Method of kinetic energy reconstruction from time-of-flight mass spectra.

We present a method for the reconstruction of ion kinetic energy distributions from ion time-of-flight mass spectra through ion trajectory simulations. In particular, this method is applicable to complicated spectrometer geometries with largely anisotropic ion collection efficiencies. A calibration procedure using a single ion mass peak allows the accurate determination of parameters related to the spectrometer calibration, experimental alignment, and instrument response function, which improves the agreement between simulations and experiment. The calibrated simulation is used to generate a set of basis functions for the time-of-flight spectra, which are then used to transform from time-of-flight to kinetic-energy spectra. We demonstrate this reconstruction method on a recent pump-probe experiment by Asmussen et al. [Asmussen et al., Phys. Chem. Chem. Phys., 23, 15138, (2021)] on helium nanodroplets and retrieve time-resolved kinetic-energy-release spectra for the ions from ion time-of-flight spectra.

Relaxation dynamics in excited helium nanodroplets probed with high resolution, time-resolved photoelectron spectroscopy.

Superfluid helium nanodroplets are often considered as transparent and chemically inert nanometer-sized cryo-matrices for high-resolution or time-resolved spectroscopy of embedded molecules and clusters. On the other hand, when the helium nanodroplets are resonantly excited with XUV radiation, a multitude of ultrafast processes are initiated, such as relaxation into metastable states, formation of nanoscopic bubbles or excimers, and autoionization channels generating low-energy free electrons. Here, we discuss the full spectrum of ultrafast relaxation processes observed when helium nanodroplets are electronically excited. In particular, we perform an in-depth study of the relaxation dynamics occurring in the lowest 1s2s and 1s2p droplet bands using high resolution, time-resolved photoelectron spectroscopy. The simplified excitation scheme and improved resolution allow us to identify the relaxation into metastable triplet and excimer states even when exciting below the droplets' autoionization threshold, unobserved in previous studies.

Efficacy and safety of caspofungin in solid organ transplant recipients.

Efficacy and safety data for the echinocandins in solid organ transplant (SOT) recipients are limited. We reviewed data from three clinical trials that enrolled SOT patients receiving caspofungin therapy for an invasive fungal infection (IFI). Caspofungin was administered at doses ranging from 50 to 100 mg/day. Efficacy was assessed in all patients at the end of caspofungin therapy (EOT). Adverse events (AE) and laboratory data were collected from all patients. We identified data from 22 SOT patients (aged 34-67 years) with proven invasive candidiasis (IC; 6 patients) or proven or probable invasive aspergillosis (IA; 16 patients) who received at least one dose of caspofungin therapy. All patients with IC received caspofungin as primary therapy. Caspofungin success against IC at EOT was 83% (5 of 6), with responses seen across Candida spp. Success by SOT type was: kidney 4 of 5 and liver 1 of 1. All 16 patients with IA (all pulmonary) received caspofungin as salvage therapy. Caspofungin success against IA at EOT was 50% (8 of 16), with responses seen for both definite (3 of 4) and probable IA (5 of 12). Success by SOT type was: heart 2 of 2, heart/lung 0 of 2, kidney 3 of 3, liver 1 of 3, and lung 2 of 6. The outcome was not influenced by caspofungin dose. Caspofungin, dosed for 2 to 162 (mean 36.8) days, was well tolerated. No patient had a serious drug-related adverse event or discontinued caspofungin due to toxicity. Based on these limited data, caspofungin appears to be an effective and well-tolerated option for the treatment of IC and IA in SOT recipients.

Retrospective study of the hepatic safety profile of patients concomitantly treated with caspofungin and cyclosporin A.

BACKGROUND: Mild, transient alanine aminotransferase (ALT) elevations were seen in Phase I studies of caspofungin and cyclosporin A (CsA). METHODS: We conducted a retrospective chart review at four sites to characterize the hepatic safety in patients receiving > or =1 day of both drugs over a 20-month period. Investigators assessed reasons for discontinuing concomitant therapy and the presence/etiology of any hepatotoxicity. RESULTS: Forty patients receiving concomitant therapy for 1-290 days (median 17.5 days) were identified. Although common, liver enzyme abnormalities were frequently attributed to other comorbidities or medications. ALT and/or aspartate aminotransferase (AST) elevations occurred in 14 patients (35%). Five had AST elevations at least possibly related to caspofungin/CsA, but none were >3.6 times the normal upper limit. No ALT elevations were related to caspofungin/CsA. Two of 4 patients had discontinuation of therapy because of hepatotoxicity possibly related to caspofungin/CsA. No serious adverse events occurred because of caspofungin. CONCLUSIONS: These data do not suggest a significant risk of clinically relevant hepatotoxicity with concomitant caspofungin/CsA.

Receptor subtypes mediating adenosine-induced dilation of cerebral arterioles.

The purpose of this study was to investigate the receptor subtypes that mediate the dilation of rat intracerebral arterioles elicited by adenosine. Penetrating arterioles were isolated from the rat brain, cannulated with the use of a micropipette system, and luminally pressurized to 60 mmHg. Both adenosine and the A2A receptor-selective agonist CGS-21680 induced dose-dependent vasodilation (-logEC(50): 6.5 +/- 0.2 and 8.6 +/- 0.3, respectively). However, adenosine, which is capable of activating both A2A and A2B receptors, caused a greater maximal dilation than CGS-21680. The A2A receptor-selective antagonist ZM-241385 (0.1 microM) only partially inhibited the dilation induced by adenosine but almost completely blocked CGS-21680-induced dilation. Neither 8-cyclopentyl-1,3-dipropylxanthine (0.1 microM), an A1 receptor-selective antagonist, nor MRS-1191 (0.1 microM), an A3 receptor-selective antagonist, attenuated adenosine dose responses. Moreover, ZM-241385 had no effect on the dilation induced by ATP (10 microM) or acidic (pH 6.8) buffer. We concluded that the A2A receptor subtype mediates adenosine-induced dilation of intracerebral arterioles in the rat brain. Furthermore, our results suggest that A2B receptors may also participate in the dilation response to adenosine.

Frequency-dependent changes in cerebral blood flow and evoked potentials during somatosensory stimulation in the rat.

Contrary to the concept of neuronal-vascular coupling, cortical evoked potentials do not always correlate with blood flow responses during somatosensory stimulation at changing stimulus rates. The goal of this study is to clarify the effects of stimulus frequency on the relationship between somatosensory evoked potentials (SEPs) and cerebral blood flow. In rats anesthetized with alpha-chloralose, we measured SEPs by signal-averaging field potentials recorded with an electrode placed on dura overlying the hindlimb somatosensory cortex. Regional blood flow was simultaneously assessed in the same region with a laser-Doppler flow (LDF) probe. The contralateral sciatic nerve was stimulated with 0.1 A pulses at the frequencies of 1, 2, 5, 10 and 20 Hz. SEPs (both P1 and N1 components) declined with increasing frequency regardless whether stimulus duration (20 s) or number (100) were kept constant, suggesting that frequency is an important determinant of neuronal activity. In contrast, LDF responses increased to a maximum at 5 Hz, and do not correlate with SEPs. Because CBF should reflect integrated neuronal activity, we computed the sum of SEPS (summation operatorSEP = SEP x stimulus frequency) as an index of total neuronal activity at each frequency. Summation operatorSEP indeed correlates positively (P<0.001) with LDF responses. Thus, during somatosensory stimulation at various frequencies, cerebral blood flow is coupled to integrated neuronal activity but not to averaged evoked potentials.

Safety, tolerability and immunogenicity of concomitant injections in separate locations of M-M-R II, VARIVAX and TETRAMUNE in healthy children vs. concomitant injections of M-M-R II and TETRAMUNE followed six weeks later by VARIVAX.

OBJECTIVES AND STUDY DESIGN: The primary objectives of this study were to compare immunologic responses, antibody persistence, safety and varicella breakthrough rates when VARIVAX (varicella vaccine) is given at the same time as M-M-R II (measles, mumps, rubella vaccine) and TETRAMUNE (conjugate Haemophilus influenzae type b, diphtheria, tetanus and whole cell pertussis vaccine) at separate injection sites (Group A) vs. VARIVAX given 6 weeks after M-M-R II and TETRAMUNE (Group B). Six hundred nine healthy children, 12 to 23 months of age, were randomized to one of two treatment (immunization) groups (Group A and Group B). Blood for antibody titers was drawn on the day of immunization, 6 weeks after each injection and 1 year later. Local and systemic adverse reactions were recorded. Exposure and cases of varicella were documented through a 1-year follow-up period. RESULTS: Measles, mumps and rubella seroconversion rates and geometric mean titers (GMTs) were similar for both treatment groups. Varicella seroconversion rates were also similar between groups. However, varicella GMTs and percent with a varicella-protective level [> or =5.0 glycoprotein (gp) enzyme-linked immunosorbent assay (ELISA) units] did not meet the prespecified criteria for similarity were lower for Group A (GMT 10.5; 82.8% > or =5.0 gp ELISA units) than for Group B (GMT 14.5; 91.2% > or =5.0 gp ELISA units). The GMTs between groups for other antibodies were similar. At the 1-year follow-up antibody titers were comparable in both groups and breakthrough varicella cases appeared generally similar. There were fewer local adverse events (AEs) at the VARIVAX injection sites (9.8% and 2.9%, Group A and B, respectively) than at the TETRAMUNE sites (27.9% and 24.0%). Systemic AEs were not statistically different when M-M-R II was administered alone (8.6%) or concomitantly with VARIVAX (8.9%). When VARIVAX was given alone AEs were 1.8%. The rate of fever > or =102 degrees F after M-M-R II and TETRAMUNE administered together was 10.7% on Days 0 to 3 and 23.7% on Days 7 to 21. When VARIVAX was administered alone, the rate of fever was 5.4% on Days 0 to 3 (P = 0.018) and 10.8% on Days 7 to 21 (P<0.001). CONCLUSION: Because the varicella titers were comparable and varicella breakthrough rates generally similar at 1 year in both groups, we expect that the concomitant administration of VARIVAX with M-M-R II and TETRAMUNE has clinical effectiveness similar to that with VARIVAX 6 weeks after the administration of these other two vaccines. VARIVAX appears to be less reactogenic than M-M-R II and TETRAMUNE.

Suppression of somatosensory evoked potentials by nitric oxide synthase inhibition in rats: methodological differences.

We have previously shown that topically applied N(G)-nitro-L-arginine (L-NNA), a nitric oxide synthase (NOS) inhibitor, suppressed both somatosensory evoked potentials (SEPs) and vascular responses during sciatic nerve stimulation in rats. Due to the normal tight coupling between cerebral blood flow and neuronal activity, we surmise that the vascular response attenuation may be secondary to the SEP decrease. However, a recent study, in which SEPs were recorded with a 'non-contact' electrode placed longitudinally across the cranial window without touching the cortex, did not find a SEP decrease following NOS inhibition. In the present study, we compared SEPs recorded with 'contact' and 'non-contact' electrodes. Regardless of stimulation methods (sciatic nerve or hindpaw), an electrode in contact with the pial surface overlying the hindlimb somatosensory cortex recorded a steady SEP decline during I-NNA application. In contrast, a 'non-contact' electrode did not detect a significant SEP change in the presence of I-NNA. The present results thus confirm the attenuation of SEPs by NOS inhibition.

Measles, mumps, rubella, and varicella combination vaccine: safety and immunogenicity alone and in combination with other vaccines given to children. Measles, Mumps, Rubella, Varicella Vaccine Study Group.

Eight hundred and twelve children, 12 months to 3.5 years of age, were enrolled in two clinical studies to evaluate the safety and immunogenicity of a live, attenuated combination vaccine for measles, mumps, rubella, and varicella (MMRV). Children were enrolled in one of two randomized, multicenter studies, involving administration of (1) MMRV and placebo vs. measles, mumps, and rubella vaccine (M-M-R(II)) and varicella-zoster virus vaccine (VARIVAX), given at separate anatomic sites at the same office visit; or (2) MMRV, DTaP (diphtheria, tetanus, and acellular pertussis vaccine) and OPV (oral polio vaccine) vs. M-M-R(II), DTaP, and OPV, with VARIVAX given 6 weeks later. All vaccine regimens were generally well tolerated. More than 95% of vaccinees seroconverted for measles, mumps, rubella, and varicella, regardless of the vaccine or regimen used. In each study, the level of antibody titer to varicella virus was significantly lower in vaccinees receiving MMRV than in those who received VARIVAX in a separate syringe.

Dose titration study of live attenuated varicella vaccine in healthy children. Pennridge Pediatric Associates.

To approximate the effect of prolonged storage on safety and immunogenicity, healthy children were given a single dose of the currently marketed live attenuated varicella vaccine (3625 pfu) or of a partially heat-inactivated vaccine (1125 or 439 pfu). The 3 doses had similar antigen content (attenuated plus inactive virus particles). The vaccine was well tolerated. No significant differences in adverse reactions were observed. Although the seroconversion rates were excellent at each dose (> or = 98%), the higher doses resulted in significantly greater geometric mean antibody titers at 6 weeks (10.5 and 10.6 ELISA U/mL) compared with the 439 pfu dose (5.7 ELISA U/mL), P < or = .01. One year after immunization, differences in antibodies were similar to the 6-week postimmunization results. Results indicate that until the date of expiry, the vaccine's immunogenicity will be preserved and there will be no clinically important changes in type or frequency of adverse events.

Estimation of shear and flow rates in pial arterioles during somatosensory stimulation.

We tested the hypothesis that a shear stress-dependent mechanism is involved in the dilation of pial arterioles during somatosensory stimulation. In alpha-chloralose-anesthetized rats implanted with cranial windows, we simultaneously measured the diameter and flow velocity of pial arterioles with video and dual-slit methods. Stimulation (0.2-0.3 V, 5 Hz, 0.5 ms pulses for 20 s) of the contralateral sciatic nerve evoked consistent dilator responses in pial arterioles (36 +/- 1 micron diam) without affecting blood pressure. The dilator responses consisted of an initial transient peak dilation of 30 +/- 3%, followed by a sustained dilation of 13 +/- 1% (n = 11). Mean velocity increased by 16.4 +/- 5.7% at 5 s after stimulus onset. Wall shear rate and volume flow were calculated from diameter and velocity data by assuming a parabolic flow profile. There was no significant change in wall shear rate, whereas flow rate increased significantly during sciatic nerve stimulation. The present findings suggest that a flow (shear stress)-mediated mechanism does not play an important role in the dilator response of pial arterioles to sciatic nerve stimulation.

Safety and immunogenicity of one vs. two injections of Oka/Merck varicella vaccine in healthy children.

OBJECTIVE: To compare the safety and immunogenicity of a one- vs. two-dose regimen of Oka/Merck varicella vaccine in approximately 2000 healthy children 12 months to 12 years of age. METHODOLOGY: Subjects with a negative history of varicella were randomized to receive either one or two injections of the vaccine given 3 months apart and were followed for clinical reactions and serologic response (glycoprotein-based enzyme-linked immunosorbent assay). RESULTS: Both one- and two-dose vaccine regimens were generally well-tolerated. The incidences of varicelliform rash and fever were less frequent after the second injection. However, a slight increase in the incidence of injection site reactions was noted after the second injection; these were generally mild. Seroconversion rates by glycoprotein-based enzyme-linked immunosorbent assay were 98.2% (1700 of 1731) after one injection and 99.9% (717 of 718) after two injections. A significant (P < 0.001) boost in geometric mean titers was observed in children who received a second injection of vaccine 3 months after the first injection. Of the children who seroconverted at 6 weeks postregimen (one or two doses as assigned), 99.8% (528 of 529) of the one-dose group and 99.8% (473 of 474) of the two-dose group maintained antibody to varicella at 1 year with geometric mean titers of 19.5 and 31.2, respectively. CONCLUSIONS: Administration of a one- or two-dose regimen of the live Oka/Merck varicella vaccine (VARIVAX) is immunogenic and is generally well-tolerated in healthy children 1 to 12 years old. Antibody to varicella persists in > 99% of vaccinees 1 year after vaccination regardless of a one- or two-dose regimen. Long-term follow-up studies of this cohort of children may determine whether a two-dose regimen offers superior protection against chickenpox.

L-NNA suppresses cerebrovascular response and evoked potentials during somatosensory stimulation in rats.

We studied the local cerebrovascular response and somatosensory-evoked potentials (SEPs) to stimulation of the sciatic nerve during both short- (< 30 min) and long-term (90-150 min) exposure to topically applied NG-nitro-L-arginine (L-NNA). The pial circulation was visualized through a cranial window in alpha-chloralose-anesthetized rats. The diameter of pial arterioles (25-45 microns) and laser-Doppler flow (LDF) in the hindlimb sensory cortex were simultaneously measured during sciatic nerve stimulation. Short-term (< 30 min) treatment with L-NNA (1 mM) abolished the dilation of pial arterioles induced by acetylcholine, whereas the response to sciatic nerve stimulation was not affected. When applied for > 30 min, L-NNA induced severe vasomotion and attenuated the vascular responses to sciatic nerve stimulation. Long-term exposure to topically (1 mM) or systemically (10 mg/kg i.v.) applied L-NNA also attenuated cortical SEPs to sciatic nerve stimulation. Thus L-NNA-induced inhibition of vascular responses may be secondary to suppression of neuronal activity and an L-arginine metabolite, such as nitric oxide, may be involved in neurotransmission in the cerebral cortex during somatosensory activity.

Anesthetic-dependent pial arteriolar response to ethanol.

Anesthetic agents are often administered in the presence of ethyl alcohol, both in research and in the clinical setting. The authors tested the hypothesis that anesthetic agents may affect cerebrovascular responses to ethanol. A closed cranial window preparation in the rat was used to compare the response of pial arterioles to topically applied ethanol (0.01% to 1% vol/vol) in the presence of alpha-chloralose/urethane (50 and 600 mg/kg, respectively) or halothane (0.5% to 1%) anesthesia. Heart rate, mean arterial blood pressure, and blood gas levels were maintained stable and within the physiological range throughout each experiment. Ethanol induced significant vasoconstriction in alpha-chloralose/urethane-anesthetized animals (multivariate analysis of variance (MANOVA), p = 0.039); conversely, ethanol induced significant vasodilation of the pial arterioles in halothane-anesthetized animals (MANOVA, p = 0.017). These responses were significantly different from one another (MANOVA, p = 0.001). Thus, the choice of anesthetic agent alters the cerebrovascular response to ethanol, and care should be taken to ascertain the influence of anesthesia in both research and clinical settings.

Modulation of cerebral arteriolar diameter by intraluminal flow and pressure.

We determined whether cerebral arterioles in vitro adjust their diameters in response to changes in intraluminal flow rate and pressure. Intracerebral arterioles (38- to 55-microns diameter) were isolated from Sprague-Dawley rats and cannulated with a perfusion system that permitted separate control of intraluminal pressure and flow rates. Increasing pressure at 0 flow, in 20 mm Hg steps from 20 to 100 mm Hg, resulted in myogenic constriction, which was greatest at 60 mm Hg (approximately 20%). Increasing flow rate at a constant pressure of 60 mm Hg elicited a biphasic response. At flow rates of up to 10 microL/min, the arterioles dilated by up to 14.5 +/- 2.2% of their control diameter. At higher (> 10 microL/min) flow rates, however, a progressive restoration of resting diameter was observed. Application of the nitric oxide synthase inhibitor NG-mono-methyl-L-arginine (L-NMMA, 0.1 mmol/L) caused a 15.4 +/- 1.7% decrease in control diameter (at 60 mm Hg, zero flow). Although L-NMMA did not affect the responses to increases in pressure or to vasodilators (adenosine and pH 6.8 buffer), it abolished the dilator responses to flow rate increases and to acetylcholine. In contrast, inhibition of prostaglandin synthesis by indomethacin (10 mumol/L) had no effect on flow-induced dilation. These results show that changes in intraluminal flow rates and pressure can independently influence cerebral arteriolar tone and suggest that the flow-induced dilator responses of cerebral arterioles are mediated by an arginine metabolite, such as nitric oxide.

Safety, tolerability, and immunogenicity of two regimens of Oka/Merck varicella vaccine (Varivax) in healthy adolescents and adults. Oka/Merck Varicella Vaccine Study Group.

A multicenter clinical trial was conducted among 757 healthy adolescents and adults, 13-54 years, to compare two regimens of Oka/Merck varicella vaccine with respect to safety, tolerability, and immunogenicity. Participants were randomized to receive two injections of vaccine either four or eight weeks apart and were followed for clinical reactions and serologic response. The two vaccine regimens were equally well tolerated. The seroconversion rates (gpELISA) four weeks after injection 1 and 2 were 72 and 99%, respectively, for those who received vaccine four weeks apart and 78 and 99%, respectively, for those who received vaccine eight weeks apart. The differences in seroconversion rates were not statistically significant. However, delaying the second dose to eight weeks resulted in a higher antibody titer one month after the second injection. Administration of a two-dose regimen of varicella vaccine to susceptible adolescents and adults is well tolerated and highly immunogenic.

Differential effects of alcohols on intracerebral arterioles. Ethanol alone causes vasoconstriction.

We compared the effect of the acute application of ethanol, methanol, 1-propanol, 1-butanol, urea, and mannitol (1-100 mM) on the basal tone of isolated-cannulated rat intracerebral arterioles to determine if the response of these arterioles to ethanol could be attributed to alteration of membrane fluidity or changes in osmolality. These arterioles spontaneously developed tone to 62.0 +/- 8.4% of passive diameter (44.2 +/- 11.9 vs. 70.9 +/- 14.7 microns). Ethanol caused a dose-dependent reduction in arteriolar diameter starting at 3 mM (p = 0.03), reaching a diameter of 81.4 +/- 3.0% of basal tone at 100 mM. In comparison, all other agents tested caused the arterioles to dilate, with the exception of 1-propanol, which produced inconsistent vessel responses. At 100 mM concentration, methanol, 1-butanol, urea, and mannitol dilated intracerebral arterioles by 116.1 +/- 12.7, 151.5 +/- 12.4, 131.1 +/- 17.0, and 149.8 +/- 6.6%, respectively. Thus, in a concentration range associated with acute intoxication, ethanol causes constriction of isolated intracerebral arterioles. The mechanism of action of ethanol cannot be accounted for solely based upon its physicochemical characteristics of osmolality or lipid solubility, but rather may reflect a more specific action on one or more cellular mechanisms responsible for determining basal intracerebral arteriolar tone. The characterization of the response of intracerebral arterioles to ethanol is important in view of epidemiologic links between ethanol consumption and cerebrovascular disease.

Simultaneous measurements of pial arteriolar diameter and laser-Doppler flow during somatosensory stimulation.

We simultaneously measured pial arteriolar diameter and changes in cortical blood flow during activation of the somatosensory cortex by sciatic nerve stimulation. The pial vasculature was visualized with a closed-cranial window technique in chloralose-anesthetized rats (n = 13). Local blood flow was monitored with laser-Doppler flowmetry. During stimulation of the sciatic nerve (0.2 V, 5 Hz, 20 s), vascular diameter and laser-Doppler flow consistently displayed similar response profiles. With 0.5-ms stimulation pulses, the responses showed an initial peak followed by a smaller but sustained plateau dilation. In contrast, 5-ms pulses evoked a monotonically rising response. Our results support the concept that pial arteriolar diameter changes reflect cortical blood flow responses during somatosensory stimulation.

Low incidence of adverse experiences after measles or measles-rubella mass revaccination at a college campus.

A postvaccination questionnaire and review of student and employee clinic visits were carried out at Notre Dame University in the spring of 1990 after mass campus revaccination with measles or measles-rubella vaccines in the autumn of 1989, in order to assess the incidence of adverse experiences after revaccination. Rates of adverse experiences (AE), which included chiefly local injection site discomfort and flu-like symptoms, among respondents were 6.6% and 13.4%, male and female students, respectively, and 9.3% and 25%, male and female employees, respectively. Rates of joint-related complaints (4%) were lower than reported after primary vaccination, particularly in young adult women. AEs in general, and joint reaction rates in particular, were generally mild and transient, and only 0.23% resulted in a clinic visit. Revaccination of prior vaccinees appears to be associated with relatively low AE rates.