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PubMed1992

Human T lymphotropic virus type-I (HTLV-I) immortalizes human T cells in vitro--its implication in the pathogenesis of adult T cell leukemia (ATL).

HTLV-I is the first human retrovirus that was isolated from a patient with T-cell malignancy in 1980 in the United States. HTLV-I is detected in most patients with adult T cell leukemia (ATL) and healthy carriers, who are frequently found in the southwestern parts of Kyushu and Shikoku Districts. HTLV-I-infected cells express IL-2 receptors, and HTLV-I-infected T cell lines can be established from most of ATL patients in culture in the presence of IL-2. Furthermore, these IL-2 dependent T cell lines often begin to proliferate in the absence of IL-2 and to not respond to IL-2, despite IL-2 receptors on their cell surface, thus mimicking ATL cells in vivo. These findings suggest that HTLV-I is an etiological agent of ATL. In this mini-review, the T cell immortalizing activity of HTLV-I in vitro, with special reference to the evolution of ATL cells based on our results, is described.

Antigens, CD↗

PubMed1987

Expression of HTLV-I in serum of HTLV-I-related subjects and the early detection of overt ATL in HTLV-I carriers.

Monoclonal antibodies against human T cell leukemia virus type I (HTLV-I) p24 and p19 were produced and employed in the in vivo expression of HTLV-I in some HTLV-I-related subjects by Western blot analysis. The antigenic determinants of these monoclonal antibodies were different from that of natural human anti-HTLV-I antibody examined. Serum p24 was identifiable in almost all of the overt ATL patients (17 of 18, 94%), but not in the chronic ATL cases or HTLV-I carriers. On the other hand, serum p19 was detected in one of the three patients with chronic ATL examined, but not in the overt ATL patients or the HTLV-I carriers. These results indicate that the in vivo expression of HTLV-I p24 and p19 which has reacted with natural anti-HTLV-I antibody can be detected by these monoclonal antibodies. Therefore, the investigation of serum HTLV-I expression may lead to the early detection of overt ATL in an HTLV-I carrier.

Antibodies, Monoclonal↗

PubMed1989

[Cytogenetic studies of healthy HTLV-I carriers (Report 1): Cytogenetic studies of an ATL family].

The chromosome 14q11 anomaly has been reported to be specific to adult T-cell leukemia (ATL) and this anomaly has also been confirmed in preleukemic state of ATL (pre-ATL) patients though the frequency is low. In an attempt to clarify if the same chromosome aberrations could be found also at the stage of HTLV-I carrier and if there is any cytogenetic difference from non-HTLV-I carriers, a cytogenetic study of lymphocytes stimulated with phytohemagglutinin in three HTLV-I healthy carriers and three non-HTLV-I carriers in an ATL family was performed. The results were as follows. 1. In three HTLV-I carriers, 7 of 311 cells examined (2.3%) showed chromosome aberrations, and 4 cells (1.3%) had 14q11 anomaly. 2. In three non-HTLV-I carriers, 4 of 260 cells examined (1.5%) showed chromosome aberrations, whereas no cells had 14q11 anomaly. These findings suggest that 14q11 anomaly is already present at the stage of HTLV-I carrier and seems to be an important cytogenetic clue to the pathogenesis of ATL.

Adult↗

PubMed1989

[Relationship of diffuse panbronchiolitis (DPB) and idiopathic interstitial pneumonia (IIP) with adult T cell leukemia (ATL)].

Eighteen patients with DPB and 15 with IIP were studied on the relationship between the diseases and ATL. Anti-ATL antigen (ATLA) antibody and its related reactions were examined using immunofluorescence and Western blotting techniques. Five of 18 DPB patients (28%) were anti-ATLA antibody positive, and were diagnosed as ATL because of the appearance of ATL cells after the chronic DPB clinical course. No IIP patient was diagnosed as having ATL, however, a patient's serum converted to anti-ATLA antibody positive from ATLA related reaction positive when tested with immunofluorescence. ATLA related reaction with diffuse reaction patterns in both MT-1 and MT-2 cells was detected in 7 of 18 sera in patients with DPB and in 5 of 15 IIP sera. A diffuse pattern only in MT-2 cells was found in 2 cases of DPB and 3 of IIP. Positive percentage of these anti-ATLA antibody and ATLA related reactions in DPB and IIP patients was significantly higher than that in controls. These results suggest the existence of a specific clinicopathological state namely "HTLV-1 associated bronchiolo-alveolar disorder (HABA)" in some of DPB and IIP.

Adult↗

PubMed1987

Production of interleukin 1 by adult T cell leukemia (ATL) cell lines.

The accessory function for T cell activation and the production of interleukin 1 (IL 1) of adult T cell leukemia (ATL) cell lines were studied in vitro. ATL cell lines such as Hut-102, MT-1, and MT-2 functioned as accessory cells for the stimulation of human T cell proliferative response induced with concanavalin A (Con A) and induced allogeneic mixed lymphocyte reaction. Cell lysates of three ATL cell lines and the culture supernatant of MT-2 cells had activities to stimulate murine thymocyte proliferative response. Then we studied physicochemical properties of the factors produced by MT-2 cells. The m.w. of the factors were approximately 15,000 by Sephacryl S-200 column chromatography, and their isoelectric point values were 5.4 and 4.8 by chromatofocussing technique. No fraction contained interleukin 2 (IL 2) activities to stimulate IL 2-dependent murine cytotoxic T cell line. The thymocyte-stimulating activities of the factors were absorbed with rabbit anti-IL 1 alpha antiserum, but not with anti-IL 1 beta antiserum. Furthermore, messenger RNA extracted from MT-2 cells hybridized to complementary DNA of IL 1 alpha, but not of IL 1 beta, by Northern blot hybridization analysis. The factors from MT-2 cells could stimulate the production of IL 2 and the expression of IL 2 receptors of human T cells in the presence of Con A as well as recombinant IL 1 alpha and IL 1 beta did, and these activities were also blocked by rabbit anti-IL 1 alpha antiserum, but not by anti-IL 1 beta antiserum. These results suggest that the factors produced by MT-2 cells correspond to IL 1 alpha. However, the accessory function of MT-2 cells for T cell activation was not blocked by rabbit anti-IL 1 antiserum. These results suggest that ATL cell lines produce IL 1-like factors, but the accessory function of ATL cell lines for T cell activation is mediated by some other mechanisms rather than by secreted IL 1-like factors.

Animals↗

PubMedDate not supplied

Potential impact of the advanced trauma life support (ATLS). Program in a Third World country.

Data from Trinidad and Tobago suggest there is a positive role for the ATLS program in Third World countries. Between 1970-1979 traffic accidents increased from 16,433 to 28,003 while deaths increased from 179 to 252 per year. Sixty-nine per cent of deaths were adult males mainly between 20-30 years old and most fatal accidents occurred between 6:00 and 10:00 p.m. particularly on weekends. Because expert consultants are not always immediately available within the hospital, initial trauma resuscitation is provided by emergency room physicians. Accordingly, 75% of trauma deaths occur in hospital with 65% of those dying within six hours of reaching the hospital alive. Compared to a similar sized North American population the death to injury ratio is at least doubled. The beneficial impact of the ATLS program in Third World countries is assured if ATLS quality control is maintained and can be assessed, as outlined, by comparing pre ATLS with post ATLS data.

Accidents, Traffic↗

PubMed1994

Functional comparison between HTLV-I envelopes originating from TSP/HAM or ATL cell lines.

The human T-cell leukemia type I (HTLV-I) virus is associated with two different diseases, adult T-cell leukemia (ATL) and tropical spastic paraparesis/HTLV-I-associated myelopathy (TSP/HAM). We have compared the viral envelopes originating from TSP/HAM and ATL patients, using the capacity of infected cells to form syncytia with receptor-expressing cells. We show that like the ATL cell lines, the TSP/HAM ones can form syncytia with a large panel of human target cells, including a variety of hematopoietic cell lines, as well as cell lines of neuroectodermal origin. None of the target cell lines tested was able to discriminate between TSP/HAM- and ATL-infected cell lines. When infected cells of TSP/HAM origin are cocultivated with cells of ATL origins, syncytia are never observed. This interference phenomenon suggests that the viruses expressed by the different cell lines utilize the same receptor.

Blotting, Western↗

PubMed1997

Integration patterns of HTLV-I provirus in relation to the clinical course of ATL: frequent clonal change at crisis from indolent disease.

We examined human T-lymphotropic virus type I (HTLV-I) DNA integration in 68 patients with adult T-cell leukemia/ lymphoma (ATL) by Southern blotting using EcoRI, which does not cut within the 9 kb of the genome and probes for pX and gag-pol region of HTLV-I. We detected defective proviral integration as a monoclonal band of various sizes with the pX but not with the gag-pol probe, or a monoclonal band of less than 9 kb with the pX probe, in 20 patients (29.4%). These were designated defective (D) type. With both probes, a single band greater than 9 kb was detected in 34 (50.0%), designated complete (C) type, and two or more bands greater than 9 kb, were designated multiple (M) type, in 14 (20.6%). Advanced age, a high LDH value, and hypercalcemia were more frequent in D type patients. The median survival time (MST) was 6.8, 24.4, and 33.3 months, for D, C, and M types, respectively (log rank P = .006). Among 52 sequentially examined patients, the HTLV-I integration patterns changed in 4 (7.5%). In three of these four, the rearrangements of the T-cell receptor (TCR)b gene concomitantly changed, suggesting the appearance of a new ATL clone. Another patient had the same rearrangement of the TCRb gene, indicating clonal evolution. The HTLV-I integration pattern changed at crisis from indolent to aggressive ATL in three patients. These findings suggested that the HTLV-I integration patterns have clinical implications in ATL pathophysiology. In contrast to the clonal evolution characteristic of the multistep carcinogenesis of most human malignancies, the frequent clonal change of ATL at crisis is a peculiar phenomenon, probably reflecting the emergence of multiple premalignant clones in viral leukemogenesis as suggested in Epstein-Barr virus associated lymphomagenesis in the immunocompromised host.

Aged↗

PubMed1997

[ATLS course in emergency medicine for physicians?].

Implementation of Advanced Trauma Life Support (ATLS) skills among practicing physicians and its perceived utility in their civilian practices, as well as in their potential army combat assignments, was evaluated. 177 physicians in various subspecialties, who were graduates of ATLS training courses, answered a specially designed telephone questionnaire. An unexpectedly high percentage of physicians (47%) had used their ATLS training when called to treat trauma victims. 67% of physicians stressed the contribution of the ATLS course to enhancing their skills. We believe that a properly designed ATLS course for general practitioners would be very beneficial for trauma victims.

Clinical Competence↗

PubMed2004

[The importance of Advanced Trauma Life Support (ATLS) in the emergency room].

INTRODUCTION: There is clinical evidence, that a standardized management of trauma patients in the emergency room improves outcome. METHODS: The ATLS training course teaches a systematic approach to the trauma patient in the emergency room. The aim is a rapid and accurate assessment of the patient's physiologic status, the treatment according to priorities and the decision making if transfer to a trauma center is necessary. The German Trauma Society has taken over the course concept from the American College of Surgeons (ACS) and is authorized to organize ATLS courses in Germany. RESULTS: A standardized management in the emergency room helps to prevent secondary injury, to realize timing as a relevant factor in the initial treatment and to assure a high standard of care. The ATLS course provides the participant with knowledge, skills and attitudes and is open to doctors of all specialties involved in the initial management of severely injured patients. CONCLUSION: ATLS teaches a standardized and established approach to the trauma patient in the emergency room. It has been transferred to 46 countries and the content is reviewed regularly to consider new scientific evidence. Germany has the chance to participate in this international standard of care and to introduce own experiences into the review process.

Critical Care↗

PubMed1988

Chromosome instability in preleukemic states of adult T-cell leukemia (pre-ATL).

Chromosome analysis was performed on nine patients with subclinical adult T-cell leukemia (pre-ATL), who were asymptomatic ATL virus carriers. Fewer than 30% of their peripheral blood leukocytes were abnormal T-lymphocytes with nuclear abnormalities. ATL-associated antigen (ATLA) and anti-ATLA antibody were found in all patients. Eight had variable abnormal karyotypes in a fraction (5.0%-25.4%) of peripheral blood leukocytes stimulated with phytohemagglutinin or T-cell growth factor. There were no metaphases when a mitogen was not added. Four patients had a clonal chromosome abnormality. The chromosome abnormality seen in one patient was observed in the first study but not in a second study, when a different abnormality was seen. In five patients, an abnormal chromosome #14 with a break at band 14q11 was found. These findings indicate that unstable, chromosomally abnormal clones are characteristic of pre-ATL.

Aged↗

PubMed2006

Effects of oxacillin and tetracycline on autolysis, autolysin processing and atl transcription in Staphylococcus aureus.

Autolysins are peptidoglycan hydrolases involved in cell growth and cell lysis. Atl is an important autolysin of Staphylococcus aureus and is essential for penicillin-induced autolysis. The objective of our study was to examine the effect of oxacillin, chloramphenicol and tetracycline on autolysis, peptidoglycan hydrolase profiles and transcription of atl encoding the major S. aureus autolysin on cells grown in the presence of minimum inhibitory concentrations of the antibiotics. Growth of methicillin-susceptible strains in the presence of oxacillin led to increased autolysis, a loss of low molecular weight and a gain of high molecular weight peptidoglycan hydrolase bands suggesting altered proteolytic processing of peptidoglycan hydrolases, and a decrease in atl transcription. In contrast, growth in the presence of tetracycline led to a decrease in autolysis, an increase in atl transcription, and a drastic decrease in the protein concentration of freeze-thaw extracts obtained for peptidoglycan hydrolase analysis. Growth of methicillin-resistant strains in the presence of oxacillin had only moderate effects on autolysis and peptidoglycan hydrolase profiles.

Anti-Bacterial Agents↗

PubMed2006

The effectiveness of a human patient simulator in the ATLS shock skills station.

BACKGROUND: The use of simulation as a teaching adjunct in Advanced Trauma Life Support (ATLS) has not undergone rigorous psychometric testing. We hypothesized that an advanced, computer-controlled human patient simulator (HPS) would be a useful adjunct to the ATLS shock skills station. MATERIALS AND METHODS: Forty-four PGY-1 residents enrolled in ATLS courses were randomized into control (CTL) and experimental (EXP) groups. All students took a shock-specific pre- and post-test multiple choice question examination (MCQE). The EXP group used the HPS in the shock skills station; the CTL group was taught in a traditional manner. All students participated in an experimental, shock-specific objective structured clinical examination (OSCE) session at the end and had their performance evaluated. The EXP group was asked to evaluate the teaching effectiveness of the shock skills station. RESULTS: There were no statistically significant differences between the EXP and CTL groups with respect to the pre- and post-test MCQE or the change in scores. The groups were similar in their overall performance during the shock-specific OSCE. The EXP and CTL groups were equivalent with respect to shock recognition, identification of the type of shock, and ability to select the correct treatment plan. The shock skills station was rated from very good to excellent in 91% of the EXP group versus 63% in the CTL group. The EXP group rated the simulator most helpful in learning to analyze data from the monitors. CONCLUSIONS: Use of an advanced HPS during the ATLS shock skills station was equivalent to traditional teaching scenarios based on psychometric testing. Students subjectively preferred the simulator as a teaching tool and found it most useful in learning how to integrate data from hemodynamic monitors into clinical decision making.

Clinical Competence↗

PubMed1998

Retinoic acids induce growth inhibition and apoptosis in adult T-cell leukemia (ATL) cell lines.

Adult T-cell leukemia (ATL) is a peripheral T-cell neoplasm caused by human T-cell leukemia virus type I (HTLV-I). Despite the administration of combined intensive chemotherapy, the reported survival time of patients with acute and lymphoma types of ATL is less than 10 months. We therefore examine the effects of all-trans-retinoic acid (ATRA), 9-cis-RA and 13-cis-RA and tried to elucidate the mechanisms of inducing growth inhibition and apoptosis by these RAs using four ATL cell lines established in our laboratory. All the investigated RAs inhibited cell growth and the cells were arrested at the G1 phase. Apoptosis was induced in three out of four cell lines. Among the growth regulatory proteins examined, the level of p21Waf1/Cip1 protein was found to increase after RA treatment, thus resulting in pRb hypophosphorylation which also induced the arrest of the cells at the G1 phase. In addition, the p53 level decreased at the same time. Fas-FasL system and the downregulation of CD25 (IL-2R/alpha) expression did not seem to be involved. Based on these findings, the ability of RAs to induce a remission of ATL is thus strongly suggested.

Adult↗

PubMed2000

Clinical significance of serum soluble IL-2R levels in patients with adult T cell leukaemia (ATL) and HTLV-1 carriers.

The levels of soluble IL-2Ralpha (sIL-2Ralpha) in serum were measured in HTLV-1 carriers and ATL patients in order to evaluate their possible correlation with clinical status. Mean sIL-2R levels in ATL patients were found to be 9704 U/ml for the acute/lymphoma type, 1961 U/ml for the chronic type and 788 U/ml for the smouldering type. The level for asymptomatic HTLV-1 carriers was 475 U/ml, and 165 U/ml for healthy young adult HTLV-1- controls. The serial measurement of sIL-2R in ATL patients, healthy HTLV-1 carriers, and HTLV-1 carriers with diseases other than ATL showed a good correlation between serum levels of sIL-2R and the pathophysiological status of disease. Furthermore, an increase in the sIL-2Ralpha level in serum indicated the exacerbation of HTLV-1 infection and autoimmune diseases. The measurement of sIL-2Ralpha levels is therefore a very useful parameter for determining disease status.

Adult↗

PubMed2005

Reduced expression of the atl autolysin gene and susceptibility to autolysis in clinical heterogeneous glycopeptide-intermediate Staphylococcus aureus (hGISA) and GISA strains.

OBJECTIVES: To assess a link between resistance to Triton X-100 induced autolysis (TIA) and lowered atl expression in a collection of clinical glycopeptide-intermediate Staphylococcus aureus (GISA) and heterogeneous GISA (hGISA). METHODS: Nine clinical GISA, 11 hGISA and 11 glycopeptide-susceptible S. aureus (GSSA), including three pairs of related isolates, were analysed using TIA assays. Lysostaphin MICs were determined by a broth microdilution technique and reverse transcriptase PCR was used to compare atl expression levels in all isolates. RESULTS: Eight of nine clinical GISA and six of 11 hGISA exhibited lower susceptibility to TIA and higher MICs of lysostaphin than GSSA. Eight of nine GISA and all hGISA strains had lowered atl expression levels compared with GSSA. CONCLUSIONS: The majority of GISA and hGISA isolates exhibited lowered susceptibility to TIA and lysostaphin and reduced atl expression when compared with GSSA isolates. These factors could contribute to, or predispose to the development of, a thickened cell wall and glycopeptide-intermediate resistance.

Anti-Bacterial Agents↗

PubMed1988

Polyclonal integration of HTLV-I proviral DNA in lymphocytes from HTLV-I seropositive individuals: an intermediate state between the healthy carrier state and smouldering ATL.

We have studied 15 individuals (aged 14-74 years) with antibodies to HTLV-I in their serum and random integration of HTLV-I proviral DNA in their peripheral blood lymphocytes. All but one of these patients suffered from a variety of non-specific complaints which did not correspond to those of adult T-cell leukemia (ATL). All of them were born in Kyushu and Okinawa which are endemic areas for HTLV-I infection; 25% of their family members were also seropositive for HTLV-I. The only haematological abnormality in these patients was the presence of few atypical lymphoid cells in the peripheral blood. The CD4/CD8 ratios were normal but the proportion of Tac positive cells was slightly higher than normal. These individuals with polyclonal integration of HTLV-I proviral DNA seem to represent an intermediate state between smouldering ATL (monoclonal integration) and healthy HTLV-I carriers (with antibodies but no detectable HTLV-I proviral DNA). Patients with this intermediate state of HTLV-I infection may be at risk to progress to ATL. The natural history of HTLV-I infection in humans leading to the development of ATL is reviewed in the light of these new findings.

Adolescent↗

PubMed2006

Activity of the major staphylococcal autolysin Atl.

The major autolysin of Staphylococcus aureus (AtlA) and of Staphylococcus epidermidis (AtlE) are well-studied enzymes. Here we created an atlA deletion mutant in S. aureus that formed large cell clusters and was biofilm-negative. In electron micrographs, the mutant cells were distinguished by rough outer cell surface. The mutant could be complemented using the atlE gene from S. epidermidis. To study the role of the repetitive sequences of atlE, we expressed in Escherichia coli the amidase domain encoded by the gene, carrying no repeat regions (amiE) or two repeat regions (amiE-R1,2), or the three repeat regions alone (R1,2,3) as N-terminal His-tag fusion proteins. Only slight differences in the cell wall lytic activity between AmiE and AmiE-R1,2 were observed. The repetitive sequences exhibit a good binding affinity to isolated peptidoglycan and might contribute to the targeting of the amidase to the substrate. AmiE and AmiE-R1,2 have a broad substrate specificity as shown by similar activities with peptidoglycan lacking wall teichoic acid, O-acetylation, or both. As the amidase activity of AtlA and AtlE has not been proved biochemically, we used purified AmiE-R1,2 to determine the exact peptidoglycan cleavage site. We provide the first evidence that the amidase indeed cleaves the amide bond between N-acetyl muramic acid and L-alanine.

Bacterial Adhesion↗