Pharmacological treatments that facilitate extinction of fear: Relevance to psychotherapy

A great deal is now known about the mechanisms of conditioned fear acquisition and expression. More recently, the mechanisms of inhibition of conditioned fear have become the subject of intensive study. The major model system for the study of fear inhibition in the laboratory is extinction, in which a previously fear conditioned organism is exposed repeatedly to the fear-eliciting cue in the absence of any aversive event and the fear conditioned response declines. It is well established that extinction is a form of new learning as opposed to forgetting or “unlearning” of conditioned fear, and it is hypothesized that extinction develops when sensory pathways conveying sensory information to the amygdala come to engage GABAergic interneurons through forms of experience-dependent plasticity such as long-term potentiation. Several laboratories currently are investigating methods of facilitating fear extinction in animals with the hope that such treatments might ultimately prove to be useful in facilitating exposure-based therapy for anxiety disorders in clinical populations. This review discusses the advances that have been made in this field and presents the findings of the first major clinical study to examine the therapeutic utility of a drug that facilitates extinction in animals. It is concluded that extinction is an excellent model system for the study of fear inhibition and an indispensable tool for the screening of putative pharmacotherapies for clinical use.     

A perfluorocarbon emulsion prime additive improves the electroencephalogram and cerebral blood flow at the initiation of cardiopulmonary bypass

Depression in electroencephalogram (EEG) has been documented clinically and is reproducible in swine at the initiation of cardiopulmonary bypass (CPB) utilizing a crystalloid prime. The physiological cause of this transient alteration in electrical brain activity appears to be associated with the transient drop in arterial pressure. The etiology is unknown but may be attributable to the bolus of the crystalloid prime or micro emboli, either air or fibrin-platelet. Thirteen swine (17-26 kg) were anesthetized and received 4 mg/kg dexamethasone, and following a tracheotomy were ventilated with halothane in 100% O2. Surgical preparation included: sternotomy and preparation for right atrial-aortic CPB. The CPB circuit consisted of a hollow fiber membrane oxygenator, a hard-shell venous reservoir, a roller pump, and PVC tubing. The circuit was randomly primed with either 1200 ml Plasmalyte-A or 10 ml/kg perfluorocarbon emulsion (PFE) and Plasmalyte-A to total 1200 ml. The animals were monitored continuously for systemic hemodynamics and electrocardiogram, and cerebral monitoring included blood flow and bitemporal EEG. Arterial blood gases were measured and PaCO2 was kept between 30-45 mmHg both before and during CPB. Cerebral blood flow (CBF) was measured pre-CPB and at 10 minutes after initiation of CPB. Bitemporal computerized EEG was analyzed every 60 seconds. Total power of each hemisphere, power in frequency bands, and spectral edge were recorded. All animals demonstrated a relative decrease in EEG total power at the onset of CPB. Animals that received PFE demonstrated a more stable arterial blood pressure, an increased CBF, and a lesser decrease and an earlier recovery of the EEG power.(ABSTRACT TRUNCATED AT 250 WORDS)     

An in vitro protocol for evaluation and comparison of membrane oxygenators

With the trend in open heart surgery toward normothermic bypass and warm blood cardioplegia, greater demand is being placed on the perfusionist to select an oxygenator that will perform safely and efficiently under a variety of conditions. While manufacturers report performance parameters for their products, the data is often not comparable due to widely differing conditions. Recent in vitro evaluation techniques employed to characterize membrane oxygenators do not simulate the actual oxygenator conditions observed during cardiopulmonary bypass. Biocompatibility and drug delivery are reported but comparisons of different oxygenator performance parameters are not completely addressed. We have designed a test circuit and an evaluation protocol to simultaneously characterize the performance of multiple oxygenators under identical conditions. The test circuit is designed to simulate clinical conditions and to evaluate gas exchange, blood path pressures, gas path pressures, and hemolysis. Previously reported studies have relied on a comparison of a single membrane oxygenator and a single bubble oxygenator. Our protocol will compare multiple membrane oxygenators, in vitro, under similar clinically relevant conditions. Such testing would be done prior to animal or clinical trials. Furthermore in vitro tests should be more reproducible and more discriminating than are ex vivo tests.     

Mechanisms of aortic valve incompetence: finite element modeling of aortic root dilatation

Background. Idiopathic root dilatation often results in dysfunction of an otherwise normal aortic valve. To examine the effect of root dilatation on leaflet stress, strain, and coaptation, we utilized a finite element model.

Methods. The normal model incorporated the geometry, tissue thickness, stiffness, and collagen fiber alignment of normal human roots and valves. We evaluated four dilatation models in which diameters of the aortic root were dilated by 5%, 15%, 30%, and 50%. Regional stress and strain were evaluated and leaflet coaptation percent was calculated under diastolic pressure.

Results. Root dilatation significantly increased regional leaflet stress and strain beyond that found in the normal model. Stress increases ranged from 57% to 399% and strain increases ranged from 39% to 189% in the 50% dilatation model. Leaflet stress and strain were disproportionately high at the attachment edge and coaptation area. Leaflet coaptation was decreased by 18% in the 50% root dilatation model.

Conclusions. Idiopathic root dilatation significantly increases leaflet stress and strain and reduces coaptation in an otherwise normal aortic valve. These alterations may affect valve-sparing aortic root replacement procedures.     

A Qualitative Inquiry About Pruno,an Illicit Alcoholic Beverage Linked to Botulism Outbreaks in United States Prisons

Objectives. Since 2011, 3 outbreaks of botulism in US prisons have been attributed to pruno, which is an alcoholic beverage made by inmates. Following 1 outbreak, we conducted a qualitative inquiry to understand pruno brewing and its social context to inform outbreak prevention measures.Methods. We interviewed staff, inmates, and parolees from 1 prison about pruno production methods, the social aspects of pruno, and strategies for communicating the association between botulism and pruno.Results. Twenty-seven inmates and parolees and 13 staff completed interviews. Pruno is fermented from water, fruit, sugar, and miscellaneous ingredients. Knowledge of pruno making was widespread among inmates; staff were familiar with only the most common ingredients and supplies inmates described. Staff and inmates described inconsistent consequences for pruno possession and suggested using graphic health messages from organizations external to the prison to communicate the risk of botulism from pruno.Conclusions. Pruno making was frequent in this prison. Improved staff recognition of pruno ingredients and supplies might improve detection of brewing activities in this and other prisons. Consistent consequences and clear messages about the association between pruno and botulism might prevent outbreaks.Botulism is a rare but serious illness that can lead to respiratory failure and death. Botulism patients may initially present with blurred or double vision, drooping eyelids, slurred speech, and difficulty swallowing before developing more severe signs and symptoms, such as paralysis and difficulty breathing. In the United States, an average of 145 confirmed botulism cases are reported each year, of which approximately 15% are attributable to foodborne botulism.1 Foodborne botulism is caused by ingestion of botulinum toxin, a bacterial toxin that is produced under the following rarely attained conditions: an anaerobic environment with warm temperatures and low acid, salt, and sugar concentrations.2 Alaska Native foods and home-canned vegetables are the food items most commonly associated with foodborne botulism3,4; however, in the past decade, 5 foodborne botulism outbreaks have been attributed to pruno, an illicit alcoholic beverage made in prisons.5 Pruno was initially recognized as a botulism vehicle after it was implicated in 2 outbreaks in California in 2004 and 2005; these outbreaks resulted in confirmed botulism in 5 inmates, 3 of whom were critically ill and mechanically ventilated.6 No additional outbreaks were reported until 2011, when 8 maximum security inmates in Utah developed botulism after drinking pruno. Three were mechanically ventilated, and most reported persistent symptoms, such as weakness, 11 months after the outbreak.7 The following year, 12 Arizona inmates were sickened in 2 outbreaks of botulism associated with pruno consumption; 8 were mechanically ventilated.5 In all 5 outbreaks, pruno was made with potatoes,5 an uncommon pruno ingredient according to online sources, and a food historically associated with botulism.8,9 Because of these outbreaks, pruno-related botulism accounted for 40% and 48% of foodborne botulism cases in the United States in 2011 and 2012, respectively (Centers for Disease Control and Prevention, unpublished data).Internet sources indicate that pruno is common in US prisons.10–12 Although recent trends suggest future pruno-related botulism outbreaks are likely to occur,5,7 there is a dearth of information about how pruno is made and distributed in prisons, and the social and entrepreneurial aspects of its production and use. To address these gaps and inform botulism outbreak prevention measures, 4 months after the Utah outbreak, we conducted a qualitative inquiry in the affected prison to better understand the brewing process, social context of pruno, and communication strategies for informing inmates about the risk of botulism from pruno.