Showing papers by "University of Alabama at Birmingham published in 1995"

Viral dynamics in human immunodeficiency virus type 1 infection

Abstract: The dynamics of HIV-1 replication in vivo are largely unknown yet they are critical to our understanding of disease pathogenesis. Experimental drugs that are potent inhibitors of viral replication can be used to show that the composite lifespan of plasma virus and virus-producing cells is remarkably short (half-life approximately 2 days). Almost complete replacement of wild-type virus in plasma by drug-resistant variants occurs after fourteen days, indicating that HIV-1 viraemia is sustained primarily by a dynamic process involving continuous rounds of de novo virus infection and replication and rapid cell turnover.

Increased Cortical Representation of the Fingers of the Left Hand in String Players

Abstract: Magnetic source imaging revealed that the cortical representation of the digits of the left hand of string players was larger than that in controls. The effect was smallest for the left thumb, and no such differences were observed for the representations of the right hand digits. The amount of cortical reorganization in the representation of the fingering digits was correlated with the age at which the person had begun to play. These results suggest that the representation of different parts of the body in the primary somatosensory cortex of humans depends on use and changes to conform to the current needs and experiences of the individual.

Phantom-limb pain as a perceptual correlate of cortical reorganization following arm amputation

Abstract: Although phantom-limb pain is a frequent consequence of the amputation of an extremity, little is known about its origin. On the basis of the demonstration of substantial plasticity of the somatosensory cortex after amputation or somatosensory deafferentation in adult monkeys, it has been suggested that cortical reorganization could account for some non-painful phantom-limb phenomena in amputees and that cortical reorganization has an adaptive (that is, pain-preventing) function. Theoretical and empirical work on chronic back pain has revealed a positive relationship between the amount of cortical alteration and the magnitude of pain, so we predicted that cortical reorganization and phantom-limb pain should be positively related. Using non-invasive neuromagnetic imaging techniques to determine cortical reorganization in humans, we report a very strong direct relationship (r = 0.93) between the amount of cortical reorganization and the magnitude of phantom limb pain (but not non-painful phantom phenomena) experienced after arm amputation. These data indicate that phantom-limb pain is related to, and may be a consequence of, plastic changes in primary somatosensory cortex.

In vivo emergence of HIV-1 variants resistant to multiple protease inhibitors

Abstract: INHIBITORS of the human immunodeficiency virus type 1 (HIV-1) protease have entered clinical study as potential therapeutic agents for HIV-1 infection. The clinical efficacy of HIV-1 reverse transcriptase inhibitors has been limited by the emergence of resistant viral variants. Similarly, variants expressing resistance to protease inhibitors have been derived in cell culture1-10. We now report the characterization of resistant variants isolated from patients undergoing therapy with the protease inhibitor MK-639 (formerly designated L-735,524). Five of these variants, isolated from four patients, exhibited cross-resistance to all members of a panel of six structurally diverse protease inhibitors. This suggests that com-bination therapy with multiple protease inhibitors may not prevent loss of antiviral activity resulting from resistance selection. In addition, previous therapy with one compound may abrogate the benefit of subsequent treatment with a second inhibitor.

Cerebral perfusion pressure: management protocol and clinical results

Abstract: Early results using cerebral perfusion pressure (CPP) management techniques in persons with traumatic brain injury indicate that treatment directed at CPP is superior to traditional techniques focused on intracranial pressure (ICP) management. The authors have continued to refine management techniques directed at CPP maintenance. One hundred fifty-eight patients with Glasgow Coma Scale (GCS) scores of 7 or lower were managed using vascular volume expansion, cerebrospinal fluid drainage via ventriculostomy, systemic vasopressors (phenylephrine or norepinephrine), and mannitol to maintain a minimum CPP of at least 70 mm Hg. Detailed outcomes and follow-up data bases were maintained. Barbiturates, hyperventilation, and hypothermia were not used. Cerebral perfusion pressure averaged 83 +/- 14 mm Hg; ICP averaged 27 +/- 12 mm Hg; and mean systemic arterial blood pressure averaged 109 +/- 14 mm Hg. Cerebrospinal fluid drainage averaged 100 +/- 98 cc per day. Intake (6040 +/- 4150 cc per day) was carefully titrated to output (5460 +/- 4000 cc per day); mannitol averaged 188 +/- 247 g per day. Approximately 40% of these patients required vasopressor support. Patients requiring vasopressor support had lower GCS scores than those not requiring vasopressors (4.7 +/- 1.3 vs. 5.4 +/- 1.2, respectively). Patients with vasopressor support required larger amounts of mannitol, and their admission ICP was 28.7 +/- 20.7 versus 17.5 +/- 8.6 mm Hg for the nonvasopressor group. Although the death rate in the former group was higher, the outcome quality of the survivors was the same (Glasgow Outcome Scale scores 4.3 +/- 0.9 vs. 4.5 +/- 0.7). Surgical mass lesion patients had outcomes equal to those of the closed head-injury group. Mortality ranged from 52% of patients with a GCS score of 3 to 12% of those with a GCS score of 7; overall mortality was 29% across GCS categories. Favorable outcomes ranged from 35% of patients with a GCS score of 3 to 75% of those with a GCS score of 7. Only 2% of the patients in the series remained vegatative and if patients survived, the likelihood of their having a favorable recovery was approximately 80%. These results are significantly better than other reported series across GCS categories in comparisons of death rates, survival versus dead or vegetative, or favorable versus nonfavorable outcome classifications (Mantel-Haenszel chi 2, p < 0.001). Better management could have improved outcome in as many as 35% to 50% of the deaths.

Factors affecting strength of perceived foreign accent in a second language

Abstract: This study assessed the relation between non‐native subjects’ age of learning (AOL) English and the overall degree of perceived foreign accent in their production of English sentences. The 240 native Italian (NI) subjects examined had begun learning English in Canada between the ages of 2 and 23 yr, and had lived in Canada for an average of 32 yr. Native English‐speaking listeners used a continuous scale to rate sentences spoken by the NI subjects and by subjects in a native English comparison group. Estimates of the AOL of onset of foreign accents varied across the ten listeners who rated the sentences, ranging from 3.1 to 11.6 yr (M=7.4). Foreign accents were evident in sentences spoken by many NI subjects who had begun learning English long before what is traditionally considered to be the end of a critical period. Very few NI subjects who began learning English after the age of 15 yr received ratings that fell within the native English range. Principal components analyses of the NI subjects’ responses to a language background questionnaire were followed by multiple‐regression analyses. AOL accounted for an average of 59% of variance in the foreign accent ratings. Language use factors accounted for an additional 15% of variance. Gender was also found to influence degree of foreign accent.

Diagnosis of Herpes Simplex Encephalitis: Application of Polymerase Chain Reaction to Cerebrospinal Fluid from Brain-Biopsied Patients and Correlation with Disease

Abstract: Isolation of herpes simplex virus (HSV) from brain tissue after biopsy has been considered the reference standard for the diagnosis of herpes simplex encephalitis (HSE). During the evaluation of antiviral treatment of HSE, cerebrospinal fluid (CSF) was obtained from patients with clinical disease indicative of HSE who underwent diagnostic brain biopsy. HSV DNA was detected by polymerase chain reaction (PCR) in CSF of 53 (98%) of 54 patients with biopsy-proven HSE and was detected in all 18 CSF specimens obtained before brain biopsy from patients with proven HSE. Four of 19 CSF specimens were positive after 2 weeks of antiviral therapy. Positive results were found in 3 (6%) of 47 patients whose brain tissue was culture-negative. Detection of HSV DNA in the CSF correlated significantly with age and focal radiographic findings. Thus, PCR detection of HSV DNA should be the standard for diagnosis of HSE.

Reduced incidence of preterm delivery with metronidazole and erythromycin in women with bacterial vaginosis.

Abstract: Background Pregnant women with bacterial vaginosis may be at increased risk for preterm delivery. We investigated whether treatment with metronidazole and erythromycin during the second trimester would lower the incidence of delivery before 37 weeks' gestation. Methods In 624 pregnant women at risk for delivering prematurely, vaginal and cervical cultures and other laboratory tests for bacterial vaginosis were performed at a mean of 22.9 weeks' gestation. We then performed a 2:1 double-blind randomization to treatment with metronidazole and erythromycin (433 women) or placebo (191 women). After treatment, the vaginal and cervical tests were repeated and a second course of treatment was given to women who had bacterial vaginosis at that time (a mean of 27.6 weeks' gestation). Results A total of 178 women (29 percent) delivered infants at less than 37 weeks' gestation. Eight women were lost to follow-up. In the remaining population, 110 of the 426 women assigned to metronidazole and erythromycin (26 percent...

Efficient recovery of infectious vesicular stomatitis virus entirely from cDNA clones

Abstract: Infectious vesicular stomatitis virus (VSV), the prototypic nonsegmented negative-strand RNA virus, was recovered from a full-length cDNA clone of the viral genome. Bacteriophage T7 RNA polymerase expressed from a recombinant vaccinia virus was used to drive the synthesis of a genome-length positive-sense transcript of VSV from a cDNA clone in baby hamster kidney cells that were simultaneously expressing the VSV nucleocapsid protein, phosphoprotein, and polymerase from separate plasmids. Up to 10(5) infectious virus particles were obtained from transfection of 10(6) cells, as determined by plaque assays. This virus was amplified on passage, neutralized by VSV-specific antiserum, and shown to possess specific nucleotide sequence markers characteristic of the cDNA. This achievement renders the biology of VSV fully accessible to genetic manipulation of the viral genome. In contrast to the success with positive-sense RNA, attempts to recover infectious virus from negative-sense T7 transcripts were uniformly unsuccessful, because T7 RNA polymerase terminated transcription at or near the VSV intergenic junctions.

Comparison of Surgical and Medical Group Survival in Patients With Left Main Coronary Artery Disease Long-term CASS Experience

Abstract: Background Combined severe proximal left anterior descending and proximal left circumflex coronary artery disease, or left main equivalent (LMEQ) disease, defines a prognostic high-risk angiographic subset of patients with chronic ischemic heart disease. While numerous observational and randomized clinical trials showed prolonged survival in surgically compared with medically treated patients with left main coronary artery disease, relatively few observational studies compared surgical and medical therapies in patients with LMEQ disease. The present report of 912 patients with LMEQ disease in the Coronary Artery Surgery Study (CASS) Registry extends the originally published 5-year surgical and medical group survival analysis to more than 16 years of follow-up and permits analysis of LMEQ patient subgroups. Methods and Results The CASS Registry contains 912 patients with LMEQ disease, defined as combined stenoses of ≥70% in the proximal left anterior descending coronary artery before the first septal perfo...

Antioxidant and antipromotional effects of the soybean isoflavone genistein.

Abstract: Antioxidant and antipromotional effects of the soybean isoflavone genistein have been studied in HL-60 cells and the mouse skin tumorigenesis model Effects of structure-related flavone/iso

Evidence for in vivo peroxynitrite production in human acute lung injury.

Abstract: Oxidant-mediated toxicity resulting from acute pulmonary inflammation has been demonstrated in acute lung injury. A potent biological oxidant, peroxynitrite, is formed by the near diffusion-limited reaction of nitric oxide with superoxide. In addition to having hydroxyl radical-like oxidative reactivity, peroxynitrite is capable of nitrating phenolic rings, including protein-associated tyrosine residues. Nitric oxide does not directly nitrate tyrosine residues, therefore, demonstration of tissue nitrotyrosine residues infers the action of peroxynitrite or related nitrogen-centered oxidants. Lung tissue was obtained from formalin-fixed, paraffin-embedded autopsy specimens, and specific polyclonal and monoclonal antibodies to nitrotyrosine were visualized by diaminobenzidene-peroxidase staining. Acute lung injury resulted in intense staining throughout the lung, including lung interstitium, alveolar epithelium, proteinaceous alveolar exudate, and inflammatory cells. In addition, staining of the vascular endothelium and subendothelial tissues was present in those patients with sepsis-induced acute lung injury. Antibody binding was blocked by coincubation with nitrotyrosine or nitrated bovine serum albumin but not by aminotyrosine, phosphotyrosine, or bovine serum albumin. Reduction of tissue nitrotyrosine to aminotyrosine by sodium hydrosulfite also blocked antibody binding. In control specimens with no overt pulmonary disease, there was only slight staining of the alveolar septum. These results demonstrate that nitrogen-derived oxidants are formed in human acute lung injury and suggest that peroxynitrite may be an important oxidant in inflammatory lung disease.

A randomized controlled trial of an HIV sexual risk-reduction intervention for young African-American women.

Abstract: Objective. —To evaluate the efficacy of a community-based social skills human immunodeficiency virus (HIV) prevention intervention to enhance consistent condom use. Design. —A randomized, single-blind controlled trial. Setting. —Bayview-Hunter's Point neighborhood of San Francisco, Calif, a predominantly African-American community that is economically disadvantaged. Participants. —A sample of 128 sexually active, heterosexual, African-American women 18 through 29 years of age was recruited using street outreach techniques. Participants completed a structured baseline interview; 100 women (78.1%) completed 3-month follow-up interviews. Intervention. —Women randomized to the social skills intervention completed five sessions that emphasized ethnic and gender pride, HIV risk—reduction information, sexual self-control, sexual assertiveness and communication skills, proper condom use skills, and developing partner norms supportive of consistent condom use. Women randomized to the HIV education condition participated in a single session that provided HIV risk—reduction information. Women randomized to the delayed HIV education control condition received no HIV risk—reduction information until all follow-up interviews were completed. Main Outcome Measures. —Consistent condom use, HIV risk—reduction knowledge, sexual self-control, sexual assertiveness, sexual communication, and partner norms supportive of consistent condom use. Results. —Compared with the delayed HIV education control condition, women in the social skills intervention demonstrated increased consistent condom use (adjusted odds ratio [OR], 2.1; 95% confidence interval [CI], 1.03 to 4.15;P=.04), greater sexual self-control (adjusted OR, 1.9; 95% CI, 1.00 to 3.60;P=.05), greater sexual communication (adjusted OR, 4.1; 95% CI, 1.67 to 10.01;P=.002), greater sexual assertiveness (adjusted OR, 1.8; 95% CI, 1.01 to 3.27;P=.05), and increased partners' adoption of norms supporting consistent condom use (adjusted OR, 2.1; 95% CI, 1.08 to 3.87;P=.03). No statistically significant differences in outcome variables were observed between the HIV education condition relative to the delayed HIV education control condition. Conclusion. —Community-based HIV risk—reduction programs that are gender relevant and culturally sensitive and provide social skills training can effectively enhance consistent condom use. (JAMA. 1995;274:1271-1276)

Recombination in aids viruses

Abstract: Recombination contributes to the generation of genetic diversity in human immunodeficiency viruses (HIV) but can only occur between viruses replicating within the same cell. Since individuals have not been found to be simultaneously coinfected with multiple divergent strains of HIV-1 or HIV-2, recombination events have been thought to be restricted to the rather closely related members of the quasispecies that evolves during the course of HIV infection. Here we describe examples of both HIV-1 and HIV-2 genomes that appear to be hybrids of genetically quite divergent viruses. Phylogenetic analyses were used to examine the evolutionary relationships among multiple HIV strains. Evolutionary trees derived from different genomic regions were consistent with respect to most of the viruses investigated. However, some strains of HIV-1 and HIV-2 exhibited significantly discordant branching orders indicative of genetic exchanges during their evolutionary histories. The crossover points of these putative recombination events were mapped by examining the distribution of phylogenetically informative sites supporting alternative tree topologies. A similar example of a recombinant simian immunodeficiency virus identified in West African green monkeys has also been described recently. These results indicate that coinfection with highly divergent viral strains can occur in HIV-infected humans and SIV-infected primates and could lead to the generation of hybrid genomes with significantly altered biological properties. Thus, future characterization of primate lentiviruses should include careful phylogenetic investigation of possible genomic mosaicism.

Mucosal adjuvant effect of cholera toxin in mice results from induction of T helper 2 (Th2) cells and IL-4.

Abstract: Despite pathophysiologic effects including diarrhea, cholera toxin (CT) is a potent mucosal immunogen and adjuvant. We investigated the influence of CT on T helper (Th)-type 1 (Th1) and Th2 cell-regulated Ag-specific B cell isotype and IgG subclass Ab responses elicited when the toxin was co-administered orally with different protein Ags. When mice were orally immunized with tetanus toxoid (TT) and CT as adjuvant, this regimen induced TT-specific secretory IgA responses in the gastrointestinal tract as well as serum IgG, including IgG1 and IgG2b subclasses, and IgA responses. This oral regimen also induced TT- and CT-B-specific IgE responses. In addition, CT also elicited adjuvant effects for Ag-specific IgG1, IgE, and IgA responses when two other protein Ags, OVA and hen egg white lysozyme, were given by the oral route. Quantitative reverse transcriptase-PCR was performed to assess levels of mRNA for Th1 (IFN-gamma) and Th2 (IL-4) cytokine expression in TT-stimulated CD4+ T cell cultures. Both Peyer's patches and splenic CD4+ T cells expressed markedly increased levels of IL-4-specific message, but did not result in changes in IFN-gamma mRNA expression. To determine whether the route of immunization influenced IgE responses, mice were immunized s.c. with TT and CT as adjuvant. Significant increases in total and TT-specific IgE Abs were induced when CT was co-administered. Taken together, these results show that CT acts as a mucosal adjuvant to enhance Th2-type responses and in particular, the IL-4 produced results in a characteristic Ab isotype pattern associated with this cytokine.

Fibromyalgia in women. Abnormalities of regional cerebral blood flow in the thalamus and the caudate nucleus are associated with low pain threshold levels.

Abstract: Objective. To determine if regional cerebral blood flow (rCBF) in the left and right hemithalami or the left and right heads of the caudate nucleus is abnormal in women with fibromyalgia (FM). Methods. Resting-state rCBF in the hemithalami and left and right heads of the caudate nucleus of 10 untreated women with FM and 7 normal control women was measured by single-photon–emission computed tomography. Pain threshold levels at tender and control points also were assessed in both the women with FM and the controls. Results. The rCBF in the left and right hemithalami and the left and right heads of the caudate nucleus was significantly lower in women with FM than in normal controls (P = 0.01, P = 0.003, P = 0.01, and P = 0.02, respectively). Compared with controls, the women with FM also were characterized by significantly lower cortical rCBF (P = 0.001) and lower pain threshold levels at both tender points (P = 0.0001) and control points (P = 0.0001). Conclusion. The findings of low rCBF and generalized low pain thresholds support the hypothesis that abnormal pain perception in women with FM may result from a functional abnormality within the central nervous system.

The Fidelity of Initial Acquisition of Mutans Streptococci by Infants from Their Mothers

Abstract: Previous cross-sectional studies using bacteriocin profiles, serotyping, or genotyping suggest that mothers are the principle source of mutans streptococci (MS) to their infants. This study determined the commonality of MS genotypes between mothers and their infants at the time of initial acquisition. Oral bacteria of mothers and their infants were monitored from birth for approximately 3 years at three-month intervals. Genotypes of MS in infants appeared identical to those present in mothers in approximately 71% of 34 mother-infant pairs studied. Interestingly, female infants acquired MS genotypes identical to their mothers' with significantly greater fidelity than male infants (88% vs. 53%). Homology of genotypes between mothers and their infants at initial acquisition strongly suggests that MS strains were transmitted from mother to infant and that this transfer exhibited gender specificity. In no instance did we observe homology of genotypes between fathers and infants or fathers and mothers, further supporting the notion that acquisition of MS in humans follows maternal lines. Although the prevalence of dental caries was low in this young child population (11/34; 32%), we observed that male children who harbored the same genotype as their mothers had a 13 times greater likelihood of having caries than female children who acquired their mothers' strain; this difference was statistically significant (p < 0.01). Although we do not know the biological mechanisms governing fidelity of acquisition between a mother and her infant, our data suggest that caries outcome may be, in part, determined by both the source of MS and the presence of a specific genotype of MS.(ABSTRACT TRUNCATED AT 250 WORDS)

Influenza type A virus neuraminidase does not play a role in viral entry, replication, assembly, or budding.

Abstract: We have used a neuraminidase-deficient influenza virus, NWS-Mvi, which was selected by supplying bacterial neuraminidase in the medium (C. Liu and G. M. Air, Virology 194:403-407, 1993), to define the role of neuraminidase in influenza virus replication. Electron microscopy showed that virions of the NWS-Mvi mutant assembled normally and formed large aggregates associated with cell surfaces. The NWS-Mvi virus grown in the absence of neuraminidase was able to carry out a second round of replication in MDCK cells without added neuraminidase, indicating that the virus particles contained in these aggregates were infectious. Aggregates of virus were also found in cytoplasmic vacuoles. When virus-infected cells were incubated in the presence of ferritin, such aggregates were found to be labeled with ferritin, indicating that they are derived from uptake at the cell surface. When the neuraminidase-deficient virus was administered intranasally to C57BL/6 mice, low titers of virus were recovered from the lungs and major histocompatibility complex class I-restricted cytotoxic T cells were generated: evidence that cells were infected in vivo. In C57BL/6 nu/nu mice, the low level of virus persisted for at least 28 days but never increased. These results suggest that neuraminidase is not required for influenza virus entry, replication, or assembly in cell culture or in mice.

Effect of genistein on in vitro and in vivo models of cancer.

Abstract: In two-thirds of studies on the effect of genistein-containing soy materials in animal models of cancer, the risk of cancer (incidence, latency or tumor number) was significantly reduced. In addition, purified genistein delayed mammary tumor appearance in association with increased cell differentiation in mammary tissue in rats treated with 7, 12-dimethylbenz[a]anthracene when administered neonatally, inhibited phorbol ester-induced H2O2 production in a model of skin cancer, and inhibited aberrant crypt formation in a model of colonic cancer. In in vitro models, genistein inhibited the proliferation of human tumor cell lines in culture with a wide variation in IC50 values (2.6-79 mumol/L, or 1-30 micrograms/mL). In only a few cases was the IC50 below 13.2 mumol/L (5 micrograms/mL), the presumed upper limit for the serum genistein concentration in those on a high soy diet. In future studies, greater emphasis should be placed on the effect of genistein on nontransformed, normal cell lines from the tissues where cancer can occur rather than established tumor cell lines. Similarly, the effect of genistein on the progression and/or promotion of cancer may be more clearly examined using nontransformed cell lines transfected with specific oncogenes thought to be activated during oncogenesis.

Physical crosslinking of collagen fibers: Comparison of ultraviolet irradiation and dehydrothermal treatment

Abstract: The strength, resorption rate, and biocompatibility of collagenous biomaterials are profoundly influenced by the method and extent of crosslinking. We compared the effects of two physical crosslinking methods, ultraviolet irradiation (UV) (254 nm) and dehydrothermal (DHT) treatment, on the mechanical properties and molecular integrity of collagen fibers extruded from an acidic dispersion of type I bovine dermal collagen. Collagen fibers exposed to UV irradiation for 15 min had ultimate tensile strength (54 MPa) and modulus (184 MPa) values greater than or equivalent to values for fibers crosslinked with DHT treatment for 3 or 5 days. UV irradiation is a rapid and easily controlled means of increasing the mechanical strength of collagen fibers. Characterization of collagen extracted from the crosslinked samples by dilute acetic acid and limited pepsin digestion indicate that both UV and DHT treatments cause fragmentation of at least a portion of the collagen molecules. Partial loss of the native collagen structure may influence attachment, migration, and proliferation of cells on collagen fiberbased ligament analogs. These issues are currently being addressed in our laboratory. © 1995 John Wiley & Sons, Inc.