Showing papers by "University of Alabama at Birmingham published in 1997"
TL;DR: The results by this method agree very well with those obtained by electrophoresis and salt fractionation and the method is simple, it has excellent precision and the reagents are stable.
3,406 citations
TL;DR: Identification of CAR as a receptor for these two unrelated and structurally distinct viral pathogens is important for understanding viral pathogenesis and has implications for therapeutic gene delivery with adenovirus vectors.
Abstract: A complementary DNA clone has been isolated that encodes a coxsackievirus and adenovirus receptor (CAR). When transfected with CAR complementary DNA, nonpermissive hamster cells became susceptible to coxsackie B virus attachment and infection. Furthermore, consistent with previous studies demonstrating that adenovirus infection depends on attachment of a viral fiber to the target cell, CAR-transfected hamster cells bound adenovirus in a fiber-dependent fashion and showed a 100-fold increase in susceptibility to virus-mediated gene transfer. Identification of CAR as a receptor for these two unrelated and structurally distinct viral pathogens is important for understanding viral pathogenesis and has implications for therapeutic gene delivery with adenovirus vectors.
3,128 citations
Harvard University1, University of Alabama at Birmingham2, University of London3, University of Rochester4, University of Southern California5, University of North Carolina at Chapel Hill6, University of Cincinnati7, University of Minnesota8, National Institutes of Health9, Merck & Co.10, University of Miami11, Northwestern University12, Bristol-Myers Squibb13
TL;DR: In this article, the efficacy and safety of adding a protease inhibitor to two nucleoside analogues to treat human immunodeficiency virus type 1 (HIV-1) infection are not clear.
Abstract: Background The efficacy and safety of adding a protease inhibitor to two nucleoside analogues to treat human immunodeficiency virus type 1 (HIV-1) infection are not clear. We compared treatment with the protease inhibitor indinavir in addition to zidovudine and lamivudine with treatment with the two nucleosides alone in HIV-infected adults previously treated with zidovudine. Methods A total of 1156 patients not previously treated with lamivudine or protease inhibitors were stratified according to CD4 cell count (50 or fewer vs. 51 to 200 cells per cubic millimeter) and randomly assigned to one of two daily regimens: 600 mg of zidovudine and 300 mg of lamivudine, or that regimen with 2400 mg of indinavir. Stavudine could be substituted for zidovudine. The primary end point was the time to the development of the acquired immunodeficiency syndrome (AIDS) or death. Results The proportion of patients whose disease progressed to AIDS or death was lower with indinavir, zidovudine (or stavudine), and lamivudine (...
2,615 citations
TL;DR: In this three-month trial TNFR:Fc was safe, well tolerated, and associated with improvement in the inflammatory symptoms of rheumatoid arthritis.
Abstract: Background Tumor necrosis factor (TNF) is a proinflammatory cytokine involved in the pathogenesis of rheumatoid arthritis, and antagonism of TNF may reduce the activity of the disease. This study evaluated the safety and efficacy of a novel TNF antagonist — a recombinant fusion protein that consists of the soluble TNF receptor (p75) linked to the Fc portion of human IgG1 (TNFR:Fc). Methods In this multicenter, double-blind trial, we randomly assigned 180 patients with refractory rheumatoid arthritis to receive subcutaneous injections of placebo or one of three doses of TNFR:Fc (0.25, 2, or 16 mg per square meter of body-surface area) twice weekly for three months. The clinical response was measured by changes in composite symptoms of arthritis defined according to American College of Rheumatology criteria. Results Treatment with TNFR:Fc led to significant reductions in disease activity, and the therapeutic effects of TNFR:Fc were dose-related. At three months, 75 percent of the patients in the group assig...
1,628 citations
Brown University1, Harvard University2, International AIDS Society3, Stanford University4, University of British Columbia5, University of California, San Diego6, University of Alabama at Birmingham7, University of Colorado Denver8, Istituto Superiore di Sanità9, University of Paris10, University of California, San Francisco11
TL;DR: Accumulating data from clinical and pathogenesis studies continue to support early institution of potent antiretroviral therapy in patients with HIV infection, and increased complexity in HIV management requires ongoing monitoring of new data for optimal treatment of HIV infection.
Abstract: Objective. —To provide current recommendations for antiretroviral therapy for human immunodeficiency virus (HIV) disease. Participants. —The original International AIDS Society—USA 13-member panel representing international expertise in antiretroviral research and care of patients with HIV infection. Evidence. —The following were considered: Newly available clinical and basic science study results, including phase 3 controlled trials; clinical, virological, and immunologic end-point data; interim analyses of studies presented at national and international research conferences; studies of HIV pathophysiology; and expert opinions of panel members. Recommendations were limited to the drugs available in mid 1997. Process. —The full panel met on a regular basis (July 1996, September 1996, November 1996, January 1997, and April 1997) since the publication of its initial recommendations in mid 1996 to review new research reports and interim results. The panel discussed whether and how new information changed its initial recommendations. The recommendations contained herein were determined by group consensus. Conclusions. —New data have provided a stronger rationale for earlier initiation of more aggressive therapy than previously recommended and reinforce the importance of careful selection of initial drug regimen for each patient for optimal long-term clinical benefit and adherence. The plasma viral load is a crucial element of clinical management for assessing prognosis and the effectiveness of therapy, and such testing must be done properly. Treatment failure is most readily indicated by a rising plasma HIV RNA level and should be confirmed prior to a change of treatment. Therapeutic approaches must be updated as new data, particularly on the long-term clinical effect of aggressive antiretroviral treatment, continue to emerge.
1,317 citations
TL;DR: It is shown that in a patient whose early CTL response was focused on a highly immunodominant epitope in gp160, there was rapid elimination of the transmitted virus strain and selection for a virus population bearing amino acid changes at a single residue within this epitope, which conferred escape from recognition by epitope-specific CTL.
Abstract: The HIV-1-specific cytotoxic T lymphocyte (CTL) response is temporally associated with the decline in viremia during primary HIV-1 infection, but definitive evidence that it is of importance in virus containment has been lacking. Here we show that in a patient whose early CTL response was focused on a highly immunodominant epitope in gp160, there was rapid elimination of the transmitted virus strain and selection for a virus population bearing amino acid changes at a single residue within this epitope, which conferred escape from recognition by epitope-specific CTL. The magnitude (> 100-fold), kinetics (30–72 days from onset of symptoms) and genetic pathways of virus escape from CTL pressure were comparable to virus escape from antiretroviral therapy, indicating the biological significance of the CTL response in vivo. One aim of HIV-1 vaccines should thus be to elicit strong CTL responses against multiple codominant viral epitopes.
1,254 citations
TL;DR: There is strong evidence that peroxynitrite is involved in oxidative damage of Alzheimer’s disease, and the widespread occurrence of nitrotyrosine in neurons suggests that oxidative damage is not restricted to long-lived polymers such as NFTs, but instead reflects a generalized oxidative stress that is important in disease pathogenesis.
Abstract: Increasing evidence suggests that oxidative damage to proteins and other macromolecules is a salient feature of the pathology of Alzheimer’s disease. Establishing the source of oxidants is key to understanding what role they play in the pathogenesis of Alzheimer’s disease, and one way to examine this issue is to determine which oxidants are involved in damage.
In this study, we examine whether peroxynitrite, a powerful oxidant produced from the reaction of superoxide with nitric oxide, is involved in Alzheimer’s disease. Peroxynitrite is a source of hydroxyl radical-like reactivity, and it directly oxidizes proteins and other macromolecules with resultant carbonyl formation from side-chain and peptide-bond cleavage. Although carbonyl formation is a major oxidative modification induced by peroxynitrite, nitration of tyrosine residues is an indicator of peroxynitrite involvement. In brain tissue from cases of Alzheimer’s disease, we found increased protein nitration in neurons, including but certainly not restricted to those containing neurofibrillary tangles (NFTs). Conversely, nitrotyrosine was undetectable in the cerebral cortex of age-matched control brains. This distribution is essentially identical to that of free carbonyls.
These findings provide strong evidence that peroxynitrite is involved in oxidative damage of Alzheimer’s disease. Moreover, the widespread occurrence of nitrotyrosine in neurons suggests that oxidative damage is not restricted to long-lived polymers such as NFTs, but instead reflects a generalized oxidative stress that is important in disease pathogenesis.
1,230 citations
TL;DR: The systematic process of choosing, orienting, and using content experts in the judgment-qualification stage of instrument development is addressed, with particular attention to the often neglected, important step of familiarizing these experts with the conceptual underpinnings and measurement model of the instrument.
Abstract: Content experts frequently are used in the judgment-quantification stage of content validation of instruments. However, errors in instrumentation may arise when important steps in selecting and using these experts are not carefully planned. The systematic process of choosing, orienting, and using content experts in the judgment-quantification stage of instrument development is addressed, with particular attention to the often neglected, important step of familiarizing these experts with the conceptual underpinnings and measurement model of the instrument. An example using experts to validate content for a measure of caregiver burden is used to illustrate this stage of instrument review. © 1997 John Wiley & Sons, Inc. Res Nurs Health 20: 269–274, 1997
946 citations
TL;DR: The authors assessed the effect of English language experience on non-native speakers' production and perception of English vowels and found that the experienced nonnative subjects produced and perceived English vowel more accurately than did the relatively inexperienced nonnative subject.
773 citations
TL;DR: Initial analysis of 200 patients with SLE indicates a strong association of the low binding phenotype with disease, especially in patients with nephritis who have an underrepresentation of the homozygous high binding phenotype.
Abstract: A novel polymorphism in the extracellular domain 2 (EC2) of FcgammaRIIIA affects ligand binding by natural killer (NK) cells and monocytes from genotyped homozygous normal donors independently of receptor expression. The nonconservative T to G substitution at nucleotide 559 predicts a change of phenylalanine (F) to valine (V) at amino acid position 176. Compared with F/F homozygotes, FcgammaRIIIa expressed on NK cells and monocytes in V/V homozygotes bound more IgG1 and IgG3 despite identical levels of receptor expression. In response to a standard aggregated human IgG stimulus, FcgammaRIIIa engagement on NK cells from V/V (high-binding) homozygotes led to a larger rise in [Ca2+]i, a greater level of NK cell activation, and a more rapid induction of activation-induced cell death (by apoptosis). Investigation of an independently phenotyped normal cohort revealed that all donors with a low binding phenotype are F/F homozygotes, while all phenotypic high binding donors have at least one V allele. Initial analysis of 200 patients with SLE indicates a strong association of the low binding phenotype with disease, especially in patients with nephritis who have an underrepresentation of the homozygous high binding phenotype. Thus, the FcgammaRIIIa polymorphism at residue 176 appears to impact directly on human biology, an effect which may extend beyond autoimmune disease characterized by immune complexes to host defense mechanisms.
738 citations
TL;DR: A novel gene for an O-GlcNAc transferase (OGT) that shares no sequence homology or structural similarities with other glycosyltransferases is cloned and characterized and suggests that OGT may be regulated by protein interactions that are independent of the enzyme's catalytic site.
University of North Carolina at Chapel Hill1, University of Alabama at Birmingham2, Baylor College of Medicine3, University of Texas Health Science Center at San Antonio4, Wayne State University5, University of Texas Health Science Center at Houston6, George Washington University7, Virginia Commonwealth University8, Janssen Pharmaceutica9, Washington University in St. Louis10
TL;DR: For the initial treatment of AIDS-associated cryptococcal meningitis, the use of higher-dose amphotericin B plus flucytosine is associated with an increased rate of cerebrospinal fluid sterilization and decreased mortality at two weeks, as compared with regimens used in previous studies.
Abstract: Background Treatment with low-dose amphotericin B (0.4 mg per kilogram of body weight per day) or oral azole therapy in patients with the acquired immunodeficiency syndrome (AIDS) and cryptococcal meningitis has been associated with high mortality and low rates of cerebrospinal fluid sterilization. Methods In a double-blind multicenter trial we randomly assigned patients with a first episode of AIDS-associated cryptococcal meningitis to treatment with higher-dose amphotericin B (0.7 mg per kilogram per day) with or without flucytosine (100 mg per kilogram per day) for two weeks (step one), followed by eight weeks of treatment with itraconazole (400 mg per day) or fluconazole (400 mg per day) (step two). Treatment was considered successful if cerebrospinal fluid cultures were negative at 2 and 10 weeks or if the patient was clinically stable at 2 weeks and asymptomatic at 10 weeks. Results At two weeks, the cerebrospinal fluid cultures were negative in 60 percent of the 202 patients receiving amphotericin ...
TL;DR: In this article, the feasibility and safety of percutaneous carotid angioplasty and elective stenting was evaluated prospectively in a consecutive series of 107 patients, including patients with previous ipsilateral endarterectomy and severe medical comorbidity.
Abstract: Background Surgical endarterectomy has been shown to be superior to medical management in the management of severe carotid stenosis in both symptomatic and asymptomatic patients. Endarterectomy, although effective, does have limitations, and percutaneous techniques may offer an alternative method of treatment. Methods and Results The feasibility and safety of percutaneous carotid angioplasty and elective (primary) stenting was evaluated prospectively in a consecutive series of 107 patients. One hundred twenty-six carotid arteries with significant stenosis were treated. This series represented a high-risk subset that included patients with previous ipsilateral endarterectomy and severe medical comorbidity. Forty-five percent of the patients were referred by surgeons. Patients had independent neurological examinations before and after the procedure and follow-up cerebral angiography at 6 months. The mean (±SD) stenosis was reduced from 78±14% to 2±5%. There were 7 minor strokes, 2 major strokes, and 1 death...
TL;DR: Results reveal that peroxynitrite, hypochlorous acid, and H2O2 plus peroxidase all oxidize DCDHF and DHR to varying degrees but that neither superoxide, H2 O2 alone, nor physiological levels of nitric oxide are capable of indicator oxidation.
TL;DR: An increased understanding of the biochemistry and molecular biology of the STs should also provide additional information as to their functions in many normal physiologic processes.
Abstract: Conjugation of many xenobiotics, drugs, and endogenous compounds with a sulfonate moiety is an important reaction in their biotransformation. Sulfation of these compounds generally results in a decrease in biological activity and an increase in their urinary excretion. However, in certain instances, sulfation results in bioactivation to reactive electrophilic or therapeutically active forms. At least four cytosolic sulfotransferases (STs) have been identified and characterized from human tissues. These enzymes are two forms of phenol ST (PST), the phenol-sulfating and the monoamine-sulfating forms of PST (P-PST and M-PST, respectively), an estrogen sulfotransferase (EST), and a hydroxysteroid ST, dehydroepiandrosterone ST (DHEA-ST). Although four cytosolic STs have been well characterized in human tissues, evidence is accumulating for the presence of allelic forms or additional distinct forms of the STs in human tissues. The STs possess distinct but overlapping substrate specificities, and all of the STs ...
TL;DR: An irregular sequence of RR intervals produces adverse hemodynamic consequences that are independent of heart rate, and is compared with VVI pacing at the same average rate.
TL;DR: This review focuses on the role of the microglia in multiple sclerosis, a chronic inflammatory demyelinating disease of the central nervous system, and in the animal model of MS, experimental allergic encephalomyelitis (EAE).
Abstract: One of the characteristic features of microglia is their rapid activation in response to injury, inflammation, neurodegeneration, infection, and brain tumors. This review focuses on the role of the microglia in multiple sclerosis (MS), a chronic inflammatory demyelinating disease of the central nervous system (CNS), and in the animal model of MS, experimental allergic encephalomyelitis (EAE). Microglial activation in MS and EAE is thought to contribute directly to CNS damage through several mechanisms, including production of proinflammatory cytokines, matrix metalloproteinases, and free radicals. In addition, activated microglia serve as the major antigen-presenting cell in the CNS, likely contributing to aberrant immune reactivity at this site. A mechanistic understanding of the way in which microglia are activated and ultimately inhibited is crucial for the formulation of therapeutic modalities to treat MS and other CNS autoimmune diseases.
TL;DR: Calcium supplementation did not significantly reduce the incidence or severity of preeclampsia or delay its onset in healthy nulliparous women.
Abstract: Background Previous trials have suggested that calcium supplementation during pregnancy may reduce the risk of preeclampsia. However, differences in study design and a low dietary calcium intake in the populations studied limit acceptance of the data. Methods We randomly assigned 4589 healthy nulliparous women who were 13 to 21 weeks pregnant to receive daily treatment with either 2 g of elemental calcium or placebo for the remainder of their pregnancies. Surveillance for preeclampsia was conducted by personnel unaware of treatment-group assignments, using standardized measurements of blood pressure and urinary protein excretion at uniformly scheduled prenatal visits, protocols for monitoring these measurements during the hospitalization for delivery, and reviews of medical records of unscheduled outpatient visits and all hospitalizations. Results Calcium supplementation did not significantly reduce the incidence or severity of preeclampsia or delay its onset. Preeclampsia occurred in 158 of the 2295 wome...
TL;DR: HIV prevention programs for women should address domestic violence prevention strategies and women in abusive relationships were less likely than others to use condoms and were more likely to experience verbal abuse, emotional abuse, or threats of physical abuse when they discussed condoms.
Abstract: OBJECTIVES: This study examined the consequences of having a physically abusive primary partner on the condom use and sexual negotiation practices of young African-American women. METHODS: Interviews were conducted with 165 sexually active African-American women aged 18 through 29 in San Francisco, Calif. RESULTS: Women in abusive relationships were less likely than others to use condoms and were more likely to experience verbal abuse, emotional abuse, or threats of physical abuse when they discussed condoms. They were more fearful of asking their partners to use condoms, worried more about acquiring the human immunodeficiency virus (HIV), and felt more isolated than did women not in abusive relationships. CONCLUSIONS: HIV prevention programs for women should address domestic violence prevention strategies.
TL;DR: Evidence is mounting that O-GlcNAcylation is an important regulatory modification that may have a reciprocal relationship with O-phosphorylation and may modulate many biological processes in eukaryotes.
Abstract: Modification of Ser and Thr residues by attachment of O-linked N-acetylglucosamine [Ser(Thr)-O-GlcNAcylation] to eukaryotic nuclear and cytosolic proteins is as dynamic and possibly as abundant as Ser(Thr) phosphorylation. Known O-GlcNAcylated proteins include cytoskeletal proteins and their regulatory proteins; viral proteins; nuclear-pore, heat-shock, tumor-suppressor, and nuclear-oncogene proteins; RNA polymerase II catalytic subunit; and a multitude of transcription factors. Although functionally diverse, all of these proteins are also phosphoproteins. Most O-GlcNAcylated proteins form highly regulated multimeric associations that are dependent upon their posttranslational modifications. Evidence is mounting that O-GlcNAcylation is an important regulatory modification that may have a reciprocal relationship with O-phosphorylation and may modulate many biological processes in eukaryotes.
TL;DR: The experimental evidence for microbial adhesion to host cell proteoglycans is compelling, and future molecular studies may provide a basis for designing therapeutic strategies based on these interactions.
Abstract: A large array of glycoproteins, glycolipids, and proteoglycans decorate the surfaces of animal cells. These glycoconjugates mediate many fundamental cellular processes, including cell-cell and cell-matrix adhesion, motility, growth, and signaling (28, 110). Over time, many pathogenic microorganisms have learned to exploit cell surface glycoconjugates as receptors for attachment, a process which ultimately facilitates tissue colonization and invasion. The interaction of specific proteins on the surface of microorganisms (adhesins) with carbohydrate chains on the glycoconjugate (receptors) enables the microbes to take their first step towards establishing an infection. This review concentrates on proteoglycans as adhesion receptors for bacteria, viruses, and parasites. Microbial binding to glycolipids and glycoproteins also occurs and has been discussed elsewhere (27, 40, 61–63, 85, 94). Proteoglycans are ubiquitous among animal cells, and as discussed below, their carbohydrate chains (glycosaminoglycans) bind many different protein ligands. Different experimental criteria have been used to establish a role for proteoglycans in attachment and invasion of host cells, including direct binding measurements, identification of microbial carbohydrate-binding proteins, competition studies with defined polysaccharides, loss of adhesion upon enzymatic removal of host glycans, and altered adherence to animal cell mutants with defective glycosaminoglycan biosynthesis. Overall, the experimental evidence for microbial adhesion to host cell proteoglycans is compelling, and future molecular studies may provide a basis for designing therapeutic strategies based on these interactions.
TL;DR: This work supports previous reports of an association between apoE-4 and the development of AD and demonstrates that apo E-4 exerts its maximal effect before age 70 and has important implications for the potential use of ApoE genotyping for diagnosis and prediction of disease.
Abstract: Objective: To explore the impact of apoE-4 on Alzheimer9s disease (AD) and its age at onset. Design: A genetic linkage study using affected relative pairs, predominantly siblings. Setting: Three academic medical centers ascertained subjects from memory disorder clinics, nursing homes, and the local community. Subjects: 310 families including 679 subjects with AD by NINCDS/ADRDA and/or Khachaturian criteria and 231 unaffected subjects. Outcome measure: ApoE genotype. Analytic methods: Association, affected pedigree member, sibling pair, and lod score analyses. Results: ApoE-4 was strongly associated with AD in this sample (allele frequency = 0.46 vs. 0.14 in controls, p NEUROLOGY 1997;48: 139-147
University of Tennessee Health Science Center1, University of Cincinnati2, University of Oklahoma3, University of Alabama at Birmingham4, George Washington University5, University of Southern California6, Wake Forest University7, University of Chicago8, Ohio State University9, Medical University of South Carolina10, Wayne State University11, University of Colorado Denver12, University of Pittsburgh13, National Institutes of Health14
TL;DR: It is recommended that women with expectantly managed PPROM remote from term receive antibiotics to reduce infant morbidity, and among GBS-negative women, significant pregnancy prolongation was seen with antibiotics.
Abstract: Context. —Intrauterine infection is thought to be one cause of preterm premature rupture of the membranes (PPROM). Antibiotic therapy has been shown to prolong pregnancy, but the effect on infant morbidity has been inconsistent. Objective. —To determine if antibiotic treatment during expectant management of PPROM will reduce infant morbidity. Design. —Randomized, double-blind, placebo-controlled trial. Setting. —University hospitals of the National Institute of Child Health and Human Development Maternal-Fetal Medicine Units Network. Patients. —A total of 614 of 804 eligible gravidas with PPROM between 24 weeks' and 0 days' and 32 weeks' and 0 days' gestation who were considered candidates for pregnancy prolongation and had not received corticosteroids for fetal maturation or antibiotic treatment within 1 week of randomization. Intervention. —Interavenous ampicillin (2-g dose every 6 hours) and erythromycin (250-mg dose every 6 hours) for 48 hours followed by oral amoxicillin (250-mg dose every 8 hours) and erythromycin base (333-mg dose every 8 hours) for 5 days vs a matching placebo regimen. Group B streptococcus (GBS) carriers were identified and treated. Tocolysis and corticosteroids were prohibited after randomization. Main Outcome Measures. —The composite primary outcome included pregnancies complicated by at least one of the following: fetal or infant death, respiratory distress, severe intraventricular hemorrhage, stage 2 or 3 necrotizing enterocolitis, or sepsis within 72 hours of birth. These perinatal morbidities were also evaluated individually and pregnancy prolongation was assessed. Results. —In the total study population, the primary outcome (44.1% vs 52.9%;P=.04), respiratory distress (40.5% vs 48.7%;P=.04), and necrotizing enterocolitis (2.3% vs 5.8%;P=.03) were less frequent with antibiotics. In the GBS-negative cohort, the antibiotic group had less frequent primary outcome (44.5% vs 54.5%;P=.03), respiratory distress (40.8% vs 50.6%;P=.03), overall sepsis (8.4% vs 15.6%;P=.01), pneumonia (2.9% vs 7.0%;P=.04), and other morbidities. Among GBS-negative women, significant pregnancy prolongation was seen with antibiotics (P Conclusions. —We recommend that women with expectantly managed PPROM remote from term receive antibiotics to reduce infant morbidity.
TL;DR: The Kamchatka arc (Russia) is divided into three segments by major sub-latitudinal fault zones (crustal discontinuities) as mentioned in this paper, where the southern (SS) and central (CS) segments are associated with the subduction of old Pacific lithosphere, whereas the northern, inactive segment (NS) was formed during westward subduction in young (< 15 Ma) Komandorsky Basin oceanic crust.
TL;DR: The continued deterioration of hearing and delayed onset of SNHL in these children emphasizes the need for continued monitoring of their hearing status, and asymptomatic congenital CMV infection is likely a leading cause ofSNHL in young children.
TL;DR: Findings suggest that cortical reorganization and phantom limb pain might have a causal relationship and methods designed to alter corticalorganization should be examined for their efficacy in the treatment of phantom limbPain.
Abstract: The causes underlying phantom limb pain are still unknown. Recent studies on the consequences of nervous system damage in animals and humans reported substantial reorganization of primary somatosensory cortex subsequent to amputation, and one study showed that cortical reorganization is positively correlated with phantom limb pain. This paper examined the hypothesis of a functional relationship between cortical reorganization and phantom limb pain. Neuroelectric source imaging was used to determine changes in cortical reorganization in somatosensory cortex after anesthesia of an amputation stump produced by brachial plexus blockade in six phantom limb pain patients and four pain-free amputees. Three of six phantom limb subjects experienced a virtual elimination of current phantom pain attributable to anesthesia (mean change: 3.8 on an 11-point scale; Z = −1.83; p < 0.05) that was mirrored by a very rapid elimination of cortical reorganization in somatosensory cortex (change = 19.8 mm; t (2) = 5.60; p < 0.05). Cortical reorganization remained unchanged (mean change = 1.6 mm) in three phantom limb pain amputees whose pain was not reduced by brachial plexus blockade and in the phantom pain-free amputation controls. These findings suggest that cortical reorganization and phantom limb pain might have a causal relationship. Methods designed to alter cortical reorganization should be examined for their efficacy in the treatment of phantom limb pain.
Journal Article•
TL;DR: This Phase I study demonstrated the feasibility, safety, and bioactivity of an autologous GM-CSF gene-transduced tumor vaccine for RCC patients.
Abstract: Granulocyte-macrophage colony-stimulating factor (GM-CSF) gene-transduced, irradiated tumor vaccines induce potent, T-cell-mediated antitumor immune responses in preclinical models. We report the initial results of a Phase I trial evaluating this strategy for safety and the induction of immune responses in patients with metastatic renal cell carcinoma (RCC). Patients were treated in a randomized, double-blind dose-escalation study with equivalent doses of autologous, irradiated RCC vaccine cells with or without ex vivo human GM-CSF gene transfer. The replication-defective retroviral vector MFG was used for GM-CSF gene transfer. No dose-limiting toxicities were encountered in 16 fully evaluable patients. GM-CSF gene-transduced vaccines were equivalent in toxicity to nontransduced vaccines up to the feasible limits of autologous tumor vaccine yield. No evidence of autoimmune disease was observed. Biopsies of intradermal sites of injection with GM-CSF gene-transduced vaccines contained distinctive macrophage, dendritic cell, eosinophil, neutrophil, and T-cell infiltrates similar to those observed in preclinical models of efficacy. Histological analysis of delayed-type hypersensitivity responses in patients vaccinated with GM-CSF-transduced vaccines demonstrated an intense eosinophil infiltrate that was not observed in patients who received nontransduced vaccines. An objective partial response was observed in a patient treated with GM-CSF gene-transduced vaccine who displayed the largest delayed-type hypersensitivity conversion. No replication-competent retrovirus was detected in vaccinated patients. This Phase I study demonstrated the feasibility, safety, and bioactivity of an autologous GM-CSF gene-transduced tumor vaccine for RCC patients.
TL;DR: It is found that Sp1 becomes hyperglycosylated when cells are exposed to 5 mM glucosamine, whereas under glucose starvation, stimulation with cyclic AMP (cAMP) results in nearly complete deglycosylation of this protein.
Abstract: Sp1 is a ubiquitously expressed transcription factor that is particularly important for the regulation of TATA-less genes that encode housekeeping proteins. Most growth factors and receptors are also encoded by such genes. Sp1 is multiply O glycosylated by covalent linkage of the monosaccharide N-acetylglucosamine (O-GlcNAc) to serine and threonine residues. Based on an earlier observation that growth factor gene transcription can be regulated by glucose and glucosamine in vascular smooth muscle cells, we determined whether Sp1 glycosylation could be regulated and if this modification altered Sp1 function. We found that Sp1 becomes hyperglycosylated when cells are exposed to 5 mM glucosamine, whereas under glucose starvation, stimulation with cyclic AMP (cAMP) results in nearly complete deglycosylation of this protein. Correlating with this hypoglycosylated state, Sp1 is rapidly proteolytically degraded by an enzyme(s) that can be inhibited by specific proteasome inhibitors, lactacystin and LLnL. Treatment of cells with glucose or glucosamine protects Sp1 from cAMP-mediated degradation, whereas blockade of glucosamine synthesis abrogates glucose but not glucosamine protection. This effect on Sp1 is specific, in that the Stat-3 and E2F transcription factors did not undergo degradation under these conditions. The O-GlcNAc modification of Sp1 may play a role as a nutritional checkpoint. In the absence of adequate nutrition, Sp1 becomes hypoglycosylated and thereby subject to proteasome degradation. This process could potentially result in reduced general transcription, thereby conserving nutrients.
TL;DR: Results indicate that CD38high CD21high CD23low/− MZ B cells are specially suited to play a unique role in response to antigens delivered to the MZ area.
Abstract: Mouse splenic B cells can be separated based on their distinctive expression of cell surface antigens. Marginal zone (MZ) B cells are CD38high CD21high CD23low/-, while follicular (FO) B cells are CD21int CD23int and newly formed (NF) B cells are CD21dim/- CD23-. Exploiting these phenotypic distinctions, we isolated the three B cell subsets and assessed their other phenotypic differences and functional capabilities in vitro. FO B cells proliferate more than the other B cell subsets in response to either IgM or CD38 cross-linking. MZ B cells proliferate better than FO B cells when stimulated with lipopolysaccharide (LPS), sub-optimal levels of LPS and CD38 cross-linking or CD40 ligation. When NF, FO and MZ B cells were stimulated with either LPS or LPS and interleukin-4, MZ B cells secreted more IgM and IgG3 than the other two subsets. Similarly, calcium fluxes measured within MZ B cells are larger in amplitude and more sustained after B cell receptor cross-linking than those found in the other two subsets. Collectively, these results indicate that CD38high CD21high CD23low/- MZ B cells are specially suited to play a unique role in response to antigens delivered to the MZ area.
TL;DR: Results indicate that selenium deficiency is an independent predictor of survival for those with HIV-1 infection.
Abstract: To determine the independent contribution of specific immunologic and nutritional factors on survival in HIV-1 disease, CD4 cell count, antiretroviral treatment, plasma levels of vitamins A, E, B6, and B12 and minerals selenium and zinc were considered in relation to relative risk for HIV-related mortality. Immune parameters and nutrients known to affect immune function were evaluated at 6-month intervals in 125 HIV-1-seropositive drug-using men and women in Miami, FL, over 3.5 years. A total of 21 of the HIV-1-infected participants died of HIV-related causes during the 3.5-year longitudinal study. Subclinical malnutrition (i.e., overly low levels of prealbumin, relative risk [RR] = 4.01, p < 0.007), deficiency of vitamin A (RR = 3.23, p < 0.03), vitamin B12 deficiency (RR = 8.33, p < 0.009), zinc deficiency (RR = 2.29.1, p < 0.04), and selenium deficiency (RR = 19.9, p < 0.0001) over time, but not zidovudine treatment, were shown to each be associated with HIV-1-related mortality independent of CD4 cell counts <200/mm3 at baseline, and CD4 counts over time. When all factors that could affect survival, including CD4 counts <200/mm3 at baseline, CD4 levels over time, and nutrient deficiencies were considered jointly, only CD4 counts over time (RR = 0.69, p < 0.04) and selenium deficiency (RR = 10.8, p < 0.002) were significantly associated with mortality. These results indicate that selenium deficiency is an independent predictor of survival for those with HIV-1 infection.