"Virtual patch clamp analysis" for predicting the functional significance of pathogenic variants in sodium channels.

OBJECTIVE: Opening of voltage-gated sodium channels is crucial for neuronal depolarization. Proper channel opening and influx of Na+ through the ion pore, is dependent upon binding of Na+ ion to a specific amino-acid motif (DEKA) within the pore. In this study we used molecular dynamic simulations, an advanced bioinformatic tool, to research the dysfunction caused by pathogenic variants in SCN1a, SCN2a and SCN8a genes. METHOD: Molecular dynamic simulations were performed in six patients: three patients with Dravet syndrome (p.Gly177Ala,p.Ser259Arg and p.Met1267Ile, SCN1a), two patients with early onset drug resistant epilepsy(p.Ala263Val, SCN2a and p.Ile251Arg, SCN8a), and a patient with autism (p.Thr155Ala, SCN2a). After predicting the 3D-structure of mutated proteins by homology modeling, time dependent molecular dynamic simulations were performed, using the Schrödinger algorithm. The opening of the sodium channel, including the detachment of the sodium ion to the DEKA motif and pore diameter were assessed. Results were compared to the existent patch clamp analysis in four patients, and consistency with clinical phenotype was noted. RESULTS: The Na+ ion remained attached to DEKA filter longer when compared to wild type in the p.Gly177Ala, p.Ser259Arg,SCN1a, and p.Thr155Ala, SCN2a variants, consistent with loss-of-function. In contrast, it detached quicker from DEKA than wild type in the p.Ala263Val,SCN2a variant, consistent with gain-of-function. In the p.Met1267Ile,SCN1a variant, detachment from DEKA was quicker, but pore diameter decreased, suggesting partial loss-of-function. In the p.Leu251Arg,SCN8a variant, the pore remained opened longer when compared to wild type, consistent with a gain-of-function. The molecular dynamic simulation results were consistent with the existing patch-clamp analysis studies, as well as the clinical phenotype. SIGNIFICANCE: Molecular dynamic simulation can be useful in predicting pathogenicity of variants and the disease phenotype, and selecting targeted treatment based on channel dysfunction. Further development of these bioinformatic tools may lead to "virtual patch-clamp analysis".

Respiratory responses and rating of perceived exertion of severely obese adolescents during continuous and intermittent graded walking protocols: Application to cardiorespiratory field tests.

During 20 m shuttle tests, obese adolescents may have difficulty achieving maximum cardiorespiratory performance due to the presence of braking-relaunch phases (BRP). Nineteen obese adolescents aged 15.2 ± 1.5 years (body mass index [BMI] = 39.7 ± 5.9 kg.m-2) performed three graded walking exercises on a 50 m track at speeds between 3 and 6 km/h: a continuous-straight-line protocol (C), a continuous protocol that required turning back every 30 sec (C-BRP) and an intermittent protocol that consisted of successively walking then resting for 15 sec (15-15). Oxygen uptake (VO2), aerobic cost of walking (Cw), ventilation (VE) and rating of perceived exertion (RPE) were measured at each stage during the protocols. During C-BRP, the responses were not significantly higher compared with C (p > 0.30). During 15-15, the VO2, Cw and VE were ~ 15 to 25% lower than during C beginning at 4 km/h (p < 0.05). In obese adolescents, the respiratory impact of sudden directional changes during the 20 m shuttle-type test appeared to be minor at walking speeds. During the 15-15 test, the intensity increases more progressively, and this design may encourage obese adolescents to walk further than during a continuous test.

Acute cocoa flavanols intake improves cerebral hemodynamics while maintaining brain activity and cognitive performance in moderate hypoxia.

INTRODUCTION: Acute cocoa flavanols (CF) intake has been suggested to modulate cognitive function and neurovascular coupling (NVC). Whether increased NVC is solely driven by improved vascular responsiveness or also by neuronal activity remains unknown. This study investigated the effects of acute CF intake on cognitive performance, NVC, and neuronal activity in healthy subjects in normoxia and hypoxia (4000 m simulated altitude; 12.7% O2). METHODS: Twenty healthy subjects (age 23.2 ± 4.3 years) performed four trials. Participants performed a Stroop task and "cognition" battery 2 h after acute CF (530 mg CF, 100 mg epicatechin) or placebo intake, and 30 min after initial exposure to hypoxia or normoxia. Electroencephalogram and functional near-infrared spectroscopy were used to analyze hemodynamic changes and neuronal activity. RESULTS: CF enhanced NVC in the right prefrontal cortex during several tasks (risk decision making, visual tracking, complex scanning, spatial orientation), while neuronal activity was not affected. CF improved abstract thinking in normoxia, but not in hypoxia and did not improve other cognitive performances. Hypoxia decreased accuracy on the Stroop task, but performance on other cognitive tasks was preserved. NVC and neuronal activity during cognitive tasks were similar in hypoxia vs. normoxia, with the exception of increased ß activity in the primary motor cortex during abstract thinking. CONCLUSIONS: Acute CF intake improved NVC, but did not affect neuronal activity and cognitive performance in both normoxia and hypoxia. Most cognitive functions, as well as NVC and neuronal activity, did not decline by acute exposure to moderate hypoxia in healthy subjects.

Detection of copy number variations in epilepsy using exome data.

Epilepsies are common neurological disorders and genetic factors contribute to their pathogenesis. Copy number variations (CNVs) are increasingly recognized as an important etiology of many human diseases including epilepsy. Whole-exome sequencing (WES) is becoming a standard tool for detecting pathogenic mutations and has recently been applied to detecting CNVs. Here, we analyzed 294 families with epilepsy using WES, and focused on 168 families with no causative single nucleotide variants in known epilepsy-associated genes to further validate CNVs using 2 different CNV detection tools using WES data. We confirmed 18 pathogenic CNVs, and 2 deletions and 2 duplications at chr15q11.2 of clinically unknown significance. Of note, we were able to identify small CNVs less than 10 kb in size, which might be difficult to detect by conventional microarray. We revealed 2 cases with pathogenic CNVs that one of the 2 CNV detection tools failed to find, suggesting that using different CNV tools is recommended to increase diagnostic yield. Considering a relatively high discovery rate of CNVs (18 out of 168 families, 10.7%) and successful detection of CNV with <10 kb in size, CNV detection by WES may be able to surrogate, or at least complement, conventional microarray analysis.

Insulin-based strategies to prevent hypoglycaemia during and after exercise in adult patients with type 1 diabetes on pump therapy: the DIABRASPORT randomized study.

AIMS: To validate strategies to prevent exercise-induced hypoglycaemia via insulin-dose adjustment in adult patients with type 1 diabetes (T1D) on pump therapy. METHODS: A total of 20 patients randomly performed four 30-min late post-lunch (3 h after lunch) exercise sessions and a rest session: two moderate sessions [50% maximum oxygen consumption (VO2 max)] with 50 or 80% basal rate (BR) reduction during exercise + 2 h and two intense sessions (75% VO2 max) with 80% BR reduction or with their pump stopped. Two additional early post-lunch sessions (90 min after lunch) were analysed to compare hypoglycaemia incidence for BR reduction versus bolus reduction. RESULTS: In all, 100 late post-lunch sessions were analysed. Regardless of exercise type and BR reduction, no more hypoglycaemic events occurred in the period until the next morning than occurred after the rest sessions. In the afternoon, no more hypoglycaemic events occurred with 80% BR reduction/moderate exercise or with pump discontinuation/intense exercise than for the rest session, whereas more hypoglycaemic events occurred with 50% BR reduction/moderate exercise and 80% BR reduction/intense exercise. After early post-lunch exercise (n = 37), a trend towards fewer hypoglycaemic episodes was observed with bolus reduction versus BR reduction (p = 0.07). Mean blood glucose fell by ∼3.3 mmol/l after 30 min of exercise, irrespective of dose reduction, remaining stable until the next morning with no rebound hyperglycaemia. CONCLUSION: In adults with T1D, to limit the hypoglycaemic risk associated with 30 min of exercise 3 h after lunch, without carbohydrate supplements, the best options seem to be to reduce BR by 80% or to stop the pump for moderate or intense exercise, or for moderate exercise 90 min after lunch, to reduce the prandial bolus rather than the BR.

BDNF, IGF-I, Glucose and Insulin during Continuous and Interval Exercise in Type 1 Diabetes.

Type 1 diabetes (T1D) can have a significant impact on brain function, mostly ascribed to episodes of hypoglycemia and chronic hyperglycemia. Exercise has positive effects on acute and chronic glycemic control in T1D, and has beneficial effects on cognitive function by increasing neurotrophins such as BDNF and IGF-I in non-diabetic humans. The present study examines the effects of different types of exercise intensities on neurotrophins in T1D. 10 participants with type 1 diabetes were evaluated in 3 sessions: high-intensity exercise (10×[60 s 90%Wmax, 60 s 50 W]), continuous exercise (22 min, 70% VO2 max) and a control session. Blood glucose, serum free insulin, serum BDNF and IGF-I were assessed pre/post all the trials and after recovery. Blood glucose significantly decreased after both exercise intensities and BDNF levels increased, with a dose-response effect for exercise intensity on BDNF. IGF-I changed over time, but without a difference between the different exercise protocols. Both exercise intensities change neurotrophins in T1D, but also exhibit a dose response effect for BDNF. The intensity-dependent findings may aid in designing exercise prescriptions for maintaining or improving neurological health in T1D, but both types of exercise can be implemented.

The role of the endocannabinoid system in skeletal muscle and metabolic adaptations to exercise: potential implications for the treatment of obesity.

The results of recent studies add the endocannabinoid system, and more specifically CB1 receptor signalling, to the complex mechanisms that negatively modulate insulin sensitivity and substrate oxidation in skeletal muscle. CB1 receptors might become overactive in the skeletal muscle during obesity due to increased levels of endocannabinoids. However, quite surprisingly, one of the most studied endocannabinoids, anandamide, when administered in a sufficient dose, was shown to improve muscle glucose uptake and activate some key molecules of insulin signalling and mitochondrial biogenesis. This is probably because anandamide is only a partial agonist at CB1 receptors and interacts with other receptors (PPARγ, TRPV1), which may trigger positive metabolic effects. This putative beneficial role of anandamide is worth considering because increased plasma anandamide levels were recently reported after intense exercise. Whether the endocannabinoid system is involved in the positive exercise effects on mitochondrial biogenesis and glucose fatty acid oxidation remains to be confirmed. Noteworthy, when exercise becomes chronic, a decrease in CB1 receptor expression in obese metabolically deregulated tissues occurs. It is then tempting to hypothesize that physical activity would represent a complementary alternative approach for the clinical management of endocannabinoid system deregulation in obesity, without the side effects occurring with CB1 receptor antagonists.

Metabolic dysfunction in late-puberty adolescent girls with type 1 diabetes: relationship to physical activity and dietary intakes.

AIMS: At puberty, type 1 diabetes (T1D) among young girls can lead to excess body weight, insulin resistance, deterioration of glycaemic control and dyslipidaemia. Although biological factors contribute largely to such metabolic dysfunction, little is known of the role of behavioural factors such as physical activity and diet. METHODS: This study investigated the association between metabolic dysfunction measured after a 12-h overnight fast and behavioural factors, including diet (4-day diary) and physical activity (validated questionnaire), in 19 postmenarchal adolescent girls with T1D compared with 19 healthy girls. RESULTS: T1D girls displayed higher levels of fat mass, insulin resistance (higher plasma glucose, serum leptin and waist-to-hip ratios) and dyslipidaemia (higher LDL-C and apolipoprotein B levels, lower HDL-C and apolipoprotein A-1 levels). Also, contrary to what is usually observed in T1D adults, serum adiponectin, an important vessel protector, was not raised in T1D adolescent girls compared with healthy controls. Quantity and quality of dietary macronutrient intakes as well as physical activity levels were comparable in both groups, although the T1D girls with the poorest metabolic profiles reported having the healthiest diets (fewer total calories, more protein and less carbohydrates). However, in T1D girls, less physical activity and more time spent watching television were associated with poorer metabolic profiles (higher waist-to-hip ratios, fat mass and leptin levels, and lower adiponectin, HDL-C and apolipoprotein A-1 levels). CONCLUSION: Collectively, these data suggest that physical inactivity is linked to metabolic dysfunction to a greater extent than unhealthy dietary habits in postmenarchal T1D adolescent girls.

Intense exercise increases circulating endocannabinoid and BDNF levels in humans--possible implications for reward and depression.

The endocannabinoid system is known to have positive effects on depression partly through its actions on neurotrophins, such as Brain-Derived Neurotrophic Factor (BDNF). As BDNF is also considered the major candidate molecule for exercise-induced brain plasticity, we hypothesized that the endocannabinoid system represents a crucial signaling system mediating the beneficial antidepressant effects of exercise. Here we investigated, in 11 healthy trained male cyclists, the effects of an intense exercise (60 min at 55% followed by 30 min at 75% W(max)) on plasma levels of endocannabinoids (anandamide, AEA and 2-arachidonoylglycerol, 2-AG) and their possible link with serum BDNF. AEA levels increased during exercise and the 15 min recovery (P<0.001), whereas 2-AG concentrations remained stable. BDNF levels increased significantly during exercise and then decreased during the 15 min of recovery (P<0.01). Noteworthy, AEA and BDNF concentrations were positively correlated at the end of exercise and after the 15 min recovery (r>0.66, P<0.05), suggesting that AEA increment during exercise might be one of the factors involved in exercise-induced increase in peripheral BDNF levels and that AEA high levels during recovery might delay the return of BDNF to basal levels. AEA production during exercise might be triggered by cortisol since we found positive correlations between these two compounds and because corticosteroids are known to stimulate endocannabinoid biosynthesis. These findings provide evidence in humans that acute exercise represents a physiological stressor able to increase peripheral levels of AEA and that BDNF might be a mechanism by which AEA influences the neuroplastic and antidepressant effects of exercise.

Wave analysis of Airy beams.

The Airy beams are analyzed in order to provide a cogent physical explanation to their intriguing features which include weak diffraction, curved propagation trajectories in free-space, and self healing. The asymptotically exact analysis utilizes the method of uniform geometrical optics (UGO), and it is also verified via a uniform asymptotic evaluation of the Kirchhoff-Huygens integral. Both formulations are shown to fully agree with the exact Airy beam solution in the paraxial zone where the latter is valid, but they are also valid outside this zone. Specifically it is shown that the beam along the curved propagation trajectory is not generated by contributions from the main lobe in the aperture, i.e., it is not described by a local wave-dynamics along this trajectory. Actually, this beam is identified as a caustic of rays that emerge sideways from points in the initial aperture that are located far away from the main lobe. The field of these focusing rays, described h e by the UGO, fully agrees with the Airy beam solution. These observations explain that the "weak-diffraction" and the "self healing" properties are generated, in fact, by a continuum of sideways contributions to the field, and not by local self-curving dynamics. The uniform ray representation provides a systematic framework to synthesize aperture sources for other beam solutions with similar properties in uniform or in non-uniform media.

Epilepsy in children with infantile thiamine deficiency.

OBJECTIVE: To report the follow-up findings of 7 children with severe epilepsy as a result of thiamine deficiency in infancy caused by a defective soy-based formula. METHODS: The medical records of 7 children aged 5-6 years with thiamine deficiency in infancy who developed epilepsy were reviewed and their clinical data, EEG tracings, and neuroimaging results were recorded. The clinical course and present outcome of these children, now 5 years after exposure to thiamine deficiency, are described. RESULTS: All infants displayed seizures upon presentation, either tonic, myoclonic, or focal. Six infants had an EEG recording at this stage and all showed slow background. Five of them had no epileptic activity and only 1 displayed focal activity. Following a seizure-free period of 1-9 months, the seizures recurred, and all 7 children displayed either myoclonic or complex partial seizures. Multifocal or generalized spike wave complexes were recorded on the EEGs of all 7 patients, and the tracings of 3 children evolved into hypsarrhythmia. The seizures were refractory to most antiepileptic drugs, and 4 children remain with uncontrolled seizures. All children have mental retardation and motor disabilities as well as symptoms of brainstem dysfunction. CONCLUSIONS: Our findings indicate that severe infantile thiamine deficiency may result in epilepsy.

Ergonomics for children: an educational program for elementary school.

Studies indicate that musculoskeletal discomfort and back pain problems are evident not only in adults, but also in children. We believe that educating towards a balanced-posture, body-function and movement patterns, as well as their ergonomic implications, can minimize and even prevent these problems. Such an ergonomics awareness educational program has to start at childhood and should be an integral part of the curriculum in the schools. This article presents the educational program "Ergonomics, Movement & Posture" (EMP), which is taught in elementary schools by Physical Education (PE) students of the Kibbutzim College of Education in Israel, as part of their practicum. Although there has been no formal evaluation of the effectiveness of the program, so far, participating children, their parents, the teachers and the principles have offered positive feedback.

Ergonomics for children: an educational program for elementary school.

Studies indicate that musculoskeletal discomfort and back pain problems are evident not only in adults, but also in children [11,13]. We believe that educating towards a balanced-posture, body-function and movement patterns, as well as their ergonomic implications, can minimize and even prevent these problems. Such an ergonomics awareness educational program has to start at childhood and should be an integral part of the curriculum in the schools. This article presents the educational program "Ergonomics, Movement and Posture" (EMP), which is taught in elementary schools by Physical Education (PE) students of the Kibbutzim College of Education in Israel, as part of their practicum. Although there has been no formal evaluation of the effectiveness of the program, so far, participating children, their parents, the teachers and the principles have offered positive feedback.

The stethoscope as a vector of infectious diseases in the paediatric division.

AIM: Nosocomial infections are of great concern in hospital settings, and even more so in the paediatric ward. Health professionals and their medical equipment have long been known to act as vectors of infectious diseases. This study aimed at evaluating the presence of bacterial pathogens on the stethoscopes of medical personnel in the paediatric division. METHODS: Forty-three stethoscopes belonging to senior physicians, residents, interns and medical students at the paediatric ward were sampled. Bacterial cultures and antibiotic sensitivity testing were carried out. RESULTS: All but six bacterial cultures were positive (85.7%). Staphylococcal species were the most common contaminants (47.5%). One case of methicillin-resistant Staphylococcus aureus was encountered. Gram-negative organisms were isolated in nine different samples (21%) including one case of Acinetobacter baumannii in the neonatal intensive care unit. CONCLUSION: Most stethoscopes harbour potential pathogens. The isolation of Gram-negative organisms pose a real risk of spreading potentially serious infections, especially in the setting of intensive care departments. Apparently, the current recommendations of regular disinfection of stethoscopes are not carried out by health personnel that participated in the study.

Alteration in sympathoadrenergic activity at rest and during intense exercise despite normal aerobic fitness in late pubertal adolescent girls with type 1 diabetes.

BACKGROUND: An impaired sympathoadrenergic response to hypoglycaemic episodes has been described in young Type 1 diabetic subjects. It is unknown if this altered response occurs with exercise, and if it could influence aerobic power. METHODS: Body composition (skinfold thickness), physical activity (questionnaire) and aerobic power (PWC170 and VO2max) were assessed in 19 post-menarcheal Type 1 diabetic (T1D) girls (13.3-18.2 years) and 19 healthy siblings. At rest and at each stage of the graded exhaustive exercise, plasma glucose, insulin, epinephrine and norepinephrine, were monitored via an intravenous catheter. RESULTS: Only when expressed per kilograms of body weight, was aerobic power impaired in T1D girls compared to controls, probably because they were overweight. Throughout exercise, plasma glucose remained stable while plasma insulin decreased in the healthy girls, whereas glucose diminished significantly with no change in plasma insulin in T1D girls. During exercise catecholamines increased in the same way in both groups. However, at rest and throughout all stages of exercise, norepinephrine levels were significantly lower by a mean difference of 1.2 nmol/L, while epinephrine levels were significantly higher by a mean difference of 0.14 nmol/L, in T1D girls compared to healthy girls. Heart rates of T1D girls were not affected by the sympathoadrenergic alteration. CONCLUSION: T1D adolescent girls display an altered sympathoadrenergic activity at rest and during intense exercise. Their reduced sympathetic activity, albeit probably compensated for by higher adrenomedullary responsiveness or sensitivity, does not affect their heart rate adaptations to exercise.

Accuracy of physical working capacity 170 to estimate aerobic fitness in prepubertal diabetic boys and in 2 insulin dose conditions.

AIM: Exercise tests evaluate the effects of physical activity, which is one of the four recommendations for diabetes treatment. An adjusted and accurate measure of aerobic capacity in diabetic patients is thus needed. This study compared two estimates of aerobic fitness (maximal oxygen uptake vs physical working activity PWC170, i.e., the workload at a pulse of 170) and the usual versus a reduced insulin dose in preadolescent boys with type 1 diabetes mellitus. METHODS: Sixteen prepubertal type 1 diabetic boys performed a submaximal test, the PWC(170). Gas exchange values and capillary blood glucose levels were monitored and, when possible, the test was extended to exhaustion. In 7 boys, the test was performed twice on separate days. On one day they received their usual insulin dose and on the other, their short-acting insulin was reduced by 1/3; the two tests were held in random order. The 9 other children were tested only once after receiving their usual insulin dose. RESULTS: For the 16 boys who performed the test with the usual insulin dose, PWC(170) (W) and peak oxygen uptake (peak VO(2)) (L.min(-1)) correlated closely (r=0.81, P=0.002). Aerobic fitness did not change with insulin dose, but some hypoglycemic episodes occurred when insulin dose was not reduced. CONCLUSIONS: Since maximal effort does not add more information, routine use of the submaximal peak VO(2)-correlated test, the PWC(170), seems sufficient, possibly in association with a planned insulin dose reduction. This dose change does not interfere with performance, but could reduce the risk of hypoglycemia.

Paroxetine use throughout pregnancy: does it pose any risk to the neonate?

A newborn of a SSRI-treated mother presented with lethargy, no crying, and no response to tactile stimulation. EEG findings were abnormal. Laboratory and clinical evaluations were normal. He recovered at the age of two weeks. Serotonin is a neurotransmitter that has an important roll in pain modulation during fetal neurodevelopment. We suspect these symptoms are attributed to the intrauterine exposure to paroxetine, through modulation of pain signals.

Copper and zinc blood levels among children with nonorganic failure to thrive.

BACKGROUND AND AIMS: Copper and zinc deficiency are commonly reported among children with organic failure to thrive. In contrast, reports on copper and zinc status in children with non-organic failure to thrive are scarce. The goal of this study was to evaluate copper and zinc blood levels and nutritional intake among children with non-organic failure to thrive. METHODS: A study group of 32 children with non-organic failure to thrive were investigated and compared with 32 healthy controls. Each child had copper and zinc blood level measurements. In addition, the study group underwent evaluation of thyroid function, immunoglobulins, endomesial antibodies and xylose test. A dietary questionnaire that included a diet history and a 24-h dietary recall was administered to parents by a dietician. Weight for height, height for age and mean daily intake of calories, protein, copper and zinc were calculated. RESULTS: There were no significant differences between the two groups in either socioeconomic status or caloric, copper or zinc intake. Protein intake was significantly lower in the study group (P<0.0001). Plasma copper levels were within the normal range in both groups (P=0.3). Zinc plasma levels were significantly higher in the study group as compared to controls (P=0.03); however, they remained within the normal range in both groups. CONCLUSIONS: Children with non-organic failure to thrive can maintain plasma copper and zinc levels within normal range and similar to normal controls.

Wave propagation in media having negative permittivity and permeability.

Wave propagation in a double negative (DNG) medium, i.e., a medium having negative permittivity and negative permeability, is studied both analytically and numerically. The choices of the square root that leads to the index of refraction and the wave impedance in a DNG medium are determined by imposing analyticity in the complex frequency domain, and the corresponding wave properties associated with each choice are presented. These monochromatic concepts are then tested critically via a one-dimensional finite difference time domain (FDTD) simulation of the propagation of a causal, pulsed plane wave in a matched, lossy Drude model DNG medium. The causal responses of different spectral regimes of the medium with positive or negative refractive indices are studied by varying the carrier frequency of narrowband pulse excitations. The smooth transition of the phenomena associated with a DNG medium from its early-time nondispersive behavior to its late-time monochromatic response is explored with wideband pulse excitations. These FDTD results show conclusively that the square root choice leading to a negative index of refraction and positive wave impedance is the correct one, and that this choice is consistent with the overall causality of the response. An analytical, exact frequency domain solution to the scattering of a wave from a DNG slab is also given and is used to characterize several physical effects. This solution is independent of the choice of the square roots for the index of refraction and the wave impedance, and thus avoids any controversy that may arise in connection with the signs of these constituents. The DNG slab solution is used to critically examine the perfect lens concept suggested recently by Pendry. It is shown that the perfect lens effect exists only under the special case of a DNG medium with epsilon(omega)=mu(omega)=-1 that is both lossless and nondispersive. Otherwise, the closed form solutions for the field structure reveal that the DNG slab converts an incident spherical wave into a localized beam field whose parameters depend on the values of epsilon and mu. This beam field is characterized with a paraxial approximation of the exact DNG slab solution. These monochromatic concepts are again explored numerically via a causal two-dimensional FDTD simulation of the scattering of a pulsed cylindrical wave by a matched, lossy Drude model DNG slab. These FDTD results demonstrate conclusively that the monochromatic electromagnetic power flow through the DNG slab is channeled into beams rather then being focused and, hence, the Pendry perfect lens effect is not realizable with any realistic metamaterial.

Gaussian beam and pulsed-beam dynamics: complex-source and complex-spectrum formulations within and beyond paraxial asymptotics.

Paraxial Gaussian beams (GB's) are collimated wave objects that have found wide application in optical system analysis and design. A GB propagates in physical space according to well-established quasi-geometric-optical rules that can accommodate weakly inhomogeneous media as well as reflection from and transmission through curved interfaces and thin-lens configurations. We examine the GB concept from a broad perspective in the frequency domain (FD) and the short-pulse time domain (TD) and within as well as arbitrarily beyond the paraxial constraint. For the formal analysis, which is followed by physics-matched high-frequency asymptotics, we use a (space-time)-(wavenumber-frequency) phase-space format to discuss the exact complex-source-point method and the associated asymptotic beam tracking by means of complex rays, the TD pulsed-beam (PB) ultrawideband wave-packet counterpart of the FD GB, GB's and PB's as basis functions for representing arbitrary fields, GB and PB diffraction, and FD-TD radiation from extended continuous aperture distributions in which the GB and the PB bases, installed through windowed transforms, yield numerically compact physics-matched a priori localization in the plane-wave-based nonwindowed spectral representations.