Polygenic contributions to performance on the Balloon Analogue Risk Task.

Risky decision-making is a common, heritable endophenotype seen across many psychiatric disorders. Its underlying genetic architecture is incompletely explored. We examined behavior in the Balloon Analogue Risk Task (BART), which tests risky decision-making, in two independent samples of European ancestry. One sample (n = 1138) comprised healthy participants and some psychiatric patients (53 schizophrenia, 42 bipolar disorder, 47 ADHD); the other (n = 911) excluded for recent treatment of various psychiatric disorders but not ADHD. Participants provided DNA and performed the BART, indexed by mean adjusted pumps. We constructed a polygenic risk score (PRS) for discovery in each dataset and tested it in the other as replication. Subsequently, a genome-wide MEGA-analysis, combining both samples, tested genetic correlation with risk-taking self-report in the UK Biobank sample and psychiatric phenotypes characterized by risk-taking (ADHD, Bipolar Disorder, Alcohol Use Disorder, prior cannabis use) in the Psychiatric Genomics Consortium. The PRS for BART performance in one dataset predicted task performance in the replication sample (r = 0.13, p = 0.000012, pFDR = 0.000052), as did the reciprocal analysis (r = 0.09, p = 0.0083, pFDR=0.04). Excluding participants with psychiatric diagnoses produced similar results. The MEGA-GWAS identified a single SNP (rs12023073; p = 3.24 × 10-8) near IGSF21, a protein involved in inhibitory brain synapses; replication samples are needed to validate this result. A PRS for self-reported cannabis use (p = 0.00047, pFDR = 0.0053), but not self-reported risk-taking or psychiatric disorder status, predicted behavior on the BART in our MEGA-GWAS sample. The findings reveal polygenic architecture of risky decision-making as measured by the BART and highlight its overlap with cannabis use.

Treatment options to manage pain at the end of life.

Experts believe that the time preceding death can be comfortable if people die without pain, with dignity, and in their own way. Given current analgesic options, psychological and spiritual interventions, and an effective health care delivery system, all these goals are achievable. Pain management is one of the most important aspects of end-of-life care. Effective analgesics should be chosen carefully, in keeping with the patient's overall condition, level and stability of pain, and specific patient/family wishes. Ideally, analgesics should be initiated as soon as appropriate. The variety of routes of delivery, ranging from oral to transdermal or epidural to intrathecal, allows a selection that will achieve comfort and yet be least troublesome for the caregiver and patient. As the palliative care specialty continues to grow in the United States, it is imperative that health care professionals in the field develop basic to advanced primers to assist in equipping colleagues in all specialties with an understanding of effective opioid use, as well as the multidimensional aspects of helping patients achieve comfort at the end of life.

Management of emergent conditions in palliative care.

Emergent conditions arising in patients with advanced terminal disease are inevitable and create stressful situations for patients, caregivers, and health care personnel. Discussions regarding appropriate levels of intervention based on parameters such as patient wishes, proper access to documentation of those wishes, location of care, cognitive status and extent of clinical decline are important to have before crisis situations. Common emergencies to be addressed include those that may or may not be associated with advanced malignancies, including compression syndromes, superior vena cava syndrome, hypercalcemia, acute dyspnea, seizures, acute urinary and bowel obstructions, massive hemorrhage, cardiac tamponade, acute embolic phenomenon, and psychiatric emergencies. Although not all clinical scenarios will be addressed in this article, the more common ones will be discussed.

Selecting clinical quality improvement projects: getting a bigger return for your investment.

An urban medical center developed and implemented a process for selecting clinical quality-improvement projects. The process was designed to select projects that would deliver greater returns than had previous projects. The four-step process involved: (1) establishing project selection criteria, (2) identifying potential projects, (3) assigning points and ranking projects, and (4) selecting projects based on rank and available resources. This process won physician commitment and secured administrative support. It identified projects that had unprecedented success in improving clinical outcomes, increasing patient satisfaction, and reducing cost.

Hypoxia-ischemia-induced apoptotic cell death correlates with IGF-I mRNA decrease in neonatal rat brain.

Hypoxia-ischemia induces apoptotic and necrotic cell death, which results partially from persistent alterations in cellular energy homeostasis. Insulin-like growth factor I (IGF-I) is an anabolic pleiotrophic factor required by developing neurons for their optimal proliferation, differentiation, and survival. To determine how cell death and changes in IGF-I gene expression relate to the extent of hypoxia-ischemia, we evaluated the time course of apoptosis in a neonatal hypoxia-ischemia model in relation to the cellular distribution of IGF-I and IGFBP5 mRNA. Severe hypoxia-ischemia results in an immediate decrease in neuronal IGF-I and IGFBP5 mRNA. The decrease in neuronal IGF-I mRNA was concurrent with an increase in the number of apoptotic cells. It is conceivable that the immediate decrease in IGF-I gene expression may contribute to the impending neuronal death and selective vulnerability of myelinogenesis during the perinatal period.

Regulating and assessing risks of cholinesterase-inhibiting pesticides: divergent approaches and interpretations.

This document presents a revised framework for conducting worker and dietary risk assessments for less-than-lifetime exposures to organophosphate or carbamate pesticides based on red blood cell (RBC) or brain acetylcholinesterase (AChE) inhibition or the presence of clinical signs and symptoms. The proposals for appropriate uncertainty factors are based on the biological significance of the cholinesterase (ChE) inhibition noted at the lowest-observed-effect level (LOEL) and the degree of uncertainty in the extrapolation between human and animal data. An extensive evaluation of industry data, not previously summarized, and the available literature indicate that the following risk assessment principles are supportable and protective of human health: Plasma ChE inhibition is not an adverse effect, and therefore should not be utilized in risk assessments. Red blood cell AChE is not associated with the nervous system and inhibition is not per se an adverse (neurotoxic) effect. When available, cholinergic effects or brain AChE inhibition data should take precedence over RBC AChE for determining no-observed-effect levels (NOELs). When available, human RBC AChE inhibition or cholinergic effects data should take precedence over animal data for determining NOELs. Due to the lack of adversity associated with inhibition of RBC AChE, the use of a 10-fold (10x) uncertainty factor from the NOEL is adequate when RBC AChE inhibition data from either animal or human studies are used to assess human risk. Due to greater potential for adversity, NOELs for brain AChE inhibition and cholinergic effects identified in animal studies should receive a default uncertainty factor of 100x; lower uncertainty factors may be used on a case-by-case basis. NOELs based on cholinergic effects noted in human studies should only require a 10x uncertainty factor, since an interspecies extrapolation factor from animals to humans is unnecessary. For RBC and brain AChE activity the threshold for defining a NOEL should be less than or equal to 20% difference from control activity in all species. For risk assessment purposes, duration and route of the study should reflect the expected duration and route of exposure for humans (i.e., a 21-d or 28-d dermal study for subchronic occupational dermal exposure assessment). When dermal data are not available, a subchronic oral toxicity study and an appropriate dermal penetration factor should be used. A general default of 10% absorption should be used, analogous to the United Kingdom and German exposure models that are widely used in Europe. The recommendations in this document are generally consistent with current risk assessment procedures used by Canada, the European Community (EC), and the United Kingdom (UK).

Perinatal hypoxia-ischemia decreased neuronal but increased cerebral vascular endothelial IGFBP3 expression.

In adults, insulin-like growth factor binding protein 3 (IGFBP3) is the main carrier protein for circulating insulin-like growth factors (IGFs) (IGF-I and -II). While most IGFBP3 is synthesized in the liver, it is also expressed locally by many cell types including vascular endothelial cells. The regulation of this endothelial IGFBP3 expression, especially in response to hypoxic-ischemic injury, has not been investigated in vivo. Using in situ hybridization histochemistry, we studied the cellular distribution of IGFBP3 mRNA in rat brains following hypoxic-ischemic injury at 1, 5, 24, and 72 h of recovery. In normal P7 rat brain, IGFBP3 mRNA was found in neurons within the thalamus, hippocampus, and amygdaloid. Low levels of IGFBP3 mRNA were also detected in cerebral vascular endothelial cells. After the hypoxic-ischemic injury, the levels of neuronal IGFBP3 mRNA substantially decreased within 24 h in areas that were normally supplied by the middle cerebral artery. In the meantime, there was an immediate increase in IGFBP3 expression in vascular endothelial cells throughout the affected hemisphere. This vascular IGFBP3 expression was further enhanced with the highest level at 24 h of recovery whereas neuronal IGFBP3 expression was further decreased. By 72 h of recovery, IGFBP3 was no longer expressed in vascular endothelial cells. Taken together, the activation of IGFBP3 is a likely mechanism by which vascular endothelial cells respond to hypoxic-ischemic insult. In addition, increased endothelial IGFBP3 may modulate the interaction of IGFs with IGF-I receptors at the site of injury and/or act independently on endothelial cell growth.

Symptom management algorithms for palliative care.

In order to develop standards of care that alleviate pain and other distressing symptoms among dying patients, the Providence Hospice of Yakima team has developed and utilized pain and nonpain symptom management algorithms. In use since late 1993, the system is a success, as demonstrated by positive satisfaction surveys among physicians, staff, and family members. This article offers an introduction to the algorithmic process, key components of its success, and guidelines for further improvement in the care provided to dying patients.

Coordinate IGF-I and IGFBP5 gene expression in perinatal rat brain after hypoxia-ischemia.

Insulin-like growth factor I (IGF-I) is an anabolic pleiotrophic factor essential for postnatal rat brain development, especially during the first 21 days, the "critical growth period." Cerebral hypoxic-ischemic insults occurring during the perinatal period can result in neuronal necrosis and permanent brain damage. To understand the regulation of the action of IGF-I in response to such a metabolic insult, we investigated the gene expression of IGF-I, type I IGF receptor, IGF binding protein (IGFBP)2, and IGFBP5 during the first 72 h after hypoxia-ischemia in the immature rat. At 1 h of recovery, messenger RNA (mRNA) levels of all IGF system components were decreased throughout the hemisphere ipsilateral to the carotid artery ligation. This decrease is more pronounced at 24 h of recovery, especially in areas vulnerable to hypoxic-ischemic injury, such as the thalamus and hippocampus. At 72 h of recovery, although IGFBP2 and type 1 IGF receptor mRNA levels remain suppressed, gene expression of both IGF-I and IGFBP5 was activated in reactive astrocytes.Therefore, during the critical growth period in rats, the transcriptional levels of all IGF system components are extremely sensitive to metabolic perturbations associated with cerebral hypoxia-ischemia. The immediate decrease in IGF-I gene expression may be partially responsible for the impending neuronal death and selective vulnerability of myelinogenesis during the perinatal period.

Vulnerability to criminal exploitation: influence of interpersonal competence differences among people with mental retardation.

A study by Wilson & Brewer (1992) has indicated that people with mental retardation are at greater risk of having a crime committed against them than age-matched cohorts from the general population. The present study was designed to test the hypothesis that this heightened vulnerability is partially explained in terms of behavioural shortcomings reflecting interpersonal competence. Twenty victims of crime and 20 nonvictims, all with mental retardation, were recruited so that means for age, adaptive behaviour and IQ were similar. Groups were compared on the Test of Interpersonal Competence and Personal Vulnerability (TICPV) developed for the present study. Results showed poorer interpersonal competence among the victims, indicating that victims had difficulty in deciding on the appropriate behaviour in some interactions. Performance on the test was shown to be internally consistent, stable over time and a valid measure of vulnerability. The study concluded with recommendations for more detailed investigation of the precise behaviours which influence risk as a first step in an attempt at remediation.

Effects of hypoxia-ischemia on GLUT1 and GLUT3 glucose transporters in immature rat brain.

Cerebral hypoxia-ischemia produces major alterations in energy metabolism and glucose utilization in brain. The facilitative glucose transporter proteins mediate the transport of glucose across the blood-brain barrier (BBB) (55 kDa GLUT1) and into the neurons and glia (GLUT3 and 45 kDa GLUT1). Glucose uptake and utilization are low in the immature rat brain, as are the levels of the glucose transporter proteins. This study investigated the effect of cerebral hypoxia-ischemia in a model of unilateral brain damage on the expression of GLUT1 and GLUT3 in the ipsilateral (damaged, hypoxic-ischemic) and contralateral (undamaged, hypoxic) hemispheres of perinatal rat brain. Early in the recovery period, both hemispheres exhibited increased expression of BBB GLUT1 and GLUT3, consistent with increased glucose transport and utilization. Further into recovery, BBB GLUT1 increased and neuronal GLUT3 decreased in the damaged hemisphere only, commensurate with neuronal loss.

Glucose transport in developing rat brain: glucose transporter proteins, rate constants and cerebral glucose utilization.

Developing rat brain undergoes a series of functional and anatomic changes which affect its rate of cerebral glucose utilization (CGU). These changes include increases in the levels of the glucose transporter proteins, GLUT1 and GLUT3, in the blood-brain barrier as well as in the neurons and glia. 55 kDa GLUT1 is concentrated in endothelial cells of the blood-brain barrier, whereas GLUT3 is the predominant neuronal transporter. 45 kDa GLUT1 is in non-vascular brain, probably glia. Studies of glucose utilization with the 2-14C-deoxyglucose method of Sokoloff et al., (1977), rely on glucose transport rate constants, k1 and k2, which have been determined in the adult rat brain. The determination of these constants directly in immature brain, in association with the measurement of GLUT1, GLUT3 and cerebral glucose utilization suggests that the observed increases in the rate constants for the transport of glucose into (ki) and out of (k2) brain correspond to the increases in 55 kDa GLUT1 in the blood-brain barrier. The maturational increases in cerebral glucose utilization, however, more closely relate to the pattern of expression of non-vascular GLUT1 (45 kDa), and more specifically GLUT3, suggesting that the cellular expression of the glucose transporter proteins is rate limiting for cerebral glucose utilization during early postnatal development in the rat.

The electrical effect of two commonly used clinical stimulators on traumatic edema in rats.

The purposes of this study were to determine the effect of electrical stimulation on traumatic rat hind-paw edema and to establish whether there would be a difference in edema reduction when two types of stimulators were used. The animals were divided into a control group (n = 15) and two experimental groups, one group receiving monophasic pulsed current (MPC group, n = 15) and the other group receiving symmetrical biphasic pulsed current (SBPC group, n = 14). The right hind-paw volume of all groups was measured prior to traumatization and at 24, 48, 72, and 96 hours posttrauma. Following the 24-, 48-, and 72-hour measurements, 1 hour of electrical stimulation was administered to the experimental groups. The control group received sham treatment. Results revealed significant edema reduction in all groups over the 96-hour period, with each group's greatest change in paw volume occurring 48 hours posttrauma. At the final paw volume measurement, there was no significant difference between the MPC and control groups or between the MPC and SBPC groups. The SBPC group, however, showed less reduction in edema than did the control group. One hour of electrical stimulation per day over 3 consecutive days failed to demonstrate significant edema reduction in either the MPC group or the SBPC group as compared with the control group. The results of this study demonstrated that the electrical stimulation characteristics and procedures currently used in the clinic do not significantly reduce extant edema caused by trauma in rat hind limbs.

Organizational issues in nursing case management.

The nursing case manager has a critical role in achieving the high level of interdepartmental communication, mutual adjustment, and coordination necessary for efficient and effective patient care. This article addresses organizational factors that influence the nursing case manager's role in the interconnectedness of the departments.

Managing hypernatremia in fluid deficient elderly.

The institutionalized elderly are at risk for developing fluid volume depletion with progression to hypernatremia. This is particularly common in patients transferred to an acute care setting from a nursing home. A marked reduction in intracellular fluid and the increase in body fat associated with normal aging predispose the elderly to water loss with very little environmental prompting. Conditions contributing to the development of fluid volume deficit include febrile illness, utilization of enteral supplements, gastrointestinal bleeding, use of loop diuretics, renal failure, prolonged vomiting, diarrhea, diabetes, and disability induced fluid restriction. This can lead to apathy and confusion, which are often incorrectly attributed to dementia. The utilization of Roy's Adaptation Model to this problem focuses on the regulator subsystem and the physiologic mode.