Improvement of postischemic hepatic microhemodynamics by an endothelin converting enzyme inhibitor (FR 901533).
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Angiotensin-Converting Enzyme Inhibitors↗
Biomedical subjects
H Spiegel
Publications and source records attributed to H Spiegel.
Why do cytotoxic T lymphocytes fail to eliminate hepatitis C virus? Lessons from studies using major histocompatibility complex class I peptide tetramers.
Hepatitis C virus (HCV) infection is a major public health problem, affecting an estimated 3% of the world's population, and over 10% in some countries. Infection in most cases becomes persistent, and can lead to hepatic inflammation, fibrosis and liver failure. The T lymphocyte reponse, in particular that mediated by cytotoxic T lymphocytes (CTLs), is likely to be involved in determining the outcome of infection, although its overall role is not clear. The use of major histocompatibility complex (MHC) class I peptide tetrameric complexes (tetramers) to study antiviral CTL responses has revolutionized our approach to the study of human infection. We have used a panel of MHC class I tetramers to analyse immune responses in HCV-infected individuals at various stages of disease. We find that the CTL response against HCV is vigorous in its early phases but dwindles over time both in terms of lymphocyte number and function. A number of potential explanations for this 'CTL failure' are discussed.
Adult↗
Immunologic and virologic responses to HAART in severely immunocompromised HIV-1-infected children.
OBJECTIVE: To determine the long-term immunologic and virologic effects of highly active antiretroviral therapy (HAART) in children with AIDS. DESIGN: A prospective observational study. SETTING: Two pediatric HIV clinics. PARTICIPANTS: Twenty-five protease-inhibitor naive HIV-infected children (aged 2-18 years) with advanced disease (CD4 < or =6%). INTERVENTION: HAART (one protease inhibitor and one or more nucleoside analogs). Diphtheria and tetanus immunization in six patients after 18 months of therapy. MAIN OUTCOME MEASURES: Changes in percentage of CD4 cells and plasma HIV-1 RNA levels; post-treatment assays of lymphoproliferative responses to recall antigens; CD4 cell memory phenotype. RESULTS: Median duration of follow-up was 18.8 months (range, 7.5-28 months). At baseline the CD4 cell percentage was 2% (range, 0-6%), this increased significantly to 16% (range, 3-48%) above baseline at 12 months (P = 0.002). The mean maximum CD4 cell increase was 20.7% (range 4-48%) which corresponds to 657x10(6) cells/l (range, 30-2240x10(6) cells/l) above baseline. By contrast, the median viral load was not significantly lower at 12 months than at baseline (P = 0.34), and only 25% of the patients had sustained undetectable viral load. Of the reconstituted CD4 cells 70% were naive, and none of the subjects had lymphoproliferative responses to tetanus and diphtheria although 40% did develop responses to Candida, an environmental antigen. A single immunization with diphtheria and tetanus toxoid produced lymphoproliferative responses to tetanus in three out of six patients. CONCLUSIONS: HAART was associated with sustained increases in CD4 cell counts, despite a high incidence of 'virologic failure'. CD4 counts and the proportion of naive cells were higher than have been reported in adults, which may be a reflection of greater thymic activity in children. Memory cell clones for antigens encountered in the past which are not prevalent before therapy could not be expanded without additional antigenic exposure.
Acquired Immunodeficiency Syndrome↗
Measuring recent thymic emigrants in blood of normal and HIV-1-infected individuals before and after effective therapy.
The role of the thymus in HIV-1 pathogenesis remains unclear. We developed an assay to quantify the number of recent thymic emigrants in blood based on the detection of a major excisional DNA byproduct (termed alpha1 circle) of T cell receptor rearrangement. By studying 532 normal individuals, we found that alpha1 circle numbers in blood remain high for the first 10-15 yr of life, a sharp drop is seen in the late teen years, and a gradual decline occurs thereafter. Compared with age-matched uninfected control individuals, alpha1 circle numbers in HIV-1-infected adults were significantly reduced; however, there were many individuals with normal alpha1 circle numbers. In 74 individuals receiving highly active antiretroviral therapy, we found no appreciable effect on alpha1 circle numbers in those whose baseline values were already within the normal range, but significant increases were observed in those with a preexisting impairment. The increases in alpha1 circle numbers were, however, numerically insufficient to account for the rise in levels of naive T lymphocytes. Overall, it is difficult to invoke thymic regenerative failure as a generalized mechanism for CD4 lymphocyte depletion in HIV-1 infection, as alpha1 circle numbers are normal in a substantial subset of HIV-1-infected individuals.
Adolescent↗
Predictors of smoking abstinence following a single-session restructuring intervention with self-hypnosis.
OBJECTIVE: This study examined the relation of smoking and medical history, social support, and hypnotizability to outcome of a smoking cessation program. METHOD: A consecutive series of 226 smokers referred for the smoking cessation program were treated with a single-session habit restructuring intervention involving self-hypnosis. They were then followed up for 2 years. Total abstinence from smoking after the intervention was the criterion for successful outcome. RESULTS: Fifty-two percent of the study group achieved complete smoking abstinence 1 week after the intervention; 23% maintained their abstinence for 2 years. Hypnotizability and having been previously able to quit smoking for at least a month significantly predicted the initiation of abstinence. Hypnotizability and living with a significant other person predicted 2-year maintenance of treatment response. CONCLUSIONS: These results, while modest, are superior to those of spontaneous efforts to stop smoking. Furthermore, they suggest that it is possible to predict which patients are most likely and which are least likely to respond to such brief smoking cessation interventions.
Adult↗
First isolation of Borrelia burgdorferi from an iris biopsy.
The persistence of Borrelia burgdorferi in six patients is described. Borrelia burgdorferi has been cultivated from iris biopsy, skin biopsy, and cerebrospinal fluid also after antibiotic therapy for Lyme borreliosis. Lyme Serology: IgG antibodies to B. burgdorferi were positive, IgM negative in four patients; in two patients both IgM and IgG were negative. Antibiotic therapy may abrogate the antibody response to the infection as shown by our results. Patients may have subclinical or clinical disease without diagnostic antibody titers. Persistence of B. burgdorferi cannot be excluded when the serum is negative for antibodies against it.
Adolescent↗
Distribution of human immunodeficiency virus (HIV) in the CNS of children with severe HIV encephalomyelopathy.
The presence and distribution of human immunodeficiency virus (HIV) were examined in the CNS of two children with severe HIV encephalitis and myelitis. Using polymerase chain reaction-mediated DNA amplification and subsequent Southern analysis, proviral HIV gag sequences were identified in brain tissue of both patients. In situ hybridization using antisense oligonucleotide probes revealed abundant HIV gag and env/nef RNAs selectively in areas with histopathological evidence for HIV-induced tissue damage. The spinal cord of one patient exhibited a striking subpial accumulation of HIV RNAs strongly suggestive of a liquorigenic spread of the infection. HIV RNAs were typically associated with cells of the monocyte/macrophage lineage, as shown by a combined immunohistochemical and in situ hybridization procedure. The present study supports the view that the pattern and distribution of HIV-induced brain lesions is largely determined by the extent of focal HIV replication within the CNS.
Base Sequence↗
Follicular dendritic cells are a major reservoir for human immunodeficiency virus type 1 in lymphoid tissues facilitating infection of CD4+ T-helper cells.
Human immunodeficiency virus type 1 (HIV-1) infection causes progressive depletion of CD4/HIV-receptor-positive T helper lymphocytes, ultimately leading to AIDS. The major HIV reservoir and site of T-helper cell infection in lymphoid tissues, however, has remained poorly defined. The authors used in situ hybridization in combination with immunohistologic labeling techniques to identify the phenotype of HIV-infected cells in lymph nodes from patients at different stages of HIV-infection. The number of HIV-infected macrophages, widely considered the major site of HIV replication, was extremely low. There was no evidence for HIV-infection of endothelial and interdigitating reticulum cells. However, HIV RNA was found in small but consistent proportions of CD45RO-positive T cells and in the vast majority of follicular dendritic cells (FDC) in a pattern suggestive of active infection in addition to HIV-immunocomplex trapping on cell membranes. FDC may therefore be a major HIV reservoir and since T-helper cells travel through the FDC meshwork during their migration within lymphoreticular tissues, it appears likely that HIV-replicating T cells may infect FDC, which then infect new T cells, thus causing a gradual dissemination of the virus to all FDC and thereby a steadily increasing infection of T-helper/memory cells within germinal centers. This results in CD4+ T cell depletion, and ultimately, in immunodeficiency.
Adult↗
Personality style and hypnotizability: the fix-flex continuum.
Since Mesmer, there has been much confusion about the inter-relationship between an individual's degree of hypnotizability, the personality style of the individual and the importance of the therapeutic strategy. Empirical and experimental research supports the hypotheses that there are: 1) biopsychosocial components of hypnotizability on a continuum ranging from ecologically insensitive (not modifiable by external stimuli) to ecologically sensitive (very modifiable by external stimuli); 2) biopsychosocial components that can be measured to identify an individual's degree of hypnotic capacity and responsivity; 3) distinct personality styles which correlate with low, mid-range and high hypnotizability on a fix (ecologically insensitive)-flex (ecologically sensitive) continuum; and 4) different clinical syndromes which correlate with these categorical distinctions. We propose that measuring hypnotizability and personality style is a way to clarify diagnosis and choose appropriate treatment strategies to maximize existing biopsychosocial resources of an individual with a specific problem in a particular context.
Female↗
Neuropathology and pathogenesis of HIV encephalopathies.
The nervous system is frequently affected in patients with the acquired immune deficiency syndrome (AIDS). In addition to opportunistic CNS infections and cerebral lymphomas, approx. 20% of the patients develop HIV-associated encephalopathies. Two major histopathological manifestations are observed. HIV leukoencephalopathy (progressive diffuse leukoencephalopathy) is characterized by a diffuse loss of myelin in the deep white matter of the cerebral and cerebellar hemispheres, with scattered multinucleated giant cells and microglia but scarce or absent inflammatory reaction. HIV encephalitis (multinucleated giant cell encephalitis) is associated with accumulations of multinucleated giant cells, inflammatory reaction and often focal necroses. In some patients, both patterns may overlap. In order to identify the HIV genome in the CNS, brain tissue from 27 patients was analyzed for the presence of HIV gag sequences using the polymerase chain reaction (PCR) and primers encoding a 109 base pair segment of the gag gene. Amplification of HIV gag succeeded in all 5 patients with clinical and histopathological evidence for HIV encephalopathy but was negative in the 20 AIDS patients with opportunistic bacterial, parasitic and/or viral infections or with cerebral lymphomas. These results strongly suggest that the evolution of histopathologically recognizable HIV-encephalopathies closely correlates with the presence and/or tissue concentration of HIV. Since there were no cases with amplified HIV DNA in the absence of HIV-associated tissue lesions, we conclude that harboring and replication of HIV in the CNS rapidly causes corresponding clinical and morphological changes of HIV-associated encephalopathies. In two children with severe HIV encephalomyelitis, large amounts of HIV gag and env transcripts were detected in affected areas of the brain and spinal cord by in situ hybridization.(ABSTRACT TRUNCATED AT 250 WORDS)
AIDS Dementia Complex↗
[Sudden blindness in an AIDS patient. Simultaneous infection with cytomegalovirus and herpes simplex viruses and development of malignant non-Hodgkin lymphoma].
A 50 year old patient with non-diagnosed HIV-infection at onset of his illness developed impairment of vision and temporary double vision combined with severe hemianopsia. With normal fundus and suspicious Herpes simplex iritis therapy with Acyclovir was started. Primarily the patient showed a good response to the therapy and loss of vision could be prevented. After 4 weeks CMV-retinitis developed. In spite of Gancyclovir therapy manifestation of total loss of vision after 6 weeks. Autopsy demonstrated signs of simultaneous a CMV-infection of the retina and a herpes simplex-infection of the optic nerve combined with a Non-Hodgkin-Lymphoma of the optic tract.
Acquired Immunodeficiency Syndrome↗
Disseminated infection of the central nervous system caused by Nocardia farcinica.
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Amikacin↗
[The central nervous system of infants born to HIV-positive mothers-- neuropathology, immunohistochemistry in in situ hybridization].
The central nervous system (CNS) of 12 fetuses from human-immunodefiency-virus-seropositive mothers was investigated. Postconceptional ages ranged between 15 and 21 weeks. 3 preterm infants born to HIV positive mothers whose survival ranged from 6 hours to 6 months were included in the study. In all cases, the development of the CNS was macroscopically normal. The microscopic examination showed many ectopic neurons indicating disturbances of normal neuronal migration. As a regular finding there was a significant increase in microglia in all areas of the CNS but no microglial nodules were found. In all cases haematogenous monocytes were scattered in the perivascular space of the cerebral parenchyma as well as in the chorioid pexus. The virus-antigen p24 could neither be detected immunohistochemically in the paraffin sections nor in the frozen material of the brain or by in-situ-hybridization. In contrast, in five of the cases investigated the placenta showed macrophages, socalled Hofbauer cells with p24-associated antigen.
Antigens, Viral↗
[Lymphoid tissues and AIDS: role of lymphocytes and follicular dendritic cells (FDC)].
Currently discussed models of AIDS pathogenesis attribute a pivotal role to HIV-variants developing in T cells during the course of the disease resulting in an increasingly rapid depletion of the infected T cells. Such models do not however explain the morphological findings observed in AIDS lymphadenopathy. To clarify the significance of the hyperplasia and subsequent destruction of the lymphoid follicles in HIV-related lymphadenopathy, we used in situ hybridization in combination with immunohistological labelling techniques to identify the phenotype of HIV-infected cells in lymph nodes. In addition to few T helper cells, mainly in germinal centres, large amounts of HIV-RNA were found in CD4-negative follicular dendritic cells (FDC) rather than in macrophages or other cells. This finding is well in accordance with the recent observations made by other authors suggesting that purified FDC can be infected with HIV in vitro. Furthermore, TNF alpha expression is localized mainly in centroblasts (activated B cells) of germinal centres. TNF alpha, released by antigen-activated B cells in vitro, has been shown to induce HIV replication in latently infected T cells. On the basis of these observations we propose that latently infected CD4+ T cells, having entered germinal centres, start HIV replication under the influence of cytokines present in this microcompartment of all lymphoreticular tissues. Here the T cells infect FDC which, in turn, pass on the virus to new healthy T helper cells. This model may explain both peculiarities of the lymphadenopathy syndrome as well as the long latency period of HIV-infection, ultimately leading to AIDS.
Acquired Immunodeficiency Syndrome↗
Legal principles in the psychiatric assessment of personal injury litigants.
The authors review the legal principles that a psychiatrist must understand in assessing the emotional and psychiatric sequelae of a personal injury leading to a litigation claim. The principles of the establishment of fault or liability, the assessment of pain and suffering, causal connection, the credibility of the plaintiff, the credibility of the expert witness, the determination of prognosis, the award of damages, and the adversarial system are discussed. An appreciation of these principles will enable psychiatrists to provide assessments that will be useful to the legal system in arriving at a fair and accurate determination of the compensation to which a victim is entitled.
Accidents, Traffic↗
The Hypnotic Induction Profile and absorption.
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Attention↗
Transposition of Tn4551 in Bacteroides fragilis: identification and properties of a new transposon from Bacteroides spp.
Tn4551, a clindamycin resistance (Ccr) transposon from the R plasmid pBI136, was cloned onto an Escherichia coli-Bacteroides shuttle vector which could replicate normally in E. coli but was maintained unstably in Bacteroides fragilis. To aid in cloning and to ensure maintenance of Tn4551 in E. coli, a kanamycin resistance determinant (Kmr) was inserted in the transposon. The transposon-bearing shuttle vector pFD197 was transformed into B. fragilis 638, and putative insertions of Tn4551::Kmr were identified by screening for resistance to clindamycin and plasmid content. Southern hybridization analyses were used to verify integration of the transposon in the B. fragilis chromosome, and the frequency of insertion was estimated at 7.8 X 10(-5) events per generation. In 57% of the isolates tested a second integration event also occurred. This second insertion apparently involved just a single copy of the 1.2-kilobase repeat sequence which flanks the transposon. In addition, Tn4551::Kmr appeared to function as a transposon in E. coli. Evidence for this was obtained by the isolation of transposon insertions into the bacteriophage P1 genome. Finally, the transposon vector, pFD197, could be mobilized to other B. fragilis strains in which transposition was detected. Mobilization from the strain 638 background was via a conjugation like process, but occurred in the absence of known conjugative elements or other detectable plasmids. This result suggested the presence of a host-encoded transfer system in this B. fragilis strain.
Bacteroides fragilis↗