Controlling the Self-Injection Threshold in Laser Wakefield Accelerators.

Controlling the parameters of a laser plasma accelerated electron beam is a topic of intense research with a particular focus placed on controlling the injection phase of electrons into the accelerating structure from the background plasma. An essential prerequisite for high-quality beams is dark-current free acceleration (i.e., no electrons accelerated beyond those deliberately injected). We show that small-scale density ripples in the background plasma are sufficient to cause the uncontrolled (self-)injection of electrons. Such ripples can be as short as ∼50 µm and can therefore not be resolved by standard interferometry. Background free injection with substantially improved beam characteristics (divergence and pointing) is demonstrated in a gas cell designed for a controlled gas flow. The results are supported by an analytical theory as well as 3D particle in cell simulations.

TIMP3 is Regulated by Pericytes upon Shear Stress Detection Leading to a Modified Endothelial Cell Response.

OBJECTIVES: Atherosclerosis is a hallmark of cardiovascular disease. Shear stress on endothelial cells has been linked to atherogenesis and to fibrous cap thinning and rupture. Pericytes reside in the sub-endothelial space of vessels and have vasoprotective effects. They are subjected to shear stress when endothelial cell integrity is disrupted. The aim was to investigate the susceptibility and response of pericytes to shear stress. METHODS: Endothelial cells and pericytes were seeded in two dimensional monocultures and co-cultures, and in a novel three dimensional co-culture system and were subjected to no, low and high shear stress (0, 10, 30 dyne/cm2) for 48 h. The morphological response to flow was assessed by histology and the expression of extracellular matrix proteins was analysed using quantitative polymerase chain reaction, immunoblotting, and ELISA. RESULTS: While endothelial cells aligned into flow direction, pericytes aligned perpendicularly (p < .001), indicating that they must be capable of sensing flow. When pericytes were embedded into a 3D matrix they showed similar alignment and pericytes built long processes towards the lumen. Under shear stress endothelial cells upregulated "a disintegrin and metalloproteinase with thrombospondin motif 1" (ADAMTS-1) (p < .01) and pericytes upregulated "tissue inhibitor of matrix metalloproteinase" (TIMP) 3 (p < .05), an inhibitor of ADAMTS-1, meanwhile differential expression of extracellular matrix (ECM) proteins could be detected in co-cultures of both cells. For TIMP3 expression direct cell-cell contact between endothelial cells and pericytes was required. CONCLUSION: The experiments highlight that pericytes are able to sense direct flow thereby regulating ECM proteins known to be involved in vascular remodelling. Furthermore, pericytes counter-regulate endothelial ADAMTS-1 by protective TIMP3 expression to prevent matrix degradation and maintain vascular stability. For this protective effect direct cell contact was necessary. This observation might represent an adaptive, protective mechanism of pericytes to counteract endothelial damage in the onset of atherosclerosis.

Characterization of 700 µJ T rays generated during high-power laser solid interaction.

Laser-produced solid density plasmas are well-known as table-top sources of electromagnetic radiation. Recent studies have shown that energetic broadband terahertz pulses (T rays) can also be generated from laser-driven compact ion accelerators. Here we report the measurement of record-breaking T-Ray pulses with energies no less than 0.7 mJ. The terahertz spectrum has been characterized for frequencies ranging from 0.1-133 THz. The dependence of T-Ray yield on incident laser energy is linear and shows no tendencies of saturation. The noncollinear emission pattern and the high yield reveal that the T rays are generated by the transient field at the rear surface of the solid target.

Observation of gigawatt-class THz pulses from a compact laser-driven particle accelerator.

We report the observation of subpicosecond terahertz (T-ray) pulses with energies ≥460 µJ from a laser-driven ion accelerator, thus rendering the peak power of the source higher even than that of state-of-the-art synchrotrons. Experiments were performed with intense laser pulses (up to 5×10(19) W/cm(2)) to irradiate thin metal foil targets. Ion spectra measured simultaneously showed a square law dependence of the T-ray yield on particle number. Two-dimensional particle-in-cell simulations show the presence of transient currents at the target rear surface which could be responsible for the strong T-ray emission.

Laser-plasma acceleration of quasi-monoenergetic protons from microstructured targets.

Particle acceleration based on high intensity laser systems (a process known as laser-plasma acceleration) has achieved high quality particle beams that compare favourably with conventional acceleration techniques in terms of emittance, brightness and pulse duration. A long-term difficulty associated with laser-plasma acceleration--the very broad, exponential energy spectrum of the emitted particles--has been overcome recently for electron beams. Here we report analogous results for ions, specifically the production of quasi-monoenergetic proton beams using laser-plasma accelerators. Reliable and reproducible laser-accelerated ion beams were achieved by intense laser irradiation of solid microstructured targets. This proof-of-principle experiment serves to illuminate the role of laser-generated plasmas as feasible particle sources. Scalability studies show that, owing to their compact size and reasonable cost, such table-top laser systems with high repetition rates could contribute to the development of new generations of particle injectors that may be suitable for medical proton therapy.

Validation of the Munich Swallowing Score (MUCSS) in patients with neurogenic dysphagia: A preliminary study.

BACKGROUND: The Munich Swallowing Score (MUCSS) is a clinician rated scale for the assessment of the functional level of swallowing saliva/secretions, food and liquids. The MUCSS consists of two eight-point subscales, MUCSS-Saliva and MUCSS-Nutrition. In a previous article, content validity and interrater reliability were described. OBJECTIVE: The aim of the present study was to investigate criterion validity and sensitivity to change of the MUCSS. METHODS: The research was conducted at a tertiary care academic hospital. Data were collected retrospectively in a cohort of 100 acute and subacute neurologic patients. Criterion validity was judged by comparison to the Gugging Swallowing Screen (GUSS), the Barthel Index (BI), Early Rehabilitation Barthel Index (ERI), Extended Barthel Index (EBI) and also by comparison to three physiological scales drawn from FEES videos: The Penetration - Aspiration Scale (PAS), the Yale Pharyngeal Residue Severity Rating Scale (YPR) and the Murray Secretion Scale (MSS). Changes in oral intake and saliva swallowing were followed up for three months. RESULTS: Between MUCSS and scores directly reflecting dysphagic symptoms (GUSS, PAS, YPR, MSS, ERI), strong to moderate correlations were found, weaker but statistically significant associations were seen with global measures of disability (BI isolated, EBI-subscale cognitive functions). MUCSS was sensitive to positive change of saliva swallowing and oral intake during the recovery period. CONCLUSIONS: These preliminary data suggest that the MUCCS is a valid scale and may be appropriate for documenting clinical change in swallowing abilities of patients with neurogenic dysphagia.

Auditory-motor integration during fast repetition: the neuronal correlates of shadowing.

This fMRI study examined which structures of a proposed dorsal stream system are involved in the auditory-motor integration during fast overt repetition. We used a shadowing task which requires immediate repetition of an auditory-verbal input and is supposed to elicit unconscious imitation effects of phonologically irrelevant speech parameters. Subjects' responses were recorded in the scanner. To examine automated auditory-motor mapping of speech gestures of others onto one's own speech production system we contrasted the shadowing of pseudowords produced by multiple speakers (men, women, and children) with the shadowing of pseudowords produced by a single speaker. Furthermore, we asked whether behavioral variables predicted changes in functional activation during shadowing. Shadowing multiple speakers compared to a single speaker elicited increased bilateral activation predominantly in the superior temporal sulci. These regions may mediate acoustic-phonetic speaker normalization in preparation of a translation of perceptual into motor information. Additional activation in Broca's area and the thalamus may reflect motor effects of the adaptation to multiple speaker models. Item-wise correlational analyses of response latencies with BOLD signal changes indicated that longer latencies were associated with increased activation in the left parietal operculum, suggesting that this area plays a central role in the actual transfer of auditory-verbal information to speech motor representations. A multiple regression of behavioral with imaging data showed activation in a right inferior parietal area near the temporo-parietal boundary which correlated positively with the degree of speech rate imitation and negatively with response latency. This activation may be attributable to attentional and/or paralinguistic processes.

Protein kinase C isotypes controlled by phosphoinositide 3-kinase through the protein kinase PDK1.

Phosphorylation sites in members of the protein kinase A (PKA), PKG, and PKC kinase subfamily are conserved. Thus, the PKB kinase PDK1 may be responsible for the phosphorylation of PKC isotypes. PDK1 phosphorylated the activation loop sites of PKCzeta and PKCdelta in vitro and in a phosphoinositide 3-kinase (PI 3-kinase)-dependent manner in vivo in human embryonic kidney (293) cells. All members of the PKC family tested formed complexes with PDK1. PDK1-dependent phosphorylation of PKCdelta in vitro was stimulated by combined PKC and PDK1 activators. The activation loop phosphorylation of PKCdelta in response to serum stimulation of cells was PI 3-kinase-dependent and was enhanced by PDK1 coexpression.

Rapamycin-sensitive phosphorylation of PKC on a carboxy-terminal site by an atypical PKC complex.

BACKGROUND: The protein kinase C (PKC) family has been implicated in the control of many cellular functions. Although PKC isotypes are characterized by their allosteric activation, phosphorylation also plays a key role in controlling activity. In classical PKC isotypes, one of the three critical sites is a carboxy-terminal hydrophobic site also conserved in other AGC kinase subfamily members. Although this site is crucial to the control of this class of enzymes, the upstream kinase(s) has not been identified. RESULTS: A membrane-associated kinase activity that phosphorylates the hydrophobic site in PKCalpha was detected. This activity was suppressed when cells were pretreated with the immunosuppresant drug rapamycin or the phosphoinositide (Pl) 3-kinase inhibitor LY294002. These pretreatments also blocked specifically the serum-induced phosphorylation of the hydrophobic site in PKCdelta in vivo. The most highly purified hydrophobic site kinase preparations ( approximately 10,000-fold) reacted with antibodies to PKCzeta/iota. Consistent with this, rapamycin and LY294002 reduced the recovery of PKCzeta from the membrane fraction of transfected cells. An activated mutant of PKCzeta, but not wild-type PKCzeta, induced phosphorylation of the PKCdelta hydrophobic site in a rapamycin-independent manner, whereas a kinase-dead PKCzeta mutant suppressed this serum-induced phosphorylation. The immunopurified, activated mutant of PKCzeta could phosphorylate the PKCdelta hydrophobic site in vitro, whereas wild-type PKCzeta could not. CONCLUSIONS: PKCzeta is identified as a component of the upstream kinase responsible for the phosphorylation of the PKCdelta hydrophobic site in vitro and in vivo. PKCzeta can therefore control the phosphorylation of this PKCdelta site, antagonizing a rapamycin-sensitive pathway.

Verb generation in children and adolescents with acute cerebellar lesions.

The aim of the present study was to examine verb generation in a larger group of children and adolescents with acute focal lesions of the cerebellum. Nine children and adolescents with cerebellar tumours participated. Subjects were tested a few days after tumour surgery. For comparison, a subgroup was tested also 1 or 2 days before surgery. None of the children had received radiation or chemotherapy at or before the time of testing. Eleven age- and education-matched control subjects participated. Subjects had to generate verbs to blocked presentations of photographs of objects. As control condition, the objects had to be named. Furthermore, dysarthria was quantified by means of a sentence production and syllable repetition task. Detailed analysis of individual 3D-MR images revealed that lesions affected cerebellar hemispheres in all children and adolescents. The right cerebellar hemisphere was affected in four and the left hemisphere in five subjects. In the present study, naming and verb generation accuracy were preserved in the majority of subjects with cerebellar lesions. No significant signs of learning deficits were observed, as reduction of reaction times over blocks was not different compared to controls. There was a trend of children and adolescents with right-hemispheric lesions to perform worse compared to controls. In this group, however, significant signs of dysarthria were present. In sum, no significant signs of disordered verb generation were observed in children and adolescents with acute cerebellar lesions. Findings suggest that the role of the cerebellum in verb generation may be less pronounced than previously suggested. Findings need to be confirmed in a larger group of subjects with acute focal lesions.

Subcortical Contributions to Motor Speech: Phylogenetic, Developmental, Clinical.

Vocal learning is an exclusively human trait among primates. However, songbirds demonstrate behavioral features resembling human speech learning. Two circuits have a preeminent role in this human behavior; namely, the corticostriatal and the cerebrocerebellar motor loops. While the striatal contribution can be traced back to the avian anterior forebrain pathway (AFP), the sensorimotor adaptation functions of the cerebellum appear to be human specific in acoustic communication. This review contributes to an ongoing discussion on how birdsong translates into human speech. While earlier approaches were focused on higher linguistic functions, we place the motor aspects of speaking at center stage. Genetic data are brought together with clinical and developmental evidence to outline the role of cerebrocerebellar and corticostriatal interactions in human speech.

Incidence of dysarthria in children with cerebellar tumors: a prospective study.

The present study investigated dysarthric symptoms in children with cerebellar tumors. Ten children with cerebellar tumors and 10 orthopedic control children were tested prior and one week after surgery. Clinical dysarthric symptoms were quantified in spontaneous speech. Syllable durations were analyzed in syllable repetition and sentence production tasks. Localization of the cerebellar lesions were defined after manual transfer from individual 2D-MR images onto 3D images of a spatially normalized healthy brain. Cerebellar children showed few and mild clinical signs of dysarthria. No difference was present in the sentence production task compared to controls. In five cerebellar children, syllables were prolonged in the syllable repetition task after surgery. Syllable duration normalized in an additional four-week session in all but one case. The MR-analysis showed that superior paravermal cerebellar areas likely involved in dysarthria in adults (paravermal lobules HVI, Crus I) were not significantly affected. In children, speech impairments appear to be rare after cerebellar surgery because tumors most commonly affect posterior-inferior and medial parts of the cerebellum while critical cerebellar regions are likely spared. The results suggest a similar localization of speech functions in the cerebellum in children and adults.

Effect of bone size, not density, on the stiffness of the proximal part of normal and osteoporotic human femora.

Proximal femur fractures in the elderly lead to a high rate of hospitalization. In studying the operative treatment of such fractures, it is first necessary to understand the relationship between the morphologic properties of this part of the femur (related to both geometry and density) and its mechanical properties. Numerous investigations showed that femoral strength correlates with bone mass; however, the dimension of the bones was not taken into account. We measured the relationship between the stiffness of the proximal femur under physiologic load and its geometry and density. Conventional x-rays and quantitative computed tomography (QCT) were carried out on pairs of human cadaver femora. Eight pairs were instrumented with strain gauges. Bones were subjected to an eccentric load that simulates moderate weight bearing (single-leg stance), and the strain parallel to the bone axis was plotted as a function of the load applied. An apparent bone stiffness was calculated as the ratio between the strain gradient within the section and the load applied. Strong correlation was found between x-ray densitometry and QCT. The bone stiffness also correlates strongly with the geometry (area) and slightly with bone mass; however, an unexpectedly low correlation was found between stiffness and density. We chose stiffness as a mechanical parameter (not strength) because it describes the "normal" bone behavior under load. Our results clearly demonstrate that the cross-sectional size of the bones must be taken into account when establishing the relationship between the mechanical characteristics of the bone and its morphology. In accordance with previous predictions, our results support that bone loss due to osteoporosis is compensated for by an increase in bone diameter.

Pressor factors and cardiovascular pressor responsiveness in lean and overweight normal or hypertensive subjects.

Several blood-pressure-regulating factors including exchangeable sodium, blood volume, plasma renin, aldosterone, norepinephrine (NE), and epinephrine (E) levels, urinary catecholamine excretion rates, and cardiovascular responsiveness to infused NE and angiotensin II (AII) were compared among age-matched subgroups of normal subjects (15 with normal weight, 15 with overweight) and patients with essential hypertension (15 with either normal weight, overweight, or obesity). Exchangeable sodium, blood volume, plasma and urinary sodium and potassium, plasma renin, aldosterone and epinephrine levels, and NE or E excretion rates did not differ significantly among the five subgroups. Minimal differences included a slightly higher heart rate in overweight patients than in overweight normal subjects (p less than 0.01) and a tendency for a higher plasma NE in overweight than in normal weight patients. Plasma NE obtained immediately before NE infusion as well as the plasma clearance of NE did not differ among the five subgroups except, however, for a somewhat low NE clearance in obese patients. The NE pressor dose tended to be lower in normal-weight hypertensive than in normal-weight normotensive subjects. No alteration was apparent in overweight or obese hypertensive patients. Pressor responses to AII were similar in the different subgroups. These findings suggest that overweight does not confer a unique aberration in the body sodium-volume state, circulating renin, aldosterone or catecholamines, or cardiovascular responses to NE or AII which result in hypertension.

Low-density lipoprotein induces vascular adhesion molecule expression on human endothelial cells.

We tested the hypothesis that low-density lipoprotein (LDL) and its acetylated form influence surface expression of vascular adhesion molecules on human endothelial cells. Vascular adhesion molecule surface expression was assessed with flow cytometry on cultured endothelial cells with a modified enzyme-linked immunosorbent assay. LDL acetylation was determined by chromatography. Monocyte adhesion to endothelial cells was assessed with U937 cells by direct counting. Tumor necrosis factor-alpha (10 ng/mL), a positive control, induced a time-dependent expression of vascular adhesion molecules (P < .05), which peaked at 5 hours. Incubation of endothelial cells with LDL (1.3 to 26.0 mmol/L) led to an increase in expression at 2 and 5 hours (P < .05). Prolonged (24-hour) exposure to LDL resulted in a second peak. The effect of acetylated LDL on expression was not different from that of native LDL. Incubation with the protein kinase C inhibitor staurosporine (5 x 10(-8) mol/L) blocked the effects of both native and acetylated LDL completely (P < .05). The calcium channel blocker nitrendipine (10(-7) mol/L) did not influence the expression of vascular adhesion molecule at 2 and 5 hours but did reduce the effect of LDL on expression at 24 hours. LDL (2.6 mmol/L) also induced a significant increase in the surface expression of intercellular adhesion molecule-1 but did not affect the expression of endothelial adhesion molecules. LDL (2.6 mmol/L) induced a significant increase in monocyte binding. We conclude that LDL can induce the expression of vascular adhesion molecules on endothelial cells.(ABSTRACT TRUNCATED AT 250 WORDS)

Increased ratio between changes in blood pressure and plasma norepinephrine in essential hypertension.

The pathogenic role of the sympathetic system in essential hypertension was evaluated by combined analysis of plasma catecholamine levels and the pressor sensitivity to endogenous norepinephrine. The latter was estimated indirectly by the ratio between changes in blood pressure and those in plasma norepinephrine after adrenergic neuronal blockage with debrisoquine (given orally for 6 weeks). Normal subjects and patients with borderline or established essential hypertension had comparable pretreatment levels of plasma norepinephrine and epinephrine. Debrisoquine lowered plasma norepinephrine by a similar degree (almost 50%) in these three groups; in contrast, blood pressure decreased only slightly in normal or borderline hypertensive subjects [-3.4 +/- 3.2% and -5.4 +/- 1.6% (SE), respectively] but fell significantly more (P less than 0.005) in patients with established essential hypertension (-20.7 +/- 3.9%). The ratio between percentile changes in blood pressure and those in endogenous norepinephrine levels was comparable in normal and borderline hypertensive subjects (0.03 +/- 0.08 and 0.17 +/- 0.04, respectively), but increased (P less than 0.001) in established essential hypertension (0.62 +/- 0.11). This suggests that essential hypertension may be maintained, at least partly, by the inappropriate association of normal plasma norepinephrine levels with increased norepinephrine pressor sensitivity.

Pressor factors and cardiovascular pressor responsiveness in borderline hypertension.

The role of various pressor factors and cardiovascular responsiveness to norepinephrine or angiotensin II in the pathogenesis of borderline hypertension was evaluated. Exchangeable body sodium, blood volume, plasma renin activity, norepinephrine or dopamine levels, and norepinephrine or epinephrine excretion rates were similar between 24 patients with borderline hypertension (mean age 34 +/- 4 (SEM) years and 22 normal subjects matched for age; the patients had a slight increase in supine plasma epinephrine. Pressor doses of norepinephrine or angiotensin II were significantly lower (p less than 0.01 and 0.001, respectively) in the borderline hypertensive group. These findings suggest that borderline hypertension may be maintained by inappropriately increased cardiovascular response to norepinephrine and angiotensin II in the presence of normal sympathetic and renin activity and a normal body sodium-volume state.

Cardiovascular effects of verapamil in essential hypertension.

Calcium antagonists may affect the regulation of body sodium and adrenergic-dependent mechanisms. Exchangeable sodium, blood volume, plasma norepinephrine, renin, aldosterone, pressor responsiveness to norepinephrine, heart rate responses to isoproterenol, and lipid metabolism were studied in 15 patients with essential hypertension after 8 weeks of treatment with verapamil (348 +/- 68 (SD) mg/day). Supine blood pressure decreased from 153/103 +/- 19/12 mm Hg to 140/95 +/- 14/12 mm Hg (P less than 0.01). Exchangeable sodium, blood volume, plasma norepinephrine, renin and aldosterone, serum total cholesterol, the lipoprotein fractions, and apoprotein levels were unchanged. The norepinephrine pressor and the isoproterenol chronotropic doses tended to increase, whereas the dose-response curve of blood pressure related to plasma norepinephrine was significantly displaced to the right (F = 5.34; P less than 0.05). The antihypertensive effect of verapamil is associated with a decreased cardiovascular pressor responsiveness to norepinephrine without changes in endogenous noradrenergic activity. Moreover, verapamil does not modify the sodium/fluid volume state, the activity of the renin-angiotensin aldosterone axis, or lipid metabolism.

Interaction between grapefruit juice and midazolam in humans.

OBJECTIVE: To investigate the effects of grapefruit juice on the pharmacokinetics and dynamics of midazolam. METHODS: Eight healthy male subjects participated in this open crossover study. Intravenous (5 mg) or oral (15 mg) midazolam was administered after pretreatment with water or grapefruit juice. We measured the pharmacokinetics and pharmacodynamics (reaction time, Digit Symbol Substitution Test [DSST], general impression judged by the investigators, and drug effect judged by the subjects) of midazolam and the pharmacokinetics of alpha-hydroxymidazolam. RESULTS: In comparison to water, pretreatment with grapefruit juice did not change the pharmacokinetics or pharmacodynamics of intravenous midazolam. After oral administration, pretreatment with grapefruit juice led to a 56% increase in peak plasma concentration (Cmax), a 79% increase in time to reach Cmax (tmax), and a 52% increase in the area under the plasma concentration-time curve (AUC) of midazolam, which was associated with an increase in the bioavailability from 24% +/- 3% (water) to 35% +/- 3% (Grapefruit juice; mean +/- SEM, p < 0.01) After oral administration of midazolam, pretreatment with grapefruit juice was associated with a 105% increase in tmax and with a 30% increase in the AUC of alpha-hydroxymidazolam. For oral midazolam, pretreatment with grapefruit juice led to significant increases in tmax for all dynamic parameters and in the AUC values for the reaction time and DSST, whereas the maximal dynamic effects remained unchanged. CONCLUSIONS: Pretreatment with grapefruit juice is associated with increased bioavailability and changes in the pharmacodynamics of midazolam that may be clinically important, particularly in patients with other causes for increased midazolam bioavailability such as advanced age, cirrhosis of the liver, and administration of other inhibitors of cytochrome P450.

Effects of concentration-dependent plasma protein binding on ceftriaxone kinetics.

The kinetics of ceftriaxone, a cephalosporin, was studied in six healthy subjects who received bolus injections of 150, 500, and 1,500 mg intravenously in a random crossover fashion. Although total drug concentration time profiles after all doses could be described by biexponential equation, simple compartment analysis was inappropriate because a disproportional increase in the area under the total drug concentration time curves occurred with dose. This resulted in a dose-dependent increase in total systemic clearance (ClTS) from 9.7 ml/min at the 150-mg dose to 13 ml/min at the 1500-mg dose. The dose-dependent changes in ClTS could be explained in terms of the concentration-dependent plasma protein binding of ceftriaxone (fplasma ranging from 0.04 to 0.167), because the area under the free drug concentration time curves (AUCFO-infinity) increased proportionately to dose. Mean total clearance with reference to free (unbound) ceftriaxone (ClFS) was constant at 255 ml/min. Calculated mean renal clearance with reference to free ceftriaxone (ClFR) was 173 ml/min, or slightly more than the average glomerular filtration rate in humans. Mean plasma ceftriaxone t1/2 was not influenced by dose and averaged 8 hr. This biological t1/2 is by far the longest ever for a cephalosporin in healthy subjects.