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Nerve agents are organophosphate (OP) compounds and among the most powerful poisons known to man. A terrorist attack on civilian or military populations causing mass casualties is a real threat. The OP nerve agents include soman, sarin, cyclosarin, tabun, and VX. The major mechanism of acute toxicity is the irreversible inhibition of acetylcholinesterase. Acetylcholinesterase inhibition results in the accumulation of excessive acetylcholine levels in synapses, leading to progression of toxic signs including hypersecretions, tremors, status epilepticus, respiratory distress, and death. Miosis and rhinorrhea are the most common clinical findings in those individuals acutely exposed to OP nerve agents. Prolonged seizures are responsible for the neuropathology. The brain region that shows the most severe damage is the amygdala, followed by the piriform cortex, hippocampus, cortex, thalamus, and caudate/putamen. Current medical countermeasures are only modestly effective in attenuating the seizures and neuropathology. Anticonvulsants such as benzodiazepines decrease seizure activity and improve outcome, but their efficacy depends upon the administration time after exposure to the nerve agent. Administration of benzodiazepines may increase the risk for seizure recurrence. Recent studies document long-term neurologic and behavior deficits, and technological advances demonstrate structural brain changes on magnetic resonance imaging.

Two novel and exciting avenues of neuroscientific research involve the study of task-driven dynamic reconfigurations of functional connectivity networks and the study of functional connectivity in real-time. While the former is a well-established field within neuroscience and has received considerable attention in recent years, the latter remains in its infancy. To date, the vast majority of real-time fMRI studies have focused on a single brain region at a time. This is due in part to the many challenges faced when estimating dynamic functional connectivity networks in real-time. In this work, we propose a novel methodology with which to accurately track changes in time-varying functional connectivity networks in real-time. The proposed method is shown to perform competitively when compared to state-of-the-art offline algorithms using both synthetic as well as real-time fMRI data. The proposed method is applied to motor task data from the Human Connectome Project as well as to data obtained from a visuospatial attention task. We demonstrate that the algorithm is able to accurately estimate task-related changes in network structure in real-time. Hum Brain Mapp 38:202-220, 2017. © 2016 Wiley Periodicals, Inc.

One of the deleterious effects of acute nerve agent exposure is the induction of status epilepticus (SE). If SE is not controlled effectively, it causes extensive brain damage. Here, we review the neuropathology observed after nerve agent-induced SE, as well as the ensuing pathophysiological, neurological, and behavioral alterations, with an emphasis on their time course and longevity. Limbic structures are particularly vulnerable to damage by nerve agent exposure. The basolateral amygdala (BLA), which appears to be a key site for seizure initiation upon exposure, suffers severe neuronal loss; however, GABAergic BLA interneurons display a delayed death, perhaps providing a window of opportunity for rescuing intervention. The end result is a long-term reduction of GABAergic activity in the BLA, with a concomitant increase in spontaneous excitatory activity; such pathophysiological alterations are not observed in the CA1 hippocampal area, despite the extensive neuronal loss. Hyperexcitability in the BLA may be at least in part responsible for the development of recurrent seizures and increased anxiety, while hippocampal damage may underlie the long-term memory impairments. Effective control of SE after nerve agent exposure, such that brain damage is also minimized, is paramount for preventing lasting neurological and behavioral deficits.

The brain comprises an excitatory/inhibitory neuronal network that maintains a finely tuned balance of activity critical for normal functioning. Excitatory activity in the basolateral amygdala (BLA), a brain region that plays a central role in emotion and motivational processing, is tightly regulated by a relatively small population of γ-aminobutyric acid (GABA) inhibitory neurons. Disruption in GABAergic inhibition in the BLA can occur when there is a loss of local GABAergic interneurons, an alteration in GABAA receptor activation, or a dysregulation of mechanisms that modulate BLA GABAergic inhibition. Disruptions in GABAergic control of the BLA emerge during development, in aging populations, or after trauma, ultimately resulting in hyperexcitability. BLA hyperexcitability manifests behaviorally as an increase in anxiety, emotional dysregulation, or development of seizure activity. This Review discusses the anatomy, development, and physiology of the GABAergic system in the BLA and circuits that modulate GABAergic inhibition, including the dopaminergic, serotonergic, noradrenergic, and cholinergic systems. We highlight how alterations in various neurotransmitter receptors, including the acid-sensing ion channel 1a, cannabinoid receptor 1, and glutamate receptor subtypes, expressed on BLA interneurons, modulate GABAergic transmission and how defects of these systems affect inhibitory tonus within the BLA. Finally, we discuss alterations in the BLA GABAergic system in neurodevelopmental (autism/fragile X syndrome) and neurodegenerative (Alzheimer's disease) diseases and after the development of epilepsy, anxiety, and traumatic brain injury. A more complete understanding of the intrinsic excitatory/inhibitory circuit balance of the amygdala and how imbalances in inhibitory control contribute to excessive BLA excitability will guide the development of novel therapeutic approaches in neuropsychiatric diseases.

BACKGROUND AND PURPOSE Caramiphen is a muscarinic antagonist with potent anticonvulsant properties. Here, we investigated the efficacy of caramiphen against behavioural seizures and neuropathology induced by the nerve agent soman, and revealed two mechanisms that may underlie the anticonvulsant efficacy of caramiphen. EXPERIMENTAL APPROACH Rats were given caramiphen at 30 or 60 min after treatment with soman. Neuronal loss in the basolateral amygdala (BLA) and neuronal degeneration in the amygdala, hippocampus, piriform cortex, entorhinal cortex and neocortex, were investigated 24 h after soman, using design-based stereology and FluoroJade-C staining. The effects of caramiphen on NMDA-, AMPA- and GABA-evoked currents were studied in the BLA region of in vitro brain slices from un-treated rats, using whole-cell recordings. KEY RESULTS Caramiphen given either 30 min or 60 min after soman, suppressed behavioural seizures within 10 min, but required 1∼4.5 h for complete cessation of seizures. Neuronal loss and degeneration were significantly reduced in the caramiphen-treated, soman-exposed rats. Postsynaptic currents evoked by puff-application of NMDA on BLA principal cells were reduced by caramiphen in a dose-dependent manner (100 µM, 300 µM and 1 mM), while GABA-evoked currents were facilitated by 100 µM and 300 µM, but depressed by 1 mM caramiphen. AMPA-evoked currents were not affected by caramiphen. CONCLUSIONS AND IMPLICATIONS Caramiphen offered partial protection against soman-induced seizures and neuropathology, even when given 60 min after soman. NMDA receptor antagonism and facilitation of GABAergic inhibition in the BLA may play a key role in the anticonvulsive and neuroprotective properties of caramiphen.

Cadmium (Cd) is a pollutant that is harmful to human and animals. The liver is a target for Cd accumulation and it can disrupt Zn homeostasis. Here we examined the interaction of Zn and Cd to determine how these two metals could affect δ-aminolevulinate-dehydratase (δ-ALA-D) and metallothionein (MT), two potential molecular endpoints for Cd hepatotoxicity. Cd exposure (0.25 and 1 mg kg1 body weight, i.p., for 10 days) caused a marked increase in hepatic Zn deposition, which was not modified by treatment with Zn (2 mg kg1, i.p.). Cd caused a dose-dependent increase in hepatic Cd content that was not modified by Zn. Zn and/or Cd treatment increased hepatic δ-ALA-D activity, although the increase caused by Cd was less marked. Reactivation index of δ-ALA-D by DTT was decreased by Zn and Cd exposure, which indicates that Zn protects enzyme from oxidation. Hepatic MT was increased only after exposure to 1 mg kg−1 Cd and Zn reduced the stimulation of MT synthesis. The results presented here indicate that Cd can redistribute Zn from non-hepatic tissues to liver and the increase in hepatic Zn deposition can account for the increase in hepatic δ-ALA-D activity after Cd exposure. However, Zn blocked the increase in hepatic MT levels caused by Cd. Thus, the modulation of the two molecular endpoints of Cd toxicity used here was distinct, which indicates that the mechanism(s) involved in Zn and Cd distribution, δ-ALA-D and MT regulation are not coincident. Copyright © 2011 John Wiley & Sons, Ltd.

Objectives To evaluate the effect of patient satisfaction on health-related quality of life among dermatological outpatients, independently of patients’ sociodemographic, and clinical characteristics. Design Prospective cohort study. Satisfaction was evaluated with a standardized questionnaire three days after the visit by telephone interview. Quality of life and psychiatric disorders were measured with validated instruments (Skindex-29 and Ghq-12) before the dermatological visit and after four weeks. At the four week interview also self-reported medication adherence was assessed. Setting Outpatient clinics of a large dermatological hospital in Rome, Italy. Patients A consecutive sample of 1389 outpatients was approached, and 52% agreed to participate. Inclusion criteria were met by 424 patients, and 396 (93%) of them completed the study. Main outcome measures Improvement in health related quality of life. Results At multivariate analysis satisfied patients have approximately twice the odds for an improved quality of life on the emotions scale (OR = 1.99; 95%CI 1.1 to 3.7; P = 0.03) and on the functioning scale (OR = 2.2; 95%CI 1.1 to 4.7; P = 0.03). Patients with psychiatric disorders at baseline were less likely to have an improved quality of life on the functioning scale (OR = 0.3; 95%CI 0.2 to 0.8; P = 0.01). Conclusions This is the first prospective study showing that patient satisfaction and psychiatric disorders have a significant effect on quality of life improvement among dermatological patients, independently of patient characteristics. Particular attention should be devoted to improving physicians’ interpersonal skills, the major component of patient satisfaction.

Objective Epidemiological studies have shown that the prevalence of psychiatric disorders among dermatological patients is high. We aimed at estimating the short-term incidence of psychiatric disorders among patients with skin disease. Methods The 12-item General Health Questionnaire (GHQ-12) was used to identify subjects free from psychiatric morbidity at their first dermatological visit. The GHQ-12 was administered again after 1 month during a computer-assisted telephone interview. Results A total of 277 subjects was included in the study. At the follow-up interview, 21 (7.6%) were found to have significant psychiatric morbidity. Only lack of improvement was associated with increased incidence of psychiatric morbidity (13.6%), with an odds ratio of 3.1 (95% confidence interval 1.2–7.8), after adjustment for gender, age, educational level and clinical severity. Conclusions Physicians should devote special attention to the risk of psychiatric complications in patients who have not improved with treatment.

Objective: Intralaryngeal injection of botulinum toxin into the thyroarytenoid (TA) muscle is one of the methods for the treatment of laryngeal focal dystonia. The side effects and the modification of the laryngeal configuration are probably due to the diffusion of the botulin toxin to nearby structures. Aim: Analyze the diffusion of aniline blue (liquid substance) injected into the TA to the adjacent intrinsic laryngeal muscles.Method: Study Design: Experimental. Eighteen excised cadaveric larynges were analyzed after injection of aniline blue (0.2 mL) into the TA, using the intralaryngeal technique. After fixation by formaldehyde and decalcification using nitric acid, the larynges were sectioned in the coronal plane in 4 slices and the intrinsic muscles analyzed.Results: The aniline blue spread to the lateral cricoarytenoid muscle, the cricothyroid muscle and the posterior cricoarytenoid muscle 94.3%, 42.9%, and 8.6%, respectively. Gender, height, and width of the TA had no effect on the likelihood of d...

Through-bond and through-space interactions between nitrogen lone pairs are studied using ab initio methods for a series of symmetric bicyclic diamines with up to four -CH 2 - units in each bridge and for the molecules obtained by removing one and two of the methylene bridges. In all cases there are contributions to the odd-even splitting Δ=E(n - )-E(n + ) from through-space as well as through-bond interactions with a tendency for cancellation. The dependence of |Δ| on the number of bonds of the bridge is nonexponential at least for short bridges

An exchange-correlation potential model to be used in connection with the multiple scattering method is presented. Retaining the main advantages of the multiple scattering method with the Xα potential, particularly its low computational requirements, this new formalism does not require any adjustable parameter. Test calculations on the NiF64− system are reported and compared with experimental and ab initio results.

Onchocerciasis is a disease where often there are high levels of serum antibodies and high parasitic loads. The role of immune complexes in the development of the disease is investigated here by studying non-specific and Onchocerca volvulus specific immune complex levels, as well as the antibody concentrations, in the sera of 372 people living in either Southern (199) or Northern (173) Sudan; sera from Sudanese individuals (31) and Caucasians (21) living outside the onchocerciasis endemic area were also tested. The levels of non-specific immune complexes (NS-IC) in these sera were measured by a solid phase radio-immunoassay and those of O. volvulus-specific immune complexes (OV-IC) by an assay measuring antibody-excess complexes using C1q-coated plates. The concentrations of O. volvulus IgG antibodies were measured by ELISA. Immune complex and antibody levels of the serum donors were compared with regard to their clinical status due to onchocerciasis. These clinical changes were classified according to onchocercal lesions related to either the active destruction of microfilariae (acute changes), or the long term tissue alterations (chronic changes). Data was analysed using the Odds Ratio method. A negative association between microfilarial load and immune complex level was found, with the higher levels of OV-IC present in patients with the lower levels of dermal microfilariae (i.e., less than 10 mf/mg). Significant associations between immune complex levels and the severity of onchocercal disease were also found. Levels of OV-IC specific immune complexes were higher in infected individuals carrying dermal onchocercal lesions than in those without such clinical changes; there was no apparent relationship between these levels and the presence of ocular lesions. OV-IC levels varied considerably within each age group and from age to age. A weak positive association was detected between microfilarial load and parasite-specific IgG antibody concentration in the sera. On average younger individuals (less than 25 years) had the higher antibody levels with a gradual reduction in mean concentrations with age. The significance of these serological findings in terms of the pathogenesis of onchocerciasis is discussed.