Morphine for the relief of breathlessness in patients with chronic heart failure--a pilot study.

BACKGROUND: Chronic heart failure (CHF) patients can experience significant breathlessness despite maximum medication for their heart failure. Morphine has long been used to relieve symptoms in acute failure, but there is little evidence about this potentially useful palliative therapy in CHF. AIMS: To determine the efficacy of morphine for the relief of breathlessness in patients with CHF. METHOD: Ten out-patients with NYHA III/IV CHF entered a randomised, double-blind, placebo controlled, crossover pilot study. The active arm was 4 days of 5 mg oral morphine four times daily (2.5 mg morphine if creatinine > 200 micromol/l). There were 2 days wash-out between active and placebo arms. RESULTS: 6/10 patients indicated that morphine improved their breathlessness. On morphine, the median breathlessness score fell by 23 mm (P = 0.022) by day 2. The improvement was maintained. Sedation scores increased until day 3 (P = 0.013), reducing on day 4. Four patients developed constipation (P = 0.026). On placebo, there was no significant difference in breathlessness or sedation. One patient had constipation. There were no significant differences in either arm in nausea, quality of life scores, blood pressure, pulse, respiratory rate, or catecholamines. Brain natriuretic peptide fell in both arms; significantly in the morphine arm. CONCLUSION: Morphine relieves breathlessness due to CHF. A larger study is indicated.

Aplysia ror forms clusters on the surface of identified neuroendocrine cells.

The ror receptors are a highly conserved family of receptor tyrosine kinases genetically implicated in the establishment of cellular polarity. We have cloned a ror receptor from the marine mollusk Aplysia californica. Aplysia ror (Apror) is expressed in most developing neurons and some adult neuronal populations, including the neuroendocrine bag-cell neurons. The Apror protein is present in peripheral neuronal processes and ganglionic neuropil, implicating the kinase in the regulation of growth and/or synaptic events. In cultured bag-cell neurons, the majority of the protein is stored in intracellular organelles, whereas only a small fraction is expressed on the surface. When expressed on the cell surface, the protein is clustered on neurites, suggesting that Apror is involved in the organization of functional domains within neurons. Apror immunoreactivity partially colocalizes with the P-type calcium channel BC-alpha1A at bag-cell neuron varicosities, suggesting a role for Apror in organizing neuropeptide release sites.

Regulation of synaptic function by neurotrophic factors in vertebrates and invertebrates: implications for development and learning.

Recent studies have demonstrated that neurotrophic factors contribute to the molecular events involved in synaptic plasticity, both during vertebrate development and in the mature nervous system. Although it is well established that many of the cellular and molecular mechanisms underlying synaptic plasticity are conserved between invertebrates and vertebrates, there are, as yet, very few neurotrophic factors identified in invertebrate species. Nonetheless, vertebrate neurotrophins can influence invertebrate neuronal growth and plasticity. In addition, homologs of neurotrophic factor receptors have been identified in several invertebrate species. These studies may indicate that the roles of neurotrophins in both developmental and adult plasticity are highly conserved across diverse phyla.

A novel type of programmed neuronal death in the cervical spinal cord of the chick embryo.

We examined the massive early cell death that occurs in the ventral horn of the cervical spinal cord of the chick embryo between embryonic days 4 and 5 (E4 and E5). Studies with immunohistochemical, in situ hybridization, and retrograde-tracing methods revealed that many dying cells express Islet proteins and Lim-3 mRNA (motoneuron markers) and send their axons to the somatic region of the embryo before cell death. Together, these data strongly suggest that the dying cells are somatic motoneurons. Cervical motoneurons die by apoptosis and can be rescued by treatment with cycloheximide and actinomycin D. Counts by motoneuron numbers between E3.5 and E10 revealed that, in addition to cell death between E4 and E5, motoneuron death also occur between E6 and E10 in the cervical cord. Studies with [3H]thymidine autoradiography and morphological techniques revealed that in the early cell-death phase (E4-E5), genesis of motoneurons, axonal elongation, and innervation of muscles is still ongoing. However, studies with [3H]thymidine autoradiography also revealed that the cells dying between E4 and E5 become postmitotic before E3.5. Increased size of peripheral targets, treatment with neuromuscular blockade, and treatment with partially purified muscle or brain extracts and defined neurotropic agents, such as NGF, BDNF, neurotrophin-3, CNTF, bFGF, PDGF, S100-beta, activin, cholinergic differentiation factor/leukemia inhibitory factor, bone morphogenetic protein-2, IGF-I, interleukin-6, and TGF-beta 1, were all ineffective in rescuing motoneurons dying between E4 and E5. By contrast, motoneurons that undergo programmed cell death at later stages (E6-E10) in the cervical cord are target-dependent and respond to activity blockade and trophic factors. Experimental approaches revealed that early cell death also occurs in a notochord-induced ectopic supernumerary motoneuron column in the cervical cord. Transplantation of the cervical neural tube to other segmental regions failed to alter the early death of motoneurons, whereas transplantation of other segments to the cervical region failed to induce early motoneuron death. These results suggest that the mechanisms that regulate motoneuron death in the cervical spinal cord between E4 and E5 are independent of interactions with targets. Rather, this novel type of cell death seems to be determined by signals that either are cell-autonomous or are derived from other cells within the cervical neural tube.

The expression of trkB and p75 and the role of BDNF in the developing neuromuscular system of the chick embryo.

The neurotrophin, brain-derived neurotrophic factor, prevents motoneuron cell death during the normal development of the chick embryo. Brain-derived neurotrophic factor is a ligand for the low-affinity NGF receptor, p75, and for the high-affinity neurotrophin receptor, trkB. If motoneurons respond directly to brain-derived neurotrophic factor then they must possess at least one, and possibly both, of these receptors during the period of naturally occurring cell death. Histological sections from the lumbar region of chick embryos were probed for the presence of trkB and p75 mRNA using digoxigenin-labeled anti-sense RNA probes. p75 mRNA was present in spinal cord motoneurons at stages of development that correlate with motoneuron cell death. Immunohistochemical localization also revealed that p75 protein was present in motoneurons, primarily along the ventral roots and developing intramuscular nerves. In contrast trkB mRNA was not present in chick motoneurons until after the process of cell death was underway. The timing of trkB expression suggested that some motoneurons, i.e., those that die prior to the onset of trkB expression, may be insensitive to brain-derived neurotrophic factor. This was confirmed by comparing the number of surviving motoneurons following different in vivo treatment paradigms. The evidence indicates that motoneurons undergo a temporal shift in sensitivity to brain-derived neurotrophic factor.

Value of theophylline treatment in patients handicapped by chronic obstructive lung disease.

BACKGROUND: It is still not certain whether it is worth using theophylline in addition to inhaled bronchodilators and corticosteroids to treat obstructive airways disease. This trial was designed to test whether the addition of prescribed theophylline in doses sufficient for sustained optimal steady state plasma concentrations would produce any detectable additional advantage in spirometric or functional variables in these handicapped patients. METHODS: A randomised, double blind, placebo controlled, crossover study of added theophylline treatment was aimed at steady state plasma concentrations of 10 and 17 mg/l, the dose being calculated individually by Bayesian parameter estimation and maintained for six weeks along with the patient's previously prescribed bronchodilators and steroids. Of 20 patients sequentially recruited, 15 provided data that could be analysed. All had chronic obstructive lung disease with a mean forced expiratory volume in the first second (FEV1) up to about 30% of the predicted value and gave no history of being treated with theophylline. The protocol included spirometry, whole body plethysmography, and treadmill exercise. Measurements also included steady state plasma theophylline concentrations and trapped gas volume. Quality of life was assessed by an established questionnaire method covering breathlessness in everyday activities, fatigue, emotional function, and control over the disease. RESULTS: Both target plasma concentrations were achieved. Improvements in peak flow (PEF; mean 20%), trapped gas volumes (38%), two stage vital capacity (15%), distances walked (48%), breathlessness in everyday activities (32%), and fatigue (18%) were found at the higher plasma concentration only. FEV1, forced vital capacity (FVC), emotional function, and control did not change. CONCLUSION: Theophylline treatment with sustained steady state concentrations about 17 mg/l provides worthwhile objective and subjective further benefits for patients handicapped by chronic obstructive lung disease when it is added to bronchodilators and corticosteroids.

Lack of evidence for cell death among avian spinal cord interneurons during normal development and following removal of targets and afferents.

Chick embryos and posthatched chicks were examined at several ages for the presence of pyknotic interneurons in the lumbar spinal cord. Because no pyknotic interneurons were found, direct cell counts of healthy interneurons were carried out and a comparison made between early- and late-stage embryos and hatchlings. There was no decrease in the number of interneurons in the ventral intermediate gray matter of the spinal cord between embryonic day (E) 8 and 2 weeks posthatching (PH) or in the dorsal horn between E10 and 2 weeks PH. To study whether interneuron survival is regulated by targets or afferents, a situation known to exist in other developing neural populations, early embryos were subjected to (1) removal of one limb, resulting in the loss of lateral motor column motoneurons and dorsal root ganglion sensory afferents; (2) transection of the thoracic spinal cord, thereby removing both descending afferents and rostral targets of spinal interneurons, or (3) a combination of the two operations. No reductions in interneuron numbers were found as a result of these operations. Furthermore, morphometric analysis also revealed no change in neuronal size following these experimental manipulations. By contrast, there was a slight decrease in the total area of spinal gray matter that was most prominent in the dorsal region following limb bud removal. Our results indicate (1) that spinal interneurons fail to exhibit the massive naturally occurring death of postmitotic neurons that has been observed for several other populations of spinal neurons, and (2) spinal interneurons appear to be relatively resistant to induced cell death following the removal of substantial numbers of afferent inputs and targets.

The expression of tenascin by neural crest cells and glia.

The extracellular matrix glycoprotein tenascin is concentrated in both the embryo and adult in regions where cell motility is taking place. For example, during avian neural crest morphogenesis tenascin is concentrated in the rostral half of the sclerotome, precisely where the neural crest cells themselves are found. Previous in vitro studies indicated that somite cells were the source of this tenascin, implying a role for tenascin in directing the ventral migration of neural crest cells and thus the establishment of the periodic arrangement of the PNS. In this study, we have used a cDNA probe to identify the source of tenascin found along the pathways of the neural crest using in situ hybridization. In tissue sections, individual cells found along the neural crest migratory pathways, both before entering the somites and within the somites, are strongly labelled by the tenascin cDNA. In vitro neural crest cells are more strongly labelled with the tenascin probe than somite cells. Finally, western blotting has been used to identify tenascin in culture medium conditioned by neural crest cells. This indicates that neural crest cells themselves are the source of much of the tenascin found lining their migratory pathways, and that interactions with somite cells may not be needed to induce the expression of tenascin. We have also studied the distribution of tenascin mRNA in the developing spinal cord and spinal ganglia. At embryonic days 7 and 10, tenascin cDNA hybridizes within cells that appear to be migrating from the ependymal layer to the white matter, as well as within cells in the dorsal roots.(ABSTRACT TRUNCATED AT 250 WORDS)

Neuropsychological test performance of bulimic patients.

Thirty subjects with DSM-III diagnoses of bulimia were compared to 30 matched controls on the Luria-Nebraska Neuropsychological Battery. The bulimics showed poorer performance on tasks associated with functioning of the right frontal cortical area, primarily tasks involving speed of drawing geometric figures. The similarities of the findings to previous findings with anorexic samples and patients with affective disorders are discussed.

Frontal lobe lesions and cognitive function in craniopharyngioma survivors.

We performed neuropsychological testing using the Luria-Nebraska Neuropsychological Battery, computed tomography, and magnetic resonance imaging (MRI) in four patients one to 15 years after surgery and radiation therapy for childhood craniopharyngioma. Of three patients with impairment of frontal lobe-mediated cognitive function, two had extensive areas of prolonged spin-lattice and spin-spin relaxation times in the frontal lobes demonstrated by MRI, and one had a lipid accumulation in the anterior horn of the right lateral ventricle and beneath a burrhole defect in the skull. One patient with minimal cognitive dysfunction had no abnormality in imaging studies. We believe assessment of neuropsychological status is an important aspect of the evaluation of children with craniopharyngioma. We have found the Luria-Nebraska Neuropsychological Battery and MRI to be particularly useful in this evaluation.

Neuropsychological performance of sexual assaulters and pedophiles.

Persons who had been arrested for sexual assault were administered the Luria-Nebraska Neuropsychological Battery and the results compared to a group of normal controls. The sexual assaulters performed significantly worse on 7 of the 14 scales of the battery. The data were then broken down into three groups: (1) those who had forcibly assaulted postpubescent victims, (2) those subjects who had sexually molested a prepubescent child, and (3) normal controls. A discriminant analysis correctly classified 68% of the subjects on the basis of their neuropsychological performance alone.

Hyperactivity (attention-deficit disorder).

Hyperactivity, or attention-deficit disorder, is a common disorder of childhood and has serious sequelae. Patients with this problem present frequently to the family physician's office. The physician should be able to perform a thorough evaluation that includes a family interview, a teacher consultation, and referral for psychological testing. Once the diagnosis of hyperactivity (attention-deficit disorder) is made, a comprehensive treatment plan is initiated that includes the use of stimulants, family counseling with an emphasis on behavioral management of the child and support of the parents and siblings, and initiation of school intervention. Many parents inquire about diet therapy, which may be of help with some children but should not be used to the exclusion of other treatment approaches.

Effects of age and education on the Luria-Nebraska Neuropsychological Battery performance of selected populations.

A number of studies have reported effects of age and education on neuropsychological test performance, finding these effects to different degrees on different tasks. The present study examines effects of age and education on Luria-Nebraska Neuropsychological Battery performance. Forty normal, 38 schizophrenic, and 38 nonpsychotic psychiatric subjects and 40 brain-damaged subjects in groups matched for age, education and sex were tested. Performance on each Luria-Nebraska scale was correlated with age and education in each diagnostic group and correlations were also calculated using scores adjusted for the age and education of individual subjects. Normal subjects showed significant education effects on all scales, with age-declines on "fluid" but not on "crystallized" functions. Schizophrenics showed education effects only on "crystallized" academic skills and showed age declines consistently on sensory functions. The brain-damaged and nonpsychotic psychiatric groups generally showed little age or education effect on test performance. The significance of these findings and methodological issues are discussed.

Neuropsychological performance in schizophrenics with histories of substance abuse.

Both schizophrenia and substance abuse have been associated with cerebral impairment, although the neuro psychological performance of schizophrenic patients with substance abuse histories has not been examined. In this study, the Luria-Nebraska Neuropsychological Battery was administered to schizophrenic patients with or without histories of substance abuse. The study found that the schizophrenics without substance abuse histories showed evidence of cerebral dysfunction, while those schizophrenics with histories of substance abuse could not be differentiated from normal.

Neuropsychological correlates of auditory and visual hallucinations.

Investigations of possible mechanisms underlying hallucinations have indicated that abnormal excitation of brain tissue and abnormal regulation of cognitive activity may contribute to hallucinations. The cognitive control deficits in auditory hallucinations are in some ways similar to those in persons with damage to the frontal lobes of the brain. An examination of the Luria-Nebraska Neuropsychological Battery performance of 10 psychiatric patients with auditory hallucinations, 10 patients with visual hallucinations and 20 patients with no hallucinations showed evidence of general cognitive impairment with a left frontal focus in the auditory group and no evidence of neuropsychological impairment in the visual group. Both self-awareness and control of internal speech involve left frontal mediation and the possible contribution of deficiencies in these functions to the appearance of auditory hallucinations is discussed.

Re-examination of the factor structure of the Receptive Language scale of the Luria-Nebraska Neuropsychological Battery.

The Receptive Language scale of the Luria--Nebraska Neuropsychological Battery assesses verbal comprehension skills ranging widely in complexity. Although a relatively complex factor structure was anticipated, a previous factor analysis of the scale revealed only one strong factor, phonemic discrimination. The present study re-examined the factor structure of the Receptive Language items using a substantially larger number of subjects with a larger proportion of brain-damaged subjects than in the earlier study. Seven major factors emerged which varied on a dimension of complexity of comprehension from phonemic discrimination through comprehension of complex grammatical relationships. Reasons for the difference in results obtained in the present study are suggested and theoretical implications of the findings are discussed.

The assessment of specific neuropsychological skills using scales derived from factor analysis of the Luria-Nebraska Neuropsychological battery.

The major scales of the Luria--Nebraska Neuropsychological Battery have been factor analyzed in a series of recent studies. These factors tend to be organized around one or two basic neuropsychological skills. The present study developed 30 scales of items loading heavily on those factors and determined performance norms on the scales on a group of 81 normal subjects. The Luria--Nebraska Battery was administered to eight groups of subjects with brain-damage localized to the frontal, sensorimotor, parietal-occipital or temporal areas of the right or left hemisphere. The performance of each of these groups on the 30 factor scales is described. The factor scales appear to facilitate assessment of specific skill deficits and appear potentially useful for both diagnosis and rehabilitation.