A gas cell apparatus for measuring charge exchange cross sections with multicharged ions.

A gas cell apparatus to measure charge exchange cross sections for charge state- and energy-resolved ion beams with neutrals is described. The design features a short well-defined interaction region required for beams of multicharged ions with high cross sections. Our method includes measuring the beam transmission at four different neutral pressures and extracting the cross section from the slope of a beam loss vs pressure plot. The design and procedure were tested for Ar+ interacting with neutral Ar gas over the incident ion energy range of 1.0-5.0 keV. The charge exchange cross sections agree well with previous complementary measurement techniques.

Kinetic energy offsets for multicharged ions from an electron beam ion source.

Using a retarding field analyzer, we have measured offsets between the nominal and measured kinetic energy of multicharged ions extracted from an electron beam ion source (EBIS). By varying source parameters, a shift in ion kinetic energy was attributed to the trapping potential produced by the space charge of the electron beam within the EBIS. The space charge of the electron beam depends on its charge density, which in turn depends on the amount of negative charge (electron beam current) and its velocity (electron beam energy). The electron beam current and electron beam energy were both varied to obtain electron beams of varying space charge and these were related to the observed kinetic energy offsets for Ar4+ and Ar8+ ion beams. Knowledge of these offsets is important for studies that seek to utilize slow, i.e., low kinetic energy, multicharged ions to exploit their high potential energies for processes such as surface modification. In addition, we show that these offsets can be utilized to estimate the effective radius of the electron beam inside the trap.

Note: High density pulsed molecular beam for cold ion chemistry.

A recent expansion of cold and ultracold molecule applications has led to renewed focus on molecular species preparation under ultrahigh vacuum conditions. Meanwhile, molecular beams have been used to study gas phase chemical reactions for decades. In this paper, we describe an apparatus that uses pulsed molecular beam technology to achieve high local gas densities, leading to faster reaction rates with cold trapped ions. We characterize the beam's spatial profile using the trapped ions themselves. This apparatus could be used for preparation of molecular species by reactions requiring excitation of trapped ion precursors to states with short lifetimes or for obtaining a high reaction rate with minimal increase of background chamber pressure.

Does the cognitive measure Cog-4 show improvement among patients treated with thrombolysis after acute stroke?

BACKGROUND: Although the established measure of disability post stroke, the modified Rankin Scale emphasizes motor function and may underestimate the importance of cognitive impairment in more disabled patients. A subset of four items from the National Institutes of Health Stroke Scale has been proposed to assess cognitive function after stroke (Cog-4), and to correlate with modified Rankin Scale. Items correspond to orientation, executive function, language, and inattention. We investigated responsiveness of Cog-4 to treatment with thrombolysis and whether it offers information that supplements modified Rankin Scale. METHODS: We included 6268 patients from the Virtual International Stroke Trials Archive: 2734 received intravenous thrombolysis and 3534 were treated conservatively. We compared day 90 outcomes between treated and untreated groups, by modified Rankin Scale (illustrative) and by Cog-4 (primary measure) adjusting for age, baseline National Institutes of Health stroke scale, hemispheric lateralisation as well as baseline Cog-4 and baseline National Institutes of Health Stroke Scale excluding baseline Cog-4 separately. Analysis of Cog-4 was repeated within strata of 90 day modified Rankin Scale. Statistical analyses included proportional odds logistic regression and Cochran-Mantel-Haenszel test. RESULTS: Modified Rankin Scale showed a difference between treatment groups of expected magnitude (odds ratio 1·56; 95% confidence interval 1·43-1·72; P < 0·001). After adjustment for imbalance in baseline prognostic factors, the distribution of Cog-4 scores at 90 days was better in thrombolysed patients compared with nonthrombolysed patients (odds ratio 1·31; 95% confidence interval 1·18-1·47; P = 0·006). However, Cog-4 analysis stratified by 90-day modified Rankin Scale was neutral between treatment groups (OR 1·01; 95% CI 0·90-1·14), and Cog-4 was not responsive to treatment group even within modified Rankin Scale categories 4 and 5 despite substantial cognitive deficits in these patients. CONCLUSION: Although Cog-4 may be responsive to treatment effects, it does not provide additional information beyond modified Rankin Scale assessment.

Noninvasive vibrational mode spectroscopy of ion Coulomb crystals through resonant collective coupling to an optical cavity field.

We report on a novel noninvasive method to determine the normal mode frequencies of ion Coulomb crystals in traps based on the resonance enhanced collective coupling between the electronic states of the ions and an optical cavity field at the single photon level. Excitations of the normal modes are observed through a Doppler broadening of the resonance. An excellent agreement with the predictions of a zero-temperature uniformly charged liquid plasma model is found. The technique opens up for investigations of the heating and damping of cold plasma modes, as well as the coupling between them.

Fiber technology for reliable repair of skeletal muscle.

Conventional soft-tissue reclosure methods-sutures and staples-require substantial organized-collagen content. Some tissues lack extensive intrinsic collagenous content. Wound disruption consequences range from newly closed abdominal wounds bursting open, to post-cesarean wombs splitting at delivery, to heart valves loosening. Although sutures do approach the theoretical limit of normal force transfer-cross-sectional area times compressive strength, a different paradigm-shear force transfer across the far greater surface attainable by fine fibers parallel to the potential disruptive force could exceed that theoretical limit. Capacity is now the product of frictional coefficient, existing tissue pressure, and contact area. Using a device comprising bundles of poly(ethylene terephthalate) fibers through tissue, we previously coupled muscles to devices and bones. Here we tested an analogous device for reclosing fascia-stripped abdominal wall muscles. In 28 rabbits, fascia-deprived rectus abdominus muscles were reclosed, using the experimental device or conventional sutures. Testing muscles from the 21 three-week survivors, (with closure devices retained-the usual clinical practice) demonstrated experimental failure strength which exceeded that of controls by 58%. Histologically, solid tissue elements did in-grow between fibers for an extensive tissue-prosthetic interface. Both histology and mechanical performance suggest the fiber technology presented herein surpasses conventional sutures in closure of collagen-deficient tissues.

Confinement time exceeding one second for a toroidal electron plasma.

Nearly steady-state electron plasmas are trapped in a toroidal magnetic field for the first time. We report the first results from a new toroidal electron plasma experiment, the Lawrence Non-neutral Torus II, in which electron densities on the order of 10(7) cm(-3) are trapped in a 270-degree toroidal arc (670 G toroidal magnetic field) by application of trapping potentials to segments of a conducting shell. The total charge inferred from measurements of the frequency of the m=1 diocotron mode is observed to decay on a 3 s time scale, a time scale that approaches the predicted limit due to magnetic pumping transport. Three seconds represents approximately equal to 10(5) periods of the lowest frequency plasma mode, indicating that nearly steady-state conditions are achieved.

Neuroprotective agents for clinical trials in Parkinson's disease: a systematic assessment.

BACKGROUND: Current therapies for PD ameliorate symptoms in the early phases of disease but become less effective over time, as the underlying disease progresses. Therapies that slow the progression of PD are needed. However, there have been relatively few clinical trials aimed at demonstrating neuroprotection. The authors sought to identify potential neuroprotective agents for testing in clinical trials. METHODS: First a broad array of compounds were identified by working with clinicians and researchers in academics and industry. Specific criteria were drafted for drug evaluation, including scientific rationale, blood-brain barrier penetration, safety and tolerability, and evidence of efficacy in animal models or humans. Agents were prioritized based on these criteria. RESULTS: The authors identified 59 potential neuroprotective compounds, proposed by 42 clinicians and scientists from 13 countries. After systematic reviews using the specified criteria they found 12 compounds to be attractive candidates for further clinical trials in PD. CONCLUSIONS: Several potential neuroprotective compounds, representing a wide range of mechanisms, are available and merit further investigation in PD.

Lack of clinical significance of early ischemic changes on computed tomography in acute stroke.

CONTEXT: The prevalence and clinical significance of early ischemic changes (EICs) on baseline computed tomography (CT) scan of the head obtained within 3 hours of ischemic stroke are not established. OBJECTIVE: To determine the frequency and significance of EIC on baseline head CT scans in the National Institute of Neurological Disorders and Stroke (NINDS) rt-PA (recombinant tissue plasminogen activator) Stroke Trial. DESIGN AND SETTING: The original study, a randomized controlled trial, took place from January 1991 through October 1994 at 43 sites, during which CT images were obtained within 3 hours of symptom onset and prior to the initiation of rt-PA or placebo. For the current analysis, detailed reevaluation was undertaken after October 1994 of all baseline head CT scans with clinical data available pretreatment (blinded to treatment arm). PATIENTS: Of 624 patients enrolled in the trial, baseline CT scans were retrieved and reviewed for 616 (99%). MAIN OUTCOME MEASURES: Frequency of EICs on baseline CT scans; association of EIC with other baseline variables; effect of EICs on deterioration at 24 hours (>/=4 points increase from the baseline National Institutes of Health Stroke Scale [NIHSS] score); clinical outcome (measured by 4 clinical scales) at 3 months, CT lesion volume at 3 months, death at 90 days; and symptomatic intracranial hemorrhage (ICH) within 36 hours of treatment. RESULTS: The prevalence of EIC on baseline CT in the combined rt-PA and placebo groups was 31% (n = 194). The EIC was significantly associated with baseline NIHSS score (rho = 0.23; P<.001) and time from stroke onset to baseline CT scan (rho = 0.11; P =.007). After adjusting for baseline variables, there was no EIC x treatment interaction detected for any clinical outcome, including deterioration at 24 hours, 4 clinical scales, lesion volume, and death at 90 days (P>/=.25), implying that EIC is unlikely to affect response to rt-PA treatment. After adjusting for NIHSS score (an independent predictor of ICH), no EIC association with symptomatic ICH at 36 hours was detected in the group treated with rt-PA (P>/=.22). CONCLUSIONS: Our analysis suggests that EICs are prevalent within 3 hours of stroke onset and correlate with stroke severity. However, EICs are not independently associated with increased risk of adverse outcome after rt-PA treatment. Patients treated with rt-PA did better whether or not they had EICs, suggesting that EICs on CT scan are not critical to the decision to treat otherwise eligible patients with rt-PA within 3 hours of stroke onset.

Excitation of electronic states of Ar, H(2), and N(2) by positron impact.

We have measured the first state-resolved, absolute cross sections for positron excitation of electronic states of an atom or molecule using a high resolution (Delta E approximately 25 meV FWHM) beam of positrons from a Penning-Malmberg trap. We present cross sections for the excitation of the low-lying levels of Ar, H(2), and N(2) for incident positron energies between threshold and 30 eV. For Ar and H2, comparison can be made with theoretical calculations, and, in the case of H(2), the results resolve a significant discrepancy between the only two available calculations.

Apolipoprotein E phenotype and the efficacy of intravenous tissue plasminogen activator in acute ischemic stroke.

We used stored plasma samples from 409 patients in the National Institute of Neurological Diseases and Stroke (NINDS) tissue plasminogen activator (t-PA) Stroke Trial to examine the relationship between an apolipoprotein (Apo) E2 or an Apo E4 phenotype and a favorable outcome 3 months after stroke, the risk of intracerebral hemorrhage, and the response to intravenous t-PA therapy. For the 27 patients with an Apo E2 phenotype who were treated with t-PA, the odds ratio (OR) of a favorable outcome at 3 months was 6.4 [95% confidence interval (CI) 2.7-15.3%] compared to the 161 patients without an Apo E2 phenotype who were treated with placebo. The 190 patients treated with t-PA who did not have an Apo E2 phenotype also had a greater, though less pronounced, likelihood of a favorable outcome (OR 2.0, 95% CI 1.2-3.2%) than patients without an Apo E2 phenotype treated with placebo. For the 31 patients with an Apo E2 phenotype treated with placebo, the OR of a favorable 3 month outcome was 0.8 (95% CI 0.4-1.7%) compared to the 161 patients without an Apo E2 phenotype treated with placebo. This interaction between treatment and Apo E2 status persisted after adjustment for baseline variables previously associated with 3 month outcome, for differences in the baseline variables in the two treatment groups and in the Apo E2-positive and -negative groups, and for a previously reported time-to-treatment x treatment interaction (p = 0.03). Apo E4 phenotype, present in 111 (27%) of the 409 patients, was not related to a favorable 3 month outcome, response to t-PA, 3 month mortality, or risk of intracerebral hemorrhage. We conclude that the efficacy of intravenous t-PA in patients with acute ischemic stroke may be enhanced in patients who have an Apo E2 phenotype, whereas the Apo E2 phenotype alone is not associated with a detectable benefit on stroke outcome at 3 months in patients not given t-PA. In contrast to prior studies of head injury and stroke, we could not detect a relationship between Apo E4 phenotype and clinical outcome.

Advances in the genetics of cerebrovascular disease and stroke.

MEDLINE searches identified epidemiologic, experimental, and clinical studies on the genetics of cerebrovascular disease and stroke, including the following topics: genetic epidemiology of stroke; genetics of systemic disorders that cause ischemic stroke, including coagulation disorders, connective tissue disorders, vasculopathies, metabolic disorders, and disorders of unknown etiology; and genetics of systemic disorders that cause hemorrhagic stroke. Recent discoveries in stroke genetics involve the genetic basis of monogenic disorders such as cerebral autosomal dominant arteriopathy with subcortical infarcts and leukoencephalopathy and sickle cell disease. Reproducing similar advances in other forms of cerebrovascular disease and stroke will be more difficult because their inheritance is complex, multigenic, and heterogeneous. However, the future is promising with the application of molecular genetic approaches such as linkage analysis, allele-sharing methods, association studies, and polygenic analysis of experimental crosses as well as the transmission/disequilibrium test--a statistical method for detection of linkage between a marker and a disease-susceptibility locus.

Fetal tissue engineering: diaphragmatic replacement.

BACKGROUND/PURPOSE: Prosthetic repair of congenital diaphragmatic hernia has been associated with high complication rates. This study was aimed at applying fetal tissue engineering to diaphragmatic replacement. METHODS: Fetal lambs underwent harvest of skeletal muscle specimens. Once expanded in vitro, fetal myoblasts were suspended in a collagen hydrogel submitted to controlled radial tension. The construct was then placed in a bioreactor. After birth, all animals underwent creation of 2 diaphragmatic defects. One defect was repaired with the autologous-engineered construct placed in between 2 acellular supporting membranes and the other with an identical construct but without any cells. Each animal was its own control (graft, n = 10). Animals were killed at different time-points postimplantation for histologic examination. Statistical analysis was by analysis of variance (ANOVA). RESULTS: Fetal myoblasts expanded up to twice as fast as neonatal cells. Hydrogel-based radial tension enhanced construct architecture by eliciting cell organization within the scaffold. No eventration was present in 4 of 5 engineered constructs but in 0 of 5 acellular grafts (P<.05). At harvest, engineered constructs were thick and histologically resembled normal skeletal muscle, whereas acellular grafts were thin, floppy, and showed low cell density with increased fibrosis. CONCLUSIONS: Unlike acellular grafts, engineered cellular diaphragmatic constructs are anatomically and histologically similar to normal muscle. Fetal tissue engineering may be a viable alternative for diaphragmatic replacement.

Vascular anomalies: classification, diagnosis, and natural history.

In the past, patients with vascular anomalies went from one physician to another. No one seemed to understand the condition, and sometimes the child was harmed by the wrong treatment. Now interdisciplinary vascular anomalies centers are organizing. The disciplines may differ, depending on local interest and capabilities. Such teams form a critical mass for proper diagnosis, therapy, and clinical/basic research. The advances in genetics are leading the way to a molecular understanding of vascular anomalies, and someday, molecular-based, novel therapy. The Internet also has had a major impact on this field. Because of continued confusion about diagnosis and therapy, cyber-savvy parents will self-refer to specialists. Family support groups have arisen and provide commendable service to these patients.

Early stroke treatment associated with better outcome: the NINDS rt-PA stroke study.

BACKGROUND: The National Institute of Neurological Disorders and Stroke (NINDS) rt-PA Stroke Study showed a similar percentage of intracranial hemorrhage and good outcome in patients 3 months after stroke treatment given 0 to 90 minutes and 91 to 180 minutes after stroke onset. At 24 hours after stroke onset more patients treated 0 to 90 compared to 91 to 180 minutes after stroke onset had improved by four or more points on the NIH Stroke Scale (NIHSS). The authors performed further analyses to characterize the relationship of onset-to-treatment time (OTT) to outcome at 3 months, early improvement at 24 hours, and intracranial hemorrhage within 36 hours. METHODS: Univariate analyses identified potentially confounding variables associated with OTT that could mask an OTT-treatment interaction. Tests for OTT-treatment interactions adjusting for potential masking confounders were performed. An OTT-treatment interaction was considered significant if p < or = 0.10, implying that treatment effectiveness was related to OTT. RESULTS: For 24-hour improvement, there were no masking confounders identified and there was an OTT-treatment interaction (p = 0.08). For 3-month favorable outcome, the NIHSS met criteria for a masking confounder. After adjusting for NIHSS as a covariate, an OTT-treatment interaction was detected (p = 0.09): the adjusted OR (95% CI) for a favorable 3-month outcome associated with recombinant tissue-type plasminogen activator (rt-PA) was 2.11 (1.33 to 3.35) in the 0 to 90 minute stratum and 1.69 (1.09 to 2.62) in the 91 to 180 minute stratum. In the group treated with rt-PA, after adjusting for baseline NIHSS, an effect of OTT on the occurrence of intracranial hemorrhage was not detected. CONCLUSIONS: If the NINDS rt-PA Stroke Trial treatment protocol is followed, this analysis suggests that patients treated 0 to 90 minutes from stroke onset with rt-PA have an increased odds of improvement at 24 hours and favorable 3-month outcome compared to patients treated later than 90 minutes. No effect of OTT on intracranial hemorrhage was detected within the group treated with rt-PA, possibly due to low power.

Osteochondral reconstruction of a non-weight-bearing joint using a high-density porous polyethylene implant.

Currently, there is no reliable reconstructive modality allowing anatomic resurfacing of traumatic digital osteochondral articular defects. The purpose of the present study is to demonstrate the utility of Medpor, a high-density porous polyethylene (HDPP) scaffold biomaterial that can (1) be readily contoured to fit any joint defect, (2) permit stable internal fixation, and (3) permit osteocyte and chondrocyte ingrowth and subsequent articular cartilage resurfacing necessary to restore joint congruity. HDPP has gained wide acceptance for use in craniofacial and skeletal reconstruction and augmentation. An avian non-weight-bearing joint model was designed to study the role of the HDPP implant in small joint reconstruction. An osteochondral defect was created with a 5-mm circular punch in the humeral articular surface of both glenohumeral joints of 32 adult White Leghorn chickens. In each animal, one defect was press-fitted with a correspondingly sized HDPP implant (HDPP implant group); the contralateral defect was filled with the original osteochondral plug (isograft group) or left unrepaired (control group). At 2 weeks, and 1, 3, and 6 months,joints from each group were harvested and evaluated. Over the 6-month study period, joints in the control group demonstrated healing with dense collagenous scar tissue leaving residual defects at the articular surfaces and significant degenerative disease of the glenohumeral joints radiographically. Joints in the isograft group demonstrated near-complete resorption with some preservation of the cartilaginous cap but overall depression of the articular surface and significant degenerative joint disease. Joints in the HDPP implant group demonstrated stable fixation by highly mineralized bony trabecular ingrowth, preservation of the articular contour of the humeral head, and no evidence of significant degenerative joint disease. These findings indicate a potential role for this high-density porous polyethylene implant in the reconstruction of small joint articular and osseous defects.

Finding the most powerful measures of the effectiveness of tissue plasminogen activator in the NINDS tPA stroke trial.

BACKGROUND AND PURPOSE: We sought to identify the most powerful binary measures of the treatment effect of tissue plasminogen activator (tPA) in the National Institute of Neurological Disorders and Stroke (NINDS) rTPA Stroke Trial. METHODS: Using the Classification and Regression Tree (CART) algorithm, we evaluated binary cut points and combination of binary cut points with the 4 clinical scales and head CT imaging measures in the NINDS tPA Stroke Trial at 4 times after treatment: 2 hours, 24 hours, 7 to 10 days, and 3 months. The first analysis focused on detecting evidence of "early activity" of tPA with the use of outcome measures derived from the 2-hour and 24-hour clinical and radiographic measures. The second analysis focused on longer-term outcome and "efficacy" and used outcome measures derived from 7- to 10-day and 3-month measures. After identifying the cut points with the ability to classify patients into the tPA and placebo groups using part I data from the trial, we then used data from part II of the trial to validate the results. RESULTS: Of the 5 most powerful outcome measures for early activity of tPA, 4 involved the National Institutes of Health Stroke Scale (NIHSS) score at 24 hours or changes in the NIHSS score from baseline to 24 hours. The best overall single outcome measure was an NIHSS score

Recommendations for the establishment of primary stroke centers. Brain Attack Coalition.

OBJECTIVE: To develop recommendations for the establishment and operation of primary stroke centers as an approach to improve the medical care of patients with stroke. PARTICIPANTS: Members of the Brain Attack Coalition (BAC), a multidisciplinary group of representatives from major professional organizations involved with delivering stroke care. Supplemental input was obtained from other experts involved in acute stroke care. EVIDENCE: A review of literature published from 1966 to March 2000 was performed using MEDLINE. More than 600 English-language articles that had evidence from randomized clinical trials, meta-analyses, care guidelines, or other appropriate methods supporting specific care recommendations for patients with acute stroke that could be incorporated into a stroke center model were selected. CONSENSUS PROCESS: Articles were reviewed initially by 1 author (M.J.A.). Members of the BAC reviewed each recommendation in the context of current practice parameters, with special attention to improving the delivery of care to patients with acute stroke, cost-effectiveness, and logistical issues related to the establishment of primary stroke centers. Consensus was reached among all BAC participants before an element was added to the list of recommendations. CONCLUSIONS: Randomized clinical trials and observational studies suggest that several elements of a stroke center would improve patient care and outcomes. Key elements of primary stroke centers include acute stroke teams, stroke units, written care protocols, and an integrated emergency response system. Important support services include availability and interpretation of computed tomography scans 24 hours everyday and rapid laboratory testing. Administrative support, strong leadership, and continuing education are also important elements for stroke centers. Adoption of these recommendations may increase the use of appropriate diagnostic and therapeutic modalities and reduce peristroke complications. The establishment of primary stroke centers has the potential to improve the care of patients with stroke. JAMA. 2000.

Soft-tissue augmentation with injectable alginate and syngeneic fibroblasts.

Tissue engineering, a field that combines polymer scaffolds with isolated cell populations to create new tissue, may be applied to soft-tissue augmentation-an area in which polymers and cell populations have been injected independently. We have developed an inbred rat model in which the subcutaneous injection of a hydrogel, a form of polymer, under vacuum permits direct comparison of different materials in terms of both histologic behavior and their ability to maintain the specific shape and volume of a construct. Using this model, we compared three forms of calcium alginate, a synthetic hydrogel, over an 8-week period-standard alginate that was gelled following injection into animals (alginate post-gel), standard alginate that was gelled before injection into animals (alginate pre-gel) and alginate-RGD, to which the cell adhesion tripeptide RGD was linked covalently (RGD post-gel). Parallel groups that included cultured syngeneic fibroblasts suspended within each of these three gels were also evaluated (alginate post-gel plus cells, alginate pre-gel plus cells, and RGD post-gel plus cells). The study used 54 inbred Lewis rats (n = 9 for each of the six groups). Construct geometry was optimally maintained in the alginate post-gel group in which 58 percent of the original volume was preserved at 8 weeks and increased to 88 percent at 8 weeks when syngeneic fibroblasts were included within the gel. Volume was not as well preserved in the RGD post-gel group (25 percent of original volume at 8 weeks), but again increased when syngeneic fibroblasts were included (41 percent of original volume at 8 weeks). Maintenance of volume was poorest in the alginate pre-gel group (31 percent of original volume at 8 weeks) and failed to be augmented by the addition of fibroblasts (19 percent of original volume at 8 weeks). Histologically, the gel remained a uniform sheet surrounded by a fibrous capsule in the alginate post-gel groups. In the alginate pre-gel and RGD post-gel groups, there was significant ingrowth of a fibrovascular stroma into the gel with fragmentation of the construct. In constructs in which syngeneic fibroblasts were included, cells were visualized throughout the gel but did not extend processes or appear to contribute to new tissue formation. Material compression testing indicated that the alginate and RGD post-gel constructs became stiffer over a 12-week period, particularly in the cell-containing groups. Our results suggest that calcium alginate could be a suitable agent for soft-tissue augmentation when gelled subcutaneously following injection. The addition of syngeneic fibroblasts enhanced the ability of the gel to maintain the volume of a construct; this seems to be mediated by increased gel stiffness rather than by de novo tissue formation. Our animal model, in combination with material testing data, permits rigorous comparison of different materials used for soft-tissue augmentation.