Resumption of outpatient occupational therapy for a young woman five years after traumatic brain injury.
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Activities of Daily Living↗
Biomedical subjects
D L Nelson
Publications and source records attributed to D L Nelson.
The effects of an occupationally embedded exercise on bilaterally assisted supination in persons with hemiplegia.
OBJECTIVES: Occupationally embedded exercise is a central idea in the profession of occupational therapy. This experiment compared the effect of an occupationally embedded exercise involving a simple dice game with a rote exercise in persons with stroke with pronator spasticity. Both exercise conditions involved bilaterally assisted supination, consistent with the neurodevelopmental model of practice. METHODS: The sample consisted of 14 men and 12 women post-cerebrovascular accident with a mean age of 68.4 years (SD = 11.2) at six clinical sites in California, Texas, and Michigan. Subjects had pronator spasticity, full passive range for supination after a brief warm-up, and no functional supination. After random assignment for experimental condition, the subjects engaged in two sets of 10 repetitions of bilaterally assisted supination in either the occupationally embedded condition (dice game) or the rote condition (no game). A pen recorder electronically documented degrees of rotation of the handle that was grasped during the exercise. RESULTS: The occupationally embedded exercise resulted in significantly more handle rotation (requiring more supination) than the rote exercise, t (24) = 2.28, p (one tailed) < .05. The effect size was large. CONCLUSION: This study advances the experimental analysis of therapeutic occupation in the area of occupationally embedded exercise. Clinicians are urged to consider the multidimensional nature of occupationally embedded exercise.
Aged↗
Pharmacologic characterization of the human 5-hydroxytryptamine2B receptor: evidence for species differences.
The 5-Hydroxytryptamine2B (5-HT2B) receptor was cloned originally from rat stomach fundus and its pharmacology was determined to be consistent with that of the receptor responsible for contraction of rat fundal tissue in response to 5-HT. Recently, the cloning of the human homolog of the 5-HT2B receptor has been reported and, in this study, we report a detailed pharmacological characterization of this human receptor. The cloned human 5-HT2B receptor has high affinity for [3H]5-HT (Kd = 10.6 +/- 1.5 nM), and the pharmacology of this receptor matches closely the rat 5-HT2B receptor, consistent with the structural relatedness of these two proteins. Most compounds tested show no difference in affinity for the human or rat receptors. There were, however, groups of compounds that discriminated between the human and rat 5-HT2B receptors. Examples include certain ergolines such as methysergide and mesulergine, which have higher affinity for the human than for the rat receptor. Similarly, certain benzoylpiperidines, e.g., ketanserin, pirenperone and pipamperone, and the antipsychotics clozapine and olanzapine have higher affinity for the human 5-HT2B receptor. These pharmacological findings reinforce the desirability of having the human forms of receptors when considering drug actions.
Animals↗
FMR1 in global populations.
Fragile X syndrome, a frequent form of inherited mental retardation, results from the unstable expansion of a cryptic CGG repeat within the 5' UTR region of the FMR1 gene. The CGG repeat is normally polymorphic in length, and the content is frequently interrupted by AGG triplets. These interruptions are believed to stabilize the repeat, and their absence, leading to long tracts of perfect CGG repeats, may give rise to predisposed alleles. In order to examine the stability of normal FMR1 alleles, the repeat length of 345 chromosomes from nine global populations was examined with the content also determined from 114 chromosomes as assessed by automated DNA sequencing. The FMR1 alleles, defined by the CGG repeat, as well as by the haplotypes of nearby polymorphic loci, were very heterogeneous, although the level of variation correlated with the age and/or genetic history of a particular population. Native American alleles, interrupted by three AGG repeats, exhibited marked stability over 7,000 years. However, in older African populations, parsimony analysis predicts the occasional loss of an AGG, leading to more perfect CGG repeats. These data therefore support the suggestion that AGG interruptions enhance the stability of the FMR1 repeat and indicate that the rare loss of these interruptions leads to alleles with longer perfect CGG-repeat tracts.
Alleles↗
LY215840, a high-affinity 5-HT7 receptor ligand, blocks serotonin-induced relaxation in canine coronary artery.
The canine coronary artery possesses a smooth muscle relaxant serotonin (5-HT) receptor distinct from previously characterized 5-HT receptors. On the basis of the ability of LY53857 to block weakly coronary smooth muscle relaxation to 5-HT, we examined several structurally related ergolines in endothelium denuded rings of canine coronary artery precontracted with PGF2 alpha (10 microM). 5-HT (10 nM-100 microM)-induced relaxation was antagonized competitively by the ergoline esters LY53857 (-log KB = 6.5) and sergolexole (-log KB = 6.4) and by the ergoline amide amersergide, (-log KB = 6.7). In contrast to the relatively low affinity of these ergolines, LY215840, another ergoline amide, antagonized 5-HT-induced relaxation in a competitive manner with the highest affinity (-log KB = 8.3). This effect was independent of the 5-HT2 receptor affinity of these ergolines, because LY215840, LY53857, sergolexole and amesergide all possessed similar 5-HT2 receptor affinity. Further, all four ergolines possessed affinity for the human 5-HT7 receptor, and LY215840 had the highest 5-HT7 receptor affinity (Ki = 14.7 nM). Finally, in vascular smooth muscle under basal tone, LY215840 (1 microM) blocked the relaxant response to high concentrations of 5-HT and 5-MeOT without altering their contractile potency. LY215840 (1 microM) did not alter contraction to sumatriptan, an agent that lacks relaxant activity. In contrast, LY215840 (1 microM) markedly potentiated contraction to 5-carboxamidotryptamine, the most potent coronary relaxant agonist and the agonist with the highest 5-HT7 receptor affinity. The ability of LY215840 to block the relaxant 5-HT receptor in canine coronary artery may reflect its 5-HT7 receptor antagonist activity and make it a useful tool to probe the relationship between the 5-HT7 receptor and the coronary vasoactive properties of 5-HT.
Animals↗
Large domains of apparent delayed replication timing associated with triplet repeat expansion at FRAXA and FRAXE.
Trinucleotide repeat expansions have been implicated in the causation of a number of neurodegenerative disorders. In the case of fragile X syndrome, full expansion of the FMR1 repeat element (CGG)n has also been correlated with replication timing delay of the locus and proximal flanking sequences in male lymphoblasts. To define more extensively this altered region of DNA replication, as well as to extend these studies to female cells containing premutant and mutant alleles, study of the replication timing properties of a >2-Mb zone in the FRAXA region (Xq27.3-q28) was undertaken by using a FISH technique. In this assay, relative times of replication of specific loci are inferred from the ratios of singlet and doublet hybridization signals in interphase nuclei. In all individuals with a full expansion of the trinucleotide repeat, a large (1-1.2-Mb) region of delayed timing was observed; the apparent timing of the earlier-replicating allele in female cells in this region was intermediate between normal and affected alleles in males, which is in accordance with expectations of a mixed population of cells resulting from random X inactivation. In addition, expansion of the nearby FRAXE locus also was found to correlate with replication timing delay, although the extent of the altered region was somewhat less. Trinucleotide repeat expansion thus may be acting in the Xq27.3-q28 region to alter long-range chromatin structure that could influence transcription of gene sequences within the affected domain.
Cells, Cultured↗
Anomalous rapid electrophoretic mobility of DNA containing triplet repeats associated with human disease genes.
Eight human genetic diseases have been associated with the expansion of CTG or CGG triplet repeats. The molecular etiology behind expansion is unknown but may involve participation of an unusual DNA structure in replication, repair, or recombination. We show that DNA fragments containing CTG triplet repeats derived from the human myotonic dystrophy gene migrate up to 20% faster than expected in nondenaturing polyacrylamide gels, suggesting the presence of an unusual DNA helix structure within the CTG triplet repeats. The anomalous migration is dependent upon the number of triplet repeats, the length of the flanking DNA, and the percentage and temperature of the polyacrylamide. The effect could be reduced by the addition of actinomycin D. Applying a reptation model for electrophoresis, the results are consistent with a 20% increase in persistence length of the DNA. PCR products containing CTG or CGG repeats from the spinocerebellar ataxia type I gene (SCA1) or the fragile X FMR1 gene, respectively, also showed higher electrophoretic mobility. These are the first sequences of defined length for which a dramatic increase in mobility can be attributed to sequence-dependent structural elements in DNA.
Ataxin-1↗
Radioimmunotherapy of interleukin-2R alpha-expressing adult T-cell leukemia with Yttrium-90-labeled anti-Tac.
Adult T-cell leukemia (ATL) is a malignancy of mature lymphocytes caused by the retrovirus human T-cell lymphotropic virus-I. It is an aggressive leukemia with a median survival time of 9 months; no chemotherapy regimen appears successful in inducing long-term disease-free survival. The scientific basis of the present study is that ATL cells express high-affinity interleukin-2 receptors identified by the anti-Tac monoclonal antibody, whereas normal resting cells do not. To exploit this difference, we administered anti-Tac armed with Yttrium-90 (90Y) to 18 patients with ATL initially (first 9 patients) in a phase I dose-escalation trial and subsequently (second group of 9 patients) in a phase II trial involving a uniform 10-mCi dose of 90Y-labeled anti-Tac. Patients undergoing a remission were permitted to receive up to eight additional doses. At the 5- to 15-mCi doses used, 9 of 16 evaluable patients responded to 90Y anti-Tac with a partial (7 patients) or complete (2 patients) remission. The responses observed represent improved efficacy in terms of length of remission when compared with previous results with unmodified anti-Tac. Clinically meaningful (> or = grade 3) toxicity was largely limited to the hematopoietic system. In conclusion, radioimmunotherapy with 90Y anti-Tac directed toward the IL-2R expressed on ATL cells may provide a useful approach for treatment of this aggressive malignancy.
Adult↗
Soluble interleukin-2 receptor alpha is elevated in sera of patients with benign ovarian neoplasms and epithelial ovarian cancer.
BACKGROUND: Previous studies have established that soluble interleukin-2 receptor alpha (sIL-2R alpha) levels are elevated in ascites and sera from individuals with advanced ovarian cancer (International Federation of Gynecology and Obstetrics [FIGO] Stage III/IV). This study was undertaken to evaluate sIL-2R alpha levels in individuals with benign ovarian neoplasms and early stage ovarian cancer (FIGO Stage I/II). Comparison with CA 125 levels was performed to assess screening potential. METHODS: Sera from 92 healthy individuals, 61 with benign adnexal masses, 12 patients with FIGO Stage I/II ovarian cancers, and 27 patients with FIGO Stage III/IV ovarian cancers were assayed for sIL-2R alpha by enzyme-linked immunosorbent assay and CA 125 by radioimmunoassay. RESULTS: The mean serum sIL-2R alpha levels for benign pelvic masses, and Stage I/II and Stage III/IV epithelial ovarian cancer were 1507 +/- 82, 1631 +/- 274, and 2596 +/- 384 U/ml, respectively. The difference between mean serum sIL-2R alpha levels in individuals with benign adnexal masses and Stage III/IV epithelial ovarian cancer was statistically significant (P < 0.05). In addition, of the four individuals with FIGO Stage I/II ovarian cancer who had CA125 levels below 35 U/ml, the accepted upper limit of normal, three patients had elevated serum sIL-2R alpha levels. Eleven of 12 patients (92%) with potentially curable Stage I/II disease had elevated serum levels of either sIL-2R alpha or CA125 and 8 of 12 (67%) had elevations of both sIL-2R alpha and CA125. Sensitivity and specificity of a combination of CA 125 and soluble IL-2R alpha were 88.5% and 27.1%, respectively. CONCLUSION: Soluble interleukin-2 receptor alpha levels do not appear to differentiate between benign adnexal lesions and early malignancy; however, measurement of sIL-2R alpha levels in combination with CA125 warrants further evaluation to determine if together they will identify individuals with Stages I and II ovarian cancer.
Biomarkers, Tumor↗
Molecular genetic analysis of X-linked hypogammaglobulinemia and isolated growth hormone deficiency.
In 1980 the clinical syndrome of X-linked hypogammaglobulinemia and isolated growth hormone deficiency (XLA/GHD) was described. XLA/GHD patients have reduced serum levels of Ig and normal cell-mediated immunity, and thus resemble patients with Bruton's X-linked agammaglobulinemia (XLA). However, XLA/GHD patients also have isolated GHD. Mutations and deletions in the Bruton's tyrosine kinase gene (BTK) are responsible for Bruton's XLA. We investigated BTK gene expression in an XLA/GHD patient from the family originally described by Northern analysis, cDNA sequencing, and Western analysis of protein production using mAb to BTK. BTK mRNA was normal in size and abundance, and the mRNA sequence was normal over the coding region, except for a single silent mutation. BTK protein was present in normal amounts in PBMC of this patient. Thus, at the molecular level, XLA/GHD is a different disease entity from Bruton's XLA. These results suggest that undescribed genes critical for B cell development and growth hormone production exist on the X chromosome.
Agammaglobulinaemia Tyrosine Kinase↗
Species differences in 5-HT2A receptors: cloned pig and rhesus monkey 5-HT2A receptors reveal conserved transmembrane homology to the human rather than rat sequence.
Pig and rhesus monkey 5-HT2A receptor cDNA clones were isolated. The pig and rhesus monkey clones encode proteins that share a 94% and 95% homology, respectively, with the rat 5-HT2A receptor, and a 97% and > 99% homology, respectively, with the human 5-HT2A receptor. Within the transmembrane regions of the pig and monkey receptors, the deduced amino acid shows only three differences compared to that of the rat and are identical to the human 5-HT2A receptor clone.
Animals↗
Infectious complications and immunodeficiency in patients with human T-cell lymphotropic virus I-associated adult T-cell leukemia/lymphoma.
BACKGROUND: Adult T-cell leukemia/lymphoma (ATL) is a malignancy of mature T-cells occurring in patients infected with the human T-cell lymphotropic virus-I. These patients frequently develop a variety of infections throughout their disease course. METHODS: Charts and autopsy reports were reviewed for 41 patients with ATL with follow-up varying from 2 to 120 months. Infectious episodes were identified and documented. Analyses of humoral and cell-mediated immunity were performed. Cell-mediated immunity was assessed in vivo with the Merieux multitest skin test panel. Humoral immunity was assessed by quantitative immunoglobulin levels, by determining human antimouse antibody after murine monoclonal antibody infusion and by an in vitro immunoglobulin biosynthesis coculture system. RESULTS: A total of 112 infectious episodes were documented. Fifty-seven serious infections were identified. The incidence of total infections was 1.40/patient-year and for serious infections was 0.71/patient-year. The mean serum IgG and IgA levels were within normal range, the mean IgM level was at the lower limit of normal. Peripheral blood mononuclear cells from all patients studied failed to make meaningful amounts of IgG, M, or A when activated. Peripheral blood mononuclear cells of all of the 13 patients studied suppressed production of immunoglobulin by cocultured normal PBMC. Twenty-three of the 27 patients tested were anergic. CONCLUSIONS: ATL is a profoundly immunosuppressing malignancy. This is manifested by an extremely high incidence of infectious episodes/patient-year. The incidence of infection appears to be greater than for mycosis fungoides, Hodgkin's lymphoma and non-Hodgkin's lymphoma.
Adult↗
The gene encoding the VP16-accessory protein HCF (HCFC1) resides in human Xq28 and is highly expressed in fetal tissues and the adult kidney.
After herpes simplex virus (HSV) infection, the viral regulatory protein VP16 activates transcription of the HSV immediate-early promoters by directing complex formation with two cellular proteins, the POU-homeodomain transcription factor Oct-1 and the host cell factor HCF. The function of HCF in uninfected cells is unknown. Here we show by fluorescence in situ hybridization and somatic cell hybrid analysis that the gene encoding human HCF, HCFC1, maps to the q28 region of the X chromosome. Yeast artificial chromosome and cosmid mapping localizes the HCFC1 gene within 100 kb distal of the renal vasopressin type-2 receptor (V2R) gene and adjacent to the renin-binding protein gene (RENBP). The HCFC1 gene is apparently unique. HCF transcripts and protein are most abundant in fetal and placental tissues and cell lines, suggesting a role in cell proliferation. In adults, HCF protein is abundant in the kidney, but not in the brain, a site of latent HSV infection and where HCF levels may influence progression of HSV infection.
Animals↗
Protein substrates for cGMP-dependent protein phosphorylation in cilia of wild type and atalanta mutants of Paramecium.
In the ciliated protozoan Paramecium, swimming direction is regulated by voltage-gated Ca2+ channels in the ciliary membrane. In response to depolarizing stimuli, intraciliary Ca2+ rises, triggering reversal of the ciliary power stroke and backward swimming. One class of Ca(2+)-unresponsive behavioral mutants of Paramecium, atalanta mutants, cannot swim backward even though they have functional Ca2+ channels in their ciliary membrane. Several atalanta mutants were characterized with regard to several Ca(2+)-dependent activities, but no significant difference between wild type and the mutants was detected. However, one allelic group, atalanta A (initially characterized by Hinrichsen and Kung [1984: Genet. Res. Camb. 43:11-20]), showed a helical swimming path of opposite handedness from that of wild-type cells when detergent-permeabilized cells ("models") were reactivated with MgATP. When cGMP-dependent protein kinase purified from wild-type cells was added to atalanta A models, the handedness of the swimming path was reversed. Cyclic GMP stimulated in vitro phosphorylation of several proteins in isolated cilia, and the pattern of phosphoproteins was very similar for wild type and atalanta mutants, with one exception: a protein of 59 kDa was phosphorylated much less in the mutant ata A. When ciliary proteins were separated by gel electrophoresis and then phosphorylated "on blot" by purified cGMP-dependent protein kinase, phosphoprotein patterns were similar in wild type and ata mutants except that a 48 kDa protein (p48) from ata A3 was more heavily phosphorylated. This difference in p48 phosphorylation was also observed with cGMP-dependent protein kinase purified from ata A3 mutant cells.(ABSTRACT TRUNCATED AT 250 WORDS)
Animals↗
Molecular biology of serotonin receptors.
Over the last several years the use of molecular cloning technology has revealed a vast diversity among serotonin (5-HT) receptors, whereby what was previously thought to be a family of three pharmacologically defined classes of 5-HT receptors is actually composed of seven distinct subfamilies designated 5-HT1-7. The 5-HT1, 5-HT2, and 5-HT5 subfamilies currently consist of five, three and two subtypes respectively while the 5-HT3, 5-HT4, 5-HT6, and 5-HT7 "subfamilies" have at present one subtype each. Fourteen separate genes encode 13 receptors which fall in the superfamily of G protein-coupled receptors and one ligand-gated ion channel receptor. Our lab has contributed to the elucidation of this subtype diversity by cloning the cDNAs from both rat and human encoding the 5-HT2B receptor. This receptor subtype is equally homologous (approximately 70%) to the 5-HT2A and 5-HT2C receptors when amino acids comprising the transmembrane domains are compared and is clearly the third member of the 5-HT2 subfamily. The 5-HT2B receptor has been shown to couple to phosphoinositide hydrolysis as do the other two members of this subfamily when expressed in AV12-664 cells. Limited pharmacological analyses indicated that both rat and human 5-HT2B receptors are similar but distinguishable. With one tantalizing exception, the mRNAs for these receptors appear to be similarly distributed within rat and human. The 5-HT2B receptor mRNA is not found in rat brain, whereas in human brain it has been identified in multiple regions. This later finding suggests that the 5-HT2B receptor may be serving a unique CNS function in man that is absent in rat.
Amino Acid Sequence↗
Racial differences in serum immunoglobulin levels: relationship to cigarette smoking, T-cell subsets, and soluble interleukin-2 receptors.
To investigate the influence of race, cigarette smoking, and immunologic parameters on serum immunoglobulins, we analyzed serum IgG, IgA, and IgM levels in 455 healthy adults. The study population ranged in age from 20 to 69 years, including 282 whites and 173 blacks, 181 never-smokers, 93 ex-smokers, and 181 current smokers. Race and smoking were independently associated with alterations in serum IgG levels. Blacks had significantly higher IgG levels than whites (1,587 vs. 1,209 mg/dl; P < 0.001), and never smokers had significantly higher levels than current smokers (1,426 vs. 1,287 vs. mg/dl; P < 0.001). IgA and IgM levels were unrelated to race or smoking. Serum IgG was also found to be directly related to the proportion of HLA-DR+ cells and the level of soluble interleukin-2 receptors (sIL-2R) and inversely related to the proportion of CD4+ cells. Investigation of this racial heterogeneity may provide insights into the pathogenesis of immunologic diseases that exhibit unexplained racial variation.
Adult↗
Effects of implicit memory on explicit recall: set size and word-frequency effects.
PIER was designed to explain findings related to tasks involving an encoding phase and a testing phase in which retrieval cues prime the recovery of what has been encoded. The model assumes that retrieval cues initiate the sampling of associated memories linked to the encoded information and that sampled memories are subjected to a recognition check to determine whether they meet criteria specified by the purpose of the retrieval. The model explains how the number of implicitly activated associates linked to a studied word affects its later recovery and predicts that words infrequently experienced will be recovered with greater likelihood than words frequently experienced. This prediction was tested and confirmed in two experiments in which the associative set size and the frequency of the studied words were manipulated. Implications for the study of implicit memory are considered.
Attention↗
Levels of soluble interleukin-2 receptors are predictive of response in patients treated with interleukin-2 and lymphokine-activated killer cells.
Soluble interleukin-2 receptor (sIL-2R) alpha (CD25) levels were serially determined in the sera of 20 patients who had undergone adoptive immunotherapy with high-dose IL-2 and lymphokine-activated killer (LAK) cells for various types of metastatic solid tumors or Hodgkin's disease. The treatment course consisted of 5 days of high-dose IL-2 priming followed by the collection of peripheral blood leukocytes by leukapheresis, and in vitro activation of mononuclear cells with IL-2, and the subsequent infusion of such prepared LAK-cells together with IL-2. sIL-2R levels increased in all patients following IL-2 administration, and the ratio of baseline sIL-2R levels to those measured after 5 days of IL-2 was significantly correlated with pre-IL-2 levels (p = 0.016) in that higher pre-IL-2 levels resulted in a larger increase upon IL-2 administration. In terms of treatment outcome, the variables analysed included sIL-2R levels, total IL-2 doses administered, the expression of membrane-bound CD25 on in vitro cultured cells (pre- and post-IL-2 exposure), the total number of LAK-cells infused and in vitro cytotoxic activity of LAK-cells against the natural killer cell-resistant cell line Daudi. In a multivariate analysis, low baseline sIL-2R levels (p = 0.095) and high in vitro cytotoxic activity of LAK-cells against Daudi cells (p = 0.082) were jointly associated with response. Our data suggest that serum sIL-2R levels provide a fast and noninvasive parameter for predicting the response in patients treated with IL-2 and LAK-cells.
Cytotoxicity, Immunologic↗