Circadian and Ultradian Rhythms of Free Glucocorticoid Hormone Are Highly Synchronized between the Blood, the Subcutaneous Tissue, and the Brain

Total glucocorticoid hormone levels in plasma of various species, including humans, follow a circadian rhythm that is made up from an underlying series of hormone pulses. In blood most of the glucocorticoid is bound to corticosteroid-binding globulin and albumin, resulting in low levels of free hormone. Although only the free fraction is biologically active, surprisingly little is known about the rhythms of free glucocorticoid hormones. We used single-probe microdialysis to measure directly the free corticosterone levels in the blood of freely behaving rats. Free corticosterone in the blood shows a distinct circadian and ultradian rhythm with a pulse frequency of approximately one pulse per hour together with an increase in hormone levels and pulse height toward the active phase of the light/dark cycle. Similar rhythms were also evident in the subcutaneous tissue, demonstrating that free corticosterone rhythms are transferred from the blood into peripheral target tissues. Furthermore, in a dual-probe microdialysis study, we demonstrated that the circadian and ultradian rhythms of free corticosterone in the blood and the subcutaneous tissue were highly synchronized. Moreover, free corticosterone rhythms were also synchronous between the blood and the hippocampus. These data demonstrate for the first time an ultradian rhythm of free corticosterone in the blood that translates into synchronized rhythms of free glucocorticoid hormone in peripheral and central tissues. The maintenance of ultradian rhythms across tissue barriers in both the periphery and the brain has important implications for research into aberrant biological rhythms in disease and for the development of improved protocols for glucocorticoid therapy

Listeria Monocytogenes: a rare cause of endophthalmitis, a case report.

Listeria monocytogenes is a known cause of gastroenteritis. Invasive disease can follow bacteremia causing meningoencephalitis, endocarditis and spontaneous miscarriages in immunocompromised patients and pregnant women respectively. We present the first case in England of endogenous endophthalmitis caused by L. monocytogenes following acute gastroenteritis in an immunocompetent host. A 50-year-old South Asian female presented with acute painful unilateral visual loss occurring shortly after an episode of self-limiting gastroenteritis. On examination, the eye was very inflamed with a hypopyon uveitis. A vitreous biopsy confirmed growth of L.monocytogenes serotype 1/2a. Diagnostic delay commonly occurs in endogenous endophthalmitis and exacerbates an already poor visual prognosis. Listeria spp. must be considered in ocular inflammation following gastroenteritis. The intraocular inflammation subsided but surgical intervention was required to remove vitreous debris and improve visual acuity

Mathematical Modelling of Endocrine Systems

This is the final (in press) version. Available from Elsevier via the DOI in this recordHormone rhythms are ubiquitous and essential to sustain normal physiological functions. Combined mathematical modelling and experimental approaches have shown that these rhythms result from regulatory processes occurring at multiple levels of organisation and require continuous dynamic equilibration, particularly in response to stimuli. We review how such an interdisciplinary approach has been successfully applied to unravel complex regulatory mechanisms in the metabolic, stress, and reproductive axes. We discuss how this strategy is likely to be instrumental for making progress in emerging areas such as chronobiology and network physiology. Ultimately, we envisage that the insight provided by mathematical models could lead to novel experimental tools able to continuously adapt parameters to gradual physiological changes and the design of clinical interventions to restore normal endocrine function.Medical Research Council (MRC)Engineering and Physical Sciences Research Council (EPSRC)Wellcome Trus

A Review of Antimicrobial Therapy for Infectious Uveitis of the Posterior Segment

Treatment of infectious posterior uveitis represents a therapeutic challenge for ophthalmologists. The eye is a privileged site, maintained by blood ocular barriers, which limits penetration of systemic antimicrobials into the posterior segment. In addition, topical and subconjunctival therapies are incapable of producing sufficient drug concentrations, intraocularly. Posterior infectious uveitis can be caused by bacteria, virus, fungi, or protozoa. Mode of treatment varies greatly based on the infectious etiology. Certain drugs have advantages over others in the treatment of infectious uveitis. Topical and systemic therapies are often employed in the treatment of ocular infection, yet the route of treatment can have limitations based on penetration, concentration, and duration. The introduction of intravitreal antimicrobial therapy has advanced the management of intraocular infections. Being able to bypass blood-ocular barriers allows high drug concentrations to be delivered directly to the posterior segment with minimal systemic absorption. However, because the difference between the therapeutic and the toxic doses of some antimicrobial drugs falls within a narrow concentration range, intravitreal therapy could be associated with ocular toxicity risks.  In many cases of infectious uveitis, combination of intravitreal and systemic therapies are necessary. In this comprehensive review, the authors aimed at reviewing clinically relevant data regarding intraocular and systemic antimicrobial therapy for posterior segment infectious uveitis. The review also discussed the evolving trends in intraocular treatment, and elaborated on antibiotic pharmacokinetics and pharmacodynamics, efficacy, and adverse effects

A relativistic formalism for computation of irrotational binary stars in quasi equilibrium states

We present relativistic hydrostatic equations for obtaining irrotational binary neutron stars in quasi equilibrium states in 3+1 formalism. Equations derived here are different from those previously given by Bonazzola, Gourgoulhon, and Marck, and have a simpler and more tractable form for computation in numerical relativity. We also present hydrostatic equations for computation of equilibrium irrotational binary stars in first post-Newtonian order.Comment: 5 pages, corrected eqs.(2.10), (2.11) and (3.1

A Review of Antimicrobial Therapy for Infectious Uveitis of the Posterior Segment

Treatment of infectious posterior uveitis represents a therapeutic challenge for ophthalmologists. The eye is a privileged site, maintained by blood ocular barriers, which limits penetration of systemic antimicrobials into the posterior segment. In addition, topical and subconjunctival therapies are incapable of producing sufficient drug concentrations, intraocularly. Posterior infectious uveitis can be caused by bacteria, virus, fungi, or protozoa. Mode of treatment varies greatly based on the infectious etiology. Certain drugs have advantages over others in the treatment of infectious uveitis. Topical and systemic therapies are often employed in the treatment of ocular infection, yet the route of treatment can have limitations based on penetration, concentration, and duration. The introduction of intravitreal antimicrobial therapy has advanced the management of intraocular infections. Being able to bypass blood-ocular barriers allows high drug concentrations to be delivered directly to the posterior segment with minimal systemic absorption. However, because the difference between the therapeutic and the toxic doses of some antimicrobial drugs falls within a narrow concentration range, intravitreal therapy could be associated with ocular toxicity risks.  In many cases of infectious uveitis, combination of intravitreal and systemic therapies are necessary. In this comprehensive review, the authors aimed at reviewing clinically relevant data regarding intraocular and systemic antimicrobial therapy for posterior segment infectious uveitis. The review also discussed the evolving trends in intraocular treatment, and elaborated on antibiotic pharmacokinetics and pharmacodynamics, efficacy, and adverse effects

Testing a Simplified Version of Einstein's Equations for Numerical Relativity

Solving dynamical problems in general relativity requires the full machinery of numerical relativity. Wilson has proposed a simpler but approximate scheme for systems near equilibrium, like binary neutron stars. We test the scheme on isolated, rapidly rotating, relativistic stars. Since these objects are in equilibrium, it is crucial that the approximation work well if we are to believe its predictions for more complicated systems like binaries. Our results are very encouraging.Comment: 9 pages (RevTeX 3.0 with 6 uuencoded figures), CRSR-107

Tryptophan metabolism in the central nervous system: medical implications

The metabolism of the amino acid L-tryptophan is a highly regulated physiological process leading to the generation of several neuroactive compounds within the central nervous system. These include the aminergic neurotransmitter serotonin (5-hydroxytryptamine, 5-HT), products of the kynurenine pathway of tryptophan metabolism (including 3-hydroxykynurenine, 3-hydroxyanthranilic acid, quinolinic acid and kynurenic acid), the neurohormone melatonin, several neuroactive kynuramine metabolites of melatonin, and the trace amine tryptamine. The integral role of central serotonergic systems in the modulation of physiology and behaviour has been well documented since the first description of serotonergic neurons in the brain some 40 years ago. However, while the significance of the peripheral kynurenine pathway of tryptophan metabolism has also been recognised for several decades, it has only recently been appreciated that the synthesis of kynurenines within the central nervous system has important consequences for physiology and behaviour. Altered kynurenine metabolism has been implicated in the pathophysiology of conditions such as acquired immunodeficiency syndrome (AIDS)-related dementia, Huntington's disease and Alzheimer's disease. In this review we discuss the molecular mechanisms involved in regulating the metabolism of tryptophan and consider the medical implications associated with dysregulation of both serotonergic and kynurenine pathways of tryptophan metabolism

A Review of Antimicrobial Therapy for Infectious Uveitis of the Posterior Segment

Treatment of infectious posterior uveitis represents a therapeutic challenge for ophthalmologists. The eye is a privileged site, maintained by blood ocular barriers, which limits penetration of systemic antimicrobials into the posterior segment. In addition, topical and subconjunctival therapies are incapable of producing sufficient drug concentrations, intraocularly. Posterior infectious uveitis can be caused by bacteria, virus, fungi, or protozoa. Mode of treatment varies greatly based on the infectious etiology. Certain drugs have advantages over others in the treatment of infectious uveitis. Topical and systemic therapies are often employed in the treatment of ocular infection, yet the route of treatment can have limitations based on penetration, concentration, and duration. The introduction of intravitreal antimicrobial therapy has advanced the management of intraocular infections. Being able to bypass blood-ocular barriers allows high drug concentrations to be delivered directly to the posterior segment with minimal systemic absorption. However, because the difference between the therapeutic and the toxic doses of some antimicrobial drugs falls within a narrow concentration range, intravitreal therapy could be associated with ocular toxicity risks.  In many cases of infectious uveitis, combination of intravitreal and systemic therapies are necessary. In this comprehensive review, the authors aimed at reviewing clinically relevant data regarding intraocular and systemic antimicrobial therapy for posterior segment infectious uveitis. The review also discussed the evolving trends in intraocular treatment, and elaborated on antibiotic pharmacokinetics and pharmacodynamics, efficacy, and adverse effects

First Constraints on Iron Abundance versus Reflection Fraction from the Seyfert~1 Galaxy MCG--6-30-15

We report on a joint ASCA and RXTE observation spanning an $\sim$ 400~ks time interval of the bright Seyfert~1 galaxy MCG--6-30-15. The data clearly confirm the presence of a broad skewed iron line ($W_{K\alpha} \sim$ 266 eV) and Compton reflection continuum at higher energies reported in our previous paper. We also investigate whether the gravitational and Doppler effects that affect the iron line may also be manifest in the reflected continuum. The uniqueness of this data set is underlined by the extremely good statistics that we obtain from the approximately four million photons that make up the 2-20 keV RXTE PCA spectrum alone. This, coupled with the high energy coverage of HEXTE and the spectral resolution of ASCA in the iron line regime has allowed us to constrain the relationship between abundance and reflection fraction for the first time at the 99 per cent confidence level. The reflection fraction is entirely consistent with a flat disk, i.e. the cold material subtends $\rm 2 \pi$ sr at the source, to an accuracy of 20 per cent. Monte Carlo simulations show that the observed strong iron line intensity is explained by an overabundance of iron by a factor of $\sim$ 2 and an underabundance of the lower-Z elements by a similar factor. By considering non-standard abundances, a clear and consistent picture can be made in which both the iron line and reflection continuum come from the same material such as e.g. an accretion disk.Comment: 8 pages, 8 figures, accepted for publication MNRAS 7/9