase-centred excitations dominate close to 4.8 eV. TDDFT calculations suggest that charge-transfer transitions [Iodide n (5p6) → Uracil σ*] may contribute to the cluster absorption profile across the scanned spectral region, and the possible role of these states is also discussed.

Experiment and theory confirm that UV laser photodissociation spectroscopy can distinguish protomers formed via electrospray.

The identification of protonation sites in electrosprayed molecules remains a challenge in contemporary physical science. We present the first demonstration that low-resolution, UV laser photodissociation spectroscopy can be applied in situ to identify the protomers of para-aminobenzoic acid (PABA) formed via electrospray from a single solution. Electronic absorption spectra are recorded via photodepletion and photofragmentation for PABA electrosprayed from solutions of water and acetonitrile. Using this approach, two protomers can be straightforwardly identified, with only the carboxylic acid protomer being produced on electrospray from water while the amine-protonated isomer dominates upon electrospray from acetonitrile. High-level SORCI and MRCI calculations are presented to provide insight into the origin of the distinctive electronic spectra displayed by the protomers. Our results are in excellent agreement with previous PABA studies conducted using established techniques, and demonstrate that UV photodissociation spectroscopy of electrosprayed ions has potential as a new diagnostic tool for identifying protomeric species.

Photoexcitation of Adenosine 5'-Triphosphate Anions in Vacuo: Probing the Influence of Charge State on the UV Photophysics of Adenine.

We report the first UV laser photodissociation spectra (4.0-5.8 eV) of gas-phase deprotonated adenosine 5'-triphosphate, diphosphate and monophosphate anions. The photodepletion spectra of these anions display strong absorption bands across the region of 4.6-5.2 eV, consistent with excitation of a primarily adenine-centered π-π* transition. The spectra appear insensitive to the charge of the species (i.e., the spectrum of [ATP-2H]2- closely resembles that of [ATP-H]-), while the spectral profile is affected to a greater extent by the variation of the molecular structure, i.e. the [AMP-H]- and [ADP-H]- photodepletion spectra display similar profiles while the [ATP-H]- spectrum is distinctive. The photodepletion cross-section also decreases for the ATP anions compared to both the AMP and ADP anions, reflecting a high intrinsic photostability of ATP versus both AMP and ADP. A range of photofragments are produced across the 4.0-5.8 eV spectral range for all of the ATP analogues studied. These fragments are primarily associated with fragmentation on the ground-state electronic surface, indicative of a statistical decay process where ultrafast decay is followed by ergodic dissociation. However, while the photofragments observed following photoexcitation of the monoanionic species, [AMP-H]- to [ADP-H]- to [ATP-H]- are entirely consistent with statistical decay, an additional group of photofragments are observed for the dianionic species, [ADP-2H]2- and [ATP-2H]2-, that we associate with electron detachment, and subsequent fragmentation of the resulting electron-detached photofragment. TDDFT calculations are presented to support the interpretation of the experimental data, and confirm that the electronic structure of the adenine moiety is relatively unperturbed by varying the overall charge.

Self-Efficacy and Short-Term Adherence to Continuous Positive Airway Pressure Treatment in Children.

Study Objectives: Infants, children, and adolescents are increasingly being prescribed continuous positive airway pressure (CPAP) for treatment of obstructive sleep apnea syndrome (OSAS), yet adherence is often poor. The purpose of this study was to examine the relationship between caregiver and patient-reported health cognitions about CPAP prior to starting CPAP and CPAP adherence at 1 month. We hypothesized that greater caregiver-reported self-efficacy would be positively associated with CPAP adherence in children. We also evaluated patient-reported self-efficacy and caregiver- and patient-reported risk perception and outcome expectations as they related to adherence, as well as how demographic factors influenced these relationships. Methods: A pediatric modification of the Self-Efficacy Measure for Sleep Apnea Questionnaire was administered to children and adolescents with OSAS-prescribed CPAP and their caregivers during the clinical CPAP-initiation visit. The primary outcome variable for adherence was the average total minutes of CPAP usage across all days from the date that CPAP was initiated to 31 days later. Results: Unadjusted ordinary least-square regression showed a significant association between caregiver-reported self-efficacy and adherence (p = .007), indicating that mean daily CPAP usage increased by 48.4 minutes when caregiver-reported self-efficacy increased by one point (95% confidence interval 13.4-83.4 minutes). No other caregiver- or patient-reported cognitive health variables were related to CPAP use. Conclusions: This study indicates that caregiver CPAP-specific self-efficacy is an important factor to consider when starting youth on CPAP therapy for OSAS. Employing strategies to improve caregiver self-efficacy, beginning at CPAP initiation, may promote CPAP adherence.

Financial Analysis of an Intensive Pediatric Continuous Positive Airway Pressure Program.

Study Objectives: Continuous positive airway pressure (CPAP) is effective in treating obstructive sleep apnea in children, but adherence to therapy is low. Our center created an intensive program that aimed to improve adherence. Our objective was to estimate the program's efficacy, cost, revenue and break-even point in a generalizable manner relative to a standard approach. Methods: The intensive program included device consignment, behavioral psychology counseling, and follow-up telephone calls. Economic modeling considered the costs, revenue and break-even point. Costs were derived from national salary reports and the Pediatric Health Information System. The 2015 Medicare reimbursement schedule provided revenue estimates. Results: Prior to the intensive CPAP program, only 67.6% of 244 patients initially prescribed CPAP appeared for follow-up visits and only 38.1% had titration polysomnograms. In contrast, 81.4% of 275 patients in the intensive program appeared for follow-up visits (p < .001) and 83.6% had titration polysomnograms (p < .001). Medicare reimbursement levels would be insufficient to cover the estimated costs of the intensive program; break-even points would need to be 1.29-2.08 times higher to cover the costs. Conclusions: An intensive CPAP program leads to substantially higher follow-up and CPAP titration rates, but costs are higher. While affordable at our institution due to the local payer mix and revenue, Medicare reimbursement levels would not cover estimated costs. This study highlights the need for enhanced funding for pediatric CPAP programs, due to the special needs of this population and the long-term health risks of suboptimally treated obstructive sleep apnea.

Locating the Proton in Nicotinamide Protomers via Low-Resolution UV Action Spectroscopy of Electrosprayed Solutions.

Even in relatively simple molecules, the sites of protonation or deprotonation formed upon electrospray ionization can be controversial. This situation means that it is important to develop new approaches for identifying "protomers" and "deprotomers". In this study, we demonstrate that routine, low-resolution UV laser photodissociation spectroscopy can be applied to identify the gaseous protomers of nicotinamide formed upon electrospray. Nicotinamide is an important biological molecule that possesses multiple protonation sites associated with its pyridine and amide groups. We obtain a gas-phase absorption spectrum for protonated nicotinamide that closely resembles the solution-phase spectrum. However, photoexcitation of protonated nicotinamide produces numerous ionic photofragments, and the spectral profiles for production of these photofragments from protonated nicotinamide reveal the existence of two distinctive chromophores, which can be traced to the existence of pyridine and amide protomers. We observe that these protomers are associated with absorption bands centered at 4.96 and 4.73 eV, respectively, with the protomers appearing in an approximate ratio of ∼2:1. The fact that the considerably less favorable amide protomer is observed in substantial quantities in the gas phase is surprising given that the pyridine protomer is the lower-energy species in both solution and gas phase. The high amounts of amide protomers observed here can be explained as arising from asymmetric pyridine protomer-amide bound dimers, present in solution or in the electrosprayed droplets, which lead to enhanced formation of the unexpected amide-protonated isomers.

Photodissociation dynamics of the iodide-uracil (I(-)U) complex.

Photofragment action spectroscopy and femtosecond time-resolved photoelectron imaging are utilized to probe the dissociation channels in iodide-uracil (I(-) ⋅ U) binary clusters upon photoexcitation. The photofragment action spectra show strong I(-) and weak [U-H](-) ion signal upon photoexcitation. The action spectra show two bands for I(-) and [U-H](-) production peaking around 4.0 and 4.8 eV. Time-resolved experiments measured the rate of I(-) production resulting from excitation of the two bands. At 4.03 eV and 4.72 eV, the photoelectron signal from I(-) exhibits rise times of 86 ± 7 ps and 36 ± 3 ps, respectively. Electronic structure calculations indicate that the lower energy band, which encompasses the vertical detachment energy (4.11 eV) of I(-)U, corresponds to excitation of a dipole-bound state of the complex, while the higher energy band is primarily a π-π(∗) excitation on the uracil moiety. Although the nature of the two excited states is very different, the long lifetimes for I(-) production suggest that this channel results from internal conversion to the I(-) ⋅ U ground state followed by evaporation of I(-). This hypothesis was tested by comparing the dissociation rates to Rice-Ramsperger-Kassel-Marcus calculations.

UV laser photoactivation of hexachloroplatinate bound to individual nucleobases in vacuo as molecular level probes of a model photopharmaceutical.

Isolated molecular clusters of adenine, cytosine, thymine and uracil bound to hexachloroplatinate, PtCl6(2-), have been studied using laser electronic photodissociation spectroscopy to investigate photoactivation of a platinum complex in the vicinity of a nucleobase. These metal complex-nucleobase clusters represent model systems for identifying the fundamental photochemical processes occurring in photodynamic platinum drug therapies that target DNA. This is the first study to explore the specific role of a strongly photoactive platinum compound in the aggregate complex. Each of the clusters studied displays a broadly similar absorption spectra, with a strong λmax ∼ 4.6 eV absorption band and a subsequent increase in the absorption intensity towards higher spectral-energy. The absorption bands are traced to ligand-to-metal-charge-transfer excitations on the PtCl6(2-) moiety within the cluster, and result in Cl(-)·nucleobase and PtCl5(-) as primary photofragments. These results demonstrate how selective photoexcitation can drive distinctive photodecay channels for a model photo-pharmaceutical. In addition, cluster absorption due to excitation of nucleobase-centred chromophores is observed in the region around 5 eV. For the uracil cluster, photofragments consistent with ultrafast decay of the excited state and vibrational predissociation on the ground-state surface are observed. However, this decay channel becomes successively weaker on going from thymine to cytosine to adenine, due to differential coupling of the excited states to the electron detachment continuum. These effects demonstrate the distinctive photophysical characteristics of the different nucleobases, and are discussed in the context of the recently recorded photoelectron spectra of theses clusters.

ON or OFF?: Modulating the N-Methyl-D-Aspartate Receptor in Major Depression.

Since the discovery that a single dose of ketamine, an N-methyl-D-aspartate receptor (NMDAR) antagonist, had rapid and long-lasting antidepressant effects, there has been increased interest in using NMDAR modulators in the pharmacotherapy of depression. Ketamine's efficacy seems to imply that depression is a disorder of NMDAR hyperfunctionality. However, studies showing that not all NMDAR antagonists are able to act as antidepressants challenge this notion. Furthermore, NMDAR co-agonists have also been gaining attention as possible treatments. Co-agonists such as D-serine and sarcosine have shown efficacy in both pre-clinical models and human trials. This raises the question of how both NMDAR antagonists and agonists are able to have converging behavioral effects. Here we critically review the evidence and proposed therapeutic mechanisms for both NMDAR antagonists and agonists, and collate several theories on how both activation and inhibition of NMDARs appear to have antidepressant effects.

Cerebral Blood Flow Response to Hypercapnia in Children with Obstructive Sleep Apnea Syndrome.

STUDY OBJECTIVES: Children with obstructive sleep apnea syndrome (OSAS) often experience periods of hypercapnia during sleep, a potent stimulator of cerebral blood flow (CBF). Considering this hypercapnia exposure during sleep, it is possible that children with OSAS have abnormal CBF responses to hypercapnia even during wakefulness. Therefore, we hypothesized that children with OSAS have blunted CBF response to hypercapnia during wakefulness, compared to snorers and controls. METHODS: CBF changes during hypercapnic ventilatory response (HCVR) were tested in children with OSAS, snorers, and healthy controls using diffuse correlation spectroscopy (DCS). Peak CBF changes with respect to pre-hypercapnic baseline were measured for each group. The study was conducted at an academic pediatric sleep center. RESULTS: Twelve children with OSAS (aged 10.1 ± 2.5 [mean ± standard deviation] y, obstructive apnea hypopnea index [AHI] = 9.4 [5.1-15.4] [median, interquartile range] events/hour), eight snorers (11 ± 3 y, 0.5 [0-1.3] events/hour), and 10 controls (11.4 ± 2.6 y, 0.3 [0.2-0.4] events/hour) were studied. The fractional CBF change during hypercapnia, normalized to the change in end-tidal carbon dioxide, was significantly higher in controls (9 ± 1.8 %/mmHg) compared to OSAS (7.1 ± 1.5, P = 0.023) and snorers (6.7 ± 1.9, P = 0.025). CONCLUSIONS: Children with OSAS and snorers have blunted CBF response to hypercapnia during wakefulness compared to controls. Noninvasive DCS blood flow measurements of hypercapnic reactivity offer insights into physiopathology of OSAS in children, which could lead to further understanding about the central nervous system complications of OSAS.

Photoelectron spectroscopy of hexachloroplatinate-nucleobase complexes: Nucleobase excited state decay observed via delayed electron emission.

We report low-temperature photoelectron spectra of isolated gas-phase complexes of the hexachloroplatinate dianion bound to the nucleobases uracil, thymine, cytosine, and adenine. The spectra display well-resolved, distinct peaks that are consistent with complexes where the hexachloroplatinate dianion is largely intact. Adiabatic electron detachment energies for the hexachloroplatinate-nucleobase complexes are measured as 2.26-2.36 eV. The magnitudes of the repulsive Coulomb barriers (RCBs) of the complexes are all ∼1.7 eV, values that are lower than the RCB of the uncomplexed PtCl6 (2-) dianion as a result of charge solvation by the nucleobases. In addition to the resolved spectral features, broad featureless bands indicative of delayed electron detachment are observed in the 193 nm photoelectron spectra of the four clusters. The 266 nm spectra of the PtCl6 (2-) ⋅ thymine and PtCl6 (2-) ⋅ adenine complexes also display very prominent delayed electron emission bands. These results mirror recent results on the related Pt(CN)4 (2-) ⋅ nucleobase complexes [A. Sen et al., J. Phys. Chem. B 119, 11626 (2015)]. The observation of delayed electron emission bands in the PtCl6 (2-) ⋅ nucleobase spectra obtained in this work, as for the previously studied Pt(CN)4 (2-) ⋅ nucleobase complexes, is attributed to one-photon excitation of nucleobase-centred excited states that can effectively couple to the electron detachment continuum, producing strong electron detachment. Moreover, the selective, strong excitation of the delayed emission bands in the 266 nm spectra is linked to fundamental differences in the individual nucleobase photophysics at this excitation energy. This strongly supports our previous suggestion that the dianion within these clusters can be viewed as a "dynamic tag" which has the propensity to emit electrons when the attached nucleobase decays over a time scale long enough to allow autodetachment.

Inhibitors of the gamma-aminobutyric acid transporter 1 (GAT1) do not reveal a channel mode of conduction.

We expressed the gamma-aminobutyric acid (GABA) transporter GAT1 (SLC6A1) in Xenopus laevis oocytes and performed GABA uptake experiments under voltage clamp at different membrane potentials as well as in the presence of the specific GAT1 inhibitors SKF-89976A and NO-711. In the absence of the inhibitors, GAT1 mediated the inward translocation of 2 net positive charges across the plasma membrane for every GABA molecule transported into the cell. This 2:1 charge flux/GABA flux ratio was the same over a wide range of membrane potentials from -110 mV to +10 mV. Moreover, when GABA-evoked (500 microM) currents were measured at -50 and -90 mV, neither SKF-89976A (5 and 25 microM) nor NO-711 (2 microM) altered the 2:1 charge flux/GABA flux ratio. The results are not consistent with previous hypotheses that (i) GABA evokes an uncoupled channel-mediated current in GAT1, and (ii) GAT1 inhibitors block the putative uncoupled current gated by GABA. Rather, the results suggest tight coupling of GAT1-mediated charge flux and GABA flux.

Safety of hematopoietic stem cell transplantation in children less than three years of age.

Allogeneic hematopoietic stem cell transplantation (HSCT) is a standard treatment for a variety of hematologic conditions. However, very young children may experience different complications of HSCT compared to older patients. The authors retrospectively analyzed the results of 51 transplants performed on children less than 3 years of age between June 1987 and October 2005. Donors were matched-related (n = 21), partially mismatched related (n = 3), and unrelated (n = 27). The majority of patients had one or more grade III organ toxicities, but all nonrelapse deaths were attributable to infection. Perineal dermatitis was found in a large number (73%) of recipients of cyclophosphamide-based conditioning regimens. The 1-year transplant-related mortality (TRM) was 14%, but significantly declined in the more modern period. Grades II-IV acute graft-versus-host-disease (GvHD) was seen in 22% of patients, while chronic extensive GvHD developed in only 7% of patients. Relapse was seen in 40% of transplants performed for a malignant condition, most commonly in those patients not in remission at time of HSCT. The 5-year event-free survival (EFS) and overall survival (OS) were 53 and 64%, respectively. Recipients of fractionated total body irradiation (fTBI) were more likely to have at least one long-term sequelae than patients who received chemotherapy-based regimens (p = .014). These data demonstrate that HSCT can be performed safely in very young children, especially as supportive-care techniques improve. Cyclophosphamide-related perineal dermatitis is a unique complication in very young children. Finally, the incidence of acute and chronic GvHD in this population is low.