A mildly relativistic wide-angle outflow in the neutron-star merger event GW170817.

GW170817 was the first gravitational-wave detection of a binary neutron-star merger. It was accompanied by radiation across the electromagnetic spectrum and localized to the galaxy NGC 4993 at a distance of 40 megaparsecs. It has been proposed that the observed γ-ray, X-ray and radio emission is due to an ultra-relativistic jet being launched during the merger (and successfully breaking out of the surrounding material), directed away from our line of sight (off-axis). The presence of such a jet is predicted from models that posit neutron-star mergers as the drivers of short hard-γ-ray bursts. Here we report that the radio light curve of GW170817 has no direct signature of the afterglow of an off-axis jet. Although we cannot completely rule out the existence of a jet directed away from the line of sight, the observed γ-ray emission could not have originated from such a jet. Instead, the radio data require the existence of a mildly relativistic wide-angle outflow moving towards us. This outflow could be the high-velocity tail of the neutron-rich material that was ejected dynamically during the merger, or a cocoon of material that breaks out when a jet launched during the merger transfers its energy to the dynamical ejecta. Because the cocoon model explains the radio light curve of GW170817, as well as the γ-ray and X-ray emission (and possibly also the ultraviolet and optical emission), it is the model that is most consistent with the observational data. Cocoons may be a ubiquitous phenomenon produced in neutron-star mergers, giving rise to a hitherto unidentified population of radio, ultraviolet, X-ray and γ-ray transients in the local Universe.

A radio counterpart to a neutron star merger.

Gravitational waves have been detected from a binary neutron star merger event, GW170817. The detection of electromagnetic radiation from the same source has shown that the merger occurred in the outskirts of the galaxy NGC 4993, at a distance of 40 megaparsecs from Earth. We report the detection of a counterpart radio source that appears 16 days after the event, allowing us to diagnose the energetics and environment of the merger. The observed radio emission can be explained by either a collimated ultrarelativistic jet, viewed off-axis, or a cocoon of mildly relativistic ejecta. Within 100 days of the merger, the radio light curves will enable observers to distinguish between these models, and the angular velocity and geometry of the debris will be directly measurable by very long baseline interferometry.

Illuminating gravitational waves: A concordant picture of photons from a neutron star merger.

Merging neutron stars offer an excellent laboratory for simultaneously studying strong-field gravity and matter in extreme environments. We establish the physical association of an electromagnetic counterpart (EM170817) with gravitational waves (GW170817) detected from merging neutron stars. By synthesizing a panchromatic data set, we demonstrate that merging neutron stars are a long-sought production site forging heavy elements by r-process nucleosynthesis. The weak gamma rays seen in EM170817 are dissimilar to classical short gamma-ray bursts with ultrarelativistic jets. Instead, we suggest that breakout of a wide-angle, mildly relativistic cocoon engulfing the jet explains the low-luminosity gamma rays, the high-luminosity ultraviolet-optical-infrared, and the delayed radio and x-ray emission. We posit that all neutron star mergers may lead to a wide-angle cocoon breakout, sometimes accompanied by a successful jet and sometimes by a choked jet.

Fusidic acid resistance in Staphylococcus aureus.

This review summarises current knowledge of the microbiological and clinical aspects of fusidic acid resistance in Staphylococcus aureus, and makes recommendations about fusidic acid prescribing and further research.

Glucocorticoid feedback sensitivity and adrenocortical responsiveness in posttraumatic stress disorder.

BACKGROUND: Decreased basal cortisol levels have been reported in individuals with posttraumatic stress disorder (PTSD). There is evidence for enhanced negative feedback sensitivity of the hypothalamic-pituitary-adrenal (HPA) axis in PTSD, which could account for this, but other possible mechanisms have not been ruled out. We examined the HPA axis employing a metyrapone-cortisol infusion protocol designed to study negative feedback sensitivity. METHODS: Vietnam combat trauma-exposed subjects met DSM-IV criteria for PTSD. Exclusion criteria included substance abuse and most medications. Endogenous feedback inhibition was removed by blocking cortisol synthesis with oral metyrapone and reintroduced by intravenous infusion of cortisol. In a placebo condition, subjects received oral placebo and normal saline infusion. Serial blood samples drawn over 4 hours were assayed for adrenocorticotrophic hormone (ACTH), cortisol, and 11-deoxycortisol. Selected samples were assayed for cortisol binding globulin (CBG) and dehydroepiandrosterone (DHEA). RESULTS: Basal plasma cortisol was significantly decreased in PTSD subjects (n = 13) compared with control subjects (n = 16). No significant difference in the ACTH response to cortisol infusion following metyrapone was observed; however 11-deoxycortisol was significantly decreased in PTSD subjects. In addition, CBG was significantly increased in PTSD subjects, and DHEA was significantly decreased in both PTSD and combat-exposed control subjects. CONCLUSIONS: These observations suggest decreased adrenocortical responsiveness may be an additional or alternative mechanism accounting for low cortisol in PTSD.

Increased alpha 2-adrenergic receptor binding in locus coeruleus projection areas in dementia with Lewy bodies.

Clinical studies suggest involvement of brain noradrenergic systems in the pathophysiology of disruptive agitation in Alzheimer's disease (AD). This behavioral problem is even more prevalent in dementia with Lewy bodies (DLB). Here we used receptor autoradiography with [(125)I]para-iodoclonidine to estimate alpha-2 adrenergic receptor (A2R) density in locus coeruleus (LC) projection areas in postmortem brain tissue from age and gender comparable groups of DLB (n = 6), AD (n = 5) and normal (n = 7) subjects. LC neuronal loss was substantial and equivalent in DLB and AD. A2R density was greater in DLB than in normals in the deep layers of the frontal cortex. A2R density was greater in DLB than in AD in hippocampus (CA-1, CA-3 and dentate hilus) and in the granule layer of the cerebellum. Increased A2R binding in DLB is consistent with expression of presynaptic A2R on fibers from surviving LC neurons involved in reinnervation of LC projection areas. These areas develop compensatory noradrenergic hyperinnervation in a rat model of partial LC ablation. It is also consistent with upregulation of post-synaptic A2R in response to loss of LC noradrenergic innervation. Either mechanism could lower the threshold for increased agitation in response to noradrenergic outflow in these dementing disorders.

Binge drinking among female Veterans Affairs patients: prevalence and associated risks.

This study evaluated the prevalence and associated risks of binge drinking, defined as having > or = 4 drinks on an occasion in the past year, in a female patient population. Of 1,259 female Veterans Affairs patients surveyed, 780 reported drinking alcohol in the past year, and 305 (24% of respondents, 39% of drinkers) reported binge drinking in the past year; 84 (11% of drinkers) had done so monthly or more often. Age-adjusted logistic regression analyses indicated that women who reported past-year binge drinking monthly or more often reported significantly increased odds of morning drinking (odds ratio [OR] = 40.3), others worrying about their drinking (OR = 38.6), arguments after drinking (OR = 13.5), hepatitis or cirrhosis (OR = 3.1), frequent injuries (OR = 2.6), smoking (OR = 3.7), drug use (OR = 22.2), and multiple sexual partners (OR = 4.6).

Plasma catecholamine and cardiovascular responses to physostigmine in Alzheimer's disease and aging.

Stimulation of brain cholinergic systems increases activity of both the sympathoneural (SN) and sympathoadrenomedullary (SAM) components of the peripheral sympathetic nervous system. Because presynaptic cholinergic neuron numbers are substantially reduced in Alzheimer's disease (AD), we predicted decreased responsiveness in AD of plasma norepinephrine (NE), an estimate of SN activity, and of epinephrine (EPI), an estimate of SAM activity, to central cholinergic stimulation by the cholinesterase inhibitor physostigmine (0.0125 mg/kg i.v.). Because previous studies have demonstrated that normal human aging increases SN activity but not SAM activity, we specifically hypothesized: (1) a smaller NE response to physostigmine in subjects with mild to moderate AD (n=11; age 72+/-2 yrs; mini-mental state exam [MMSE] scores of 19+/-2) than in healthy older subjects (n=20; age 71+/-1 yrs); and (2) a smaller EPI response in AD subjects than in either healthy older or healthy young subjects (n=9; age 27+/-2 yrs). Unexpectedly, the plasma NE increase following physostigmine only achieved significance in AD subjects and plasma EPI responses were greater in both AD and older subjects than in young subjects. Blood pressure responses to physostigmine were consistent with the catecholamine responses. These data suggest that the presence of mild to moderate AD increases the SN response to cholinergic stimulation and that both AD and normal aging increase the SAM response to cholinergic stimulation. As a result, plasma catecholamine responses to physostigmine do not appear to be useful peripheral neuroendocrine estimates of the severity of brain cholinergic deficits in mild to moderate AD.

Recurrent penicillin-resistant pneumococcal sepsis after matched unrelated donor (MUD) transplantation for refractory T cell lymphoma.

Patients who undergo splenectomy and recipients of allogeneic marrow (alloBMT) or peripheral stem cell transplantation are at increased risk of overwhelming infection from encapsulated organisms such as Streptococcus pneumoniae, Haemophilus influenzae and Neisseria meningitidis. As prophylaxis against these pathogens splenectomised patients are immunised and may also receive antibiotics for life. We report relapsing overwhelming sepsis caused by penicillin-resistant pneumococcus in a patient who was immunised and received prophylactic phenoxymethylpenicillin for 8 months following splenectomy and matched unrelated donor (MUD) marrow transplantation for refractory T cell lymphoma. No obvious focus of sepsis was found during any of the three episodes and S. pneumoniae serogroup 6, subtype 6B was isolated from blood cultures on each occasion. He was treated with i.v. cephalosporins, as the organisms were resistant to penicillin with a minimum inhibitory concentration (MIC) of 2.0, and there was complete resolution of symptoms each time. In the light of recurrent sepsis with this penicillin-resistant organism the decision was made to give prophylactic levofloxacin for the next 12 months. This case illustrates that the choice of prophylactic regimen and the treatment of sepsis in immunocompromised patients remain difficult and challenging issues.

Increased plasma norepinephrine response to yohimbine in elderly men.

BACKGROUND: The effects of aging on sympathetic nervous system and adrenomedullary outflow were estimated by the measurement of plasma norepinephrine (NE) and epinephrine (EPI) responses to yohimbine and clonidine in healthy young and healthy older subjects. METHODS: Yohimbine (0.65 mg/kg), clonidine (5 microg/kg), and placebo were administered on separate days in random order to 5 healthy older men (age 74 +/- 1 years) and 18 healthy young men (age 26 +/- 1 years). NE and EPI were measured by radioenzymatic assay in plasma samples obtained before and 30, 60, and 90 minutes after drug administration. RESULTS: Plasma NE increases after yohimbine were greater in older men than in young men. but plasma NE decreases following clonidine did not differ between groups. Plasma NE and systolic blood pressure were higher in older men than in young men at baseline but no longer differed 90 minutes after clonidine. Plasma EPI increases after yohimbine and decreases after clonidine did not differ between groups. CONCLUSIONS: These results suggest increased sympathetic nervous system outflow in human aging that is not a function of reduced responsiveness of alpha-2 adrenoreceptor-mediated feedback inhibition.

The alpha1-adrenergic antagonist prazosin ameliorates combat trauma nightmares in veterans with posttraumatic stress disorder: a report of 4 cases.

BACKGROUND: Central nervous system (CNS) adrenergic hyperresponsiveness may be involved in the pathophysiology of posttraumatic stress disorder (PTSD). Two Vietnam combat veterans with PTSD prescribed the centrally active alpha1-adrenergic antagonist prazosin for symptoms of benign prostatic hypertrophy unexpectedly reported elimination of combat trauma nightmares. This observation prompted an open-label feasibility trial of prazosin for combat trauma nightmares in chronic combat-induced PTSD. METHOD: Four consecutively identified combat veterans with chronic DSM-IV PTSD and severe intractable combat trauma nightmares participated in an 8-week open trial of escalating-dose prazosin. Nightmare severity response was rated using the nightmare item of the Clinician Administered PTSD Scale and the Clinical Global Impressions-Change scale. RESULTS: The 2 patients who achieved a daily prazosin dose of at least 5 mg were markedly improved, with complete elimination of trauma nightmares and resumption of normal dreaming. The 2 subjects limited to 2 mg of prazosin to avoid excessive blood pressure reduction were moderately improved with at least 50% reduction in nightmare severity. CONCLUSION: These clinical observations, together with neurobiological evidence for alpha1-adrenergic regulation of CNS neurobiological systems relevant to PTSD, provide rationale for placebo-controlled trials of prazosin for PTSD combat trauma nightmares.

Cerebrospinal fluid epinephrine in Alzheimer's disease and normal aging.

Central nervous system (CNS) adrenergic systems are involved in regulation of behavior and blood pressure. The effects of Alzheimer's disease (AD) and normal aging on resting CNS adrenergic activity were estimated by measuring cerebrospinal fluid (CSF) epinephrine (EPI) concentrations in 74 persons with AD, 42 cognitively normal healthy older persons, and 54 healthy young persons. The responsiveness of CSF EPI to the alpha-2 adrenergic antagonist yohimbine and the alpha-2 adrenergic agonist clonidine was measured in smaller subject groups. Resting CSF EPI was higher in AD than in older or young subjects, and increased with dementia severity in AD subjects. There was no relationship between resting CSF EPI and blood pressure. CSF EPI increased following yohimbine in AD and older subjects but not in young subjects. CSF EPI was unaffected by clonidine in all subject groups. The agitation increase following yohimbine was substantially greater in AD subjects than in older or young subjects. CNS adrenergic activity seems increased in AD, may further increase as AD progresses, and may be involved in the pathophysiology of agitation.

Characterization of La Crosse virus RNA in autopsied central nervous system tissues.

A reverse transcription-PCR (RT-PCR) technique was used to detect La Crosse (LAC) virus RNA in the central nervous system (CNS) tissues of two patients who died of LAC encephalitis in 1960 and 1978. Viral RNA was readily detected by RT-PCR although the tissues had been stored frozen for up to 37 years. LAC virus was detected in the cerebral cortex but not in other CNS tissues. RT-PCR allowed detection of replicative forms of the virus, indicating that the virus was actively replicating in the specific CNS tissues. The small (S) RNA segments of the viruses from the CNS samples were demonstrated to be genetically similar by single-strand conformation polymorphism analyses. These S RNA segments were then sequenced; only two base changes were demonstrated between the 1960 and the 1978 samples, suggesting that LAC virus is genetically stable in areas of endemicity. The RT-PCR analyses of analyte directly from CNS tissues allows study of the virus without passage in cell culture.

Effects of estrogen replacement on choline acetyltransferase and trkA mRNA expression in the basal forebrain of aged rats.

The effects of one week of estrogen replacement on choline acetyltransferase (ChAT) and trkA mRNA expression are examined in young and aged rodents to determine whether estrogen continues to affect cholinergic neurons in aging brain. Significant increases in ChAT and trkA are observed in the nucleus basalis of Meynert (nBM) of both age groups. ChAT expression is also increased in the HDB without changes in trkA expression. Results indicate modulation of ChAT expression by estrogen is retained in the aged rodent brain and suggests the possibility that changes in ChAT expression may be dissociated from concurrent alterations in trkA.

Analysis of LaCrosse virus S mRNA 5' termini in infected mosquito cells and Aedes triseriatus mosquitoes.

Nucleotide sequences were determined for the 5' termini of La Crosse virus (LAC) S segment mRNA from persistently infected mosquito cell cultures (C6/36 from Aedes albopictus) and embryos (Aedes triseriatus). LAC primes transcription of its mRNA with "scavenged" 5' caps and adjacent oligonucleotides from host mRNAs, and these non-virus-encoded 5'-terminal extensions are heterogeneous in infected mammalian cells. The nature of mosquito host-derived primers has not been previously investigated. During early C6/36 cell infection, LAC mRNA 5'-terminal sequences were heterogeneous, but variability decreased as infection persisted. One predominant sequence, 5' CCACTCGCCACT (sequence 1), was observed throughout C6/36 cell infection but was more prevalent after 15 days postinfection. This LAC mRNA 5'-terminal sequence comprised 81% of the scavenged host oligonucleotides from vertically infected A. triseriatus eggs during embryogenesis. As these embryos progressed in the dormant overwintering stage (diapause), the predominant scavenged sequence became 5' AGGAAAAGATGGT (sequence 2), and sequence 1 became less prevalent. As the eggs emerged from diapause, the LAC mRNA 5' termini were more variable; 33% had sequence 1, and the remainder were heterogeneous. In post-diapausing eggs, 100% of viral mRNAs had sequence 1 at their 5' termini. Molecular analyses thus revealed continuous but selective LAC cap scavenging during persistent C6/36 cell infection and during embryogenesis and diapause in A. triseriatus eggs. The variety of host-derived sequences was limited in both biosynthetically active (embryonating) and dormant (diapausing) eggs.

EEDQ reduces the striatal neurotensin mRNA response to haloperidol.

Haloperidol is believed to induce neurotensin/neuromedin N (NT/ N) gene expression in the dorsolateral striatum (DLST) of the rat brain via dopamine D2 receptor blockade, but is also known to interact with other receptors as well. To further characterize haloperidol's effects, rats were treated with the irreversible monoaminergic receptor antagonist N-ethoxycarbonyl-2-ethoxy-1,2 hydroxyquinolone (EEDQ). In situ hybridization was performed for NT/N mRNA. D2-like and sigma receptor autoradiography was performed using 125I-sulpride and 3H-1,3-di-o-tolylguanidine (DTG), respectively. Despite antagonism of D2 receptors, pretreatment with EEDQ failed to significantly reduce the NT/N mRNA response when given 3 days prior to the haloperidol challenge. These data suggest that the acute effects of haloperidol on NT/N mRNA expression in large part result from D2 receptor antagonism. Nonetheless, a contribution of other receptors can not be excluded.

Hypothalamic-pituitary-adrenocortical axis responses to physostigmine: effects of Alzheimer's disease and gender.

We asked whether hypothalamic-pituitary-adrenocortical (HPA) axis responses to a cholinergic stimulus are blunted in patients with Alzheimer's disease (AD) of mild to moderate severity. Such a finding would be consistent with a central cholinergic deficiency early in the course of AD. To address this question, we measured the plasma adrenocorticotropic hormone (ACTH), beta-endorphin-like immunoreactivity (beta E-LI), and cortisol responses to the cholinesterase inhibitor physostigmine in 10 healthy normal older subjects (age = 71 +/- 2 years) and 11 outpatients with probable AD (age = 72 +/- 2 years; Mini Mental State Exam score = 19 +/- 2). Cortisol concentrations were higher in AD subjects throughout the study, but AD and normal older subjects had similar robust ACTH, beta E-LI, and cortisol responses to physostigmine. In all subjects combined, women had greater ACTH, beta E-LI, and cortisol responses to physostigmine than did men. Plasma physostigmine concentrations did not differ between groups. These results suggest that female gender enhances the magnitude of HPA axis responses to cholinergic stimulation in older humans; however, the HPA axis response to physostigmine does not appear to reflect central cholinergic deficiency in the early stages of AD.