Elevated Electron Temperature Coincident with Observed Fusion Reactions in a Sheared-Flow-Stabilized Z Pinch.

The sheared-flow-stabilized Z pinch concept has been studied extensively and is able to produce fusion-relevant plasma parameters along with neutron production over several microseconds. We present here elevated electron temperature results spatially and temporally coincident with the plasma neutron source. An optical Thomson scattering apparatus designed for the FuZE device measures temperatures in the range of 1-3 keV on the axis of the device, 20 cm downstream of the nose cone. The 17-fiber system measures the radial profiles of the electron temperature. Scanning the laser time with respect to the neutron pulse time over a series of discharges allows the reconstruction of the T_{e} temporal response, confirming that the electron temperature peaks simultaneously with the neutron output, as well as the pinch current and inductive voltage generated within the plasma. Comparison to spectroscopic ion temperature measurements suggests a plasma in thermal equilibrium. The elevated T_{e} confirms the presence of a plasma assembled on axis, and indicates limited radiative losses, demonstrating a basis for scaling this device toward net gain fusion conditions.

The mutation p.D313Y is associated with organ manifestation in Fabry disease.

Fabry disease (FD) is a multisystem lysosomal storage disorder caused by mutations in the GLA gene. The clinical significance of the mutation p.D313Y is still under debate. Retrospective chart analysis of clinical (neurological, cardiac, renal, and ophthalmological), genetic, and biochemical (lyso-globotriaosylsphingosine, lyso-Gb3; enzyme activity) data was performed in all our patients carrying the p.D313Y mutation. Fourteen patients from 5 families (10 female, 4 male; age range 10-51) were included. Symptoms and organ manifestations compatible with FD could be identified in 10 patients. Cerebrovascular events occurred in 4 females. Seven patients reported pain or acroparaesthesia. Cornea verticillata was found in 1 patient, mild retinal vascular tortuosity in 5 patients. Lyso-Gb3 was elevated in 2 females with cerebrovascular involvement. Classical cardiac, renal or skin manifestations could not be identified. The mutation p.D313Y in the GLA gene may lead to organ manifestations and elevation of the Fabry-specific biomarker lyso-Gb3. Neurological symptoms (stroke and pain) and ocular manifestations seem to be the leading findings. Annual routine visits are recommended for patients carrying the p.D313Y mutation. Enzyme replacement therapy might be considered in symptomatic patients.

Sexual antagonism and meiotic drive cause stable linkage disequilibrium and favour reduced recombination on the X chromosome.

Sexual antagonism and meiotic drive are sex-specific evolutionary forces with the potential to shape genomic architecture. Previous theory has found that pairing two sexually antagonistic loci or combining sexual antagonism with meiotic drive at linked autosomal loci augments genetic variation, produces stable linkage disequilibrium (LD) and favours reduced recombination. However, the influence of these two forces has not been examined on the X chromosome, which is thought to be enriched for sexual antagonism and meiotic drive. We investigate the evolution of the X chromosome under both sexual antagonism and meiotic drive with two models: in one, both loci experience sexual antagonism; in the other, we pair a meiotic drive locus with a sexually antagonistic locus. We find that LD arises between the two loci in both models, even when the two loci freely recombine in females and that driving haplotypes will be enriched for male-beneficial alleles, further skewing sex ratios in these populations. We introduce a new measure of LD, Dz', which accounts for population allele frequencies and is appropriate for instances where these are sex specific. Both models demonstrate that natural selection favours modifiers that reduce the recombination rate. These results inform observed patterns of congealment found on driving X chromosomes and have implications for patterns of natural variation and the evolution of recombination rates on the X chromosome.

Meiotic drive influences the outcome of sexually antagonistic selection at a linked locus.

Most meiotic drivers, such as the t-haplotype in Mus and the segregation distorter (SD) in Drosophila, act in a sex-specific manner, gaining a transmission advantage through one sex although suffering only the fitness costs associated with the driver in the other. Their inheritance is thus more likely through one of the two sexes, a property they share with sexually antagonistic alleles. Previous theory has shown that pairs of linked loci segregating for sexually antagonistic alleles are more likely to remain polymorphic and that linkage disequilibrium accrues between them. I probe this similarity between drive and sexual antagonism and examine the evolution of chromosomes experiencing these selection pressures simultaneously. Reminiscent of previous theory, I find that: the opportunity for polymorphism increases for a sexually antagonistic locus that is physically linked to a driving locus; the opportunity for polymorphism at a driving locus also increases when linked to a sexually antagonistic locus; and stable linkage disequilibrium accompanies any polymorphic equilibrium. Additionally, I find that drive at a linked locus favours the fixation of sexually antagonistic alleles that benefit the sex in which drive occurs. Further, I show that under certain conditions reduced recombination between these two loci is selectively favoured. These theoretical results provide clear, testable predictions about the nature of sexually antagonistic variation on driving chromosomes and have implications for the evolution of genomic architecture.

The evolution of genomic imprinting: theories, predictions and empirical tests.

The epigenetic phenomenon of genomic imprinting has motivated the development of numerous theories for its evolutionary origins and genomic distribution. In this review, we examine the three theories that have best withstood theoretical and empirical scrutiny. These are: Haig and colleagues' kinship theory; Day and Bonduriansky's sexual antagonism theory; and Wolf and Hager's maternal-offspring coadaptation theory. These theories have fundamentally different perspectives on the adaptive significance of imprinting. The kinship theory views imprinting as a mechanism to change gene dosage, with imprinting evolving because of the differential effect that gene dosage has on the fitness of matrilineal and patrilineal relatives. The sexual antagonism and maternal-offspring coadaptation theories view genomic imprinting as a mechanism to modify the resemblance of an individual to its two parents, with imprinting evolving to increase the probability of expressing the fitter of the two alleles at a locus. In an effort to stimulate further empirical work on the topic, we carefully detail the logic and assumptions of all three theories, clarify the specific predictions of each and suggest tests to discriminate between these alternative theories for why particular genes are imprinted.

Overexpression of VEGFα as a biomarker of endothelial dysfunction in aortic tissue of α-GAL-Tg/KO mice and its upregulation in the serum of patients with Fabry's disease.

Introduction: Fabry's disease is an X-linked lysosomal storage disorder caused by reduced activity of α-galactosidase A (GAL), leading to premature death on account of renal, cardiac, and vascular organ failure. Accumulation of the GAL substrate globotriaosylceramide (Gb3) in endothelial and smooth muscle cells is associated with early vascular cell damage, suggesting endothelial dysfunction as a driver of cardiorenal organ failure. Here, we studied the vascular expression of the key angiogenic factors, VEGFα and its antagonist angiostatin, in Fabry α-GAL-Tg/KO mice and determined circulating VEGFα and angiostatin serum levels in patients with Fabry's disease and healthy controls. Methods: Cryopreserved aortic vessels from six α-GAL-Tg/KO and six wild-type (WT) mice were obtained and VEGFα and angiostatin levels were determined by performing Western blot analysis. VEGFα expression was visualized by an immunohistochemical staining of paraffin aortic rings. In addition, VEGFα and angiostatin serum levels were measured by using an enzyme-linked immunosorbent assay in 48 patients with genetically verified Fabry's disease (50% male) and 22 healthy controls and correlated with disease severity markers such as lyso-Gb3, albuminuria, NTproBNP, high-sensitive troponin T (hsTNT), and myocardial wall thickness. Results: It was found that there was a significant increase in VEGFα protein expression (1.66 ± 0.35 vs. 0.62 ± 0.16, p = 0.0009) and a decrease in angiostatin expression (0.024 ± 0.007 vs. 0.053 ± 0.02, p = 0.038) in aortic lysates from α-GAL-Tg/KO compared with that from WT mice. Immunohistochemical staining revealed an adventitial VEGFα signal in α-GAL-Tg/KO mice, whereas no VEGFα signal could be detected in WT mice aortas. No differences in aortic angiostatin expression between α-GAL-Tg/KO- and WT mice could be visualized. The serum levels of VEGFα were significantly upregulated in patients with Fabry's disease compared with that in healthy controls (708.5 ± 426.3 vs. 458.5 ± 181.5 pg/ml, p = 0.048) and positively associated with albuminuria (r = 0.82, p < 0.0001) and elevated NTproBNP (r = 0.87, p < 0.0001) and hsTNT values (r = 0.41, p = 0.048) in male patients with Fabry's disease. For angiostatin, no significant difference was found between patients with Fabry's disease and healthy controls (747.6 ± 390.3 vs. 858.8 ± 599.3 pg/ml). Discussion: In conclusion, an overexpression of VEGFα and downregulation of its counter player angiostatin in aortic tissue of α-GAL-Tg/KO mice support the hypothesis of an underlying vasculopathy in Fabry's disease. Elevated VEGFα serum levels were also observed in patients with Fabry's disease and were positively associated with elevated markers of organ manifestation in males. These findings suggest that angiogenetic markers, such as VEGFα, may be potentially useful biomarkers for the detection of endothelial dysfunction in classical Fabry's disease.

The effects of contemporary processes in maintaining the genetic structure of western song sparrows (Melospiza melodia).

Historic events and contemporary processes work in concert to create and maintain geographically partitioned variation and are instrumental in the generation of biodiversity. We sought to gain a better understanding of how contemporary processes such as movement and isolation influence the genetic structure of widely distributed vagile species such as birds. Song sparrows (Melospiza melodia) in western North America provide a natural system for examining the genetics of populations that have different patterns of geographic isolation and migratory behavior. We examined the population genetics of 576 song sparrows from 23 populations using seven microsatellite loci to assess genetic differentiation among populations and to estimate the effects of drift and immigration (gene flow) on each population. Sedentary, isolated populations were characterized by low levels of immigration and high levels of genetic drift, whereas those populations less isolated displayed signals of high gene flow and little differentiation from other populations. Contemporary dispersal rates from migratory populations, estimated by assignment test, were higher and occurred over larger distances than dispersal from sedentary populations but were also probably too low to counter the effects of drift in most populations. We suggest that geographic isolation and limited gene flow facilitated by migratory behavior are responsible for maintaining observed levels of differentiation among Pacific coastal song sparrow populations.

Interleukin-1 beta induces cardiac myocyte growth but inhibits cardiac fibroblast proliferation in culture.

Interleukin-1 (IL-1), initially called "endogenous pyrogen," is primarily known as a mediator of inflammation. However, it also plays many other diverse physiologic roles including the stimulation and inhibition of both primary cells in culture and the interstitial and parenchymal cells of a number of organs including the heart. In the heart, IL-1 expression has traditionally been reported in situations where there is immunologic myocardial injury such as occurs during transplant rejection and congestive heart failure. For this reason, all of the effects of IL-1 have been presumed to be deleterious. Using a cell culture model which allows both the muscle cells (myocytes) and nonmuscle cells (fibroblasts) to be evaluated separately, we have found that IL-1 induces both cardiac myocyte hypertrophy and reinitiates myocyte DNA synthesis. In stark contrast, IL-1 exerts a potent anti-proliferative effect on cardiac fibroblasts. To our knowledge this is the first report concerning the differential effects of IL-1 on myocardial cell growth in culture and, given the inducible expression of IL-1 by myocardial cells during stress, underscores the importance of investigating the complex nature of the intracardiac cell-cell interactions that occur in the heart.

[Asymptomatic atrial fibrillation with systematic screening using tele-ECG--relevance for anticoagulation in paroxysmal atrial fibrillation]. / Asymptomatisches Vorhofflimmern bei systematischem Screening mittels Tele-EKG -Bedeutung für die Antikoagulation bei paroxysmalem Vorhofflimmern.

Event recorder monitoring plays an important role in the early detection and diagnosis of rhythm disorders such as atrial fibrillation (AF). In a recent study over 1000 patients with symptomatic paroxysmal AF were followed up by daily and symptom triggered ECG self monitoring. Independent of the presence of antiarrhythmic therapy, the incidence of AF was much higher than expected, since over 50% of AF episodes were asymptomatic. Therefore, patients symptoms are not a reliable surrogate parameter for the detection of AF. Moreover, antiarrhythmic therapy does not totally prevent atrial fibrillation, but raises the risk of silent AF episodes by reducing the mean heart rate. Based on these findings, effective anticoagulation should be taken into consideration in patients with paroxysmal AF independent of antiarrhythmic medication. The decision for anticoagulation with cumarine derivates or aspirin is dependent on the age, underlying diseases, and the individual thromboembolic risk in these patients.

The renal and neurohumoral effects of the addition of low-dose dopamine in septic critically ill patients.

OBJECTIVES: Dopamine exerts a complicated action on the cardiovascular-renal and neurohumoral systems. We evaluated the effects of the addition of different doses of dopamine on top of treatment with norepinephrine on the haemodynamics, renal function and neurohormones of septic shock patients. DESIGN: Open, uncontrolled, dose-finding study. SUBJECTS: Dopamine was administered, after fluid resuscitation, to septic shock patients who were more than 2 h haemodynamically and pulmonary stable with the use of a constant dose norepinephrine. Patients with a serum creatinine above 180 micromol x l were excluded. METHODS: Dopamine doses of 0, 2, 4, 6 and 0 microg x kg(-1) x min(-1) were given consecutively for 1 h each. Neurohormones were measured hourly after baseline levels had been taken. Systemic haemodynamics were measured using a pulmonary artery (PA) catheter every 30 min, whereas urine collections were examined every hour during the study period. RESULTS AND STATISTICAL ANALYSES: Eight patients (mean age 46 +/- 13 years, M/F 3/5) were included. The median norepinephrine dose at the start of the study was 0.29 microg x kg(-1) x min(-1) (range 0.07-0.48 microg x kg(-1) x min(-1)). Cardiac output (CO) rose during the dopamine infusion for all doses from 7.9 +/- 1.74 l/min to a maximum of 10.1 +/- 1.71 l/min, achieved at the 4 microg x kg(-1) x min(-1) dopamine dose, whereas systemic vascular rate (SVR) decreased slightly for all doses. Heart rate remained unchanged during the 2 microg x kg(-1) x min(-1) dose of dopamine but increased for the 4 and 6 microg x kg(-1) x min(-1) doses from 108 +/- 17 to a maximum of 124 +/- 24 beats/min. Filling pressures remained unchanged whereas the mean arterial blood pressure increased (from 83 +/- 7 to 93 +/- 11 mmHg). Plasma renin activity (PRA) was relatively high (but remained unchanged) as were aldosterone levels. Sodium excretion and diuresis increased for all doses, accompanied by an increase of fractional sodium excretion at the 4 and 6 microg x kg(-1) x min(-1) doses of dopamine. Creatinine clearances remained unchanged. All changed values returned to baseline values after cessation of the dopamine administration. CONCLUSION: During norepinephrine infusion, increasing doses of dopamine from 2 to 6 microg x kg(-1) x min(-1) augments CO, diuresis and sodium excretion in patients treated for septic shock, without changes in creatinine clearance. Higher doses of dopamine (4 and 6 microg x kg(-1) x min(-1)) also induce an increase in heart rate. PRA, aldosterone and norepinephrine levels remain unchanged during dopamine infusion.

Humorally mediated alterations in cardiac performance as a consequence of positive end-expiratory pressure.

Two experimental designs were used to study the mechanism of the decreased cardiac output associated with the use of positive end-expiratory pressure (PEEP). In the first study of nine dogs the application of 15 cm H2O PEEP led to a decrease in cardiac output (CO) from 2.68 +/- 1.05 to 2.01 +/- 1.26 liters/min (+/- SD) (p less than 0.05) concomitant with an increase in transmural central venous pressure of 5.2 +/- 0.9 to 8.4 +/- 2.7 mm Hg (p less than 0.05) and a slight increase in transmural left atrial pressure of 6.8 +/- 3.3 to 7.3 +/- 3.6 mm Hg (p less than 0.1). These data are consistent with altered ventricular performance. In a second study nine pairs of dogs were cross-circulated. Application of 15 cm H2O PEEP to one member of the experimental pair led to a decrease in the CO of the other member from 2.71 +/- 0.98 to 2.21 +/- 0.81 liters/min (p less than 0.001). This decrease returned toward baseline with the removal of PEEP (p less than 0.02). Results indicate that one mechanism whereby PEEP reduces the cardiac output is through the action of a humoral agent.

A method for direct coronary sinus flow measurement and blood sampling in the dog.

Various methods for sampling and measurement of coronary sinus flow in animals have been reported. All have disadvantages because of the need for fluoroscopy or for special tubing or equipment. A technique using readily available materials is described that provides direct measurement of coronary sinus blood flow and allows coronary sampling.

The ontogenesis of the dopaminergic cell in the pre- and postnatal guinea pig retina.

We have examined the development of the dopaminergic system of the guinea pig retina, a species in which retinal neuronal and synaptic differentiation occurs largely in utero. Fetal animals aged 42-69 days (full term), neonates, postnatal (pn) animals to 12 weeks, and mature animals were studied to determine retinal dopamine (DA) storage, metabolism (DOPAC), in vitro tyrosine hydroxylase (TH) activity, postsynaptic target activation (cAMP stimulation) and localization (formaldehyde-induced histofluorescence). DA-stimulated adenylate cyclase at 42 days of gestation was threefold over basal activity, preceding the onset of the accumulation of DA and DOPAC at 45 days, and the initial localization of DA in cell perikarya at 47 days and in processes at 50 days. At birth DA and DOPAC levels were 45 and 37%, respectively, of adult levels. DA levels remained stable during the first few days pn, although in vitro TH activity was capable of stimulation by light in the neonate as in the mature animal. DA and TH activity increased from 1 week pn to reach adult levels by 10 weeks pn. Although a significant degree of development of the dopaminergic neurotransmitter system in the guinea pig occurs before birth the attainment of a fully mature system postnatally may require normal photic stimulation of physiologic activity.

Amantadine-induced lipidosis. A cytological and physicochemical study.

The purpose of this study was to test whether or not the antiviral drug amantadine induces the structural features of lipidosis in intact animals (rats) and cultured cells, and to investigate the interactions between amantadine and phospholipids. Chlorphentermine was used as reference compound. When subchronically fed to rats at a daily dosage of approximately 180 mg/kg, amantadine induced ultrastructural symptoms of generalized lipidosis, the degree of which was, however, by far less marked than that previously reported for chlorphentermine. This was paralleled by the findings on cell cultures (rat peritoneal macrophages), where the lipidosis-inducing potency of amantadine was approximately 10-fold lower than that of chlorphentermine. As to drug-phospholipid interactions, amantadine had less marked effects than chlorphentermine upon the phase transition characteristics of phosphatidylcholine and phosphatidic acid; furthermore, amantadine was approximately 10-fold less potent than chlorphentermine in displacing Ca from phosphatidylserine monolayers. The present study has revealed a parallel between the comparatively low lipidosis-inducing efficacy inherent to amantadine and the comparatively low tendency to interact with phospholipids. It is suggested that the cage-like structure of the amantadine molecule hinders an effective intercalation of the drug into phospholipid aggregates, and that this is an essential factor responsible for the low inherent efficacy of amantadine with respect to lipidosis induction.

Comparison of melanoma antigens in whole tumor vaccine to those from IIB-MEL-J cells.

Immunotherapy for melanoma shows promise. Our previous whole tumor (WT) vaccine was noted to have positive clinical effects. We have now developed a new, safer melanoma vaccine that is derived from IIB-MEL-J tissue culture (TC) cells. In this study, we compare by Western blot analyses the antigens in the WT vaccine to antigens in the TC vaccine. Sera from 12 WT vaccine recipients, 8 melanoma patients who received no immunotherapy, and 8 controls served as a source of antibodies to investigate potential antigens in the vaccines. Three major antigenic peptides with approximate molecular weighs of 46, 40, and 36 kDA were present in both vaccines, while two other antigenic peptides with approximate molecular weighs of 68 and 48 kDA were present only in the TC vaccine. The reaction was similar between the patients who received the WT vaccine and those who did not receive the vaccine. Some of the individuals who did not have melanoma showed some reaction, but not to the extent of the melanoma patients. The intensity of immunostaining was greater for the TC vaccine when compared to the WT vaccine, indicating that these proteins are in a higher concentration in the TC vaccine. This new vaccine from IIB-MEL-J tissue culture cells provides a higher yield and a much more consistent source of potentially clinically relevant antigens without risk of infection or contamination by other irrelevant materials.

The impact of neuroticism upon married bipolar patients.

The NEO Personality Inventory was given to 33 married patients with bipolar disorder. Consistent with previous findings, patients with bipolar disorder did not show an abnormal personality profile as a group. Extremely wide variation on all scales indicated that the group profile tells little about individual patients. Trait neuroticism robustly predicted psychiatric symptoms at entry to the study when assessed retrospectively for the two years prior to entry and when averaged over a year of treatment. Neuroticism also negatively predicted the self-confidence of the patients in this sample. The patients identified as outliers on neuroticism form a clinically difficult group for whom the distinction between Axes I and II appears to be less meaningful.

The plasma endorphin, prostaglandin and catecholamine profile of patients with fibrositis treated with cyclobenzaprine and placebo: a 5-month study.

During a 5 month, double blind crossover study of the clinical effect of cyclobenzaprine on 7 patients with fibrositis, weekly measurements were done of plasma beta-endorphin (endorphin, prostaglandin E (PGE) and catecholamines). Endorphin levels were normal but varied with tender point tenderness. Mean plasma dopamine and PGE were elevated. Norepinephrine was normal to very high while epinephrine levels were continuously low to normal. We conclude that patients with fibrositis have a neurotransmitter plasma profile like other chronic pain states having stress and increased vasomotor activity with the possible exception of having low circulating epinephrine. This disparity may mark a failure of central nervous system pain modulation in fibrositis.