Symmetry of spherically converging shock waves through reflection, relating to the shock ignition fusion energy scheme.

We examine the properties of perturbed spherically imploding shock waves in an ideal fluid through the collapse, bounce, and development into an outgoing shock wave. We find broad conservation of the size and shape of ingoing and outgoing perturbations when viewed at the same radius. The outgoing shock recovers the velocity of the unperturbed shock outside the strongly distorted core. The results are presented in the context of the robustness of the shock ignition approach to inertial fusion energy.

A review of Parkinson's disease.

INTRODUCTION: Parkinson's disease (PD) is one of the most common neurodegenerative disorders. Sources of data Literature search using Medline with keywords Parkinson's disease supplemented with previously published papers known to the author. AREAS OF AGREEMENT: There have been significant recent advances in the understanding of the pathogenesis of the disease. There has also been a greater realization that the disorder may be associated with significant non-motor disturbances in addition to the more commonly recognized motor complications. AREAS OF CONTROVERSY: Although there is growing circumstantial evidence, it remains to be proven whether any of the current treatments for PD have a neuroprotective effect. AREAS TIMELY FOR DEVELOPING RESEARCH: Although there is no cure, there are several management options for the early treatment of PD. As the disease progresses, further treatment options are available; however, the management of late-stage motor complications and non-motor symptoms remains particularly challenging and will benefit from further clinical research.

Stroke and pregnancy.

Pregnancy-related stroke is, fortunately, a rare event. However, when it occurs, there may be implications for management of the patient and delivery of the child. This article reviews the mechanisms and risk factors for stroke related to pregnancy, the presenting features, diagnosis and management of the different stroke types, and the implications for pregnancy and delivery.

Clinical correlation of brain MRI and MRS abnormalities in patients with Wilson disease.

BACKGROUND: The progression of Wilson disease (WD), a disorder of copper metabolism, can be arrested by chelation therapy. However, neurologic deficits may persist despite adequate treatment. MRI is used to assess patients with WD, but previous attempts to correlate clinical progression with the investigation findings have often been unsuccessful. OBJECTIVE: To identify MR visible markers that could help stratify disease severity and to clarify the mechanism of persistent neurologic deficit after treatment. METHODS: MRI and proton MR spectroscopy (1H-MRS) were performed in 17 patients with WD. MRI was assessed semiquantitatively and used to locate volumes of interest (voxels) in the striatum for 1H-MRS. RESULTS: MRI showed abnormalities predominantly confined to those patients with neurologic features of WD. The 1H spectra demonstrated a reduction of N-acetylaspartate and N-acetylaspartylglutamate (2.05 mM; p < 0.01) in those patients with neurologic features but not in patients without clinical neurologic involvement (0.42 mM; p > 0.1) in comparison with age-matched normal control subjects. Choline was also reduced in both patient groups (0.08 mM; p < 0.01) compared with age-matched controls. CONCLUSIONS: There may be a biochemical correlate of tissue-specific dysfunction in patients with Wilson disease who develop neurologic features. These changes appear to be present despite prior clinical improvement and may imply a need for additional treatment.

Bioavailability of the oral selective phosphodiesterase 4 inhibitor cilomilast.

STUDY OBJECTIVE: To determine the absolute bioavailability of cilomilast, and assess the effects of food, dosing time, and coadministration of antacid agents on its bioavailability and pharmacokinetics in healthy volunteers. SETTING: Clinical pharmacology unit. DESIGN: Five prospective pharmacokinetic studies: one single-blind, dose-escalating, placebo-controlled trial; four open-label, randomized studies. SUBJECTS: Ninety-six healthy adult volunteers who were nonsmokers. INTERVENTION: In the first study, four subjects received intravenous cilomilast 1, 2, and 4 mg. In the second study, 16 subjects received oral cilomilast 15 mg or intravenous cilomilast 4 mg. In the other three studies, a total of 76 subjects were given single oral 15-mg doses; one study compared its effects in fed versus fasted subjects, one looked for differences of morning versus evening dosing, and one examined coadministration with aluminum hydroxide-magnesium hydroxide. MEASUREMENTS AND MAIN RESULTS: After intravenous administration of cilomilast, plasma concentrations increased in an approximately dose-proportional manner; the half-life, approximately 6.5 hours, was dose independent. Cilomilast clearance and volume of distribution were small. After oral dosing, the absolute bioavailability was consistently close to 100%. Absorption was slower in fed subjects than in fasted (median 2-hr delay in time to reach maximum plasma concentration, average 39% reduction in maximum plasma concentration), but the area under the concentration-time curve from time zero to infinity (systemic availability) was unaffected. Pharmacokinetic parameters were not influenced by time of dosing or coadministration of antacid. CONCLUSION: The absolute bioavailability of oral cilomilast was 100%; it was not adversely affected by time of dosing or coadministration with food or antacid.

In vivo 1H-magnetic resonance spectroscopy of the spinal cord in humans.

Magnetic resonance spectroscopy (MRS) has been used in a variety of conditions affecting the central nervous system. Until now, only the brain has been studied, and spectroscopy of the spinal cord has not been previously reported. During the past 12 months, we have been experimenting with MRS of the cervical spinal cord of healthy volunteers. We present this technique, its current limitations, and possible future technological improvements and potential applications.

Paroxysmal dystonic choreoathetosis: clinical features and investigation of pathophysiology in a large family.

Paroxysmal dystonic choreoathetosis (PDC) is an unusual hyperkinetic movement disorder characterized by attacks of chorea, dystonia, and ballism with onset in childhood. We report a large British family with dominantly inherited PDC linked to chromosome 2q and describe the clinical features in 20 affected family members. Attacks were precipitated by a variety of factors, including caffeine, alcohol, or emotion, and could be relieved by short periods of sleep in most subjects. The clinical features in the family are compared with those of 11 other PDC families in the literature and a core phenotype for PDC suggested. CSF monoamine metabolites measured at baseline and during an attack in one subject were found to increase during the attack. Magnetic resonance spectroscopy of brain and basal ganglia performed both during and between attacks was normal. Positron emission tomography using the D2 receptor ligand, 11C-raclopride, showed no abnormalities.

Lesion heterogeneity in multiple sclerosis: a study of the relations between appearances on T1 weighted images, T1 relaxation times, and metabolite concentrations.

OBJECTIVES: Multiple sclerosis lesions appear as areas of high signal on T2 weighted MRI. A proportion of these lesions, when viewed on T1 weighted MRI, appear hypointense compared with surrounding white matter. These hypointense T1 lesions are thought to represent areas of greater tissue damage compared with the more non-specific, total T2 lesion load. This study aimed to better characterise the properties of high signal T2 lesions with differing appearances on T1 weighted MRI using quantitative MR techniques. METHODS: Eleven patients with secondary progressive multiple sclerosis were studied. Two high signal T2 lesions were selected from each patient-one of which appeared hypointense and one isointense on a T1 weighted image. A voxel was positioned around each lesion and for this volume of brain the metabolite concentrations were estimated using proton MR spectroscopy ((1)H-MRS) and the T1 relaxation time within each voxel calculated from a T1 map generated using a multislice technique. RESULTS: Compared with isointense T1 lesions, hypointense T1 lesions exhibited a significantly lower absolute concentration of N-acetyl derived metabolites (tNAA) and a significantly higher absolute concentration of myo-inositol (Ins). T1 relaxation time correlated significantly with both tNAA (r=-0.8, p < 0.001) and Ins (r=0.5, p=0. 012). There was no correlation between T1 relaxation times and creatine/phosphocreatine or choline containing compounds. CONCLUSIONS: Prolonged T1 relaxation times seem to reflect the severity of axonal damage or dysfunction (inferred by a low tNAA) and possibly also gliosis (inferred by a high Ins) in chronic multiple sclerosis lesions.

Increase in the vasorelaxant potency of K(ATP) channel opening drugs by adenosine A(1) and A(2) receptors in the pig coronary artery.

Myograph recording from ring segments of pig small coronary arteries was used to investigate the effects of adenosine receptor activation on the vasorelaxant potency of ATP-sensitive K(+) channel opening drugs. Receptor activation with 2-chloroadenosine (2-CA, 300 nM) increased the potency of both nicorandil and levcromakalim, shifting the pEC(50)s from 4.68+/-0.03 to 5.05+/-0.04 and from 6.34+/-0.06 to 6.72+/-0.06, respectively (P<0.05 in each case). Experiments with selective adenosine receptor agonists (2-chloro-N(6)-cyclopentyladenosine (CCPA), 2-p-(2-carboxyethyl)phenethylamino-5'-N-ethylcarboxamidoadenosine hydrochloride (CGS 21680)) and antagonists (8-cyclopentyl-1, 3-dipropylxanthine (DPCPX), 4-(2-[7-amino-2-(2-furyl)[1,2, 4]triazolo[2,3-a] [1,3,5]triazin-5-ylamino]ethyl)phenol (ZM 241385)) suggest that both A(1) and A(2a) receptors can increase the potency of nicorandil, while that of levcromakalim is increased only by A(2) receptors. Adenosine receptor activation did not affect the potency of pinacidil. Thus, adenosine receptor activation can increase the potency of some K(+) channel opening drugs to relax coronary arteries, but the details of the interaction with adenosine receptors depend on the particular drug.

Does the extent of axonal loss and demyelination from chronic lesions in multiple sclerosis correlate with the clinical subgroup?

OBJECTIVE: To determine non-invasively the relation between the degree of axonal loss and the extent of demyelination in chronic lesions visible on MRI in patients with different subgroups of clinically definite multiple sclerosis using (1)H magnetic resonance spectroscopy ((1)H MRS) and magnetisation transfer imaging (MT). Conventional MRI is unable to differentiate between the various pathological processes occurring in the multiple sclerosis lesion. There are, however, newer MR techniques which show promise in this respect. METHODS: (1)H MRS and MT were performed in 18 patients with clinically definite multiple sclerosis who had a wide range of disability and disease duration. RESULTS: A significant correlation was found between a reduction in the concentration of N-acetyl aspartate (NAA; an in vivo marker of axonal loss or dysfunction) and a reduction in MT ratio (a probable marker of demyelination) in patients who had entered the secondary progressive stage of the disease. Patients with minimal disability after a disease duration of greater than 10 years-so called benign multiple sclerosis-showed a relative preservation of NAA and MT. CONCLUSIONS: Because a reduction in MT seems to be a relative marker for demyelination and a reduction of NAA from chronic lesions is indicative of axonal loss, this study supports the hypothesis that demyelination and axonal loss occur in the same chronic multiple sclerosis lesions. In addition, the degree of axonal loss and demyelination correlates with clinical heterogeneity.

Monoclonal antibody treatment exposes three mechanisms underlying the clinical course of multiple sclerosis.

The elective treatment of patients with multiple sclerosis, using a humanized anti-leukocyte (CD52) monoclonal antibody (Campath-1H), has illuminated mechanisms that underlie the clinical course of the disease. Twenty-seven patients were studied clinically and by magnetic resonance imaging (MRI) before and for 18 months after a single pulse of Campath-1H. The first dose of monoclonal antibody was associated with a transient rehearsal of previous symptoms caused by the release of mediators that impede conduction at previously demyelinated sites; this effect remained despite selective blockade of tumor necrosis factor-alpha. Disease activity persisted for several weeks after treatment but thereafter radiological markers of cerebral inflammation were suppressed for at least 18 months during which there were no new symptoms or signs. However, about half the patients experienced progressive disability and increasing brain atrophy, attributable on the basis of MRI spectroscopy to axonal degeneration, which correlated with the extent of cerebral inflammation in the pretreatment phase. These data support the formulation that inflammation and demyelination are responsible for relapses of multiple sclerosis; that inflammatory mediators, but not tumor necrosis factor-alpha, cause symptomatic reactivation of previously demyelinated lesions; and that axonal degeneration, conditioned by prior inflammation but proceeding despite its suppression, contributes to the progressive phase of disability. These results provide evidence supporting the emerging view that treatment in multiple sclerosis must be given early in the course, before the consequences of inflammation are irretrievably established.

Proton MR spectroscopy in clinically isolated syndromes suggestive of multiple sclerosis.

The concentration of the metabolite N-acetyl aspartate (NAA), thought to be a marker of axonal loss or damage, has been shown to be reduced in lesions, as demonstrated by high signal areas on T2-weighted MRI, and in normal-appearing white matter (NAWM) in established multiple sclerosis (MS). The stage of the disease when these changes first appear is not known. To try to determine this we studied 20 patients with clinically isolated syndromes, many of whom will be at the earliest clinical stages of MS, and 20 age- and sex-matched controls with single-voxel proton magnetic spectroscopy (MRS). MRS was performed using a General Electric 1.5T Signa EchoSpeed scanner (TR 3000 ms, TE 30 ms, PRESS). Absolute metabolite concentrations were determined using the LCModel fitting software. No significant reduction of NAA concentration was evident in the NAWM of the patients (patients: median 7.3 mM; controls: median 7.7 mM; P=0.19). There was, however, a significantly lower concentration of NAA in lesions (median 6.6 mM, P=0.015). Absolute values of choline-containing compounds, creatine and myo-inositol were significantly raised in the lesions (P=0.007, P=0.011 and P=0.002 respectively). The low NAA in lesions is consistent with axonal loss, damage or dysfunction occurring focally at the earliest clinical phase of the disease. The lack of any significant reduction in NAA in patient NAWM demonstrates that more widespread axonal changes are not yet detectable at this early clinical stage. A larger cohort and follow-up will be necessary to determine whether or not MRS findings have any prognostic significance for individual patients or sub-groups. This will also enable the clarification of the time course, pathogenesis and pathophysiological significance of the development of the low NAA, which is found in the NAWM of many patients with established MS.

Correlates of executive function in multiple sclerosis: the use of magnetic resonance spectroscopy as an index of focal pathology.

Proton magnetic resonance spectroscopy (MRS) was performed in a group of patients with multiple sclerosis (MS) and matched control subjects to examine the relationship between frontal lobe pathology and performance on tests of executive function. The N-acetyl aspartate/creatine ratio (NAA/Cr) was significantly reduced in frontal lesions and/or normal-appearing white matter in the patient group compared with the control group, but choline/creatine ratios did not differ. Although MRS abnormalities and executive deficits were not correlated for MS patients as a group, a few patients with more severe abnormalities of NAA/Cr ratio performed worse than other patients on the spatial working memory test, suggesting that subtle frontal neuropathological abnormalities detected by MRS may contribute to executive deficits. Further investigation is warranted to determine the value of MRS as an index of the pathophysiological processes leading to cognitive deficit.

1H magnetic resonance spectroscopy of normal appearing white matter in primary progressive multiple sclerosis.

Recent magnetic resonance imaging (MRI) and pathological studies have indicated that axonal loss is a major contributor to disease progression in multiple sclerosis. 1H magnetic resonance spectroscopy (MRS), through measurement of N-acetyl aspartate (NAA), a neuronal marker, provides a unique tool to investigate this. Patients with primary progressive multiple sclerosis have few lesions on conventional MRI, suggesting that changes in normal appearing white matter (NAWM), such as axonal loss, may be particularly relevant to disease progression in this group. To test this hypothesis NAWM was studied with MRS, measuring the concentration of N-acetyl derived groups (NA, the sum of NAA and N-acetyl aspartyl glutamate). Single-voxel MRS using a water-suppressed PRESS sequence was carried out in 24 patients with primary progressive multiple sclerosis and in 16 age-matched controls. Ratios of metabolite to creatine concentration (Cr) were calculated in all subjects, and absolute concentrations were measured in 18 patients and all controls. NA/Cr (median 1.40, range 0.86-1.91) was significantly lower in NAWM in patients than in controls (median 1.70, range 1.27-2.14; P = 0.006), as was the absolute concentration of NA (patients, median 6.90 mM, range 4.62-10.38 mM; controls, median 7.77 mM, range 6.60-9.71 mM; P = 0.032). There was no significant difference in the absolute concentration of creatine between the groups. This study supports the hypothesis that axonal loss occurs in NAWM in primary progressive multiple sclerosis and may well be a mechanism for disease progression in this group.

Enhancement of the vasorelaxant potency of nicorandil by metabolic inhibition and adenosine in the pig coronary artery.

OBJECTIVE: Nicorandil is used clinically to treat angina and acts in part by opening ATP-sensitive K+ channels whose opening is also enhanced by metabolic compromise. We have therefore investigated whether treatments that mimic conditions in ischaemia can increase the potency of nicorandil to dilate coronary arteries. METHODS: Ring segments from pig small coronary arteries were mounted on a myograph, contracted with 20 mM K+ Krebs solution containing 200 nM BAYK 6844, and relaxations to cumulative doses of nicorandil were measured. RESULTS AND CONCLUSIONS: Nicorandil produced a dose-dependent relaxation with a mean pEC50 (-log EC50, M) of 4.76 +/- 0.02. Inhibition of metabolism with carbonyl cyanide m-chlorophenyl hydrazone (CCCP, 100 nM) or by removal of extracellular glucose significantly increased the potency of nicorandil (pEC50s of 5.11 +/- 0.08 and 5.08 +/- 0.06, p < 0.05 in each case). The adenosine analogue 2-chloroadenosine (2-CA, 300 nM) had a similar effect (pEC50 = 5.17 +/- 0.06, p < 0.05). Reducing extracellular pH to 6.8 also significantly increased the potency of nicorandil, but to a smaller extent. Glibenclamide reduced the potency of nicorandil (pEC50 = 3.81 +/- 0.01, n = 7), and abolished its enhancement by CCCP, zero glucose, 2-CA or pH 6.8 solution. 2-CA did not affect the potency of nicorandil in relaxing contractions to 80 mM K+ or the potency of glyceryl trinitrate. We conclude that the potency of nicorandil to cause coronary vasorelaxation is increased under conditions of metabolic inhibition. This effect appears to result from the K+ channel opening action of the drug, and may have significant consequences for its therapeutic effectiveness.

Potassium channel activation and relaxation by nicorandil in rat small mesenteric arteries.

1. We used whole-cell patch clamp to investigate the currents activated by nicorandil in smooth muscle cells isolated from rat small mesenteric arteries, and studied the relaxant effect of nicorandil using myography. 2. Nicorandil (300 microM) activated currents with near-linear current-voltage relationships and reversal potentials near to the equilibrium potential for K+. 3. The nicorandil-activated current was blocked by glibenclamide (10 microM), but unaffected by iberiotoxin (100 nM) and the guanylyl cyclase inhibitor LY 83583 (1 microM). During current activation by nicorandil, openings of channels with a unitary conductance of 31 pS were detected. 4. One hundred microM nicorandil had no effect on currents through Ca2+ channels recorded in response to depolarizing voltage steps using 10 mM Ba2+ as a charge carrier. A small reduction in current amplitude was seen in 300 microM nicorandil, though this was not statistically significant. 5. In arterial rings contracted with 20 mM K+ Krebs solution containing 200 nM BAYK 8644, nicorandil produced a concentration-dependent relaxation with mean pD2 = 4.77+/-0.06. Glibenclamide (10 microM) shifted the curve to the right (pD2 = 4.32+/-0.05), as did 60 mM K+. LY 83583 caused a dose-dependent inhibition of the relaxant effect of nicorandil, while LY 83583 and glibenclamide together produced greater inhibition than either alone. 6. Metabolic inhibition with carbonyl cyanide m-chlorophenyl hydrazone (30 nM), or by reduction of extracellular glucose to 0.5 mM, increased the potency of nicorandil. 7. We conclude that nicorandil activates KATP channels in these vessels and also acts through guanylyl cyclase to cause vasorelaxation, and that the potency of nicorandil is increased during metabolic inhibition.