ASM - 100th Meeting. Vaccine developments and highlights of poster sessions.
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Journal Article↗
Biomedical subjects
J Nelson
Publications and source records attributed to J Nelson.
Childhood-onset schizophrenia: progressive brain changes during adolescence.
BACKGROUND: Previous NIMH childhood onset schizophrenia (COS) anatomic brain MRI studies found progression of ventricular volume and other structural brain anomalies at 2-year follow up across mean ages 14 to 16 years. However, studies in adult patients generally do not show progression of ventricular volume or correlation of ventricular volume with duration of illness. To address issues of progression of brain anomalies in schizophrenia, this report extends previous studies to include a third longitudinal scan, uses a larger sample size, and includes measures of the amygdala and hippocampus. METHODS: Volumes of the total cerebrum, lateral ventricles, hippocampus, and amygdala were quantified on 208 brain magnetic resonance imaging scans from 42 adolescents with COS (23 with one or more repeat scan) and 74 age- and gender-matched controls (36 with one or more repeat scan). A statistical technique permitting combined use of cross-sectional and longitudinal data was used to assess age-related changes, linearity, and diagnostic group differences. RESULTS: Differential nonlinear progression of brain anomalies was seen during adolescence with the total cerebrum and hippocampus decreasing and lateral ventricles increasing in the COS group. The developmental curves for these structures reached an asymptote by early adulthood for the COS group and did not significantly change with age in the control group. CONCLUSIONS: These findings reconcile less striking progression of anatomic brain images usually seen for adult schizophrenia and complement other data consistent with time-limited, diagnostic-specific decreases in brain tissue. Adolescence appears to be a unique period of differential brain development in schizophrenia.
Adolescent↗
Gene localization for oral-facial-digital syndrome type 1 (OFD1:MIM 311200) proximal to DXS85.
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Chromosome Mapping↗
Organization of somatosensory cortex in three species of marsupials, Dasyurus hallucatus, Dactylopsila trivirgata, and Monodelphis domestica: neural correlates of morphological specializations.
The organization of somatosensory neocortex was investigated in three species of marsupials, the northern quoll (Dasyurus hallucatus), the striped possum (Dactylopsila trivirgata), and the short-tailed opossum (Monodelphis domestica). In these species, multiunit microelectrode mapping techniques were used to determine the detailed organization of the primary somatosensory area (SI). In the striped possum and quoll, the topography of somatosensory regions rostral (R), and caudal (C) to SI were described as well. Lateral to SI, two fields were identified in the striped possum, the second somatosensory area (SII) and the parietal ventral area (PV); in the quoll, there appeared to be only one additional lateral field which we term SII/PV. Visual and auditory cortices adjacent to somatosensory cortex were also explored, but the details of organization of these regions were not ascertained. In these animals, electrophysiological recording results were related to cortical myeloarchitecture and/or cytochrome oxidase staining. In one additional species, the fat-tailed dunnart (Sminthopsis crassicaudata), an architectonic analysis alone was carried out, and compared with the cortical architecture and electrophysiological recording results in the other three species. We discuss our results on the internal organization of SI in relation to the morphological specializations that each animal possesses. In addition, we discuss the differences in the organization of SI, and how evolutionary processes and developmental and adult neocortical plasticity may contribute to the observed variations in SI.
Animals↗
Magnesium and pH imaging of the human brain at 3.0 Tesla.
Multislice, two-dimensional phosphorus 31 spectroscopic imaging (SI) of human brain was performed in 15 normal volunteers on a 3-Tesla magnetic resonance system. Images of free magnesium concentrations and pH as well as phosphoesters, inorganic phosphate, phosphocreatine, and adenosine triphosphate (ATP), were calculated from the SI data. By using the equations of Golding and Golding (Magn. Reson. Med. 1995;33: 467-474), average [Mg2+] for all brain regions studied was 0.42+/-0.05 mM, whereas average brain pH was found to be 7.07+/-0.03, with no significant regional variations. Phosphorus metabolite concentrations (relative to ATP, assumed to be 3.0 mM/kg wet weight)were 5.39+/-1.88, 1.30+/-0.39, 5.97+/-3.17, and 4.33+/-1.45 mM/kg wet weight for phosphomonoesters, inorganic phosphate, phosphodiesters, and phosphocreatine (PCr), respectively. These values are in good general agreement with those reported previously. Typical signal-to-noise ratios of 15:1 were obtained for PCr in spectra from nominal 31.5 cc voxel sizes with a 34-min scan time. Limits on spatial resolution and the likely error of the magnesium and pH values are discussed.
Adenosine Triphosphate↗
Multiple forms of the Menkes Cu-ATPase.
The 5' region of MNK cDNAs has a 45 bp insert terminating at the 5'end with an AGATG sequence. The ATG in the sequence is in-frame with the ATG downstream identified by Vulpe et al (1993) as a translation start site for MNK mRNA. Inserts of 192 bp and 45 bp have been found in the 5' region of MNK mRNAs from BeWo cells, Caco-2 cells and normal human fibroblasts. Extensions to the 5' end of these mRNAs could foretell a modified N-termini in certain forms of the Menkes Cu-ATPase. These modified H2N-terminal extensions are postulated to be targeting signals for post-translational processing and cellular localization. In this report, we provide evidence that the primary Menkes transcript in non-Menkes cells undergoes post-transcriptional splicing that gives rise to multiple transcripts. The data suggest that the Menkes gene is a copper locus that codes for more than one form of the Menkes Cu-ATPase and one of these forms could be a small Cu transport protein.
Adenosine Triphosphatases↗
Development of the human corpus callosum during childhood and adolescence: a longitudinal MRI study.
1. Interest in the morphologic development of the corpus callosum (CC) during childhood and adolescence stems from adolescent changes in cognitive functions subserved by the CC, reports of CC anomalies for a wide variety of childhood neuropsychiatric illnesses, and controversy regarding sexual dimorphism. 2. Characterization of the normal developmental pattern of the CC is hindered by enormous variability of its size. This is especially problematic for cross-sectional studies seeking to assess possible non-linear developmental curves. 3. To more accurately characterize developmental changes, a longitudinal brain magnetic resonance imaging study with subjects rescanned at approximately 2 year intervals was conducted resulting in 251 scans from 139 healthy children and adolescents. 4. Midsagittal area of the CC, especially the posterior regions, increased robustly from ages 5 to 18 years. 5. Although the genu of the CC was significantly larger in males there were no sex differences in mean area after adjustment for total cerebral volume and the growth patterns did not differ between sexes. 6. Analysis revealed a non-linear increase in the splenium, the most posterior region, with increases greatest in the younger years. 7. The results of this longitudinal study, in addition to confirming and extending previous cross-sectional reports, provide an increasingly accurate yardstick from which to assess pathological development.
Adolescent↗
Relationships between aggressive behavior in cognitively impaired nursing home residents and use of restraints, psychoactive drugs, and secured units.
This study examined relationships between aggressive behavior in cognitively impaired nursing home residents and physical restraints, psychoactive drugs, and placement on a secured unit. Data were obtained from 116 residents who were consistently aggressive as measured by the Ryden Aggression Scale 2. Subjects averaged 9.5 aggressive behaviors per day. Forty-seven percent of subjects were restrained, and 62% were regularly receiving psychoactive drugs. Use of restraints, antipsychotics, and placement on a secured unit were all significantly related to increased physical aggression scores. Four variables accounted for 23% of the variance in physical aggression scores: location on a secured unit, not receiving an antidepressant, being restrained, and number of psychotropic and/or anxiolytic medications administered. Significantly lower physical aggression scores were noted for subjects receiving antidepressants.
Aged↗
Pharmacokinetics and tissue disposition in monkeys of an antisense oligonucleotide inhibitor of Ha-ras encapsulated in stealth liposomes.
PURPOSE: This study examined the pharmacokinetics and tissue distribution of an antisense oligonucleotide ISIS 2503, formulated in stealth (pegylated) liposomes (encapsulated) or in phosphate-buffered saline (unencapsulated). METHODS: Encapsulated or unencapsulated ISIS 2503 was administered to rhesus monkeys by intravenous infusion. The concentrations of ISIS 2503 and metabolites in blood, plasma, and tissue samples were determined by capillary gel electrophoresis. RESULTS: Plasma concentrations of encapsulated ISIS 2503 decreased mono-exponentially after infusion with a mean half-life of 57.8 hours. In contrast, the concentration of unencapsulated ISIS 2503 in plasma decreased rapidly with a mean half-life of 1.07 hours. Both encapsulated and unencapsulated ISIS 2503 distributed widely into tissues. Encapsulated ISIS 2503 distributed primarily to the reticulo-endothelial system and there were few metabolites observed. In contrast, unencapsulated ISIS 2503 distributed rapidly to tissue with highest concentration seen in kidney and liver. Nuclease-mediated metabolism was extensive for unencapsulated oligonucleotide in plasma and tissues. CONCLUSIONS: The data suggest that stealth liposomes protect ISIS 2503 from nucleases in blood and tissues, slow tissue uptake, and slow the rate of clearance from the systemic circulation. These attributes may make these formulations attractive for delivering oligonucleotides to sites with increased vasculature permeability such as tumors or sites of inflammation.
Animals↗
Breast cancer cell-associated endopeptidase EC 24.11 modulates proliferative response to bombesin.
We have investigated the production, growth and inactivation of gastrin-releasing peptide (GRP)-like peptides in human breast cancer cell lines. Radioimmunoassay detected GRP-like immunoreactivity (GRP-LI) in T47D breast cancer cells but not in the conditioned medium, indicating rapid clearance. No GRP-LI was found in the ZR-75-1 or MDA-MB-436 cells or their conditioned medium. High-performance liquid chromatography (HPLC) analysis of the GRP-LI in the T47D cells revealed a major peak, which co-eluted with GRP(18-27), and a minor more hydrophilic peak. In vitro stimulation of T47D cell growth by bombesin (BN) was enhanced to 138% of control levels (bombesin alone) by the addition of the selective endopeptidase EC 3.4.24.11 inhibitor phosphoramidon (0.1 ng ml(-1)). Fluorogenic analysis using whole cells confirmed low levels of this phosphoramidon-sensitive enzyme on the T47D cells. This enzyme, previously unreported in human breast cancer cells, significantly modulates both T47D growth and its response to BN-induced growth.
Bombesin↗
Forearm venous pressures and blood back flow.
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Forearm↗
Does sexual intercourse at term influence the onset of labour? A survey of attitudes of patients and their partners.
It is not known if sexual intercourse at term influences the onset of labour, but there are several theoretical reasons why it may. Performing a definitive study to address this issue would pose practical and ethical difficulties. This study therefore sought to assess whether the scientific answer to this issue is of importance to pregnant women and their partners. Women and their partners attending antenatal clinics were asked to complete a questionnaire. Eighty-six per cent of women and 93% of men questioned wished to know if sexual intercourse did influence the onset of labour. If sexual intercourse did influence the onset of labour then a large proportion of those questioned indicated that it would have an effect on sexual activity at term. This study indicates that well-designed studies should be performed to assess whether sexual intercourse at term is implicated in the onset of labour.
Journal Article↗
Degradation products of mycophenolate mofetil in aqueous solution.
The thermal and peroxide-catalyzed degradation products of mycophenolate mofetil (1) were studied in aqueous solution at pH 2.0, 3.5, 6.0, and 8.2. The major thermal degradation product observed was mycophenolic acid (2). At pH 6.0 and 8.2, 2 was the only product observed in the absence of peroxide, while at pH 2.0 and 3.5, the lactone analogue of mycophenolic acid (5), a hydroxylactone due to oxygenation of the double bond (6), and an unidentified product were formed. Compound 6 degraded to 4-hydroxy-6-methoxy-7-methyl-3-oxo-1,3-dihydro-isobenzofuran-5-car baldehyde (9) on prolonged storage and was present in the sample stressed at pH 2. Mycophenolic acid (2), the N-oxide of mycophenolate mofetil (3), the hydroxylactone of mycophenolic acid (6), and the erythro form of 4-methoxy-5-methyl- 2-(2-methyl-5-oxo-tetrahydro-furan-2-yl)-3,6-dihydro-2H-1, 7-dioxa-as-indacen-8-one (8) were observed in the presence of hydrogen peroxide at pH 3.5, 6.0, and 8.2. In addition, at pH 8.2, 4-hydroxy-4-(4-methoxy-5-methyl-8-oxo-2,3,6, 8-tetrahydro-1,7-dioxa-as-indacen-2-yl)-pentanoic acid (7) was seen. Peroxide-stressed samples at pH 2.0 gave no major degradation peaks, but a small amount of the hydroxylactone of mycophenolic acid (6) was formed.
Chromatography, High Pressure Liquid↗
Perinatal outcome after in-vitro fertilization-surrogacy.
The perinatal outcome of pregnancies (both single and multiple) established after in-vitro fertilization (IVF)-surrogacy was evaluated and compared to the outcome of pregnancies that resulted from standard IVF. Analysis of medical records and a telephone interview with physicians, IVF-surrogates, and commissioning mothers were conducted to assess prenatal follow up and delivery care in several hospitals. 95 IVF-surrogates delivered 128 liveborn (65 singletons, 27 sets of twins and two sets of triplets). The commissioning mothers and the IVF-surrogates average ages were 37.7 +/- 5.0 and 30.4 +/- 4.7 years old respectively. IVF-surrogates carrying twin and triplet gestations delivered substantially earlier than those who gestated singleton pregnancies (36.2 +/- 0.4 versus 35.5 versus 38.7 +/- 0.3 weeks gestation respectively; P < 0.001). Twin newborns were significantly lighter than singleton infants born through IVF-surrogacy (2.7 +/- 0.06 versus 3.5 +/- 0.07 kg; P < 0.001). The incidence of low birth weight infants rose from 3.3% in the single births to 29.6% (P < 0.01) in the twins and to 33.3% in the triplets born through IVF-surrogacy. The incidence of prematurity was significantly greater in both twins delivered by IVF-surrogates (20.4%) and infertile IVF patients (58%). The occurrence of pregnancy-induced hypertension and bleeding in the third trimester was four to five times lower in the IVF-surrogates, independently of whether they were carrying multiples. The incidence of Caesarean section was 21.3% for singleton gestations, while two times higher in the IVF-surrogates carrying multiples (56.3%). Postpartum complications occurred in 6.3% of patients and the incidence of malformation was similar to those reported for the general population. The results provide general reassurance regarding perinatal outcome to couples who wish to pursue IVF-surrogacy.
Adult↗
Erythropoietic protoporphyria: identification of novel mutations in the ferrochelatase gene and comparison of biochemical markers versus molecular analysis as diagnostic strategies.
BACKGROUND: Erythropoietic protoporphyria (EPP) results from an inherited deficiency of the last enzyme of the heme biosynthetic pathway, ferrochelatase (FC). EPP is usually inherited in an autosomal dominant fashion, and the mutations in the FC gene on chromosome 18q21.3 detected in EPP patients are heterogeneous. METHODS: In this study, we screened the FC gene for mutations in 12 patients from 10 unrelated families with EPP and their family members using heteroduplex analysis, automated sequencing, and restriction enzyme digestion. RESULTS: We detected 8 different mutations in these patients, including 1 missense mutation, 5 frameshift mutations, and 2 splice site mutations, 6 of which are previously undescribed. CONCLUSIONS: We have established the molecular basis of EPP in 10 unrelated families, thereby providing further evidence for the heterogeneity in this disorder. Importantly, molecular diagnosis allowed revisions in the status of several clinically unaffected silent mutation carriers within the families. We compare the value of genetic research strategies with the combination of biochemical data and clinical phenotype as diagnostic tools to confirm a putative diagnosis in EPP.
Biomarkers↗
Guidelines for the clinical use of benzodiazepines: pharmacokinetics, dependency, rebound and withdrawal. Canadian Society for Clinical Pharmacology.
Principles of benzodiazepine selection are outlined for various psychiatric indications and diverse populations (the elderly, and drug and alcohol abusers). Benzodiazepines are still among the most commonly used classes of medications, and they differ in their pharmacodynamic properties. They have varied uses as monotherapy or as adjunctive medication because of their efficacy in the treatment of conditions involving a dysfunction of the GABAergic system or where neuronal inhibition is required. In multiple therapy, benzodiazepines augment the efficacy of other drugs such as lithium in mania, antipsychotics in psychotic agitation and selective serotonin reuptake inhibitors in panic disorder. Benzodiazepines can produce dependence and tolerance in most patients; predisposed individuals are at greater risk. Short- and intermediate-beta half-life compounds carry a greater risk of rebound and withdrawal reactions, and drug dependence than long acting agents. Adverse effects include sedation, psychomotor and cognitive impairment, memory loss, potentiation of other central nervous system depressants and treatment-emergent depression. Drug potency and beta elimination half-life are reviewed and compared as pharmacokinetic variables.
Aged↗
Collection, tumor contamination, and engraftment kinetics of highly purified hematopoietic progenitor cells to support high dose therapy in multiple myeloma.
Unfractionated peripheral blood stem cell (PBSC) grafts contain measurable quantities of myeloma cells and are therefore a potential source of relapse posttransplantation. In contrast, fluorescence-activated cell sorting (FACS)-sorted CD34+ Thy1+ Lin- peripheral blood cells are substantially enriched for stem cell activity, yet contain virtually no clonal myeloma cells. A study was performed in patients with symptomatic myeloma, who had received 12 months or less of preceding standard chemotherapy, to evaluate the feasibility of large scale purification of primitive hematopoietic stem cells in order to study engraftment kinetics posttransplantation and the degree of tumor cell contamination of this cell population, based on polymerase chain reaction (PCR) analysis for the patient-specific complementarity-determining region III (CDR III). PBSC were mobilized with high dose cyclophosphamide and granulocyte-macrophage colony-stimulating factor (GM-CSF). A combination of elutriation and chemical lysis was used to deplete PBSC collections of monocytes, granulocytes, erythrocytes, and platelets. Subsequently, CD34+ Thy1+ Lin- progenitor cells were purified with high speed cell sorting. Of the 10 evaluable patients, nine met the required minimum criteria of >/=7.2 x 10(5) cells/kg to support tandem transplants. After high dose melphalan (200 mg/m2) eight engrafted successfully, although granulocyte (absolute neutrophil count [ANC] >0.5 x 10(9)/L, 16 days) and platelet recovery (platelets > 50 x 10(9)/L, 39 days) was substantially delayed when compared with unmanipulated PBSC grafts; one patient required infusion of a reserve graft because of lack of evidence of engraftment by day +28. Three patients proceeded to a second graft with high dose melphalan and total body irradiation; two required infusion of a reserve graft and both died of infectious complications; one showed delayed, but complete, engraftment after this myeloablative regimen. Two of the nine evaluable patients attained a clinical complete remission (CR). The grafts from three patients were tested for tumor contamination and contained no detectable clonal myeloma cells. Larger quantities of purified cells may be required to resolve the problem of delayed engraftment.
Adult↗
Identification of intron and exon sequences involved in alternative splicing of insulin receptor pre-mRNA.
The insulin receptor exists as two isoforms, A and B, that result from alternative splicing of exon 11 in the primary transcript. We have shown previously that the alternative splicing is developmentally and hormonally regulated. Consequently, these studies were instigated to identify sequences within the primary RNA transcript that regulate the alternative splicing. Minigenes containing exons 10, 11, and 12 and the intervening introns were constructed and transfected into HepG2 cells, which contain both isoforms of the insulin receptor. The cells were able to splice the minigene transcript to give both A (- exon 11) and B-like (+ exon 11) RNAs. A series of internal deletions within intron 10 were tested for their ability to give A and B RNAs. Intron 10 contained two sequences that modulated exon 11 inclusion; a 48-nucleotide purine-rich sequence at the 5' end of intron 10 that functions as a splicing enhancer and causes an increase in exon 11 inclusion, and a 43-nucleotide sequence at the 3' end of intron 10 upstream of the branch point sequence that favors skipping of exon 11. Increasing the length of the polypyrimidine tract at the 3' end of intron 10 caused exon 11 to be spliced constitutively, indicating that a weak splice site is required for alternative splicing. Finally, point mutations, insertions, and deletions within exon 11 itself were able to regulate inclusion of the exon both positively and negatively.
Alternative Splicing↗