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.

Effects of Alzheimer's disease and normal aging on cerebrospinal fluid norepinephrine responses to yohimbine and clonidine.

BACKGROUND: The resting cerebrospinal fluid (CSF) norepinephrine concentration is unchanged or even increased in patients with Alzheimer's disease (AD). These in vivo findings appear to be inconsistent with the post-mortem locus ceruleus neuronal loss that is reported in patients with AD. METHODS: The effects of AD and advanced age on central nervous system noradrenergic status were estimated by comparing CSF norepinephrine concentrations following the administration of yohimbine hydrochloride, clonidine hydrochloride, and placebo in outpatients with AD and older and young normal subjects. Levels of yohimbine, its metabolite 11-hydroxy-yohimbine, and clonidine were measured in CSF and plasma samples. Behavioral responses were quantified by rating the Tension, Excitement, and Anxiety items on the Brief Psychiatric Rating Scale. RESULTS: Yohimbine-induced increases of CSF norepinephrine concentrations were greater in both patients with AD and normal older subjects than in normal young subjects. Clonidine-induced decreases of CSF norepinephrine concentrations did not differ among groups. Behavioral arousal following the administration of yohimbine was greater in patients with AD than in the other groups. CONCLUSIONS: Central nervous system noradrenergic responsiveness is enhanced in normal older subjects, and this age effect is retained in patients with AD. Behavioral sensitivity to increased central nervous system noradrenergic activity is enhanced in patients with AD.

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.

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.

Age-related decline of vasopressin mRNA in the bed nucleus of the stria terminalis.

To determine whether aging influences arginine vasopressin (AVP) biosynthesis in the extrahypothalamic neurons of the bed nucleus of the stria terminalis (BNST), we used in situ hybridization and quantitative autoradiography to compare AVP mRNA in 3-month-old, 14-month-old, and 24-month-old male Fischer 344 rats. As AVP synthesis in the BNST has previously been shown to be steroid-dependent, plasma testosterone (T) was measured by radioimmunoassay. The 24-month-old animals had significantly fewer AVP-labelled cells than either the 3-month-old (p less than 0.01) or 14-month-old (p less than 0.05) animals. The cells that were present in the 24-month animals were less intensely labelled than in the other groups, as indicated by a significantly reduced number of grains per cell (p less than 0.01). Plasma T was also significantly lower in 24-month-old animals when compared with 3-month (p less than 0.01) or 14-month (p less than 0.05) groups. The results indicate that there is a marked age-related decline in vasopressin biosynthetic activity in neurons of the BNST.

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.

Estrogen increases GAP-43 (neuromodulin) mRNA in the preoptic area of aged rats.

Estrogen has been shown to affect the growth, differentiation, and survival of brain neurons and to modulate processes involved in synapse formation and connectivity. These trophic effects are diminished with aging as secretion of estrogen declines. The growth associated protein GAP-43 is found concentrated in axonal growth cones and is implicated in neuronal growth and regeneration. Previous studies have established that expression of GAP-43 can be modulated by estrogen in the preoptic area of developing and adult rat brain. This study was undertaken to determine whether this estrogenic regulation of GAP-43 mRNA is retained in aged rat brain. Young (3 months) and aged (24 months) rats were ovariectomized to remove endogenous estrogen and GAP-43 mRNA in the preoptic area was evaluated using in situ hybridization to compare estrogen and vehicle treatments between age groups. The results demonstrate an age-related decline in GAP-43 mRNA hybridization signal that can be restored to levels comparable to that seen in young animals with estrogen treatment.

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.

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.

Hypertonic saline infusion increases plasma norepinephrine concentrations in normal men.

We recently demonstrated in patients with panic disorder that hypertonic saline infusion induces acute panic with the same frequency and intensity as the standard hypertonic sodium lactate infusion. We now report the effects in normal men of hypertonic saline infusion on neuroendocrine systems possibly relevant to panic and anxiety. We administered a 150-min infusion of hypertonic saline (5% sodium chloride) which increased plasma osmolality from 288 +/- 1 to 303 +/- 2 mOsm/kg and produced the appropriate increase of plasma arginine vasopressin (AVP). Plasma norepinephrine (NE) increased substantially during hypertonic saline infusion compared to a normal saline infusion of equal volume and duration. Mean arterial pressure (MAP) also increased and there were significant positive correlations between MAP and NE, but not between MAP and AVP during hypertonic saline infusion. Plasma epinephrine and cortisol did not differ between conditions. Although the pattern of plasma adrenocorticotrophic hormone (ACTH) response differed between hypertonic saline and normal saline conditions, ACTH concentrations did not increase compared to baseline in either condition. These data suggest that hypertonic saline infusion increases sympathetic nervous system activity in normal men.

The effects of normal aging on cortisol and adrenocorticotropin responses to hypertonic saline infusion.

To assess the effects of aging on hypothalamic-pituitary-adrenal (HPA) axis responsivity, we compared the plasma cortisol and adrenocorticotropin (ACTH) responses to hypertonic saline infusion between normal older and young human volunteers. We administered a 90 min hypertonic saline infusion (5% sodium chloride at 0.06 ml/kg/min) and a 90 min placebo infusion (0.9% sodium chloride at 0.06 ml/kg/min) to normal young subjects (n = 13, age = 29 +/- 2 years) and normal older subjects (n = 8, age = 63 +/- 3 years). Plasma cortisol, ACTH, osmolality and arginine vasopressin (AVP) were measured before and at 30 min intervals during the infusions. The rate of increase in plasma osmolality and AVP induced by hypertonic saline infusion was similar between groups. The plasma cortisol increase during hypertonic saline infusion was greater in normal older subjects than in young subjects (p = .03), but a stimulatory effect of hypertonic saline infusion on plasma ACTH was not apparent in either older or young subjects. These results suggest increased sensitivity with human aging to stimulation of cortisol release by hypertonic saline infusion at the adrenocortical level of the HPA axis.

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.

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.

Expression of the proneurotensin gene in the rat brain and its regulation by antipsychotic drugs.

In this chapter, we have presented evidence for several potential levels of interaction of NT/N gene products with dopaminergic systems of the brain. We have focused on one manifestation of this interaction related to the effects of antipsychotic drugs on expression of the NT/N gene in two anatomically discrete populations of neurons. It appears that certain antipsychotic drugs can dramatically increase expression of this gene in the dorsolateral striatum by blocking dopamine D2 receptors, perhaps by increasing expression of the gene encoding the transcriptional regulator fos. In addition, a second group of NT cells in the shell region of the nucleus accumbens also respond to these drugs by increasing NT/N gene expression. Several other peptides have been suggested to respond to treatment with antipsychotic drugs. However, there are some important differences with respect to their effects on the NT cells we have studied. The most important of these is the differential responsiveness of the DLSt and nucleus accumbens NT neurons to typical and atypical antipsychotics. We showed that all antipsychotic drugs tested increased NT/N mRNA gene expression in the accumbens, a region thought to be involved in dopaminergic disturbances underlying psychosis. However, only the typical neuroleptics that have a high propensity to induce acute extrapyramidal motor side effects influenced NT/N gene expression in the dorsolateral striatum, a structure importantly involved in regulation of motor functions. We hypothesize, therefore, that NT/N-expressing neuronal systems in the nucleus accumbens may mediate some or all of the antipsychotic effects, whereas those in the dorsolateral striatum may be involved in motor effects of neuroleptic drugs. Thus, examination of the effects of these drugs on these neuronal populations will not only clarify their mechanism of action, but in addition may provide a useful "screening" assay for new drugs with enhanced antipsychotic activity, but reduced propensity to induce the debilitating extrapyramidal side effects that are a major cause of patient noncompliance. Future studies will focus on the effects of antipsychotic drugs on NT neurons in clinically relevant models of chronic administration, and on the molecular events involved in their effects on expression of the NT/N gene in the brain.

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.

Enhanced hypothalamic-pituitary-adrenocortical axis responses to physostigmine in normal aging.

BACKGROUND: The purpose of this study was to determine the effects of normal human aging on the hypothalamic-pituitary-adrenocortical (HPA) axis response to the centrally active cholinesterase inhibitor physostigmine. This drug stimulates the HPA axis at a suprapituitary level by increasing central nervous system (CNS) cholinergic activity. METHODS: Plasma ACTH, beta-endorphin (beta E) and cortisol responses to a 10-minute infusion of physostigmine (.0125 mg/kg) were compared between groups of 10 normal older subjects (71 +/- 2 years [mean +/- SEM]) and 9 normal young subjects (27 +/- 2 years). Plasma physostigmine concentrations were measured to assess the comparability of the pharmacologic stimulus between groups. RESULTS: Endocrine responses were substantially greater in older subjects than young subjects for ACTH (p < .01), beta E (p < .01) and cortisol (p < .01). Plasma physostigmine concentrations did not differ between older and young subjects. CONCLUSION: This study demonstrated increased HPA axis responsivity to a CNS cholinergic stimulus in normal human aging.

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.

Testosterone reverses a senescent decline in extrahypothalamic vasopressin mRNA.

The biosynthetic activity of extra-hypothalamic vasopressin (VP) neurons in the bed nucleus of the stria terminalis (BNST) is regulated by gonadal steroids. These neurons have also been implicated in a number of behaviors that are impaired in aging. We previously reported that VP mRNA labelling in the BNST is decreased in senescent rats. We hypothesized that the age-related decrease in VP mRNA labelling is due to the decline in circulating testosterone (T) levels in aged animals. T or saline was administered peripherally for 1 month in physiologic or superphysiologic doses to 3 month old or 24 month old Fischer 344 male rats. In situ hybridization and quantitative autoradiography for VP mRNA in the BNST were performed using a 48-base 35S-labelled oligonucleotide probe. Administration of T completely reversed the decline in VP mRNA labelling in the aged animals. Superphysiologic T further increased VP gene expression in both age groups. These data are consistent with a previous report of T-induced increase in VP immunoreactive fiber density in other extrahypothalamic regions of the brain in aged rats. This study offers further evidence that alterations in the hormonal milieu may play an important role in modulating neuronal biosynthetic activity in senescence.