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S Gartner

Publications and source records attributed to S Gartner.

At least 37 records · Page 2Linked to original sources
PubMed2000

DNase use in the daily care of cystic fibrosis: who benefits from it and to what extent? Results of a cohort study of 199 patients in 13 centres. DNase National Study Group.

UNLABELLED: Short-term clinical trials with DNase have shown minor to moderate benefits in cystic fibrosis patients. This study was performed to analyse the effectiveness of DNase use in daily practice and to obtain information on its effects in the long term and at different disease stages. Patients being treated in 13 specialised units were included if they started DNase treatment before June 1996. Baseline data before DNase use and data during the DNase treatment period were recorded. Of the 199 patients included in the study 166 continued on DNase treatment while the data were being collected. The mean age (95% CI) was 14.5 (13.7; 15,2) years; 103 (51.8%) patients were female. The mean maximum change in forced expiratory volume in 1 s (FEV(1)) was observed during the first month of treatment [11.1% (6.1; 16.1)]. By the end of the first and the second year of treatment mean changes in FEV(1) were 3.3% (-1.1; 7. 6) and 5.1% (-0.7; 10.9) respectively; at the end of the same periods 34% of patients had improved their baseline FEV(1) by 10% or more but in around 50% of patients the level fell below the baseline. A large inter-individual variability in changes in pulmonary function after the start of DNase treatment was documented. In addition, the medium-term response to treatment was correlated with early response during the first 3 months. No consistent changes in exacerbation pattern were found during the first year of treatment. CONCLUSIONS: The benefits of DNase use in daily practice are limited but apparently can be maintained in the medium term in some patients. A large inter-individual variability in response to DNase treatment has been documented and the benefits are doubtful in around 50% of patients. This observation points to the need to set up a withdrawal trial in these patients, using as an eligibility criterion the early response observed during the first 3 months of treatment.

Adolescent↗
PubMed2000

Analysis of human immunodeficiency virus type 1 gp160 sequences from a patient with HIV dementia: evidence for monocyte trafficking into brain.

Towards understanding the pathogenesis of HIV dementia, we molecularly cloned and sequenced human immundeficiency virus type 1 (HIV-1) gp160 genes from uncultured post-mortem tissues collected from a patient with HIV dementia. Sequences from bone marrow, lymph node, lung, and four regions of brain - the deep white matter, head of caudate, choroid plexus and meninges - were compared. Also included were gp160 sequences recovered from blood monocytes collected 5 months prior to death. Phylogenetic analyses showed that the sequences from deep white matter were more closely related to those from bone marrow, than to those from the other tissues, and moreover, were most closely related to sequences from the blood monocytes. These findings suggest trafficking of bone marrow-derived monocytes into the deep white matter during this late stage of infection. Another cluster included sequences from choroid plexus, meninges and lymph node, and interestingly, identical patterns of four or nine stop codons were shared among these tissues. These mutations appear to be the consequence of G-->A hypermutation, and could reflect independent events, or the movement of virions or infected cells, from the choroid plexus into the cerebrospinal fluid and ultimately, into the lymph node. We propose that a critical step towards the development of HIV dementia is an increase in monocyte trafficking into the brain, and that this process is either initiated and/or accelerated during late-stage infection, which could explain why dementia occurs primarily during this time.

AIDS Dementia Complex↗
PubMed1999

Apoptosis induced by infection of primary brain cultures with diverse human immunodeficiency virus type 1 isolates: evidence for a role of the envelope.

Apoptosis of neurons and astrocytes is induced by human immunodeficiency type 1 (HIV-1) infection in vitro and has been demonstrated in brain tissue from patients with AIDS. We analyzed a panel of diverse HIV-1 primary isolates for the ability to replicate and induce neuronal and astrocyte apoptosis in primary human brain cultures. Apoptosis was induced three- to eightfold by infection with the blood-derived HIV-1 isolates 89.6, SG3, and ADA. In contrast, the brain-derived HIV-1 isolates YU2, JRFL, DS-br, RC-br, and KJ-br did not induce significant levels of apoptosis. The ability of HIV-1 isolates to induce apoptosis was independent of their replication capacity. Studies of recombinant chimeras between the SG3 and YU2 viruses showed that replacement of the YU2 Env with the SG3 Env was sufficient to confer the ability to induce apoptosis to the YU2 virus. Replacement of the Env V3 regions alone largely conferred the phenotypes of the parental clones. The SG3 Env used CXCR4 and CCR3 as coreceptors for virus entry, whereas YU2 used CCR5 and CCR3. The V3 regions of SG3 and YU2 conferred the ability to use CXCR4 and CCR5, respectively. In contrast, the 3' region of Env, particularly the C3V4 region, was required in conjunction with the V3 region for efficient use of CCR3. These results provide evidence that Env is a major determinant of neurodegenerative mechanisms associated with HIV-1 infection in vitro and raise the possibility that blood-derived viruses which emerge during the late stages of disease may affect disease progression in the central nervous system.

Animals↗
PubMed1998

Enhanced oxidative damage in cystic fibrosis patients.

Antioxidant depletion and increased free radical production by inflammatory cells have been described in cystic fibrosis (CF) patients. To evaluate oxidative damage intensity, we measured plasma concentrations of malondialdehyde, hydroperoxides and protein carbon groups as markers of oxidative injury to lipids and proteins in a group of 101 CF patients free of acute exacerbation, and in 43-112 controls. Moreover, we estimated antioxidant function by measuring activities of erythrocyte superoxide dismutase, glutathione reductase and vitamin E concentrations. In CF patients, malondialdehyde and hydroperoxide plasma levels were significantly higher than in controls (p < 0.001). Increased lipid peroxidation was documented by these two markers. Parallel rises in protein carbonyls in plasma of CF patients were observed (p < 0.0001). These patients presented biochemical but not clinical vitamin E deficiency. Glutathione reductase and superoxide dismutase activities were significantly higher than in controls. These results show a serious imbalance of CF patients between oxidant-antioxidant status leading to oxidative stress.

Adolescent↗
PubMed1998

[Acral papular lichen myxedematosus].

In 1986 Rongioletti introduced the term acral persistent papular mucinosis for persistent papules on the dorsum of the hands and distal forearms. Skin specimens reveal mucin deposits which resemble those in lichen myxedematosus (LM). Laboratory results are usually unremarkable. Our 54-year-old female patient showed a 2 1/2 year history of skin lesions in the typical acral distribution pattern. This entity appears to be an acral papular subtype of LM. In the classification of LM, acral papular lichen myxedematosus should replace the discrete papular form. This latter form has been well known for many years, but is not sufficiently definable and is of secondary clinical importance.

Biopsy↗
PubMed1998

Chemokine receptor utilization by human immunodeficiency virus type 1 isolates that replicate in microglia.

The role of human immunodeficiency virus (HIV) strain variability remains a key unanswered question in HIV dementia, a condition affecting around 20% of infected individuals. Several groups have shown that viruses within the central nervous system (CNS) of infected patients constitute an independently evolving subset of HIV strains. A potential explanation for the replication and sequestration of viruses within the CNS is the preferential use of certain chemokine receptors present in microglia. To determine the role of specific chemokine coreceptors in infection of adult microglial cells, we obtained a small panel of HIV type 1 brain isolates, as well as other HIV strains that replicate well in cultured microglial cells. These viruses and molecular clones of their envelopes were used in infections, in cell-to-cell fusion assays, and in the construction of pseudotypes. The results demonstrate the predominant use of CCR5, at least among the major coreceptors, with minor use of CCR3 and CXCR4 by some of the isolates or their envelope clones.

Adult↗
PubMed1998

[Exhaled and nasal nitric oxide in normal and asthmatic children].

OBJECTIVE: Our aim was to study the concentration of nitric oxide in the exhaled (ENO) and nasal (NNO) air of normal children and asthmatic children who are clinically and functionally stable. PATIENTS AND METHODS: Using a nitric oxide chemiluminescence analyze and a register for CO2, pressure and flow, we studied 73 schoolchildren (6-17 years of age). This included 37 controls and 36 asthmatic children, 21 with mild asthma without antiinflammatory treatment and 15 treated with inhaled corticosteroids. We used the technique of slow exhalation against resistance for (ENO) determination and aspiration with stable flow in nasal cavity while holding the breath for (NNO) determination. RESULTS: The mean ENO was 3.1 ppb (1-6) in the control group, 8.3 ppb (1.7-29.3) in the mild asthma group and 7.7 ppb (2-18.3) in the asthmatics treated with corticosteroids. There were significant differences (p = 0.0001) between the controls and both asthmatic groups. The mean NNO in the controls was 898 ppb and differences between this group and the asthmatic children were found. The ENO and NNO did not change in relation to age or sex. We did not find any relationship between ENO and lung function. There is a significant correlation between ENO and NNO in both asthmatic groups, but not in the control group. CONCLUSIONS: The ENO was higher in asthmatics than in control children. The slow exhalation against resistance technique prevents the contamination of exhaled air with nasal air and this technique can be applied to children over 6 years of age. The NNO was similar in the asthmatic groups and the control group.

Analysis of Variance↗
PubMed1997

CCR3 and CCR5 are co-receptors for HIV-1 infection of microglia.

Several members of the chemokine receptor family are used together with CD4 for HIV-1 entry into target cells. T cell line-tropic (T-tropic) HIV-1 viruses use the chemokine receptor CXCR4 as a co-receptor, whereas macrophage-tropic (M-tropic) primary viruses use CCR5 (refs 2-6). Individuals with defective CCR5 alleles exhibit resistance to HIV-1 infection, suggesting that CCR5 has an important role in vivo in HIV-1 replication. A subset of primary viruses can use CCR3 as well as CCR5 as a co-receptor, but the in vivo contribution of CCR3 to HIV-1 infection and pathogenesis is unknown. HIV-1 infects the central nervous system (CNS) and causes the dementia associated with AIDS. Here we report that the major target cells for HIV-1 infection in the CNS, the microglia, express both CCR3 and CCR5. The CCR3 ligand, eotaxin, and an anti-CCR3 antibody inhibited HIV-1 infection of microglia, as did MIP-1beta, which is a CCR5 ligand. Our results suggest that both CCR3 and CCR5 promote efficient infection of the CNS by HIV-1.

Adult↗
PubMed1997

Virus-induced cytokines regulate circulating lymphocyte levels during primary SIV infections.

Decline in blood CD4+ lymphocytes during primary symptomatic infections with HIV is usually attributed to viral killing, and has not been considered in terms of altered lymphocyte migration and sequestration. We therefore sought to examine whether CD4+ cell loss from blood of macaques undergoing an acute primary SIV infection might be due to increased synthesis of cytokines, known to profoundly affect lymphocyte trafficking, rather than to direct lymphocyte destruction by virus. The findings indicate that rapid lymphocyte depletion following acute infection is not selective for CD4+ cells, correlates precisely with increased plasma IFN-gamma and tumor necrosis factor-alpha levels, and is reversible. CD4/CD8 ratios in lymph nodes with high viral burdens remain relatively unchanged despite lymphocyte loss from blood. Levels of cytokine mRNA measured in lymphoid organs reflect neither cytokine plasma levels nor their potential to induce sequestration. These results support a model of cytokine-induced lymphocyte extravasation to account for the acute HIV/SIV-induced CD4+ cell lymphopenia and raise questions regarding the extent to which altered lymphocyte migration plays a role in the gradual CD4+ cell depletion throughout infection.

Acute Disease↗
PubMed1997

Characteristics of the CD8+ lymphocytosis during primary simian immunodeficiency virus infections.

OBJECTIVE: To investigate the source of the expanded blood CD8+ subsets during an acute primary simian immunodeficiency virus (SIV) infection of macaques and the potential role of these cells in disease progression. DESIGN AND METHODS: The primary CD8+ lymphocytosis, which occurs at 1-2 weeks following infection with SIVsmm/PBj-14, was examined in rhesus and cynomolgus macaques. Extensive subset analysis of the expanded blood CD8+ cell pool in a rhesus macaque was compared phenotypically with those in thymus, lymph nodes, spleen, ileum and lung washouts obtained at necropsy during blood lymphocytosis. The influence of the primary CD8+ cells expansion on disease progression was assessed at days 175-679 post-infection in long-term PBj-14 survivors staged according to immunological, virological and histopathological changes in their lymphoid organs. RESULT: The very rapid and transient blood lymphocytosis following infection consisted of two distinct CD45RA(low), CD8+ and CD28-, lymphocyte function-associated antigen (LFA)-1(high), CD45RA(high), CD8+ populations. These populations were present in low levels in thymus, lymph and spleen but were highly represented in mucosal tissues, such as long washout, in which CD28- LFA-1(high) CD45RA(high) CD8+ cells comprised 86% of CD8+ cells, and gut, which was predominantly CD45RA(low) CD28- CD8+ cells. A comparison of progressor and non-progressor PBj-14-infected rhesus and cynomolgus macaques also indicated that the existence or magnitude of a blood CD8+ lymphocytosis during the acute phase of infection did not by itself appear to influence or be predictive of disease progression. CONCLUSION: The marked blood CD8+ lymphocytosis observed during acute SIV infection did not result from expansion of virus-specific precursors in peripheral lymph node and did not appear to influence the rate of disease progression. The findings provide a novel explanation for the primary CD8+ cell lymphocytosis and invoke a mechanism whereby virus-induced cytokine/chemokine production in mucosal sites initiate the transient migration of a pre-existing CD8+ population into the blood from compartments such as lung and gut. Such results suggest that the magnitude of lymphocytosis may depend on the level of viral replication in mucosal tissues and the presence of other infections, for example, cytomegalovirus.

Animals↗
PubMed1996

Exposure of human CD34+ cells to human immunodeficiency virus type 1 does not influence their expansion and proliferation of hematopoietic progenitors in vitro.

The susceptibility of highly purified human CD34+ cells to monocytotropic (Ba-L) and lymphotropic (A018-post) strains of human immunodeficiency virus-1 (HIV-1) was examined. Liquid cultures initiated with fresh immunomagnetically purified CD34+ cells using the K6.1 CD34 monoclonal antibody (MoAb) (K6.1/CD34+) were positive for HIV expression 2 weeks after exposure to HIV-1 Ba-L. These cells were initially greater than 90% CD34+ and had undetectable monocyte contamination by flow-cytometric staining and side-scatter analyses, respectively, and undetectable T-cell contamination by CD3 polymerase chain reaction (PCR) analysis. However, secondary CD34+ liquid cultures reselected from the primary liquid cultures 24 hours after HIV exposure by panning with the ICH3 CD34 MoAb (ICH3/CD34+) and maintained for an additional 14 days were negative for HIV expression. The ICH3-unbound cells were positive for both spliced and unspliced HIV RNA when exposed to HIV-1 Ba-L, and were DNA PCR positive when exposed to either monocytotropic or lymphotropic HIV-1. To further test that CD34+ cells were not infectible by HIV-1, we exposed K6.1/CD34+ cells continuously to HIV-1 in a culture system capable of maintaining and expanding primitive CD34+ cells. HIV-exposed K6.1/CD34+ cells proliferated and expanded as efficiently as uninfected cultures. However, when reselected magnetically using the K6.1 CD34 MoAb after expansion for 7 days, bound K6.1/CD34+ cells were again negative for HIV-1 expression, whereas unbound cells were positive for HIV-1 expression. These findings suggest that a sequential CD34+ cell-selection process, in which the two selections are separated by a brief culture period, can yield a population of CD34+ cells that are not infected with HIV-1. This process may be useful in the design of stem or progenitor cell-based transplantation therapies for HIV infection.

Antigens, CD34↗
PubMed1994

Characterization of substance P binding to human monocytes/macrophages.

Substance P (SP), a member of the tachykinin family of neuropeptides, can immunomodulate human T cells and monocytes. SP has been shown to stimulate human monocytes to produce inflammatory cytokines and superoxide ions, and it enhances tumoricidal activity in vitro. A specific SP receptor, however, has not been identified on human monocytes/macrophages. In this study, we report that 125I-SP binds to human monocytes/macrophages with high affinity and specificity (Kd = 2.7 x 10(-8) to 5.5 x 10(-8) M). Our measurements of binding affinity to this single class of receptors were possible only when experiments were performed in the presence of excess serine proteinase inhibitor (serpin) enzyme complex receptor ligand. We determined that 125I-SP bound to a specific receptor on human monocytes/macrophages and that this binding was detectable as early as 6 h and was maintained throughout 6 to 8 weeks in culture. Modulation of the diverse immunological and inflammatory effects of SP on human monocytes may be mediated through this specific SP receptor.

Humans↗
PubMed1994

HIV-1 infection in pigtailed macaques.

Four pigtailed macaques were inoculated with autologous cells expressing low levels of human immunodeficiency virus type 1 (HIV-1). During the first 10 weeks, infectious virus was recovered from peripheral blood mononuclear cells (PBMCs) and lymph nodes from three of the animals. Subsequently, HIV-1 DNA was frequently detected in uncultured PBMCs from all three animals, and virus was isolated from one of them at weeks 38 and 61. The fourth animal, which was rechallenged at week 10 with cell-free virus isolated from one of the others, never became virus isolation positive, but harbored HIV-1 proviral genomes. These virus infections were accompanied by the development of varied HIV-1-specific humoral immune responses. Antibodies to gp160 were first apparent at week 8 in the three initially infected animals and persisted. The animal from whom virus was isolated at late times also developed persisting antibodies to HIV-1 p24 and gp120. Antibodies to gp120 and gp160 became apparent in the rechallenged animal at 1 week following reinoculation, but they waned with time. In vivo passage of the virus was attempted at week 6. One recipient pigtailed macaque and one recipient cynomolgus monkey failed to become detectably infected following transfusion of virus-positive blood and lymph node cells. The long-term presence of HIV-1-specific antibodies and proviral genomes in these animals, and the recovery of infectious virus more than 1 year following inoculation, are indicative of persistent infection, and confirm previous reports that pigtailed macaques are susceptible to HIV-1.

Animals↗
PubMed1992

Isolation of human immunodeficiency virus type 1 from human epidermis: virus replication and transmission studies.

For a better understanding of the pathogenetic events operative in the cutaneous manifestations of human immunodeficiency virus type 1 (HIV-1) disease, we investigated whether epidermal cells (EC) from HIV-1-seronegative persons can be infected with HIV-1 and, vice versa, whether HIV-1 can be rescued from the epidermis of HIV-1-infected individuals. In a series of three experiments, we consistently found that exposure of EC from HIV-1-seronegative donors to HIV-1 led to viral replication in these cells as evidenced by the detection of HIV-1 p24 in culture fluids. Because EC had been substantially enriched for Langerhans cells (LC) before being exposed to HIV-1, it is reasonable to assume that these CD1a+/CD4+/MHC class II+ antigen-presenting cells of the epidermis represented the actual targets of infection. This assumption is further strengthened by the observation that T cell-depleted cell suspensions from Langerhans cell histiocytosis (LCH) lesions could be productively infected with HIV-1. Conversely, co-culture of epidermal sheets from HIV-1-seropositive individuals with mononuclear phagocytes (MNP) from HIV-1-seronegative donors resulted, after 3 to 5 weeks, in the detection of HIV-1 p24 in 12 of 23 cases. Immunocytochemical analysis, using a monoclonal antibody specific for p24, revealed the presence of HIV-1 in adherent MNP in three cocultures tested. In addition, cellular DNA from these cultures showed strong signals when hybridized to a HIV-1-specific DNA probe. The further finding that two isolates examined exhibited different restriction enzyme patterns indicates that they are separate entities rather than contaminants. Transmission of these isolates to MNP, B- or T-cell lines resulted in cultures strongly positive for p24 and, in the case of H9 cells, for viral particles as detected by electron microscopy. Our results therefore strongly suggest that EC not only can serve as targets for HIV-1, but also can allow efficient virus replication and transmit HIV-1 to various cell types of the hematopoietic lineage.

Cell Line↗
PubMed1992

HIV neutralization assay using polymerase chain reaction-derived molecular signals.

Characterization of the capacity of human polyclonal antibody to neutralize wild-type patient isolates has important implications for vaccine development. We report the development of a polymerase chain reaction-based neutralization assay that quantitatively measures each infection using HIV proviral formation. These molecular end points identified the absence or quantitative diminution of DNA provirus formation as well as a delay in the kinetics of HIV DNA provirus formation. Using both laboratory strain prototype isolates (HIV-1-MN, HIV-IIIb) and primary wild-type patients' isolates, neutralization end points were reproducibly determined. End points were reached within 72 h, thereby minimizing the impact of subsequent rounds of infection on interpretation of results. Although the neutralization titer of polyclonal sera was usually comparable using standard technology, this assay did find isolate-dependent variation in the relationship between p24 production and HIV proviral DNA formation. Finally, we noted the disparity between the ability of human sera to neutralize prototype and wild-type isolates in primary peripheral blood mononuclear cell targets. We believe this assay provides unique opportunities to characterize the initial events of virus-antibody interaction and will help to elucidate clinically relevant neutralization immunoregulatory mechanisms.

Base Sequence↗
PubMed1991

Virus-host cell interactions in human immunodeficiency virus infections.

The isolate HTLV-IIIB is used by a large number of investigators for a variety of studies. The data shown here emphasize the uniqueness of this isolate with respect to certain biological behaviors, in particular, the ability to infect cells other than T lymphocytes and mononuclear phagocytes, and the ability to infect chimpanzee T cells. Data also presented indicates that HTLV-IIIB has a greater binding affinity for the CD4 receptor molecule, which may help to explain its observed biological uniqueness. Caution in generalizing from findings based on studies with HTLV-IIIB alone is recommended. In addition, evidence demonstrating CD4-mediated entry of HIV-1 into normal human monocyte/macrophages is included.

Animals↗