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Biomedical subjects

K Asadullah

Publications and source records attributed to K Asadullah.

52 records · Page 3Linked to original sources
PubMed1997

Demonstration of frequent occurrence of clonal T cells in the peripheral blood of patients with primary cutaneous T-cell lymphoma.

Clonal T cells have been demonstrated in skin lesions of all stages of cutaneous T-cell lymphomas (CTCLs). However, there are conflicting data regarding the CTCL stage at which dissemination of clonal cells into peripheral blood occurs. Although the multifocal occurrence of cutaneous CTCL lesions and T-cell recirculation suggest an early appearance of neoplastic cells in the blood, circulating clonal T cells have only been detected in advanced stages. We investigated their occurrence by a highly sensitive polymerase chain reaction (PCR) assay amplifying T-cell receptor gamma rearrangements and subsequent heteroduplex temperature gradient gel electrophoresis (HD-TGGE) of the amplification products. Circulating clonal T cells were found in 26 of 45 patients with mycosis fungoides (MF), six of seven with Sezary's syndrome (SS), 10 of 13 pleomorphic CTCLs, and three of four unclassified CTCLs. Corresponding skin specimens carried clonal T cells in 29 of 40 MF, three of four SS, 12 of 12 pleomorphic, and two of two unclassified CTCL patients. Except for the blood specimen of a psoriatic patient, all samples of 60 controls (psoriasis vulgaris, atopic dermatitis, and healthy volunteers) revealed polyclonal amplification products. In 30 of 32 CTCL patients carrying a clonal rearrangement in blood and skin, identity of both clones was indicated by HD-TGGE and confirmed by sequencing six of these cases. We found an unexpected high frequency of identical clonal T cells in peripheral blood and skin of CTCL patients, including early stages of MF. This supports the concept of an early systemic disease in CTCL and raises new questions concerning the pathogenesis.

Adult↗
PubMed1997

Interferon gamma-1b in the treatment of compensatory anti-inflammatory response syndrome. A new approach: proof of principle.

BACKGROUND: Immunoparalysis is defined as a decrease in the level of HLA-DR expression on monocytes during the course of sepsis. OBJECTIVE: To evaluate whether interferon gamma-1b has an immunoregulatory effect in patients with immunoparalysis during the compensatory anti-inflammatory response syndrome. METHODS: Of the patients admitted consecutively to the intensive care unit for the management of sepsis, 10 received interferon gamma-1b, 100 micrograms per 0.5 mL, after confirmation of HLA-DR expression of less than 30% on 2 consecutive days. The therapy was continued until HLA-DR expression remained more than 50% for 3 days. RESULTS: Interferon gamma-1b therapy resulted in the recovery of diminished levels of HLA-DR expression on monocytes. Of the 10 patients, 8 responded to treatment within 1 day. On the first day of interferon gamma-1b therapy, HLA-DR expression increased from mean (+/- SEM) pretreatment levels of 27% +/- 6% to 62% +/- 8% (P < .01) and remained high during the 28-day study period in 8 patients. The therapy was given to 2 patients a second time when HLA-DR expression on monocytes was less than 30%. The recovery of monocytic HLA-DR expression levels after administration of interferon gamma-1b was associated with restitution of monocytic function, reflected by a significant increase of plasma interleukin-6 (P < .05) and tumor necrosis factor alpha (P < .05) levels in 9 patients. CONCLUSIONS: This study shows that HLA-DR expression is a good marker of compensatory anti-inflammatory response syndrome. It also shows that interferon gamma-1b not only restored the levels of HLA-DR expression but also reestablished the ability of monocytes to secrete the cytokines interleukin-6 and tumor necrosis factor alpha.

Adult↗
PubMed1997

Different release of cytokines into the cerebrospinal fluid following surgery for intra- and extra-axial brain tumours.

To elucidate the role of cytokines in brain repair processes and in local inflammation after neurosurgical procedures, cerebrospinal fluid (CSF) samples from 8 patients with intra-axial tumours and 8 patients with extra-axial tumours were analysed for interleukin (IL)-1 beta, IL-1 receptor antagonist (IL-1 ra), IL-6, IL-8, IL-10, and tumour necrosis factor (TNF)-alpha at the beginning and after surgery. Levels of IL-6 and IL-8 increased dramatically in all patients just hours after surgery and fell during subsequent days. IL-1 beta was found only in low amounts in the CSF of both patient groups. Other cytokines demonstrated different courses. In patients with intra-axial tumours IL-1 ra peaked two to four hours after surgery with a subsequent decrease. In patients with extra-axial tumours there was a continuous low-level IL-1 ra release into the CSF without a peak. TNF-alpha was not present in detectable levels in the CSF after surgery for extra-axial tumours but was found to peak two to four hours after surgery for intra-axial tumours. IL-10 was detected in the CSF of both patient groups, but a higher peak was seen after surgery for extra-axial tumours. These results suggest different requirements for the cytokine response and an involvement of different cell types in cytokine release. However, the analysis of the CSF from both patient groups showed no differences in cell counts and populations, with a mild pleocytosis being present in both patient groups after surgery. Therefore, we conclude that after surgery for extra-axial tumours cytokines were predominately produced by non-immune cells stimulated through hypoxia or mechanical irritation. After surgery for intra-axial tumours with a significant brain injury immune cells-activated by necrotic material-seen to be involved in the process of cytokine synthesis. In these cases an additional IL-1ra and TNF-alpha peak was found and these cytokines may be markers for cerebral injury.

Adult↗
PubMed1997

Influence of monomethylfumarate on monocytic cytokine formation--explanation for adverse and therapeutic effects in psoriasis?

Although the effectiveness of systemic antipsoriatic treatment with fumaric acid esters has been proven, their mode of action is still not understood. Recent results indicate their potency in inducing cytokine production in stimulated T cells. Since monocytes and their cytokines are also considered to be of pathogenic importance in psoriasis, we investigated the effect of monomethylfumarate (MMF) on proinflammatory (TNF-alpha, IL-12) and antiinflammatory (IL-10, IL-1RA) cytokine production by peripheral blood mononuclear cells (PBMC) and separated monocytes. In 24-h PBMC cultures from both psoriatic patients (n = 6-13) and healthy volunteers (n = 7-9), MMF at 100 microM induced secretion of TNF-alpha, IL-10, and IL-1RA. Kinetics of IL-10 protein and mRNA expression indicated de novo production. Moreover, MMF significantly augmented endotoxin-induced synthesis of TNF-alpha, IL-10 and IL-1RA. In contrast, no influence on IL-12 secretion was found. Similar effects of MMF in purified monocytes indicated these cells to be responsible for aberrant cytokine formation. Furthermore, enhanced expression of costimulatory molecules after MMF stimulation confirmed monocyte activation. Multiple restimulation with fumaric acid esters in vitro, however, and immunomonitoring in a patient during Fumaderm initial therapy suggested that initial monocyte activation is followed by subsequent deactivation associated with an antiinflammatory response. Our results may explain the well-known effects of therapy with fumaric acid esters. Thus, initial treatment is often accompanied by adverse effects which may be caused by MMF-induced TNF-alpha formation. The change in the IL-10/IL-12 balance as a result of elective induction of IL-10, however, may have antipsoriatic activity by diminishing type-1/proinflammatory cytokine over-expression and the antigen-presenting capacity of monocytes/macrophages, and by upregulation of IL-1RA.

Cells, Cultured↗
PubMed1997

Verrucosis of hands and feet in a patient with combined immune deficiency.

In immunocompromised patients, warts occur frequently and can be extensive. We describe a 24-year-old patient with severe therapy-resistant warts. In addition to human papillomavirus infection, he had chronic sinusitis, candidiasis, and atopic dermatitis. Anergy to delayed-type hypersensitivity skin test reaction, significant CD4 lymphopenia, and diminished in vitro T-cell proliferative response and interferon-gamma production indicated a deficiency of cellular immunity. Extremely low concentrations of serum IgM and IgG2 and a severe deficiency of in vitro IgM production pointed also to a humoral immunodeficiency syndrome. This case represents a combination of cellular and humoral immunodeficiencies that has not been previously described in association with warts.

Adult↗
PubMed1997

Monocyte deactivation in septic patients: restoration by IFN-gamma treatment.

Neutralization of proinflammatory cytokines, such as tumor necrosis factor-alpha (TNF-alpha) or interleukin-1 (IL-1), decreases mortality in several animal models of sepsis. However, recent clinical trials did not show an unequivocal improvement in survival. In contrast to animals, which succumb to shock during the first 72 hours, we found that many patients die much later with signs of opportunistic infections accompanied by downregulation of their monocytic HLA-DR expression and reduced ability to produce lipopolysaccharide (LPS)-induced TNF-alpha in vitro. This phenomenon of monocyte deactivation in septic patients with fatal outcome shows similarities to experimental monocytic refractoriness induced by LPS desensitization or by pretreatment with its endogenous mediators IL-10 and transforming growth factor-beta (TGF-beta). In order to strengthen their antimicrobial defense, here we tested whether interferon-gamma (IFN-gamma) can improve monocytic functions in these patients and in experimental monocytic deactivation. The considerably lowered in vitro levels of LPS-induced TNF-alpha in these situations were significantly enhanced by IFN-gamma, but did not reach the extremely high levels of IFN-gamma primed naive cells from healthy donors. Moreover, IFN-gamma applied to septic patients with low monocytic HLA-DR expression restored the deficient HLA-DR expression and in vitro LPS-induced TNF-alpha secretion. Recovery of monocyte function resulted in clearance of sepsis in eight of nine patients. These data suggest that IFN-gamma treatment in carefully selected septic patients is a novel therapeutic strategy worth pursuing.

Adolescent↗
PubMed1997

Enhanced expression of T-cell activation and natural killer cell antigens indicates systemic anti-tumor response in early primary cutaneous T-cell lymphoma.

Indolent, primary cutaneous T-cell lymphomas (CTCL) are characterized by hyper-proliferation of malignant T-helper cells in the skin with a favorable prognosis in the early stages. Cytotoxic T cells (CTLs) are believed to be of major importance for tumor surveillance, but there is not yet sufficient evidence for a systemic anti-tumor response in mycosis fungoides (MF). On the contrary, there are hints of systemic immunodepression. We wondered whether signs of a systemic anti-tumor response were demonstrable in peripheral blood of patients with MF and CD30+ pleomorphic T cell lymphoma. Using multiparameter flow cytometry, we investigated blood samples from 39 CTCL patients at different stages and compared them with those from patients with psoriasis, atopic dermatitis, and healthy volunteers. In CTCL patients, an elevated number of lymphocytes expressing natural killer cell markers were found, as well as considerable T-cell activation, indicated by increased percentages of T cells expressing HLA-DR, IL-2 receptor alpha-chain, and transferrin receptor. The CD8+ T cells, which were the most strongly activated T-cell subset, were of polyclonal origin, as shown by their usage of different T-cell receptor families. The enhanced expression of activation antigens was associated with an increased proportion of CD8+ T cells with high expression of the adhesion molecule LFA-1, demonstrating the capacity for migration of these cells. These CD8+ effector cells are suspected to be CTLs and may be responsible for the favorable prognosis of indolent, primary CTCL. Interestingly, a stage-dependent decrease in T-cell activation antigen expression was observed, suggesting the development of a lack in tumor surveillance in advanced MF stages. Further investigations are necessary to verify whether any of the parameters determined are of predictive value for prognosis and response to therapy in CTCL.

Adult↗
PubMed1996

Monocyte deactivation--rationale for a new therapeutic strategy in sepsis.

Inflammatory cells, in particular monocytes/macrophages, release pro-inflammatory mediators in response to several infectious and non-infectious stimuli. The excessive release of these mediators, resulting in the development of whole body inflammation, may play an important role in the pathogenesis of sepsis and septic shock. TNF-alpha, acting synergistically with cytokines such as IL-1, GM-CSF and IFN-gamma, is the key mediator in the induction process of septic shock, as shown in several experimental models. Based on this concept and on the encouraging results obtained in several experimental models, a number of clinical sepsis trials targeting the production or action of TNF-alpha or IL-1 have been performed in recent years. Unfortunately, these trials have failed to demonstrate a therapeutic benefit. One reason for this may be the lack of exact immunologic analyses during the course of septic disease. Recently, we demonstrated that there is a biphasic immunologic response in sepsis: an initial hyperinflammatory phase is followed by a hypo-inflammatory one. The latter is associated with immunodeficiency which is characterized by monocytic deactivation, which we have called "immunoparalysis". While anti-inflammatory therapy (e.g. anti-TNF antibodies, IL-1 receptor antagonist, IL-10) makes sense during the initial hyperinflammatory phase, immune stimulation by removing inhibitory factors (plasmapheresis) or the administration of monocyte activating cytokines (IFN-gamma, GM-CSF) may be more useful during "immunoparalysis".

HLA-DR Antigens↗
PubMed1996

IL-7 mRNA is not overexpressed in mycosis fungoides and pleomorphic T-cell lymphoma and is likely to be an autocrine growth factor in vivo.

Interleukin-7 (IL-7) is thought to be a growth factor for cutaneous T-cell lymphoma (CTCL) since it has been shown that IL-7 transgenic mice develop a cutaneous disorder characterized by enhanced T-cell proliferation with progression to malignancy and that in vitro growth of Sézary cell lines is IL-7 dependent. However, no direct in vivo evidence exists for the involvement of IL-7 in the pathogenesis of CTCL. Therefore, we examined IL-7 mRNA expression in skin biopsies from patients with mycosis fungoides (MF) (n = 20) and pleomorphic T-cell lymphoma (n = 5). By semiquantitative RT-PCR, IL-7 mRNA was not detectable in any of the CTCL samples, or in normal human skin (n = 8) or in skin from patients with psoriasis (n = 7) or atopic dermatitis (n = 5). In contrast, IL-7 mRNA was detected in a biopsy from a kidney allograft transplant, in normal keratinocytes under various culture conditions and in several cell lines. Interestingly, using a highly sensitive nested PCR, IL-7 mRNA was detectable in all specimens tested, but there was no indication of IL-7 overexpression in MF then analysing lesions of patch, plaque or tumour stages. In contrast, increasing CD3 expression was found, which was most likely a consequence of the enhanced density of malignant T cells in advanced tumour stages. In summary, by the use of semiquantitative RT-PCR we were not able to detect IL-7 overexpression in MF or pleomorphic T-cell lymphoma. This indicates that IL-7 is probably not an autocrine growth factor in these CTCLs.

Adult↗
PubMed1996

Progression of mycosis fungoides is associated with increasing cutaneous expression of interleukin-10 mRNA.

Cytokines are believed to play an important role in the pathogenesis of cutaneous T cell lymphoma. Data regarding the local cytokine pattern in mycosis fungoides (MF) are partly conflicting. Recent studies have suggested a shift from type 1 to type 2 cytokine pattern because IL-4 and IL-5 mRNA have been more frequently detected in lesions of advanced stages. Another study has described a type 1 cytokine pattern in MF lesions. None of the previous studies of cytokine mRNA expression in MF, however, used quantitative methods, and therefore only the presence of a cytokine, but not the level of expression, could be determined. To gain better insight into the development of cytokine pattern during tumor progression we used semiquantitative reverse transcriptase-polymerase chain reaction to analyze cytokine mRNA expression in MF skin lesions at different stages. Biopsies from patients with patch (n = 11), plaque (n = 6), and tumor (n = 3) stage MF were compared with biopsies from patients with pleomorphic T cell lymphoma (n = 5), psoriasis (n = 7), atopic dermatitis (n = 5), and nonlesional skin (n = 8). MF progression was associated with significantly higher IL-10 and lower interferon-gamma mRNA expression. Moreover, the stage-dependent increase in IL-10 mRNA expression was also found in paired samples from individual patients. Unlike in pleomorphic T cell lymphoma, however, typical T helper 2 cells did not seem to be the source of increasing IL-10 in advanced MF, because stage-independent IL-4 mRNA was rarely detected, suggesting contribution of nonlymphoid cells to local IL-10 production. The overexpression of IL-10 in MF may be of importance for tumor progression, because this immunosuppressive cytokine might be involved in downregulation of immunologic tumor surveillance.

Disease Progression↗
PubMed1995

Immunodepression following neurosurgical procedures.

OBJECTIVE: To determine the influence of a selective, sterile central nervous system surgery on immune reactivity, particularly whether a decrease of monocytic human leukocyte antigen-DR expression, indicating immunodepression, occurs after neurosurgery and if this measurement is useful for identification of patients with a high risk of infection. DESIGN: Prospective study. SETTING: Department of neurosurgery and intensive care unit in a university hospital. PATIENTS AND INTERVENTIONS: Blood samples were obtained from 46 patients at least once during the first 3 days after undergoing sterile central nervous system surgery. Fourteen of these patients developed infectious complications as defined by clinical and microbiological criteria. In ten of 46 patients, paired samples of blood and cerebrospinal fluid were collected from a ventricle drain at the following times: 1 day before surgery; several times on the day of surgery; and every day after surgery for at least 6 days. MEASUREMENTS AND MAIN RESULTS: Monocytic human leukocyte antigen-DR expression, as measured by flow cytometry on days 1 through 3 after surgery in 46 patients, was lower in 14 patients who developed infection after neurosurgery (p < .0001). In all ten closely monitored patients, monocytic human leukocyte antigen-DR expression decreased temporarily after surgery. Of these patients, only one patient showed a persistent and considerably decreased monocytic human leukocyte antigen-DR expression. This patient was the only patient in this subgroup who developed sepsis syndrome. In order to assess whether the monocytic human leukocyte antigen-DR decrease was associated with a preceding inflammatory response, local and systemic concentrations of interleukin (IL)-1 beta, IL-6, IL-8, tumor necrosis factor-alpha, and interferon-gamma were measured in this subgroup. These cytokines were not detectable in plasma during the first days after surgery. In contrast, considerable increases of IL-6 and IL-8 concentrations were detectable in cerebrospinal fluid within hours after surgery. CONCLUSIONS: A decrease of monocytic human leukocyte antigen-DR expression occurs after neurosurgery and is associated with a preceding, strong, intracranial (but not systemic) inflammatory response. A very low monocytic human leukocyte antigen-DR expression (< 30% positive monocytes) suggests the possibility of infection. Measurement of monocytic human leukocyte antigen-DR expression could help to detect patients with a high risk of infection after neurosurgery. Our results suggest that even sterile central nervous system surgery may contribute to general immunodepression. The local intracranial inflammatory response may be involved in this process.

Adult↗
PubMed1995

Very low monocytic HLA-DR expression indicates high risk of infection--immunomonitoring for patients after neurosurgery and patients during high dose steroid therapy.

In patients with disturbed immunoreactivity caused by trauma or immunosuppressive therapy infections are still a severe problem. To determine whether measurement of monocytic HLA-DR expression is useful for identifying patients with a high risk of infection after elective neurosurgery, blood was obtained from 57 patients during the first 3 days after surgery. HLA-DR expression was lower in 14 patients who developed infection, compared with patients with an uncomplicated postoperative course (p < 0.0001). Out of ten patients with less than 30% HLA-DR positive monocytes, nine developed infection. In 11 neurosurgical patients additional investigations were performed. Measurements in these patients show that HLA-DR expression decreased temporarily within hours after surgery, coinciding with a considerable increase of inflammatory cytokines in CSF, but, surprisingly, not in plasma. High plasma concentrations of ACTH and cortisol hours after surgery indicated a hypothalamus-pituitary axis response, probably involved in the downregulation of monocytic HLA-DR expression. Likewise, monitoring of dermatological patients (n = 10) who received high dose systemic steroids revealed a very low HLA-DR expression in those patients who later developed infection. Our studies show that very low HLA-DR expression indicates high risk of infection. We recommend the measurement of this parameter for immunomonitoring.

Adult↗
PubMedDate not supplied

[Addressing the problem of terminal care in medical education--results of a survey of 565 students and physicians].

Care for the dying is an important task for physicians. The ways in which this problem is dealt with during the medical training and the expectations of the people concerned were examined in 1989 and in 1994 by means of a questionnaire developed for this purpose. Altogether 565 junior doctors and medical students in Germany were asked. The number of people who declared that this topic was dealt with during their studies increased from 32.7% to 51%. The number of junior doctors and medical students who stated that they felt sufficiently prepared for care for the dying was low both in 1889 with 4.3% and in 1994 with 12.7%. Dealing with this problem seemed necessary to more than 97% of the people asked on both occasions. Results regarding the expectations and ideas of how and when this topic should be dealt with are also shown. Our results show that while there is a deficit in dealing with the topic "care for the dying" during medical training, there is a considerable interest in this subject among junior doctors and medical students.

Aged↗