Differential actions of the dopamine agonist bromocriptine on growth of SMtTW tumors exhibiting a prolactin and/or a somatotroph cell phenotype: relation to dopamine D2 receptor expression

We have studied microtubule-associated protein 2 (MAP2) expression in anterior horn neurons in the cervical and lumbar spinal cords of 19 cases of adult-onset sporadic amyotrophic lateral sclerosis (ALS) using immunohistochemistry. Specimens from 7 patients without neurological disease served as controls. MAP2 expression decreased in the anterior gray horn of all ALS cases and in the intermediate gray of several ALS cases. Such reduction correlated with the degree of degeneration or neuronal loss in anterior horn cells and with the clinical symptoms of limb weakness. Cytopathologically, the MAP2 immunoreactivity decreased corresponding to the occurrence of individual signs of neuronal degeneration, such as chromatolytic neurons, shrunken neurons and pigmented neurons. MAP2 expression was relatively well preserved in the specimens in which spheroids are conspicuous. The findings of this study demonstrate MAP2 to be an excellent marker for the detection and quantification of anterior horn degeneration in ALS.     

Biosynthesis of 2-aceto-2-hydroxy acids: acetolactate synthases and acetohydroxyacid synthases

Two groups of enzymes are classified as acetolactate synthase (EC 4. 1.3.18). This review deals chiefly with the FAD-dependent, biosynthetic enzymes which readily catalyze the formation of acetohydroxybutyrate from pyruvate and 2-oxobutyrate, as well as of acetolactate from two molecules of pyruvate (the ALS/AHAS group). These enzymes are generally susceptible to inhibition by one or more of the branched-chain amino acids which are ultimate products of the acetohydroxyacids, as well as by several classes of herbicides (sulfonylureas, imidazolinones and others). Some ALS/AHASs also catalyze the (non-physiological) oxidative decarboxylation of pyruvate, leading to peracetic acid; the possible relationship of this process to oxygen toxicity is considered. The bacterial ALS/AHAS which have been well characterized consist of catalytic subunits (around 60 kDa) and smaller regulatory subunits in an alpha2beta2 structure. In the case of Escherichia coli isozyme III, assembly and dissociation of the holoenzyme has been studied. The quaternary structure of the eukaryotic enzymes is less clear and in plants and yeast only catalytic polypeptides (homologous to those of bacteria) have been clearly identified. The presence of regulatory polypeptides in these organisms cannot be ruled out, however, and genes which encode putative ALS/AHAS regulatory subunits have been identified in some cases. A consensus sequence can be constructed from the 21 sequences which have been shown experimentally to represent ALS/AHAS catalytic polypeptides. Many other sequences fit this consensus, but some genes identified as putative 'acetolactate synthase genes' are almost certainly not ALS/AHAS. The solution of the crystal structures of several thiamin diphosphate (ThDP)-dependent enzymes which are homologous to ALS/AHAS, together with the availability of many amino acid sequences for the latter enzymes, has made it possible for two laboratories to propose similar, reasonable models for a dimer of catalytic subunits of an ALS/AHAS. A number of characteristics of these enzymes can now be better understood on the basis of such models: the nature of the herbicide binding site, the structural role of FAD and the binding of ThDP-Mg2+. The models are also guides for experimental testing of ideas concerning structure-function relationships in these enzymes, e.g. the nature of the substrate recognition site. Among the important remaining questions is how the enzyme suppresses alternative reactions of the intrinsically reactive hydroxyethylThDP enamine formed by the decarboxylation of the first substrate molecule and specifically promotes its condensation with 2-oxobutyrate or pyruvate.     

Lessons Learned from a Lifetime of Applied Social Psychology Research.

I started life as an experimental social psychologist but migrated to applied social psychology research. Each time I have been involved in a major applied project I have learned things that have helped in subsequent projects. Most of the time the lesson has been about research design (e.g., you must know how the study should be done before you deal with the reality of how it has to be done). Examples of other lessons include using appropriate research technology, and the importance of program planner awareness of psychological research. In this paper I describe some of the major studies in which I was the investigator and the lesson (s) I learned from each. I also touch on the relevance of the scientist/practitioner model for the applied researcher. (PsycINFO Database Record (c) 2010 APA, all rights reserved)     

Things I have learned (so far).

This is an account of what I have learned (so far) about the application of statistics to psychology and the other sociobiomedical sciences. It includes the principles "less is more" (fewer variables, more highly targeted issues, sharp rounding off), "simple is better" (graphic representation, unit weighting for linear composites), and "some things you learn aren't so." I have learned to avoid the many misconceptions that surround Fisherian null hypothesis testing. I have also learned the importance of power analysis and the determination of just how big (rather than how statistically significant) are the effects that we study. Finally, I have learned that there is no royal road to statistical induction, that the informed judgment of the investigator is the crucial element in the interpretation of data, and that things take time. (PsycINFO Database Record (c) 2010 APA, all rights reserved)     

A placebo-controlled trial of recombinant human ciliary neurotrophic (rhCNTF) factor in amyotrophic lateral sclerosis. rhCNTF ALS Study Group

Preclinical investigations indicated that recombinant human ciliary neurotrophic factor (rhCNTF) may have potential as therapy for amyotrophic lateral sclerosis (ALS). We evaluated the safety and efficacy of rhCNTF in a prospective, double-blind, placebo-controlled trial in 570 patients with ALS. Patients were randomized to receive 0.5, 2, or 5 micrograms/kg/day rhCNTF, or placebo, for 6 months. The primary efficacy end point was the change from baseline to the last on-treatment value of a combination megascore for limb strength (maximum voluntary isometric contraction) and pulmonary function. Secondary end points included individual arm and leg megascores, pulmonary function tests, an activities-of-daily-living outcome measure, and survival. The four treatment groups were similar at baseline with respect to age, sex, disease duration, and muscle strength values. At all doses tested, rhCNTF had no beneficial effect on the primary or secondary end points. Certain adverse events, as follows, appeared to be dose related: injection site reactions, cough, asthenia, nausea, anorexia, weight loss, and increased salivation. There was an increased number of deaths at the highest dose level. rhCNTF had no beneficial effect on any measure of ALS progression. There were increased adverse events in the 5 micrograms/kg group and increased deaths.     

Discrimination of artificial categories structured by family resemblances: A comparative study in people (Homo sapiens) and pigeons (Columba livia).

Adult humans (Homo sapiens) and pigeons (Columba livia) were trained to discriminate artificial categories that the authors created by mimicking 2 properties of natural categories. One was a family resemblance relationship: The highly variable exemplars, including those that did not have features in common, were structured by a similarity network with the features correlating to one another in each category. The other was a polymorphous rule: No single feature was essential for distinguishing the categories, and all the features overlapped between the categories. Pigeons learned the categories with ease and then showed a prototype effect in accord with the degrees of family resemblance for novel stimuli. Some evidence was also observed for interactive effects of learning of individual exemplars and feature frequencies. Humans had difficulty in learning the categories. The participants who learned the categories generally responded to novel stimuli in an all-or-none fashion on the basis of their acquired classification decision rules. The processes that underlie the classification performances of the 2 species are discussed. (PsycINFO Database Record (c) 2010 APA, all rights reserved)     

The role of immune processes in amyotrophic lateral sclerosis pathogenesis

Despite many efforts, the etiopathogenesis of ALS remains unknown. During the last decade evidence for an autoimmune involvement in motoneuron degeneration and death has remarkably increased. Multiple reports have documented significant expression of proteins associated with immune function in affected areas of ALS patients. Two animal models of immune-mediated motoneuron destruction have been developed that closely resemble clinical, electrophysiological and morphological features of human ALS. Inflammatory foci within the spinal cord, and IgG at the neuromuscular junction as well as within upper and lower motoneurons found in the animal models support the role of autoimmune mechanisms of motoneuron destruction in this model. IgG from ALS patients and from the animal models can passively transfer physiological changes at the neuromuscular junction in mice. That ALS IgG interact with calcium channels and induce an alteration of their function is now electrophysiologically and biochemically evident. Furthermore, it has been documented that motoneurons may be selectively vulnerable since they have a deficient calcium buffering capacity. Although further research efforts are necessary to elucidate the interaction of the ALS antibodies with the calcium channel function and how defective calcium handling by the motoneurons is important in their degeneration, the current data strongly suggest the involvement of autoimmune mechanisms in ALS etiopathogenesis.     

The role of the family in the development of psychopathology.

Psychologists generally make the assumption that the experiences to which the individual is exposed over a period of time lead to the development of learned patterns of behavior. From this, psychologists have reasoned that the experiences the individual has in his early life at home, with his family, in general, and his mother, in particular, are major determinants in the learning of the constellation of behaviors subsumed under the rubric, personality, and in particular, the development of psychopathology. A review of the research of the past 40 yr. failed to support this assumption. No factors were found in the parent-child interaction of schizophrenics, neurotics, or those with behavior disorders which could be identified as unique to them or which could distinguish one group from the other, or any of the groups from the families of the controls. (PsycINFO Database Record (c) 2010 APA, all rights reserved)     

Aberrant RNA processing in a neurodegenerative disease: the cause for absent EAAT2, a glutamate transporter, in amyotrophic lateral sclerosis

Amyotrophic lateral sclerosis (ALS) is a neurodegenerative disease that is characterized by selective upper and lower motor neuron degeneration, the pathogenesis of which is unknown. About 60%-70% of sporadic ALS patients have a 30%-95% loss of the astroglial glutamate transporter EAAT2 (excitatory amino acid transporter 2) protein in motor cortex and spinal cord. Loss of EAAT2 leads to increased extracellular glutamate and excitotoxic neuronal degeneration. Multiple abnormal EAAT2 mRNAs, including intron-retention and exon-skipping, have now been identified from the affected areas of ALS patients. The aberrant mRNAs were highly abundant and were found only in neuropathologically affected areas of ALS patients but not in other brain regions. They were found in 65% of sporadic ALS patients but were not found in nonneurologic disease or other disease controls. They were also detectable in the cerebrospinal fluid (CSF) of living ALS patients, early in the disease. In vitro expression studies suggest that proteins translated from these aberrant mRNAs may undergo rapid degradation and/ or produce a dominant negative effect on normal EAAT2 resulting in loss of protein and activity. These findings suggest that the loss of EAAT2 in ALS is due to aberrant mRNA and that these aberrant mRNAs could result from RNA processing errors. Aberrant RNA processing could be important in the pathophysiology of neurodegenerative disease and in excitotoxicity. The presence of these mRNA species in ALS CSF may have diagnostic utility.     

Chronic immobilization stress alters aspects of emotionality and associative learning in the rat.

Chronic stress significantly alters limbic neuroarchitecture and function, and potentiates emotionality in rats. Chronic restraint stress (CRS) increases aggression among familiar rats, potentiates anxiety, and enhances fear conditioning. Chronic immobilization stress (CIS) induces anxiety behavior and dendritic hypertrophy in the basolateral amygdala, which persist beyond a recovery period. However, little else is known about the emotional impact of CIS as a model of chronic stress or depression. Therefore, the authors present two experiments examining emotional and learned responses to CIS. In Experiment I, the authors examine individual differences in behaviors during and after CIS, specifically: struggling, aggression, learned helplessness, inhibitory avoidance, and escape behavior. In Experiment II, the authors confirm the effects of CIS on aggression and struggling during immobilization, and correlate individual responses with aspects of conditioned fear. Here the authors report significant effects of CIS on aggression, inhibitory avoidance, escape, as well as learned aspects of fear (i.e., fear conditioning) and inescapable stress (i.e., struggling and helplessness). These results emphasize the emotional and learned responses to CIS evident during and after the stress treatment, as well as the importance of individual differences. (PsycINFO Database Record (c) 2010 APA, all rights reserved)     

The Three Faces of Evelyn: A Case Report. III. Reactions to the Blind Analysis.

This article discusses the blind analysis of the test data of a case of multiple personality (Gina). I am glad that the blind analysis reveals Evelyn to be a fusion of Gina and Mary. This confirms my view of what happens in the successful treatment of a case of multiple personality: The prejudice of each ego state against the others is made weaker and weaker until the barriers between them disappear and the individual becomes psychologically whole again. As to the comparative validity of intimate clinical versus remote objective interpretation, I have learned as a result of this experience that they are complementary, and that there is nothing to lose and much to be gained by their complementarity. The pressure of practice and a certain confidence in my clinical ability had prevented me from drawing as much meaning from my data as I could when confronted with the results of the blind analysis. (PsycINFO Database Record (c) 2010 APA, all rights reserved)     

Sibling recognition in the beaver: a field test for phenotype matching

The hypothesis of kin recognition by phenotype matching predicts that relatives can be identified without previous contact, and/or that cues used for recognition can be learned indirectly from a third but related individual. This hypothesis was tested in the field using 22 beaver, Castor canadensisfamilies. Individually identifiable beavers were provided with a two-way choice between two experimental scent mounds, one of which was scented with the anal gland secretion (AGS) from an unfamiliar sibling of the test subjects, the other with AGS from an unfamiliar non-relative. Beavers showed less strong territorial responses to AGS from their siblings than to that from non-relatives. The mates of the test subjects, which were not related to, or familiar with, either of the AGS donors, also responded less strongly to the AGS from their mates' siblings than to that from other unfamiliar non-relatives. This discrimination was not shown when castoreum samples were tested instead of AGS. Therefore, it was concluded that (1) information about kinship in the beaver is coded in the AGS but not in the castoreum, (2) the mechanism of phenotype matching is used in beaver sibling recognition, and (3) the cue used in phenotype matching can be learned and used for recognition of related individuals by an unrelated individual.1997The Association for the Study of Animal Behaviour     

Animal models of ALS

Animal models of amyotrophic lateral sclerosis (ALS) provide a unique opportunity to study this incurable and fatal human disease both clinically and pathologically. This is particularly true for certain pathological and therapeutic studies that are impractical or impossible to perform in human patients. Nonetheless, postmortem ALS tissue remains the "gold standard" against which pathologic findings in animal models must be compared. Four natural disease models have been most extensively studied, including three mouse models: motor neuron degeneration (Mnd), progressive motor neuronopathy (pmn), wobbler, and one canine model: hereditary canine spinal muscular atrophy (HCSMA). The wobbler mouse has been the most extensively studied of these models with analyses of clinical, pathological (perikaryon, axon, muscle), and biochemical features. Experimentally induced ALS animal models have allowed controlled testing of various neurotoxic, viral and immune-mediated mechanisms. Molecular techniques have recently generated mouse models in which genes relevant to the human disease or motor neuron biology have been manipulated. The most clinically relevant of these is a transgenic mouse overexpressing the mutated SOD1 gene of FALS patients, which has already provided significant insights into mechanisms of motor neuron degeneration in this disease. Because no single animal model perfectly reflects all the clinical and pathological characteristics of ALS, study of selected features from the most relevant models will contribute to a better understanding of the pathogenesis and/or etiology of this disease.     

Acute paresis of extraocular muscles associated with IgG anti-GQ1b antibody

There have been several case reports of acute ophthalmoparesis without ataxia subsequent to infection or immunization. The nosological position and therapy for acute ophthalmoparesis have yet to be established. Sera from patients are reported to have IgG anti-GQ1b antibody, which is frequently found in sera from patients with Fisher's syndrome. To establish the etiology of acute ophthalmoparesis, I tested sera from 8 patients with acute ophthalmoparesis for anti-GQ1b antibody. High IgG anti-GQ1b antibody titers were present in sera from patients in the acute phase of the illness. I describe the successful treatment with plasmapheresis and intravenous immunoglobulin. Some cases of acute ophthalmoparesis following infection or immunization may be categorized as an auto-immune disease related to Fisher's syndrome.     

Mutual inhibition in collaborative recall: Evidence for a retrieval-based account.

In Experiment 1 participants gave 3 successive free recalls of items learned either individually or in pairwise collaboration. The first and third recalls were performed individually, the second alone or in collaboration. Collaborative recall led to an inhibitory effect after individual learning but not after collaborative learning, in which partners had similar retrieval strategies. Consistent with a retrieval locus for collaborative inhibition, non-recalled items reappeared in subsequent individual recall. Experiment 2 showed that collaborative inhibition was eliminated when a separate retrieval cue was given for each item. Experiments 2 and 3 also showed that when participants learned items in the same order, their retrieval strategies were more similar and they showed less collaborative inhibition. It is concluded that mutual interference in collaborative recall is due to the mutual disruption of individual retrieval strategies. (PsycINFO Database Record (c) 2010 APA, all rights reserved)     

Heritable variation for latent inhibition and its correlation with reversal learning in honeybees (Apis mellifera).

Latent inhibition (LI) in honeybees (Apis mellifera) was studied by using a proboscis extension response conditioning procedure. Individual queens, drones, and workers differed in the degree to which they revealed LI. The authors hypothesized that individual differences would have a substantial genetic basis. Two sets of progeny were established by crossing virgin queens and individual drones, both of which had been selected for differential expression of inhibition. LI was stronger in the progeny from the queens and drones that had shown greater inhibition. The expression of LI was also dependent on environmental factors that are most likely associated with age, foraging experience outside of the colony, or both. Furthermore, there was a correlated response in the speed at which progeny reversed a learned discrimination of 2 odors. These genetic analyses may reveal underlying mechanisms that these 2 learning paradigms have in common. (PsycINFO Database Record (c) 2010 APA, all rights reserved)     

Effects of microgravity and bone morphogenetic protein II on GFAP in rat brain

Enzyme activities and protein levels of several protein and lipid kinases were measured in postmortem tissue from patients who died with amyotrophic lateral sclerosis (ALS) as well as from control subjects. Patients who died with ALS had increased activities and protein levels of phosphatidylinositol 3-kinase (PI 3-K) in particulate fractions of spinal cord tissue compared with control subjects. The PI 3-K activity increased with PI 3-K protein level, indicating no change in specific PI 3-K activity in ALS. No differences in PI 3-K activities were found in cytosolic fractions of spinal cord, or in motor and visual cortices, from ALS patients compared with those from controls. PI 3-K activities and protein levels were unchanged in brain tissue from patients who died with Alzheimer's disease compared with those from controls. PI 3-K is a lipid kinase that is important for cell survival and is activated in response to many growth factors. Increased PI 3-K activities in particulate fractions of spinal cord from ALS patients may be related to the increase of PI 3-K protein levels found in this tissue. The protein kinases Erk2, protein kinase B (PKB), and p70 ribosomal S6 kinase (S6K) showed no differences in activities in spinal cord tissue between ALS patients and controls. However, the amounts of PKB and S6K protein were significantly higher in ALS patients, whereas Erk2 protein amount was unchanged compared with controls. Protein kinase C activity was increased in spinal cord tissue from ALS patients, which is consistent with our previous report. The increased activity of PI 3-K in spinal cord tissue from patients with ALS implicates the involvement or activation of PI 3-K in ALS, as either a cause or a consequence of the neuron loss. The lack of up-regulation in the activities of PKB and S6K in ALS tissue supports an impairment in signal transduction cascades mediated by PI 3-K in this neurodegenerative disease.     

Measuring individual differences with an information-processing model.

An information-processing model was fitted to individual learning curves for 378 5th–10th graders. Two types of learning materials were examined: paired associates and word definitions. Two parameters of the model displayed reliable individual differences: acquisition rate and long-term retention. Some individual differences also were found in how well students learned definitions under experimenter-paced drill vs student-controlled independent study. Learning scores based on the definitions material had moderately high correlations with traditional aptitude and achievement scores; correlations were lower for paired associates. No significant sex or Spanish-surname vs White group differences were found for the learning scores. Possible classroom applications of the learning scores and parameters are discussed. (16 ref) (PsycINFO Database Record (c) 2010 APA, all rights reserved)