Activation of cholinergic tone by pyridostigmine reverses the inhibitory effect of corticotropin-releasing hormone on the growth hormone-releasing hormone-induced growth hormone secretion.

Previous studies have shown that corticotropin-releasing hormone (CRH) is capable of inhibiting growth hormone (GH) secretion in response to GH-releasing hormone (GHRH). In an attempt to clarify the mechanism of the CRH action, we have studied the effect of enhanced cholinergic tone induced by pyridostigmine on the CRH inhibition of the GH response to GHRH in a group of six normal men and six normal women. All subjects presented a normal GH response to 50 micrograms i.v. GHRH administration (mean peak +/- SEM plasma GH levels 20 +/- 2.9 micrograms/l in men and 28.9 +/- 2.9 micrograms/l in women) with a further significant increase after pyridostigmine pretreatment (60 mg orally given 60 min before GHRH) in men (GH peaks 43.1 +/- 6.9 micrograms/l, p less than 0.005) but not in women (GH peaks 39.2 +/- 3.0 micrograms/l). In the same subjects, peripherally injected CRH (100 micrograms) significantly inhibited the GH response to GHRH (GH peaks 8.1 +/- 0.6 micrograms/l in men, p less than 0.005 and 9.9 +/- 0.7 micrograms/l in women, p less than 0.005). Pyridostigmine (60 mg) given orally at the same time of CRH administration (60 min before GHRH) reversed the CRH inhibition of GHRH-induced GH secretion (GH peaks 35.3 +/- 8.2 micrograms/l in men and 35 +/- 3.3 micrograms/l in women) with a response not significantly different to that seen in the pyridostigmine plus GHRH test. Our data confirm that pyridostigmine is capable of potentiating the GHRH-induced GH release in normal male but not female subjects.(ABSTRACT TRUNCATED AT 250 WORDS)     

Effects of disopyramide on cycle length, effective refractory period and excitable gap of atrial flutter, and relation to arrhythmia termination by overdrive pacing

The administration of class IA antiarrhythmic drugs facilities termination of atrial flutter by overdrive pacing. To investigate the electrophysiologic determinants of this effect, changes in the cycle length, the effective refractory period and the excitable gap of spontaneous type I atrial flutter were studied in 11 patients given intravenous disopyramide (3 mg/kg in 1 hour). After drug infusion, the cycle length of atrial flutter increased from 238 +/- 26 to 298 +/- 38 ms (+25%; p less than 0.001) and the effective refractory period prolonged from 169 +/- 19 to 192 +/- 25 ms (+14%; p less than 0.01). The excitable gap prolonged from 62 +/- 16 to 96 +/- 27 ms (+55%; p less than 0.001). Atrial flutter was terminated by overdrive pacing (mean cycle 203) in 10 of 11 patients; in 1 patient atrial fibrillation resulted after high rate stimulation. In the setting of an anatomically defined reentry circuit, as in type I atrial flutter, the administration of disopyramide prolongs both cycle length and refractory period. The finding of an increased excitable gap suggests that the drug exerts its prominent effect by depressing conduction velocity. A wider excitable gap allows easier penetration of the stimulus in the reentry circuit and accounts for the beneficial effects of type IA antiarrhythmic drugs on the termination of atrial flutter by overdrive pacing.     

Dynamic reorganization of human resting-state networks during visuospatial attention

Fundamental problems in neuroscience today are understanding how patterns of ongoing spontaneous activity are modified by task performance and whether/how these intrinsic patterns influence task-evoked activation and behavior. We examined these questions by comparing instantaneous functional connectivity (IFC) and directed functional connectivity (DFC) changes in two networks that are strongly correlated and segregated at rest: the visual (VIS) network and the dorsal attention network (DAN). We measured how IFC and DFC during a visuospatial attention task, which requires dynamic selective rerouting of visual information across hemispheres, changed with respect to rest. During the attention task, the two networks remained relatively segregated, and their general pattern of within-network correlation was maintained. However, attention induced a decrease of correlation in the VIS network and an increase of the DAN→VIS IFC and DFC, especially in a top-down direction. In contrast, within the DAN, IFC was not modified by attention, whereas DFC was enhanced. Importantly, IFC modulations were behaviorally relevant. We conclude that a stable backbone of within-network functional connectivity topography remains in place when transitioning between resting wakefulness and attention selection. However, relative decrease of correlation of ongoing “idling” activity in visual cortex and synchronization between frontoparietal and visual cortex were behaviorally relevant, indicating that modulations of resting activity patterns are important for task performance. Higher order resting connectivity in the DAN was relatively unaffected during attention, potentially indicating a role for simultaneous ongoing activity as a “prior” for attention selection.The function of the brain has been traditionally studied in response to controlled stimuli at the level of single neurons, cortical circuits, or systems, and spontaneous activity has been modeled as stochastic noise, with its variability randomly affecting the threshold of postsynaptic firing (hence, the forward transmission of information through cortical circuits) (1). However, in the last two decades, it has become apparent that spontaneous activity is far from random but organized in space and time at the level of micro- and macrocircuitries (2) as well as at the level of large-scale distributed neuroanatomical systems (3). The large-scale organization of spontaneous activity has been most effectively studied by computing the temporal correlation of the blood oxygenation level-dependent (BOLD) signal (or functional connectivity) measured at rest with functional magnetic resonance imaging (fMRI) in the absence of any task or stimulus. The whole cerebral cortex has been subdivided in a relatively small number of networks formed by regions that show correlated activity over long periods of time [resting-state networks (RSNs)] (4, 5). The relatively small number of RSNs raises the question of how these networks can support the presumably very large number of sensory–motor–cognitive states that form our behavior, which undoubtedly must require the dynamic and flexible coordination of brain regions.One leading idea is that RSNs represent spatiotemporal “priors” for task networks and that their modulation contributes to task-evoked responses (6, 7). According to this view, the connectivity at rest reflects experience-dependent plasticity that constrains subsequent activity during stimulus processing and maintains predictions about forthcoming stimuli. Another hypothesis considers RSNs as reflecting a state of “idling” (or inactivity) of the brain that must be reorganized for task-dependent interactions to emerge (8). The former view is supported by the stability of RSNs topography across behavioral states (9, 10) and the similarity of RSNs to task networks recruited by common cognitive tasks (7, 11). The latter view is, instead, supported by studies showing that task execution reconfigures resting connectivity to allow task-dependent interactions (12, 13).To address this fundamental question, we examined how resting functional connectivity is modulated during the execution of a spatial attention task with underlying circuitry that is well-understood (14–19). The task involves either maintaining attention to a stream of sensory stimuli or shifting attention to a different stream simultaneously presented in the opposite visual field. After each attention shift, visual information must be then dynamically rerouted from one visual field/hemisphere to the other. Task activation studies have shown that this task recruits both frontal and parietal control regions of the dorsal attention network (DAN) and occipital visual (VIS) network regions involved in sensory processing, but their dynamic interaction has never been studied. Critically, in a state of idle wakefulness (visual fixation), regions in the DAN and VIS are largely segregated (i.e., their within-network temporal correlation is stronger than their between-network correlation) (4, 5). Therefore, these networks represent an ideal system for examining the questions of how RSNs are modified by task performance and specifically, how functional connections are dynamically modulated when transitioning from a resting to an attentive state. If RSNs represent priors of task networks, then performing the attention task should maintain and even strengthen RSNs interaction. If, however, RSNs represent idling cortical rhythms, then task performance should induce a reorganization of functional connectivity patterns in a task- and behavior-dependent manner.     

Antiretroviral blood levels in HIV/HCV‐coinfected patients with cirrhosis after liver transplant: a report of three cases

Since the introduction of combined antiretroviral therapy, human immunodeficiency virus (HIV) infection is no longer a contraindication for solid organ transplantation. In HIV/hepatitis C virus (HCV)‐coinfected patients undergoing liver transplantation, HCV‐related cirrhosis, drug‐drug interactions, and calcineurin inhibitors‐related toxicity affect clinical outcomes. Therapeutic drug monitoring can be useful to assess antiretroviral over‐ or underexposure in this cohort. We report the clinical characteristics along with antiretroviral trough levels of maraviroc, darunavir, and etravirine in 3 HIV/HCV‐coinfected liver transplant recipients who developed post‐transplant liver cirrhosis.     

Neurofibromatosis Type 1 Associated with Vertebrobasilar Dolichoectasia and Pontine Ischemic Stroke

Neurofibromatosis type 1 (NF1) is a heterogeneous, common, neurocutaneous disorder presenting different complications during a life span, including cerebrovascular dysplasia. To our knowledge this is the first reported case of NF1 associated with vertebrobasilar dolichoectasia and pontine ischemic stroke. We describe a 57‐year‐old man with NF1 who presented an acute onset right‐sided facial palsy and hemiplegia, dysarthria, and gait imbalance. Magnetic resonance imaging showed an acute left paramedian pontine infarct and a hypoplastic right vertebral artery. Brain Computed Tomography Angiography revealed the occurrence of vertebrobasilar dolichoectasia. Co‐occurrence of VBD and NF1 might not be merely casual and it may significantly heighten the mortality rate in this multisystem disorder. We suggest a possible role of VBD in the genesis of our patient's clinical‐radiological features and prompt the early detection of asymptomatic arteriopathy in individuals with NF1 in order to ameliorate patients’ quality of life and life expectancy.     

Renal dysfunction and intragraft proMMP9 activity in renal transplant recipients with interstitial fibrosis and tubular atrophy

Chronic renal allograft injury is reflected by interstitial fibrosis and tubular atrophy (IF/TA) and by the accumulation of extracellular matrix (ECM). Metalloproteinases (MMPs) are renal physiologic regulators of ECM degradation. Changes in MMPs expression or activity may disturb ECM turnover leading to glomerular scarring and worsening renal function. Our goal was to investigate intragraft MMP2 and MMP9 activities and their correlation with renal dysfunction. Plasma MMP2 and MMP9 activities were analyzed as noninvasive markers of renal allograft deterioration. Transplanted patients were biopsied and histopathologically characterized as IF/TA+ or IF/TA?. Renal function was evaluated by serum creatinine, glomerular filtration rate (GFR) estimated by Modification of Diet in Renal Disease equation and urinary protein/creatinine ratio. Kidney and plasma MMP2 and MMP9 activities were analyzed by zymography. A significant renal dysfunction was observed in IF/TA+ patients. Intragraft proMMP9 showed a significant higher activity in IF/TA+ than in IF/TA? samples and was inversely correlated with the GFR. Intragraft proMMP2 activity tended to increase in IF/TA+ samples, although no statistic significance was reached. Circulating proMMP2 and proMMP9 activities did not show significant differences between groups. Our data provide evidence that correlates intragraft proMMP9 activity with the fibrotic changes and renal dysfunction observed in IF/TA.