Optical interferometry-based array of seafloor environmental sensors using a transoceanic submarine cable.

Optical fiber-based sensing technology can drastically improve Earth observations by enabling the use of existing submarine communication cables as seafloor sensors. Previous interferometric and polarization-based techniques demonstrated environmental sensing over cable lengths up to 10,500 kilometers. However, measurements were limited to the integrated changes over the entire length of the cable. We demonstrate the detection of earthquakes and ocean signals on individual spans between repeaters of a 5860-kilometer-long transatlantic cable rather than the whole cable. By applying this technique to the existing undersea communication cables, which have a repeater-to-repeater span length of 45 to 90 kilometers, the largely unmonitored ocean floor could be instrumented with thousands of permanent real-time environmental sensors without changes to the underwater infrastructure.

Inflammatory heart disease: a role for cytokines.

Inflammatory heart disease is a rising concern worldwide. Similar mechanisms link autoimmune diseases, including the association of increased disease with proinflammatory cytokines and the importance of regulatory mechanisms in the control of chronic inflammation. Many pathogens including bacteria, protozoa and viruses have been associated with heart disease in patients, and are able to induce similar disease in animal models. Recognition of pathogens by the innate immune system leads to release of proinflammatory cytokines that both reduce infection and increase chronic inflammatory heart disease. Elevated levels of proinflammatory cytokines are able to overcome tolerance to chronic disease, indicating that environmental factors are important in determining progression to chronic heart disease. Understanding the mechanisms leading to chronic heart disease will be critical for developing effective therapies to reduce cardiac dysfunction and heart failure.

Immunomodulation of murine cytomegalovirus-induced myocarditis in mice treated with lipopolysaccharide and tumor necrosis factor.

Murine cytomegalovirus (MCMV) infection of BALB/c mice produces acute and chronic myocarditis similar to clinical disease in humans. In contrast, MCMV-infected C57BL/6 mice develop only mild acute myocarditis. We have investigated the effect of administration of the immunomodulator lipopolysaccharide (LPS) on the development of postviral myocarditis in mice. LPS exacerbated heart inflammation in both strains of MCMV-infected mice, with normally resistant C57BL/6 mice developing chronic myocarditis. Autoantibodies to cardiac myosin were enhanced with LPS treatment in both MCMV-infected mouse strains. LPS treatment also increased the production of TNF in the sera without affecting virus titers in the spleen, liver, or salivary glands, a target organ most affected during persistent virus infection. In LPS/MCMV-infected BALB/c mice, TNF, IL-6, and IL-10 levels were detected in cultures of heart infiltrating cells but not in splenocytes. Importantly, administration of the bioactive synthetic TNF peptide (amino acids 114-130) increased myocarditis in C57BL/6 mice, similar to that seen with LPS treatment. TNF peptide/MCMV-infected BALB/c and C57BL/6 mice showed distinct differences in the expression pattern of IFN-gamma, IL-10, and TNF. These data show that the disease may be partly regulated by TNF among other select cytokines and autoantibodies to cardiac myosin. The immunopathological nature of MCMV-induced myocarditis is thus highlighted.

Contribution of the innate immune system to autoimmune myocarditis: a role for complement.

Myocarditis is a principal cause of heart disease among young adults and is often a precursor of heart failure due to dilated cardiomyopathy. We show here that complement is critical for the induction of experimental autoimmune myocarditis and that it acts through complement receptor type 1 (CR1) and type 2 (CR2). We also found a subset of CD44(hi)CD62L(lo) T cells that expresses CR1 and CR2 and propose that both receptors are involved in the expression of B and T cell activation markers, T cell proliferation and cytokine production. These findings provide a mechanism by which activated complement, a key product of the innate immune response, modulates the induction of an autoimmune disease.

From infection to autoimmunity.

We have investigated two models of virally-induced autoimmune myocarditis in mice using widely different infectious agents. Infection of susceptible BALB/c mice with either Coxsackievirus or murine cytomegalovirus results in the development of acute myocarditis from day 7-14 after infection, and chronic myocarditis from day 28 onwards. The chronic phase of myocarditis is associated with mononuclear infiltration of the myocardium and the production of autoantibodies to cardiac myosin, although infectious virus cannot be detected past day 14 of infection. T cells and autoantibodies have been shown to be important for the development of autoimmune myocarditis. Many researchers have investigated the role of molecular mimicry in the development of myocarditis after viral infection. This review explores the 'adjuvant' effect of infection on the innate immune response and how this determines the progression to autoimmune disease. We show that NK cells protect against the development of disease, while complement and complement receptors are involved in the development of autoimmune myocarditis induced by inoculation with virus or cardiac myosin, respectively. Our results suggest that the innate immune response to viral and self-antigens may determine whether susceptible strains of mice progress to chronic autoimmune disease. These findings have broad implications for understanding the role of infection in inducing autoimmune disease.

A double-blind, placebo-controlled investigation of the effects of fexofenadine, loratadine and promethazine on cognitive and psychomotor function.

AIMS: To assess whether fexofenadine in a range of doses from 80 to 180 mg has any disruptive effects on aspects of psychomotor and cognitive function in comparison with placebo, loratadine and promethazine, an antihistamine known to produce psychomotor and cognitive impairment. METHODS: Twenty-four healthy volunteers received fexofenadine 80 mg, 120 mg and 180 mg, loratadine 10 mg, promethazine 30 mg (as a positive internal control) and placebo in a six-way crossover, double-blind study. Following each dose, subjects were required to perform a series of tests of cognitive function and psychomotor performance at 1.5, 3, 6, 9, 12 and 24 h post dose. The test battery included critical flicker fusion (CFF), choice reaction time (CRT) and assessment of subjective sedation (LARS). Overall levels of activity were monitored by means of wrist mounted actigraphs throughout each of the 24 h experimental periods. RESULTS: Fexofenadine at all doses tested was not statistically different from placebo in any of the tests used and loratadine did not cause any significant impairment of cognitive function. Significant impairments were found following promethazine. Promethazine caused a significant reduction in CFF threshold and this effect was evident up to 12 h post dose (P<0.05). There was a significant increase in recognition reaction time at 3 and 6 h post promethazine administration, and the drug caused a significant (P<0. 002) increase in the percentage of 'sleep-like' activity from actigraph records during the daytime. CONCLUSIONS: Fexofenadine at doses up to 180 mg appears free from disruptive effects on aspects of psychomotor and cognitive function in a study where the psychometric assessments have been shown to be sensitive to impairment, as evidenced by the effects of the verum control promethazine 30 mg.

Effects of fluoxetine and dothiepin on 24-hour activity in depressed patients.

Psychomotor retardation is a recognised symptom of depressive illness, and improvement in psychomotor function is associated with the amelioration of the severity of depressive symptoms. Actigraphy permits behavioural activity to be continuously assessed, allowing changes in psychomotor activity to be monitored over time. A randomised, parallel-group, double-blind study was conducted in 14 general practice patients with a diagnosis of major depression. This pilot study was designed to investigate the utility of actigraphy in this patient population and to investigate possible differences between fluoxetine and dothiepin in their effects on 24-hour behavioural activity monitored for the first 10 days of treatment. Patients taking dothiepin (75 mg rising to 150 mg in the second week, nocte) were found to be significantly (p < 0.05) less active over the course of the day compared to those treated with fluoxetine (20 mg, mane). This lower level of behavioural activity in the dothiepin group was particularly noticeable in the early morning (06:00-08:00 h).

Wild isolates of murine cytomegalovirus induce myocarditis and antibodies that cross-react with virus and cardiac myosin.

The laboratory-adapted K181 strain of murine cytomegalovirus (MCMV) induces both acute and chronic myocarditis, associated with autoantibodies to cardiac myosin, in susceptible BALB/c mice. However, the K181 MCMV strain has been maintained in the laboratory for many years and may not resemble naturally occurring strains of MCMV in its ability to induce myocarditis. Accordingly, six different isolates of MCMV from wild Mus domesticus were compared with K181 MCMV for their ability to induce myocarditis and autoantibodies to cardiac myosin in BALB/c mice. These isolates were shown to induce acute myocarditis similar to K181 MCMV, with associated focal and diffuse myocardial inflammation. However, the levels of myocarditis induced by the wild isolates during the chronic phase of the disease (days 32-56 post-infection) were low in contrast to the K181 strain. Interestingly, 30% of wild-trapped mice showed histological evidence of myocarditis and all were sero-positive to MCMV. Sera from BALB/c mice infected with wild MCMV isolates and from wild-trapped mice contained antibodies that cross-reacted with MCMV and cardiac myosin (S2 region). The cross-reactive region of MCMV was found to be a 50,000-55,000 MW viral polypeptide. These findings suggest that molecular mimicry may be involved in the pathogenesis of autoimmune myocarditis following infection with both laboratory and wild MCMV strains.

The effects of cigarette smoking on overnight performance.

Fifteen healthy smokers and 15 non-smokers were enrolled into this study investigating the effects of smoking on overnight performance. Subjects arrived at the test centre at 1930 hours and were assessed at baseline (2000 hours) and at 2200, 0000, 0200, 0400, 0600, and 0800 hours on a battery of tests (including Critical Flicker Fusion, CFF; Choice Reaction Time, CRT; Compensatory Tracking Task, CTT; Short Term Memory Task, STM; and the Line Analogue Rating Scale, LARS). Results showed that the performance of the smokers was more consistent with baseline measures than that of the non-smokers, which became more impaired throughout the night on a number of tasks [CFF (P < 0.005), Total Reaction Time (TRT, P < 0.05), CTT (P < 0.05) and the Reaction Time (RT) aspect of the CTT task (P < 0.0005)]. The Recognition Reaction Time (RRT) aspect of the CRT task showed that the performance of the non-smokers became more impaired from baseline (P < 0.005), while that of the smokers remained at baseline levels until 0400 hours, when it deteriorated to become comparable to that of the non-smoking controls. Subjective sedation ratings (LARS) resulted in comparable levels of impairment for both study groups (P < 0.00005). Findings from the STM task failed to reach significance. These data suggest that when performance is being measured overnight, smokers show little or no impairment, whilst the performance of non-smokers showed performance decrements.

Effects of fluvoxamine and dothiepin on psychomotor abilities in healthy volunteers.

We gave 12 healthy male volunteers single doses of 50 mg fluvoxamine, 100 mg fluvoxamine, 75 mg dothiepin, and placebo in a double-blind crossover study. Subjects completed a test battery that was sensitive to the behaviourally toxic effects of psychoactive drugs prior to dosing, and then at 1, 2, 3, 4, and 6 h after dose. The test battery included tasks of choice reaction time, tracking, critical flicker fusion threshold, and memory scanning. Subjective feelings were assessed using the line analogue rating scales and the Milford-Epworth sleepiness scale. Daytime activity was recorded by means of wrist actigraphy. The results show that the positive internal control (dothiepin) had a sedative effect in that it impaired performance in the majority of the tests and also reduced daytime activity. Both doses of fluvoxamine remained relatively neutral throughout and did not impair psychomotor performance or cognitive ability in any of the tests. These results indicate that fluvoxamine may be a safe and efficacious antidepressant for outpatients who wish to carry on with the tasks of everyday life without being sedated.

The behavioral toxicity of reversible inhibitors of monoamine oxidase A: laboratory and clinical investigations.

Measuring the effect of an antidepressant on performance tests of psychomotor ability and cognitive processing is important in order to obtain an objective assessment of its psychotropic activity. It is also essential to identify potential interference with everyday activities such as driving, operating machinery, and performing domestic tasks and to assess the extent to which central nervous system side effects may compound the cognitive and psychomotor impairment resulting from depressive illness. Older compounds such as amitriptyline impair performance on these tests, whereas the newer antidepressant moclobemide appears to have no effect. What remains to be clarified is whether these tests are predictive of the behavioral side effects that may occur in depressed patients.

The psychomotor and cognitive effects of litoxetine in young and middle aged volunteers.

1. The effects of a range of doses of litoxetine (twice daily for 4 days), a novel specific serotonin re-uptake inhibitor, were evaluated in young and middle aged volunteers. 2. Psychometric testing was carried out at various time points on days 1 and 4 of each treatment period. The test battery consisted of critical flicker fusion (CFF), choice reaction time (CRT), compensatory tracking (CTT), Stroop and Sternberg memory scanning tests. Subjective feelings of sleep and sedation were measured by the Leeds Sleep Evaluation Questionnaire (LSEQ) and line analogue rating scales (LARS). 3. Pharmacokinetic profiles were determined from analyses of blood samples taken after the final dose on day 5. 4. Overall, there were few changes in any of the psychometric tests and although the higher doses of litoxetine improved CFF, these effects were weak in that differences could only be detected when the results were pooled against time. 5. The pharmacokinetic profile of litoxetine was very similar in both the young and middle aged subjects, and there was no difference regarding tolerability. 6. There is little evidence from this study to suggest that litoxetine has any intrinsic sedative activity which is likely to interfere with the performance of activities of everyday life.

Assessing the residual effects of hypnotics.

The therapeutic efficacy of a hypnotic can not be judged solely on its ability to induce and improve sleep. Many of the older compounds produce residual effects the next morning, such as impaired performance, lack of concentration and day-time sedation. This "hangover" phenomena will only serve to make the problem worse rather than better. The patient's quality of life would suffer, and this is particularly apparent in older patients. Zopiclone and zolpidem, two novel compounds, are superior to the older benzodiazepines in that they do not impair performance on tests of cognition, reaction time and memory the day following drug ingestion. These drugs may prove to be more beneficial and safer in people with sleep disorders who want to carry on with everyday life.

A placebo controlled double-blind evaluation of the pharmacodynamics of fengabine vs amitriptyline following single and multiple doses in elderly volunteers.

1. The effects of fengabine were compared with those of amitriptyline in healthy elderly volunteers. Doses were administered double-blind and assessments were made before and after ingestion. 2. Psychomotor performance and cognitive ability were measured using tests of choice reaction time, tracking, critical flicker fusion threshold, memory scanning and word recognition. Subjective feelings were assessed using the Leeds sleep evaluation questionnaire (LSEQ) and line analogue rating scales (LARS). 3. Pharmacokinetic data suggest that fengabine may induce its own metabolism following repeated dosing. 4. The findings of this study show that fengabine 200 mg and 400 mg does not produce any noticeable behavioural toxicity in elderly volunteers, in contrast to amitriptyline which had a disruptive effect throughout.

The effects of moclobemide on psychomotor performance and cognitive function.

Sixteen young male volunteers received single doses of moclobemide 200 mg, moclobemide 400 mg, amitriptyline 50 mg and placebo in a double-blind crossover study. Subjects then completed a test battery which is sensitive to the effects of psychoactive drugs at 1, 2, and 4 h post-dose. The test battery included tasks of choice reaction time, tracking, critical flicker fusion threshold and memory scanning. Subjective feelings were assessed using the Leeds sleep evaluation questionnaire (LSEQ) and line analogue rating scales (LARS). The results show that the positive internal control (amitriptyline) has a sedative effect in that it increased critical flicker fusion threshold, reaction time and tracking error. Moclobemide 400 mg increased reaction time in the tracking task but neither dose of moclobemide impaired psychomotor performance or cognitive ability in any of the other tests.

The effects of paroxetine, alone and in combination with alcohol on psychomotor performance and cognitive function in the elderly.

Fifteen healthy male volunteers aged over 60 years received acute and repeated doses of paroxetine 20 mg or placebo, and acute doses of lorazepam 1 mg (as a positive internal control) with or without alcohol (0.6 g/kg of body weight) administered openly in a double blind balanced crossover study in which each subject acted as his own control. Psychomotor performance and cognitive function were assessed using a test battery which included critical flicker fusion, choice reaction time, compensatory tracking, Stroop and memory scanning tests. Subjective ratings of mood and sleep were recorded using line analogue rating scales. The pattern of results indicated that paroxetine had little or no effect on most of the test variables, and in some instances (critical flicker fusion thresholds) improved information processing ability. This was in marked contrast to the lorazepam verum which produced sedation and disruption of performance. Paroxetine had a slight antagonistic effect on alcohol induced sedation whereas impairment of performance with lorazepam was potentiated by co-administration of alcohol. The low behavioural toxicity of paroxetine in elderly volunteers has important implications for the pharmacotherapy of depression.