Nanopore formation by low-energy focused electron beam machining.

The fabrication of nanopores in thin silicon nitride and aluminum oxide membranes by water vapor assisted, low-energy (0.2-20 kV) electron beam machining using a scanning electron microscope (SEM) is described. Using this technique, pores with diameters ranging in size from < 5 to 20 nm are easily formed. The nanopores are characterized by SEM, transmission electron microscopy (TEM) and atomic force microscopy (AFM). The mechanism of etching is briefly discussed.

Percutaneous revascularization in women with coronary artery disease: we've come so far, yet have so far to go.

Coronary artery disease (CAD) has traditionally been thought of as a disease that predominantly affects men. Women, however, are more likely than men to die from a myocardial infarction (MI). In this article, the data on access to cardiovascular care, treatment of stable and unstable coronary disease, and outcomes in women undergoing percutaneous coronary intervention (PCI) will be reviewed. Despite increased awareness of heart disease in women, and improved outcomes after PCI, women with MI have more mortality and delays to treatment than men. Women with CAD have symptoms that differ from men with CAD. Improved understanding of the symptoms of CAD in women by patients and health care providers may improve treatment and outcomes in women with CAD.

Learning: rapid aversive conditioning in the gastropod mollusk Pleurobranchaea.

Untrained Pleurobranchaea feed voraciously when presented food and withdraw from electrical shocks. We trained experimental animals in ten trials spaced 1 hour apart to withdraw from food alone by electrically shocking them if they fed or were indifferent to food. The greatest increase in the number of learned withdrawal responses occurred within 12 hours after conditioning, and was accompanied by long-lasting increased in the threshold and latency of feeding responses. Control animals, which received food and shock alternately (unpaired) every half hour, showed considerably weaker changes than experimentals. These control responses quickly returned to initial levels after conditioning.

Electron beam stimulated oxidation of carbon.

The patterning of carbon nanostructures by electron beam stimulated oxidation is described. Sputter deposited carbon thin films and carbon nanotubes are locally oxidized in a scanning electron microscope using injected water vapor. The resulting structures are examined with scanning electron microscopy and transmission electron microscopy. The electrical resistance obtained postprocessing is comparable to the as-deposited values. Linewidths are demonstrated down to 20 nm along with sub-2 nm nanowire fabrication in sputtered carbon films. A carbon nanowire is fabricated using this process and electrically characterized.

The distribution of small and intermediate conductance calcium-activated potassium channels in the rat sensory nervous system.

Small (SK) and intermediate (IK) conductance calcium-activated potassium channels are candidate ion channels for the regulation of excitability in nociceptive neurones. We have used unique peptide-directed antisera to describe the immunocytochemical distribution of the known isoforms of these ion channels in dorsal root ganglia (DRG) and spinal cord of the rat. These investigations sought to characterize further the phenotype and hence possible functions of nociceptive neurone subpopulations in the rat. In addition, using Western blotting, we sought to determine the level of protein expression of SK and IK channels in sensory nervous tissues following induction of inflammation (Freund's Complete Adjuvant (FCA) arthritis model) or nerve injury (chronic constriction injury model). We show that SK1, SK2, SK3 and IK1 are all expressed in DRG and spinal cord. Morphometric analysis revealed that SK1, SK2 and IK1 were preferentially localized to neurones having cell bodies <1000 microm2 (putative nociceptors) in DRG. Dual labeling immunocytochemistry showed that these ion channels co-localize with both CGRP and IB4, known markers of nociceptor sub-populations. SK2 was localized almost exclusively in the superficial laminae of the spinal cord dorsal horn, the region in which many sensory afferents terminate; the distribution of SK1 and IK1 was more widespread in spinal cord, although some preferential labeling within the dorsal horn was observed in the case of IK1. Here we show evidence for a distinctive pattern of expression for certain members of the calcium-activated potassium channel family in the rat DRG.

Management issues for women with epilepsy: a review of the literature.

OBJECTIVE: A review of literature referable to management issues for women with epilepsy (WWE) was undertaken for the development of a practice parameter. BACKGROUND: Epilepsy is a common neurologic condition with gender-related management implications. Although reviews of this topic often focus on pregnancy-related issues for WWE, specific health concerns for WWE are present throughout all phases of reproductive life. METHODS: An OVID MEDLINE literature search was conducted for 1965 to 1997 using the following key words/phrases and cross referencing: epilepsy/ seizures and pregnancy, anticonvulsants, antiepileptic drugs (AEDs), teratogenesis, oral contraceptives, birth defects, folate/folic acid, vitamin K, metabolic bone disease, and breast-feeding. RESULTS: Pregnancy outcome literature for WWE spans several decades. Methodology varies and interpretation is complicated by modern management strategies. Contributions of socioeconomic factors, AEDs, maternal epilepsy, and seizures during pregnancy to adverse pregnancy outcomes have not been clearly delineated. There is a biologic basis for recommendations concerning contraception, folate supplementation, vitamin K use in pregnancy, breast-feeding, metabolic bone disease, catamenial epilepsy, and reproductive endocrine disorders, but no outcome studies afford a strong evidence base for practice recommendation. CONCLUSIONS: WWE face health issues for which there is no available outcome literature to guide decision making. The urgent need for studies in many of these areas is highlighted by expanded treatment options with new AEDs and epilepsy surgery.

A randomized trial of divalproex sodium extended-release tablets in migraine prophylaxis.

OBJECTIVE: To evaluate the efficacy and safety of extended-release divalproex sodium compared with placebo in prophylactic monotherapy treatment of migraine headache. METHODS: This was a double-blind, randomized, placebo-controlled, parallel-group study. Subjects with more than two migraine headache attacks during a 4-week baseline were randomly assigned in a 1:1 ratio at each center to receive either extended-release divalproex sodium or matching placebo once daily for 12 weeks. Subjects initiated treatment on 500 mg once daily for 1 week, and the dose was then increased to 1,000 mg once daily with an option, if intolerance occurred, to permanently decrease the dose to 500 mg during the second week. Reduction from baseline in 4-week migraine headache rate was the primary efficacy variable. Migraine headaches separated by a < 24-hour headache-free interval were counted as single migraines in calculating migraine headache rates. Tolerance and safety were also evaluated. RESULTS: The mean reductions in 4-week migraine headache rate were 1.2 (from a baseline mean of 4.4) in the extended-release divalproex sodium group and 0.6 (from a baseline mean of 4.2) in the placebo group (p = 0.006); reductions with extended-release divalproex sodium were significantly greater than with placebo in all three 4-week segments of the treatment period. No significant differences were detected between treatment groups in either the overall incidence or in the incidence of any specific treatment-emergent adverse event; 8% of subjects treated with extended-release divalproex sodium and 9% of those treated with placebo discontinued for adverse events. CONCLUSION: Extended-release divalproex sodium is an efficacious, well-tolerated, safe, and easy-to-use once-a-day prophylactic antimigraine medication.

Vagus nerve stimulation therapy for partial-onset seizures: a randomized active-control trial.

OBJECTIVE: The purpose of this multicenter, add-on, double-blind, randomized, active-control study was to compare the efficacy and safety of presumably therapeutic (high) vagus nerve stimulation with less (low) stimulation. BACKGROUND: Chronic intermittent left vagus nerve stimulation has been shown in animal models and in preliminary clinical trials to suppress the occurrence of seizures. METHODS: Patients had at least six partial-onset seizures over 30 days involving complex partial or secondarily generalized seizures. Concurrent antiepileptic drugs were unaltered. After a 3-month baseline, patients were surgically implanted with stimulating leads coiled around the left vagus nerve and connected to an infraclavicular subcutaneous programmable pacemaker-like generator. After randomization, device initiation, and a 2-week ramp-up period, patients were assessed for seizure counts and safety over 3 months. The primary efficacy variable was the percentage change in total seizure frequency compared with baseline. RESULTS: Patients receiving high stimulation (94 patients, ages 13 to 54 years) had an average 28% reduction in total seizure frequency compared with a 15% reduction in the low stimulation group (102 patients, ages 15 to 60 year; p = 0.04). The high-stimulation group also had greater improvements on global evaluation scores, as rated by a blinded interviewer and the patient. High stimulation was associated with more voice alteration and dyspnea. No changes in physiologic indicators of gastric, cardiac, or pulmonary functions occurred. CONCLUSIONS: Vagus nerve stimulation is an effective and safe adjunctive treatment for patients with refractory partial-onset seizures. It represents the advent of a new, nonpharmacologic treatment for epilepsy.

Acute neurologic and psychiatric complications associated with cocaine abuse.

This report reviewed 996 emergency room visits and 279 hospital admissions of patients with complications of cocaine abuse seen at the San Francisco General Hospital between 1979 and 1986. In 143 cases, acute neurologic or psychiatric symptoms were the primary complaint, and case-notes provided sufficient detail for analysis. The major neurologic complications included one or more seizures (n = 29), focal neurologic symptoms or signs (12), headache (10), and transient loss of consciousness (six). Psychiatric disturbances included agitation, anxiety, or depression (33), psychosis and paranoia (24), and suicidal ideation (18). The most serious consequences were found in patients with prolonged seizures or strokes, those who jumped out of buildings, and those who attempted suicide by overdosing with other drugs. There was no correlation between the appearance of complications and the reported route of administration, the amount of cocaine used, or prior experience with cocaine. The number of patients who are seeking hospital attention for these or related complaints appears to be rising substantially. Cocaine abuse, regardless of the use pattern, is associated with a variety of potentially severe neurologic and psychiatric complications.

S-nitrosoglutathione reduces nonocclusive thrombosis rate following balloon overstretch injury and intracoronary irradiation of porcine coronary arteries.

PURPOSE: Intracoronary radiation (IR) suppresses neointima formation following balloon injury in animal models. High doses of radiation exacerbate thrombosis and delay re-endothelialization. The free radical nitric oxide (NO) has been reported to inhibit platelet aggregation, reduce neointimal hyperplasia, and stimulate re-endothelialization. This study examined the effects of a chemical NO donor on neointima formation, thrombosis, and healing of irradiated porcine coronary arteries. METHODS AND MATERIALS: Vascular lesions were created in the coronary arteries of 59 domestic swine by overstretch balloon injury. Arteries were then left untreated or were treated with intracoronary gamma-radiation using Iridium-192 in each artery to deliver 5 or 15 Gy at 2 mm from the center of the source. The chemical NO donor S-nitrosoglutathione (GSNO) was infused i.v. at a rate of 250 microg/min for 10 min before injury, followed by a continuous infusion for 60 min. Animals were euthanized at 14 days and their arteries were analyzed for histomorphometric indices of proliferation and thrombosis. RESULTS: A dose of 15 Gy reduced the ratio of intimal area to medial fracture length (IA/FL) versus control (0.06 +/- 0.05 0.54 +/- 0.10 [p < 0. 001]) but increased the nonocclusive thrombosis rate compared to controls (85% vs. 30%; p < 0.05). A low dose of 5 Gy did not affect neointima formation. Treatment with GSNO reduced thrombosis in all treated groups: control, 15%; 5 Gy, 18%; and 15 Gy, 35% (p < 0.05) without affecting neointima formation. CONCLUSION: Systemic administration of GSNO during balloon injury and IR was tolerated well by the swine and resulted in reduction of the thrombosis rate, especially at high doses, without apparent effect on neointima formation.

Anti-restenotic effect of copper-62 liquid-filled balloon in porcine coronary arteries: novel use of a short half-life positron emitter.

PURPOSE: To determine the efficacy of the use of copper-62, a positron emitter with a half-life of 9.7 minutes, as an intracoronary brachytherapy (IRBT) source in the prevention of neointima formation (NF) following overstretch balloon injury (BI) in the porcine model. METHODS AND MATERIALS: Sixteen swine were treated after BI to their left anterior descending (LAD), left circumflex (LCX), and/or right coronary artery (RCA). Twelve of the injured arteries received placebo and 10 received 25 Gy, delivered to 0.5 mm from the surface of the treatment balloon filled with liquid (62)Cu. Dosimetry was based on Monte Carlo calculations. Two weeks after treatment, the animals were sacrificed, and the treated coronaries were perfusion-fixed and stained. Intimal area (IA) and medial fracture length (FL) were analyzed by computer-aided histomorphometry. RESULTS: The ((62)Zn/(62)Cu) generator, together with a rapid concentration process, was successful in delivering the short-lived (62)Cu at the high concentration required for intravascular brachytherapy (IVBT). The fracture length in the two groups was similar (2.10 +/- 0.57; 2.02 +/- 0.77; p = NS). Arteries studied showed significant reduction in NF (IA: 0.23 +/- 0.47 mm(2) vs. 1.08 +/- 0.57 mm(2); p < 0.01. IA/FL = 0.09 +/- 0.17 mm vs. 0.51 +/- 0.21 mm; p < 0.01). CONCLUSIONS: This study demonstrated that use of liquid (62)Cu as an IVBT source is safe and feasible. All 16 swine tolerated the treatment well with no radiation-induced side effects or symptoms throughout the 2-week period. The isotope delivered the dose necessary to inhibit NF in the porcine coronary BI model.

Safety and tolerance of rapidly infused Depacon. A randomized trial in subjects with epilepsy.

BACKGROUND: Valproate sodium injection (Depacon(R)) is an intravenous form of valproate for use in absence and complex partial seizures when circumstances preclude oral administration. Certain situations may warrant larger and more rapid infusions than permitted by the original labeling. This study evaluated the safety of more rapid infusions. METHODS: Subjects with epilepsy were randomized in a 2:1 ratio to receive up to 15 mg/kg of valproate sodium infused at 3.0 or 1.5 mg/kg/min. Up to four infusions were allowed within 24 h to achieve target plasma valproate concentrations of 50-100 mcg/ml. Primary safety endpoints were the changes in the 5-min and minimum post-first infusion blood pressures (BPs). RESULTS: One hundred twelve subjects were treated, (3.0 mg/kg/min group: n=72, 1.5 mg/kg/min group: n=40). No significant treatment differences were detected for changes in the primary BP endpoints. Two subjects in the 3.0 mg/kg/min group had potentially clinically significant low systolic BP values during the study. Similar proportions of subjects in the two groups reported adverse events during or within 6 h following the first infusion. CONCLUSIONS: Valproate sodium injection dosages up to 15 mg/kg and rates of 1.5 and 3.0 mg/kg/min were well tolerated in this population.

Electromechanical characterization of acute experimental myocardial infarction.

OBJECTIVE: A new cardiac mapping system combines harmless magnetic field energy and tip-deflecting catheters (equipped with location sensors) to obtain real-time 3-dimensional electromechanical maps of the left ventricle endocardial surface without using x-ray fluoroscopy. This experimental study assessed electromechanical changes during acute coronary occlusion and reperfusion in a canine model. METHODS: Group 1 (n = 10) underwent coronary occlusion for 45 minutes followed by reperfusion (n = 6) and group 2 (n = 11) underwent coronary occlusion for 90 minutes. Endocardial peak-to-peak voltage amplitudes and local endocardial shortening values were measured in ischemic and non-ischemic zones at baseline, following coronary occlusion and reperfusion. RESULTS: In ischemic zones, local shortening was significantly reduced during coronary occlusion compared to baseline (Group 1: 4.7 +/- 2.0% at 45 minutes vs. 15.5 +/- 3.4%, p < 0.001, 6.2 +/- 2.1% at 90 minutes vs. 15.5 +/- 3.4%, p < 0.001; Group 2: 5.0 +/- 2.9% at 90 minutes vs. 13.9 +/- 3.3%, p = 0.007). Coronary occlusion caused a significant reduction in voltage potentials in the ischemic area (unipolar voltage at 45 minutes: 32.2 +/- 7.3 mV vs. 36.2 +/- 8.5 mV at baseline, p = 0.03; unipolar voltage at 90 minutes: 30.5 +/- 11.3 mV vs. 38.3 +/- 14.2 mV, p = 0.003; bipolar voltage at 45 minutes: 7.6 +/- 5.5 mV vs. 10.1 +/- 6.0 mV, p < 0.04; bipolar voltage at 90 minutes: 7.6 +/- 4.4 mV vs. 9.8 +/- 6.2 mV, p < 0.02). Voltage amplitudes were no longer reduced during reperfusion (unipolar voltage: 34.3 +/- 10.5 mV vs. 36.2 +/- 8.5 mV, p = 0.26; bipolar voltage: 9.1 +/- 4.5 mV vs. 10.1 +/- 6.0 mV at baseline, p = 0.37), or in non-ischemic regions during either coronary occlusion or reperfusion. CONCLUSIONS: Electromechanical mapping study provides unique insights into acute myocardial infarction and stunning by detection and localization of early electromechanical changes during coronary occlusion and/or reperfusion.

Neuro-ophthalmological signs during rapid intravenous administration of phenytoin.

We prospectively studied eye movement after rapid intravenous administration of phenytoin. Nineteen healthy young adults participated in a study of i.v. phenytoin pharmacokinetics. Subjects received a standard dose of 15 mg/kg at a rate of 25 mg/min, and were examined neuro-ophthalmologically before and at the end of the infusion. All patients had horizontal gaze-evoked nystagmus (HGN), and impairment of horizontal smooth pursuit (SP). Other signs were present in the following percentages: vertical gaze-evoked nystagmus (16 19 ,84%), and impairment of vertical SP (15 19 , 79%). Total and free phenytoin levels did not directly correlate with the degree of any of the neurological signs tested. By review of the past studies of nystagmus during phenytoin therapy, we propose that nystagmus is present consistently during toxicity with initial phenytoin therapy, but occurs less consistently during ongoing phenytoin use or chronic toxicity.

A pilot study of gabapentin as treatment for acquired nystagmus.

The effects of the anticonvulsant gabapentin were measured on vision and eve movements in three patients with acquired pendular nystagmus. In two patients, the nystagmus was associated with multiple sclerosis and, in the other, it followed brainstem stroke. A single oral 600 mg dose of gabapentin produced improvement of vision due to changes in ocular oscillations in all three patients. The effect was sustained after five weeks of treatment in two patients who elected to continue taking gabapentin 900-1500 mg/day. The results of this pilot study suggest that a controlled trial of gabapentin should be conducted to evaluate its role in the treatment of acquired forms of nystagmus.

Supplemental protein and postnatal growth of very low birth weight infants: a randomized trial.

BACKGROUND: Providing adequate nutritional support to promote optimal postnatal growth for very low birth weight (VLBW) infants has been a difficult problem to surmount in the NICU. During the past 4 decades, improvements in neonatal critical care have made it possible for more VLBW infants to survive to discharge from NICUs. The NICHD Neonatal Network reported that while intrauterine growth restriction was present in 22% of VLBW infants at birth, 91% demonstrated postnatal growth restriction by 36 weeks post menstrual age. The persistence of this nearly universal growth deficit is associated with the inadequacy of protein and energy intake, which may account for 45-50% of the postnatal growth restriction. OBJECTIVE: The purpose of this study was to assess whether increasing enteral intake, using supplemental protein, would improve postnatal growth for VLBW infants. STUDY DESIGN: Randomized clinical trial. Sixty-four infants were enrolled (34 in control group with 15 infants <1000 g, and 30 in intervention group with 13 infants <1000 g). RESULT: There were no sustained statistical differences between weekly measurements of weight, length, head circumference, and skinfold thickness between groups. There were no significant differences between laboratory results except blood urea nitrogen at time of peak protein intake for intervention group. CONCLUSIONS: Supplemental enteral protein had minimal to no effect on postnatal weight, length, head circumference, body mass, or length of stay. It may be most important to provide consistent sustained nutritional support with protein from birth to reduce postnatal growth restriction, especially for those infants <1000 g at birth.

Microneedle array for measuring wound generated electric fields.

A microneedle array has been fabricated and applied to the measurement of transdermal skin potentials in human subjects. Potential changes were recorded in the vicinity of superficial wounds, confirming the generation of a lateral electric field in human skin. The measured electric field decays with distance from the wound edge, and is directed towards the wound. The measurement of endogenous fields in skin is a prelude to the study of the therapeutic efficacy of applied electric fields to chronic non-healing wounds.

Magnetically actuated fiber-optic switch with micromachined positioning stages.

A new microfabrication technology for the design and realization of 1 x n and n x n fiber-optic switches, x, xy, and xyz translational stages, optical scanners, fiber-fiber couplers, and fiber-planar-waveguide couplers is presented. This technology is based on bulk anisotropic etching and offers significant improvements over present micro-optical and microphotonic devices. With this new enabling technology we have fabricated 200-mum -2-cm translational stages for use in beam steering and fiber-optic switching applications. We present the fabrication and characterization of a 1 x n micromechanical fiber-optic switch using this new technology. These nonoptimized devices have switching times of <10 ms with <-1-dB loss.

Safety of divalproex sodium in migraine prophylaxis: an open-label, long-term study. Long-term Safety of Depakote in Headache Prophylaxis Study Group.

CONTEXT: The adverse event profile of long-term divalproex therapy for epilepsy is well established, but little is known about the tolerability or safety of divalproex in long-term migraine prophylaxis. OBJECTIVE: Evaluate the long-term safety and efficacy of divalproex sodium in migraine prophylaxis. DESIGN: Open-label, long-term study, of up to 3 years, of patients who completed one of two multicenter, double-blind, randomized, placebo-controlled studies. SETTING: Eighteen headache/neurology centers throughout the United States. PATIENTS: One hundred sixty-three patients: 46 treated with placebo, 117 treated with divalproex for migraine in previous studies. INTERVENTION: Divalproex therapy initiated at 500 mg/day (250 mg twice daily), with adjustment in dose and dosing frequency possible after 1 to 3 days. MAIN OUTCOME MEASURES: Number and proportion of patients reporting treatment-emergent adverse events, prevalence and incidence for each treatment-emergent adverse event, vital signs, body weight, 4-week migraine rates and proportion of patients with 50% or greater reduction in rate over time. RESULTS: Treatment lasted more than 180 days for 71% of patients and more than 360 days for 48% of patients. Improvements in the 4-week, change-from-baseline migraine rates were seen during each of the 3- and 6-month time intervals. CONCLUSIONS: Divalproex is effective for migraine prophylaxis, and initial benefits are maintained for periods in excess of 1080 days.