Showing papers by "University of Alabama at Birmingham published in 1988"

Population coding of saccadic eye movements by neurons in the superior colliculus

Abstract: The deeper layers of the superior colliculus are involved in the initiation and execution of saccadic (high velocity) eye movements. A large population of coarsely tuned collicular neurons is active before each saccade. The mechanisms by which the signals that precisely control the direction and amplitude of a saccade are extracted from the activity of the population are unknown. It has been assumed that the exact trajectory of a saccade is determined by the activity of the entire population and that information is not extracted from only the most active cells in the population at a subsequent stage of neural processing. The trajectory of a saccade could be based on vector summation of the movement tendencies provided by each member of the population of active neurons or be determined by a weighted average of the vector contributions of each neuron in the active population. Here we present the results of experiments in which a small subset of the active population was reversibly deactivated with lidocaine. These results are consistent with the predictions of the latter population-averaging hypothesis and support the general idea that the direction, amplitude and velocity of saccadic eye movements are based on the responses of the entire population of cells active before a saccadic eye movement.

The chemistry and biology of unusual DNA structures adopted by oligopurine.oligopyrimidine sequences.

Abstract: A family of unusual DNA structures has been discovered in segments with predominantly purines in one strand (pur.pyr sequences). These sequences are overrepresented in eukaryotic DNA and have been mapped near genes and recombination hot spots. When cloned into recombinant plasmids, many pur.pyr sequences are reactive to chemical and enzymic probes that are generally specific for single-stranded DNA. An intramolecular triplex is adopted by mirror repeats of G's and A's. Other non-B DNA structures adopted by similar sequences remain to be fully clarified but may be a family of related conformations. It is likely that these unorthodox structures play an important role in the function of the eukaryotic genome.

Familial deficiency of dihydropyrimidine dehydrogenase. Biochemical basis for familial pyrimidinemia and severe 5-fluorouracil-induced toxicity.

Abstract: Severe neurotoxicity due to 5-fluorouracil (FUra) has previously been described in a patient with familial pyrimidinemia. We now report the biochemical basis for both the pyrimidinemia and neurotoxicity in a patient we have recently studied. After administration of a "test" dose of FUra (25 mg/m2, 600 microCi[6-3H]FUra by intravenous bolus) to a patient who had previously developed neurotoxicity after FUra, a markedly prolonged elimination half-life (159 min) was observed with no evidence of FUra catabolites in plasma or cerebrospinal fluid and with 89.7% of the administered dose being excreted into the urine as unchanged FUra. Using a sensitive assay for dihydropyrimidine dehydrogenase in peripheral blood mononuclear cells, we demonstrated complete deficiency of enzyme activity in the patient and partial deficiency of enzyme activity in her father and children consistent with an autosomal recessive pattern of inheritance. Patients who are deficient in this enzyme are likely to develop severe toxicity after FUra administration.

Thin Stage I Primary Cutaneous Malignant Melanoma

Abstract: Although wide surgical excision is the accepted treatment for thin malignant melanomas, there is reason to believe that narrower margins may be adequate. We conducted a randomized prospective study to assess the efficacy of narrow excision (excision with 1-cm margins) for primary melanomas no thicker than 2 mm. Narrow excision was performed in 305 patients, and wide excision (margins of 3 cm or more) was performed in 307 patients. The major prognostic criteria were well balanced in the two groups. The mean thickness of melanomas was 0.99 mm in the narrow-excision group and 1.02 mm in the wide-excision group. The subsequent development of metastatic disease involving regional nodes and distant organs was not different in the two groups (4.6 and 2.3 percent, respectively, in the narrow-excision group, as compared with 6.5 and 2.6 percent in the wide-excision group). Disease-free survival rates and overall survival rates (mean follow-up period, 55 months) were also similar in the two groups. Only three patients had a local recurrence as a first relapse. All had undergone narrow excision, and each had a primary melanoma with a thickness of 1 mm or more. The absence of local recurrence in the group of patients with a primary melanoma thinner than 1 mm and the very low rate of local recurrences indicate that narrow excision is a safe and effective procedure for such patients.

Extensive variation of human immunodeficiency virus type-1 in vivo.

Abstract: Genotypic variation among independent isolates of human immunodeficiency virus type-1 (HIV-1) is well known, but its molecular basis and biological consequences are poorly understood. We examined the genesis of molecular variation in HIV-1 by sequential virus isolations from two chronically infected individuals and analysis of recombinant HIV-1 genomic clones. In three different virus isolates full-length HIV-1 clones were identified and found to consist, respectively, of 17, 9 and 13 distinguishable, but highly-related, viral genotypes. Thirty-five viral clones derived from two HIV-1 isolates obtained from the same individual but 16 months apart showed progressive change, yet were clearly related. Similar changes in the HIV-1 genome did not occur in vitro during virus isolation and amplification. The results indicate that HIV-1 variation in vivo is rapid, that a remarkably large number of related but distinguishable genotypic variants evolve in parallel and coexist during chronic infection, and that 'isolates' of HIV-1, unless molecularly or biologically cloned, generally consist of complex mixtures of genotypically distinguishable viruses.

Entropic elastic processes in protein mechanisms. I. Elastic structure due to an inverse temperature transition and elasticity due to internal chain dynamics.

Abstract: Numerous physical characterizations clearly demonstrate that the polypentapeptide of elastin (Val1-Pro2-Gly3-Val4-Gly5)n in water undergoes an inverse temperature transition. Increase in order occurs both intermolecularly and intramolecularly on raising the temperature from 20 to 40 degrees C. The physical characterizations used to demonstrate the inverse temperature transition include microscopy, light scattering, circular dichroism, the nuclear Overhauser effect, temperature dependence of composition, nuclear magnetic resonance (NMR) relaxation, dielectric relaxation, and temperature dependence of elastomer length. At fixed extension of the cross-linked polypentapeptide elastomer, the development of elastomeric force is seen to correlate with increase in intramolecular order, that is, with the inverse temperature transition. Reversible thermal denaturation of the ordered polypentapeptide is observed with composition and circular dichroism studies, and thermal denaturation of the crosslinked elastomer is also observed with loss of elastomeric force and elastic modulus. Thus, elastomeric force is lost when the polypeptide chains are randomized due to heating at high temperature. Clearly, elastomeric force is due to nonrandom polypeptide structure. In spite of this, elastomeric force is demonstrated to be dominantly entropic in origin. The source of the entropic elastomeric force is demonstrated to be the result of internal chain dynamics, and the mechanism is called the librational entropy mechanism of elasticity. There is significant application to the finding that elastomeric force develops due to an inverse temperature transition. By changing the hydrophobicity of the polypeptide, the temperature range for the inverse temperature transition can be changed in a predictable way, and the temperature range for the development of elastomeric force follows. Thus, elastomers have been prepared where the development of elastomeric force is shifted over a 40 degrees C temperature range from a midpoint temperature of 30 degrees C for the polypentapeptide to 10 degrees C by increasing hydrophobicity with addition of a single CH2 moiety per pentamer and to 50 degrees C by decreasing hydrophobicity.(ABSTRACT TRUNCATED AT 400 WORDS)

Resection of the liver for colorectal carcinoma metastases. A multi-institutional study of long-term survivors.

Abstract: In this review of a collected series of patients undergoing hepatic resection for colorectal metastases, 100 patients were found to have survived greater than five years from the time of resection. Of these 100 long-term survivors, 71 remain disease-free through the last follow-up, 19 recurred prior to five years, and ten recurred after five years. Patient characteristics that may have contributed to survival were examined. Procedures performed included five trisegmentectomies, 32 lobectomies, 16 left lateral segmentectomies, and 45 wedge resections. The margin of resection was recorded in 27 patients, one of whom had a positive margin, nine of whom had a less than or equal to 1-cm margin, and 17 of whom had a greater than 1-cm margin. Eighty-one patients had a solitary metastasis to the liver, 11 patients had two metastases, one patient had three metastases, and four patients had four metastases. Thirty patients had Stage C primary carcinoma, 40 had Stage B primary carcinoma, and one had Stage A primarycarcinoma. The disease-free interval from the time of colon resection to the time of liver resection was less than one year in 65 patients, and greater than one year in 34 patients. Three patients had bilobar metastases. Four of the patients had extrahepatic disease resected simultaneously with the liver resection. Though several contraindications to hepatic resection have been proposed in the past, five-year survival has been found in patients with extrahepatic disease resected simultaneously, patients with bilobar metastases, patients with multiple metastases, and patients with positive margins. Five-year disease-free survivors are also present in each of these subsets. It is concluded that five-year survival is possible in the presence of reported contraindications to resection, and therefore that the decision to resect the liver must be individualized.

Specific Chromosomal Abnormalities in Malignant Human Gliomas

Abstract: Karyotypic analysis of 54 malignant human gliomas (5 anaplastic astrocytomas, 43 glioblastoma multiformes, 3 gliosarcomas, 2 giant cell glioblastomas, 1 anaplastic mixed glioma) has demonstrated that 12 tumors contained normal stemlines or only lacked one sex chromosome. The 42 tumors with abnormal karyotypes included 38 tumors which could be completely analyzed. Six of these 38 cases had near-triploid or near-tetraploid stemlines and 32 had near-diploid stemlines. Statistically significant numerical deviations in the near-diploid group were gains of chromosome 7 (26 of 32; P less than 0.001), and losses of chromosome 10 (19 of 32; P less than 0.001). Double minutes occurred in 18 of 32 near diploid tumors. The distribution of structural abnormalities was analyzed statistically by comparing the incidence of breakpoint in each chromosomal arm to the expected value based on chromosomal arm length. This analysis demonstrated that structural abnormalities of 9p and 19q were significant statistically (P less than 0.005 and P = 0.02, respectively). Although chromosome 1, 6p, the centromeric region of chromosome 11, 13q, and 15q were also frequently involved in structural abnormalities, the incidence of these breaks did not reach statistical significance. This demonstration of specific chromosomal abnormalities in near-diploid gliomas provides the basis for the investigation of genes which may be quantitatively or qualitatively altered in these neoplasms.

Factors affecting degree of perceived foreign accent in English sentences.

Abstract: This study used interval scaling to assess degree of perceived foreign accent in English sentences spoken by native and non‐native talkers Native English listeners gave significantly higher (ie, more authentic) pronunciation scores to native speakers of English than to Chinese adults who began learning English at an average age of 76 years The results for the ‘‘child learners’’ suggest that a sensitive period for speech learning is reached long before the age of 12 years, as commonly supposed Adults who had lived in the US for 5 years did not receive higher scores than those who had lived there for only 1 year, suggesting that amount of unaided second‐language (L2) experience does not affect adults’ L2 pronunciation beyond an initial rapid stage of learning Native speakers of Chinese who rated the sentences for foreign accent showed the same pattern of between‐group differences as the native English listeners The more experienced of two groups of Chinese listeners differentiated native and non‐native talkers to a significantly greater extent than a less experienced group, even though the subjects in both groups spoke English with equally strong foreign accents This suggests that tacit knowledge of how L2 sentences ‘‘ought’’ to sound increases more rapidly than the ability to produce those sentences

Biologically diverse molecular variants within a single HIV-1 isolate.

Abstract: AIDS is a disorder characterized by a slow progressive impairment of immune function and by infection of human immunodeficiency viruses (HIV-1, HIV-2)1–4. Our knowledge of how these viruses cause disease in man, or how the related lentiviruses (visna and equine infectious anaemia virus) cause disease in animals, is still fragmentary. In particular, the significance of genetic variation in HIV-1, occurring within populations, within individuals and over periods of time5,6, and the mechanisms of viral persistence remain unclear. To address these issues we prepared a series of proviral clones of HIV-1 originating from a single patient and compared their biological properties. Here we show that hybrid genomes (in which the envelope region of six viral clones were separately substituted into a prototype HIV-1 genome) generated viruses with widely differing capacity to grow in human T cells, cell lines and monocytoid cultures. These data suggest that extensive biological variation exists in vivo within an infected individual and is in part determined at the level of the viral envelope.

Identification of the avian homologues of mammalian CD4 and CD8 antigens.

Abstract: Two mAb were produced against chicken T cells. The CT4 antibody precipitated a polypeptide of Mr 64,000 under both reducing and non-reducing conditions. The CT8 antibody precipitated a molecule of Mr 63,000 under non-reducing conditions and polypeptide chains of Mr 34,000 under reducing conditions, suggesting that the CT8 molecule is a disulfide-linked homodimer. Tissue distribution studies by immunofluorescence revealed that the CT4 and CT8 Ag were expressed by the majority of thymocytes and by subpopulations of CT3+ cells in peripheral tissues. The CT4 reactive molecule was found on approximately 70% of thymocytes, 10% splenocytes, and 45% of lymphoid cells in blood. The CT8 reactive molecule was expressed on approximately 80% of thymocytes, 50% of spleen cells, and 15% of blood lymphocytes. Two-color immunofluorescence indicated that the CT4 and CT8 Ag were expressed together on most thymocytes and on mutually exclusive subsets of cells in the spleen and blood. Ontogenic studies revealed a sharp increase in the frequencies of CT4+ and CT8+ cells in the thymus between days 13 and 16 embryonic life. Both CT4 and CT8 antibodies inhibited PHA- and Con A-induced proliferative responses of splenocytes, and the degree of inhibition correlated with the frequencies of CT4+ and CT8+ lymphoblasts. Treatment of spleen cells with CT4 antibody and inhibited PWM-induced IL-2 production, and removal of CT8+ cells inhibited the cytolytic activity induced by allogeneic lymphocyte stimulation. Macrophages did not express detectable CT4 reactivity. These results suggest that the CD4 and CD8 molecules and their tissue-restricted patterns of expression are highly conserved in birds and mammals.

Changing Presentation of Herpes Simplex Virus Infection in Neonates

Abstract: We compared the clinical presentation of 95 newborns with herpes simplex virus (HSV) infection from 1973 through 1981 (first period) with data from 196 newborns evaluated from 1982 through 1987 (second period). There was a significant change in the presentation of infection in these infants. From the first to the second period, the frequency of disseminated disease decreased from 50.5% to 22.9%, whereas the frequency of skin, eye, and mouth (SEM) diseases increased from 17.9% to 43.4% (P less than .001). The frequency of infants with central nervous system (CNS) disease remained relatively unchanged--31.6% versus 33.7%. We also compared the demographic and clinical characteristics of the infants and their mothers. For neonates with CNS or disseminated infection, disease duration and frequency of prematurity were significantly decreased in the second period, as was the frequency of skin vesicles for newborns with SEM or disseminated infection. These changes are most likely the consequence of recognizing and treating SEM infection before its progression to more-severe disease.

Conversion of xanthine dehydrogenase to oxidase in ischemic rat intestine: a reevaluation

Abstract: Oxygen radicals derived from xanthine oxidase (XO) are important mediators of the cellular injury associated with reperfusion of ischemic intestine, stomach, liver, kidney, and pancreas. XO exists in nonischemic tissue predominantly as xanthine dehydrogenase (XDH) and converts to oxygen radical-producing XO with ischemia. Grinding intestine under liquid nitrogen and placing the powder in phosphate buffer (pH 7.0) containing thiol reductants and protease inhibitors adequately preserved total XDH + XO activity and the percentage in the oxidase form (%XO) for 24 h. Total activity in nonischemic intestine ranged from 374 nmol.min-1.g-1 in duodenum to 138 nmol.min-1.g-1 in ileum, while XO activity was approximately 19% of total activity throughout the entire small intestine. The rate of XDH conversion to XO during normothermic ischemia varied only slightly throughout the intestine, increasing 13% per hour to 34, 46, and 61% XO after 1, 2, and 3 h of ischemia, respectively. Our results contrast with previous reports where XDH conversion to XO occurred within 60 s ischemia but are consistent with physiological and morphological evidence of ischemic injury and provide further support for involvement of XO in intestinal injury associated with ischemia.

Radiographic assessment and psychologic variables as predictors of pain and functional impairment in osteoarthritis of the knee or hip.

Abstract: Sixty-five outpatients with osteoarthritis of the knee and/or hip were assessed using radiographic ratings of disease severity, measures of psychologic coping, and multidimensional clinical outcomes of degree of pain and functional impairment. Disease severity accounted for little of the individual variability in clinical outcomes. Even after controlling for disease severity, psychologic variables remained strong predictors of individual differences in functional impairment and pain. Psychologic processes deserve greater clinical and research attention as potential mediators between disease severity and clinical outcome.

Differential activation requirements for virgin and memory T cells.

Abstract: Most studies of the activation requirements for T cells have used either T cell lines or populations of normal T cells that consist of a mixture of virgin and Ag-primed T cells. These two subpopulations of T cells can now be distinguished in humans by their reactivity with mAb. The anti-CD45R antibody HB10 identifies virgin T cells (T degrees) that are non-reactive to recall Ag and relatively poor at providing help for B cell differentiation. Conversely, memory T cells (T') that can react to recall Ag and enhance Ig production are non-reactive with anti-CD45R, but can be identified with the UCHL1 antibody. We have used these antibodies to separate the T degrees and T' populations and examine their activation requirements. On activation CD45R+ cells rapidly began to lose the CD45R Ag and express the UCHL1 Ag in increased amounts, whereas the UCHL1+ cells retained this phenotype. Both populations responded to PHA in the presence of monocytes, but when triggered by an antibody to CD3 only the T' cells were induced to express IL-2R, produce IL-2, and to proliferate. The T degrees population of cells remained relatively quiescent by all of these parameters. However, anti-CD3 stimulation conditioned the T degrees cells for IL-2 responsiveness, inasmuch as the addition of rIL-2 resulted in significant IL-2R expression and proliferation. When the CD4+ T degrees and CD4+ T' subpopulations were isolated and examined in the same assays similar results were obtained. The data indicate that fundamental differences exist in the triggering requirements for T degrees and T' cells.

A large subpopulation of avian T cells express a homologue of the mammalian T gamma/delta receptor.

Abstract: This report describes an avian TCR molecule, TCR1, whose molecular characteristics, signal-transducing property, and tissue distribution suggest that it is a homologue of the mammalian TCR-gamma/delta. TCR1+ cells are the first to be generated in the thymus during ontogeny, preceding other T3+ cells by approximately 3 d. Unlike their mammalian counterpart, TCR1+ cells constitute a relatively large subpopulation of peripheral T cells in mature chickens. These results suggest a phylogenetically important role for this receptor in T cell development and function.

Pulmonary vascular resistance and the risk of heart transplantation.

Abstract: Elevated pulmonary vascular resistance was an incremental risk factor for premature death after heart transplantation (p = 0.0002). Its effect was continuously variable and not dichotomous (yes or no). The rate of rise in risk of death corresponded quite evenly to the progressive increase in pulmonary vascular resistance from low to high values, rather than abruptly increasing at a certain point. This effect was incremental to the risk imposed by congenital heart disease (in contrast to idiopathic or ischemic cardiomyopathy). Expression of the pulmonary vascular resistance in units times square meters provides more accurate predictions than expression in Wood units (p for difference = 0.03).

Recombinant murine IL-5 induces high rate IgA synthesis in cycling IgA-positive Peyer's patch B cells.

Abstract: Recent studies have shown that purified IL-5 from T cell lines and clones enhances IgA synthesis in LPS-triggered splenic B cell cultures, and that this effect is augmented by IL-4. In this study we have examined the ability of rIL-5 and rIL-4 to support spontaneous Ig synthesis in normal Peyer's patch (PP) B cell cultures. The rIL-4 supported proliferation of the HT-2 and in vivo adapted BCL-1 cell lines, increased Ia expression on normal spleen B cells, co-stimulated splenic B cell proliferation in the presence of anti-mu and enhanced IgG1 synthesis in LPS triggered splenic B cell cultures. The rIL-5 supported BCL-1 proliferation, co-stimulated splenic B cell proliferation in the presence of dextran sulfate, and increased IgA synthesis in LPS-stimulated splenic B cell cultures. Markedly enhanced IgA responses occurred in PP B cell, but not splenic B cell cultures supplemented with rIL-5 in the absence of an added B cell trigger. However, rIL-4 alone did not enhance IgA synthesis or increase the IgA synthesis of PP B cell cultures stimulated with rIL-5. The rIL-5 receptive PP B cells were present in the blast cell subpopulation, inasmuch as a low density fraction isolated on Percoll gradients accounted for the enhanced IgA synthesis. Further, cell cycle analysis of whole PP B cells using propidium iodide in conjunction with staining for surface B220, demonstrated that approximately 12 to 16% of the B cells were in the S and G2/M stages of cell cycle, the remainder being in Go + G1. The surface IgM+ B cells were predominantly in Go + G1, whereas the sIgA+ B cell subpopulation was enriched for cells in the S and G2/M compartments. The PP B cell subset responsible for enhanced IgA synthesis in the presence of rIL-5 was sIgA-positive because FACS-depletion of the sIgA+ B cells resulted in the total loss of rIL-5 enhanced IgA synthesis. Further, when PP B cells were enriched for sIgA+ B cells by cell sorting, these cells responded to rIL-5 with increased IgA synthesis in a dose-dependent manner. When the actual numbers of IgA secreting cells were assessed in PP B cell cultures with supplemental rIL-5, no significant increase in total IgA-producing cells was noted when compared with B cells cultured without rIL-5.(ABSTRACT TRUNCATED AT 400 WORDS)

Tumor Formation Dependent on Proteoglycan Biosynthesis

Abstract: The role proteoglycans play in tumor formation was examined by measuring the tumorigenicity of proteoglycan-deficient Chinese hamster ovary cell mutants in nude mice. When 10(7) cells were injected subcutaneously, mutants with less than about 15% of the wild-type level of proteoglycan synthesis did not produce tumors. Mutants defective in the synthesis of heparan sulfate proteoglycans also did not form tumors, whereas mutants with altered chondroitin sulfate proteoglycans were tumorigenic. Tumors arose from mixtures of wild-type and nontumorigenic mutant cells and contained both cell types, suggesting that wild-type cell proteoglycans enabled mutant cells to survive. The failure of heparan sulfate-deficient mutants to form tumors depended on the ability of the host to mount a B cell-mediated immune reaction.

Improvement in Bronchial Squamous Metaplasia in Smokers Treated With Folate and Vitamin B12: Report of a Preliminary Randomized, Double-blind Intervention Trial

Abstract: To test whether changes in folate and vitamin B12nutrition modify the severity of potentially premalignant lesions identified by cytology in sputum samples of smokers, we conducted a randomized, controlled prospective intervention trial in smokers with bronchial squamous metaplasia. Seventy-three men with a history of 20 or more pack-years of cigarette smoking who had metaplasia on one or more sputum samples were stratified according to smoking level and randomly assigned to four months' treatment with either placebo or 10 mg of folate plus 500 μg of hydroxocobalamin. Direct cytological comparison of the two groups after four months showed significantly greater reduction of atypia in the supplemented group. This provides preliminary evidence that atypical bronchial squamous metaplasia may be reduced by supplementation with folate and vitamin B12. However, the significance of these findings is tempered by substantial spontaneous variation in sputum cytologies, the small study population, the short duration of the trial, and the supraphysiological doses of folate and B12used. The results should not be construed as pointing to a potential way of preventing lung cancer in individuals who continue to smoke or as supporting self-medication with large doses of folate or B12by smokers. (JAMA1988;259:1525-1530)