Targeting neurons in the gastrointestinal tract to treat Parkinson's disease.

BACKGROUND: Parkinson's disease (PD) is associated with α-synuclein (αS) aggregation within the enteric nervous system (ENS) and constipation. Squalamine displaces proteins that are electrostatically bound to intracellular membranes and through this mechanism suppresses aggregation of αS monomers into neurotoxic oligomers. OBJECTIVE: We sought to evaluate the safety of ENT-01 oral tablets (a synthetic squalamine salt), its pharmacokinetics, and its effect on bowel function in PD patients with constipation. METHODS: In Stage 1, 10 patients received escalating single doses from 25 to 200 mg/day or maximum tolerated dose (MTD). In Stage 2, 34 patients received daily doses escalating from 75 to a maximum of 250 mg/day, a dose that induced change in bowel function or MTD, followed by a fixed dose for 7 days, and a 2-week washout. Primary efficacy endpoint was defined as an increase of 1 complete spontaneous bowel movement (CSBM)/week, or 3 CSBM/week over the baseline period, as defined by FDA guidelines for prokinetic agents. Safety was also assessed. RESULTS: Over 80% of patients achieved the primary efficacy endpoint, with the mean number of CSBM/week increasing from 1.2 at baseline to 3.6 during fixed dosing (p = 1.2 × 10-7). Common adverse events included nausea in 21/44 (47%) and diarrhea in 18/44 (40%) patients. Systemic absorption was <0.3%. CONCLUSIONS: Orally administered ENT-01 was safe and significantly improved bowel function in PD, suggesting that the ENS is not irreversibly damaged in PD. Minimal systemic absorption suggests that improvements result from local stimulation of the ENS. A double-blind, placebo-controlled study is now ongoing.

Maternal stress and effects of prenatal air pollution on offspring mental health outcomes in mice.

BACKGROUND: Low socioeconomic status is consistently associated with reduced physical and mental health, but the mechanisms remain unclear. Increased levels of urban air pollutants interacting with parental stress have been proposed to explain health disparities in respiratory disease, but the impact of such interactions on mental health is unknown. OBJECTIVES: We aimed to determine whether prenatal air pollution exposure and stress during pregnancy act synergistically on offspring to induce a neuroinflammatory response and subsequent neurocognitive disorders in adulthood. METHODS: Mouse dams were intermittently exposed via oropharyngeal aspiration to diesel exhaust particles (DEP; 50 µg × 6 doses) or vehicle throughout gestation. This exposure was combined with standard housing or nest material restriction (NR; a novel model of maternal stress) during the last third of gestation. RESULTS: Adult (postnatal day 60) offspring of dams that experienced both stressors (DEP and NR) displayed increased anxiety, but only male offspring of this group had impaired cognition. Furthermore, maternal DEP exposure increased proinflammatory interleukin (IL)-1ß levels within the brains of adult males but not females, and maternal DEP and NR both decreased anti-inflammatory IL-10 in male, but not female, brains. Similarly, only DEP/NR males showed increased expression of the innate immune recognition gene toll-like receptor 4 (Tlr4) and its downstream effector, caspase-1. CONCLUSIONS: These results show that maternal stress during late gestation increases the susceptibility of offspring-particularly males-to the deleterious effects of prenatal air pollutant exposure, which may be due to a synergism of these factors acting on innate immune recognition genes and downstream neuroinflammatory cascades within the developing brain.

Procedural care for adult bone marrow aspiration and biopsy: qualitative research findings from Australia.

BACKGROUND: This article presents a subset of findings on the experience of bone marrow aspiration and biopsy (BMAB) from an Australian hematology survivorship study. OBJECTIVE: The aim of the larger research was to document and explore issues associated with the experience of survivorship for hematology patients supported by Leukaemia Foundation of Queensland. The experience with BMABs was one of the issues explored. METHODS: The qualitative study involved in-depth interviews with 50 individuals with a diagnosis of a hematologic malignancy from a range of locations throughout Queensland, Australia. The interviews were transcribed verbatim, coded, and then analyzed thematically. RESULTS: The findings demonstrate that, for many of the hematology patients in the study, BMABs were a painful experience. The findings indicate that a major contributing factor to the pain and discomfort is the lack of effective procedural care. CONCLUSIONS: The findings emphasized the importance of the provision of choice with regard to anesthesia or sedation as part of the procedural care for BMABs. IMPLICATIONS FOR PRACTICE: The insights provide urgency to the call for further research to improve clinical practice and procedural care in relation to BMABs. The strong recommendation from the study is that procedural pain in relation to BMABs for hematology patients be managed from the initial procedure as the consequences of a traumatic experience can be far reaching, particularly in light of the need for repeated BMABs over the treatment trajectory. As specialist nurses are now increasingly taking responsibility for carrying out such procedures, the findings have implications for the nursing profession.

Prenatal air pollution exposure induces neuroinflammation and predisposes offspring to weight gain in adulthood in a sex-specific manner.

Emerging evidence suggests environmental chemical exposures during critical windows of development may contribute to the escalating prevalence of obesity. We tested the hypothesis that prenatal air pollution exposure would predispose the offspring to weight gain in adulthood. Pregnant mice were exposed to filtered air (FA) or diesel exhaust (DE) on embryonic days (E) 9-17. Prenatal DE induced a significant fetal brain cytokine response at E18 (46-390% over FA). As adults, offspring were fed either a low-fat diet (LFD) or high-fat diet (HFD) for 6 wk. Adult DE male offspring weighed 12% more and were 35% less active than FA male offspring at baseline, whereas there were no differences in females. Following HFD, DE males gained weight at the same rate as FA males, whereas DE females gained 340% more weight than FA females. DE-HFD males had 450% higher endpoint insulin levels than FA-HFD males, and all males on HFD showed decreased activity and increased anxiety, whereas females showed no differences. Finally, both DE males and females fed HFD showed increased microglial activation (30-66%) within several brain regions. Thus, prenatal air pollution exposure can "program" offspring for increased susceptibility to diet-induced weight gain and neuroinflammation in adulthood in a sex-specific manner.

Revealing context-specific conditioned fear memories with full immersion virtual reality.

The extinction of conditioned fear is known to be context-specific and is often considered more contextually bound than the fear memory itself (Bouton, 2004). Yet, recent findings in rodents have challenged the notion that contextual fear retention is initially generalized. The context-specificity of a cued fear memory to the learning context has not been addressed in the human literature largely due to limitations in methodology. Here we adapt a novel technology to test the context-specificity of cued fear conditioning using full immersion 3-D virtual reality (VR). During acquisition training, healthy participants navigated through virtual environments containing dynamic snake and spider conditioned stimuli (CSs), one of which was paired with electrical wrist stimulation. During a 24-h delayed retention test, one group returned to the same context as acquisition training whereas another group experienced the CSs in a novel context. Unconditioned stimulus expectancy ratings were assayed on-line during fear acquisition as an index of contingency awareness. Skin conductance responses time-locked to CS onset were the dependent measure of cued fear, and skin conductance levels during the interstimulus interval were an index of context fear. Findings indicate that early in acquisition training, participants express contingency awareness as well as differential contextual fear, whereas differential cued fear emerged later in acquisition. During the retention test, differential cued fear retention was enhanced in the group who returned to the same context as acquisition training relative to the context shift group. The results extend recent rodent work to illustrate differences in cued and context fear acquisition and the contextual specificity of recent fear memories. Findings support the use of full immersion VR as a novel tool in cognitive neuroscience to bridge rodent models of contextual phenomena underlying human clinical disorders.

Human fear conditioning conducted in full immersion 3-dimensional virtual reality.

Fear conditioning is a widely used paradigm in non-human animal research to investigate the neural mechanisms underlying fear and anxiety. A major challenge in conducting conditioning studies in humans is the ability to strongly manipulate or simulate the environmental contexts that are associated with conditioned emotional behaviors. In this regard, virtual reality (VR) technology is a promising tool. Yet, adapting this technology to meet experimental constraints requires special accommodations. Here we address the methodological issues involved when conducting fear conditioning in a fully immersive 6-sided VR environment and present fear conditioning data. In the real world, traumatic events occur in complex environments that are made up of many cues, engaging all of our sensory modalities. For example, cues that form the environmental configuration include not only visual elements, but aural, olfactory, and even tactile. In rodent studies of fear conditioning animals are fully immersed in a context that is rich with novel visual, tactile and olfactory cues. However, standard laboratory tests of fear conditioning in humans are typically conducted in a nondescript room in front of a flat or 2D computer screen and do not replicate the complexity of real world experiences. On the other hand, a major limitation of clinical studies aimed at reducing (extinguishing) fear and preventing relapse in anxiety disorders is that treatment occurs after participants have acquired a fear in an uncontrolled and largely unknown context. Thus the experimenters are left without information about the duration of exposure, the true nature of the stimulus, and associated background cues in the environment. In the absence of this information it can be difficult to truly extinguish a fear that is both cue and context-dependent. Virtual reality environments address these issues by providing the complexity of the real world, and at the same time allowing experimenters to constrain fear conditioning and extinction parameters to yield empirical data that can suggest better treatment options and/or analyze mechanistic hypotheses. In order to test the hypothesis that fear conditioning may be richly encoded and context specific when conducted in a fully immersive environment, we developed distinct virtual reality 3-D contexts in which participants experienced fear conditioning to virtual snakes or spiders. Auditory cues co-occurred with the CS in order to further evoke orienting responses and a feeling of "presence" in subjects. Skin conductance response served as the dependent measure of fear acquisition, memory retention and extinction.

Corticosteroids during continuation therapy for acute lymphoblastic leukemia: the psycho-social impact.

This article presents the findings of qualitative research exploring the psycho-social effects of corticosteroid use in pediatric hematology patients during continuation therapy for Acute Lymphoblastic Leukemia (ALL). The findings are from a 5-year longitudinal study that documented the experience of treatment for childhood leukemia and related disorders from the perspective of the child patient and their family from the point of diagnosis to 1 year post-treatment. To date, scant information on the serious emotional side-effects of corticosteroid administration for children with ALL during the continuation period is available. This is concerning in light of the many serious challenges corticosteroid use poses to families of children with ALL. For this group of parents, dealing with the impact of corticosteroids on their child was reported as the major and only treatment-related stress during the continuation period of treatment for ALL. The impact of these drugs, described in very negative terms, was considered exacerbated by the fact that during the continuation period they are repeatedly administered in 5-week cycles. Anger and aggression, both passive and in acts of physical violence, in combination with temper tantrums and uncontrollable behavior were major concerns. Under the influence of corticosteroids the children could be moody, grumpy, confused, emotionally labile, depressed, sullen and withdrawn. The children could quickly switch from one emotional state to another, such as from aggression to emotionality. They could experience trouble with sleeping and talk excessively. The parents outlined a range of positive strategies for coping with the difficult behavior. The authors make a number of recommendations aimed at assisting parents to deal with the impact of the administration of corticosteroids in continuation therapy, including increasing the awareness on the part of health care providers of the side-effects of these drugs and their impact on the child with ALL and their family; provision of information to families on the effects of corticosteroid use; and, ensuring that professional counseling assistance is available when required.

Delayed extinction attenuates conditioned fear renewal and spontaneous recovery in humans.

This study investigated whether the retention interval after an aversive learning experience influences the return of fear after extinction training. After fear conditioning, participants underwent extinction training either 5 min or 1 day later and in either the same room (same context) or a different room (context shift). The next day, conditioned fear was tested in the original room. When extinction took place immediately, fear renewal was robust and prolonged for context-shift participants, and spontaneous recovery was observed in the same-context participants. Delayed extinction, by contrast, yielded a brief form of fear renewal that reextinguished within the testing session for context-shift participants, and there was no spontaneous recovery in the same-context participants. The authors conclude that the passage of time allows for memory consolidation processes to promote the formation of distinct yet flexible emotional memory traces that confer an ability to recall extinction, even in an alternate context, and minimize the return of fear. Furthermore, immediate extinction can yield spontaneous recovery and prolong fear renewal. These findings have potential implications for ameliorating fear relapse in anxiety disorders.

Amygdala regulation of immediate-early gene expression in the hippocampus induced by contextual fear conditioning.

The basolateral nuclei of the amygdala (BLA) are thought to modulate memory storage in other brain regions (McGaugh, 2004). We reported that BLA modulates the memory for both an explored context and for contextual fear conditioning. Both of these memories depend on the hippocampus. Here, we examined the hypothesis that the BLA exerts its modulatory effect by regulating the expression of immediate-early genes (IEGs) in the hippocampus. The main findings of these experiments were: (1) Arc activity-regulated cytoskeletal protein (Arc), an immediate-early gene (also termed Arg 3.1) and c-fos mRNA are induced in the hippocampus after a context exposure, or context plus shock experience, but not after an immediate shock; and (2) BLA inactivation with muscimol attenuated the increase in Arc and c-fos mRNA in the hippocampus associated with contextual fear conditioning but did not influence Arc mRNA associated with context exploration. These results support the hypothesis that the amygdala modulates contextual fear memory by regulating expression of IEGs in the hippocampus.

Context pre-exposure obscures amygdala modulation of contextual-fear conditioning.

We report that post-training inactivation of basolateral amygdala region (BLA) with muscimol impaired memory for contextual-fear conditioning (as measured by freezing) and intra-BLA norepinephrine enhanced this memory. However, pre-exposure to the context eliminated both of these effects. These findings provide a likely explanation of why an earler study failed to observe that the BLA modulates contextual fear conditioning-they pre-exposed their rats to the context. These results also suggest that the amygdala modulates the storage of the context fear memory and may do so by influencing the storage of the representation of the context in which the shock occurred.

Beginning treatment for pediatric acute myeloid leukemia: the family connection.

There is a loud silence on psycho-oncology research in relation to pediatric Acute Myeloid Leukemia (AML). This article is part of a series that begins to address the psycho-social hiatus. The present article documents the less obvious, often hidden, aspect of beginning treatment for pediatric AML--the "behind the scenes" experience of the home and family connection. The findings are from the first stage of a five year longitudinal study that examines through qualitative research the experience of childhood leukemia from the perspective of the child, siblings and parents. Open-ended interviews, audio-recorded and transcribed verbatim, were thematically analyzed with the assistance of the Non-numerical Unstructured Data by processes of Indexing Searching and Theory-building (NUD*IST) computer program. The findings emphasize the disruption to normalcy in relation to home life, school, and work, which is exacerbated for families who relocate for specialist treatment. The findings emphasise the need for support for families coping with childhood AML.

Nosocomial pressure ulcer rates in critical care: performance improvement project.

Assessment, monitoring, and prevention of pressure ulcers in the hospitalized patient are required standards of care. The annual nosocomial pressure ulcer (NPU) rates for the adult intensive care units at our facility had trended up to 33% from 14% over a 13-month period. Our performance improvement team decided to track 5 variables that may have contributed to the increased incidence of NPU. Weekly skin care rounds were conducted to collect data, educate staff, and reinforce skin care policy and standards of care. Data analysis revealed 3 areas that required further emphasis with nursing staff: daily assessment with the Braden Scale, prevention of NPU beginning on the day of hospital admission, and the effect of sedation on patient mobility. Implementation of appropriate interventions targeted to specific Braden subscales needs to be included in the plan of care.

Beginning treatment for paediatric acute myeloid leukaemia: diagnosis and the early hospital experience.

Despite the plethora of clinical literature on the medical treatment for paediatric acute myeloid leukaemia (AML), there is a dearth of psycho-social literature on how families cope with either the disease or its treatments. The present article seeks to make a contribution by placing psychosocial aspects of childhood AML on the agenda. The findings are from a 5-year longitudinal, qualitative study on the psychosocial aspects of paediatric leukaemia. Qualitative data is gathered from open-ended interviews at three points in time on the experience of illness. The holistic findings from T1 present the impact of diagnosis and early treatment for childhood AML from the perspective of mothers, father, sibling and child patients. The study is also following up families with related disorders, thus it is possible to assess difference to other haematological groups. The findings indicate that the families bring scant prior understanding of the illness, and experience the diagnosis with fear and seriousness as a confrontation with death. At the point of entering treatment they are in a profound sense of shock and grief, which is exacerbated by a distressing, all pervading, sense of uncertainty. Families can be overwhelmed by the exhaustion of attending to the escalating practical demands of the situation combined with fatigue, worry and poor nutrition. All families find dealing with the invasive procedures and aggressive drug protocols emotionally challenging. However, in spite of the difficulties, parents have a strong desire to be with their child and find any separation painful. Families come to view the ward as a comfort zone where they have the support of the health and allied health team and the camaraderie of others experiencing a similar situation. However, even this support has to be qualified by the need for personal space, the difficulty of handling complex emotions, and the fear of being overwhelmed by difficulties other families face. The insights argue strongly for sensitive support for all individuals coping with childhood AML.

The amygdala modulates hippocampus-dependent context memory formation and stores cue-shock associations.

Preexposing rats to the context facilitates subsequent contextual fear conditioning. This effect depends on the hippocampus (J. W. Rudy, R. M. Barrientos, & R. C. O'Reilly, 2002). The authors report that inactivating the basolateral region of the amygdala (BLA) by injecting muscimol, a GABAA agonist, before or after preexposure reduced this effect. In contrast, bilateral injections of anisomycin, a protein synthesis inhibitor, into BLA did not impair the consolidation of the context memory. However, when injected after fear conditioning, anisomycin impaired consolidation of both contextual and auditory-cue fear conditioning. Results are consistent with 2 ideas about the amygdala's contribution to memory: (a) It modulates memory formation in other regions of the brain, and (b) it is a storage site for cue-shock associations.

Including the fathers' perspective in holistic care. Part 1: Findings on the fathers' experience with childhood acute lymphoblastic leukaemia.

There is scant work completed on the fathers' experience with the treatment for childhood cancer. The present discussion seeks to make a contribution to deepening our holistic understanding of paediatric treatment for leukaemia by presenting findings on the paternal involvement in, and experience of, treatment for paediatric acute lymphoblastic leukaemia (ALL). The understanding will be extended in Part 2 by a detailed examination of specific issues associated with the fathers' hospital experience and in particular, the difficulties they face with restraining their child-patient for treatment.

Including the fathers' perspective in holistic care. Part 2: Findings on the fathers' hospital experience including restraining the child patient for treatment.

Part 2 of this discussion provides a detailed examination of specific issues associated with the fathers' personal involvement in their child's hospital treatment for paediatric acute lymphoblastic leukaemia (ALL). In particular, fathers testify to the difficulties they encounter when involved with the restraining of their child-patient for treatment. Issues raised by parents during this study have been addressed by recommendations detailing factors which need to be considered when providing holistic care for the family and the child with leukaemia.

"Holding the child down" for treatment in paediatric haematology: the ethical, legal and practice implications.

Very little has been written about involuntary treatment for adult patients and even less about such treatment for paediatric patients. Ethical dilemmas for nurses in such situations have not been clearly articulated and there are no clear guidelines available in this area. The following findings from a qualitative, longitudinal study on the psycho-social aspects of treatment for childhood leukaemia and related diseases are offered as preliminary work on this important professional issue. The feelings of parents when confronted with the necessity of holding their child down so that they may receive probably curative treatments for acute lymphoblastic leukaemia are described and some of the ethical and legal issues confronting nurses who provide these treatments are explored.

Lead and conditioned fear to contextual and discrete cues.

Male Fischer 344 rats received either tap water or water containing 250 ppm lead for 90 days prior to training in either Pavlovian fear conditioning or consummatory contrast, an aversive reward reduction paradigm. In Experiment 1, lead-exposed and -unexposed rats were trained in operant chambers over a 6-min session. After 3 min elapsed, three tone-shock pairings were presented over the remainder of the session. Rats then received 7 days of extinction training in an identical procedure with only tones presented, no shocks. Lead-exposed rats exhibited greater behavioral suppression to both the contextual and auditory cues that predicted shock. In Experiment 2, rats were placed in operant chambers daily and allowed to consume either a 15% or a 5% fructose solution for 7 days. On Day 8, the rats consuming the 15% fructose solution were shifted to the 5% solution for 3 days. Lead-exposed rats did not differ from their controls in either initial consumption of either solution or in the suppression of their consumption after shifting to the 5% solution. Taken together, these findings suggest that lead impairs the extinction of fear conditioning and this finding is not due to a nonspecific increase in aversive emotionality.

Lead and spatial vs. cued open field performance.

Male Fischer 344 rats received chronic exposure to either water containing 250 ppm lead or tap water. On the first day of the study, rats were allowed to habituate to a 1-m(2) open field arena with a rectilinear grid pattern of food wells on the floor for a 2-min session. On the following 7 days, half the rats were trained (four trials per day, 2-4-min intertrial interval) to find a food location based on extra-maze spatial cues and the other half were trained to find a food location based on a discrete intra-maze cue placed over the baited food well. While lead did not appear to significantly affect motor activity during the habituation phase, lead-exposed spatially trained rats exhibited superior acquisition and performance of the food-rewarded task compared to their controls and their cue-trained lead-exposed and counterparts. Furthermore, by the last day of training, Day 7, lead significantly reduced the relative amount of time spent on the periphery of the maze in spatially and cued-trained rats.