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Biomedical subjects

R Knobler

Publications and source records attributed to R Knobler.

At least 19 recordsLinked to original sources
PubMed2007

Photodegradation of folic acid during extracorporeal photopheresis.

BACKGROUND: Photodegradation of folic acid (FA) by ultraviolet (UV) radiation is a well-documented photochemical reaction, and decreased serum levels of FA have been found in patients receiving photochemotherapy (psoralen plus UVA). During extracorporeal photopheresis (ECP) leucocytes and plasma are subjected to 8-methoxypsoralen (8-MOP) plus UVA. OBJECTIVES: To investigate whether ECP leads to the photodegradation of FA in the extracorporeal system. METHODS: In 30 patients undergoing ECP on two consecutive days the FA levels were measured in the extracorporeal collected plasma prior to and after UVA exposure. Healthy donor plasma was exposed to 8-MOP and increasing doses of UVA in vitro. In five patients serum folate levels were determined before and after ECP. RESULTS: We found a mean reduction of 44% and 46% on the first and second day of treatment, respectively. This effect could be reproduced in vitro: the irradiation of healthy donor plasma with UVA led to a dose-dependent reduction of FA of up to 54.75% at 16 J cm(-2). This was independent of the presence of 8-MOP and the base concentration of 5-methyltetrahydrofolate; minimal changes were observed for vitamin B(12) and homocysteine, not undergoing photodegradation. Serum folate levels did not change significantly before and after ECP. CONCLUSIONS: We conclude that extracorporeal exposure of plasma to UVA during ECP leads to photodegradation of FA. Further investigations are required to determine the biological effects of folate photoproducts and whether clinically relevant loss of FA might be a consequence of ECP.

Case-Control Studies↗
PubMed2006

Minimizing adverse side-effects of oral bexarotene in cutaneous T-cell lymphoma: an expert opinion.

Bexarotene is an oral retinoid therapy that is effective for the treatment of early and advanced-stage cutaneous T-cell lymphoma (CTCL) in patients who have failed on other therapies. However, bexarotene treatment is associated with unavoidable side-effects, in particular hypertriglyceridaemia and hypothyroidism, which are manageable with adequate concomitant medications and are reversible on cessation of treatment. A pragmatic strategy for minimizing bexarotene-associated hypertriglyceridaemia and hypothyroidism is suggested, based on data from the studies with bexarotene in CTCL and on day-to-day experience with this agent in the clinical setting. The strategy anticipates that these common adverse events are likely to occur and recommends the early use of preventive therapy to lower triglycerides and elevate thyroid hormone levels in the blood, followed by subsequent monitoring, dose adjustment during bexarotene treatment, and titration of the daily bexarotene dose from 150 to 300 mg m(-2), which is optimal for most patients. When further information becomes available on how bexarotene interacts with lipid metabolism and thyroid function, the management approach suggested here may need to be changed.

Anticarcinogenic Agents↗
PubMed2005

The course of anticoagulation after extracorporeal photochemotherapy.

During extracorporeal photochemotherapy (ECP) heparin is added to the extracorporeal circulation to avoid clotting. It has not been investigated whether and to what extend this procedure influences coagulation in patients after ECP. In this study activated partial thrombaplastin time (aPTT) and anti-factor Xa were monitored for up to 4 h after ECP in 10 patients. We found that anticoagulation followed the typical course of intravenously applied heparin: immediately after reinfusion anti-Xa was high (>1 IU/ml) and aPTT was prolonged to more than 180 s followed by a rapid decline and reaching normal values within 3-4 h in all patients. We conclude that anticoagulation and increased risk of bleeding after ECP is confined to a short period immediately following treatment. Physicians using ECP should be aware of the course of anticoagulation associated with this treatment.

Adult↗
PubMed2004

Increased transendothelial migration of scleroderma lymphocytes.

BACKGROUND: CD4+ T lymphocytes play an important part in the pathogenesis of scleroderma (systemic sclerosis, SSc) and predominate in perivascular SSc skin lesions. Both soluble and membrane bound adhesion molecules are overexpressed in SSc, possibly influencing lymphocyte/endothelial cell (EC) contact. OBJECTIVE: To assess the transendothelial migration capacity of peripheral lymphocytes in vitro. PATIENTS AND METHODS: Collagen was covered with human umbilical vein endothelial cells (HUVEC), and peripheral blood mononuclear cells (PBMC) of patients and matched healthy controls (HC) were added in parallel experiments. Before and after fractionated harvest of non-adherent, bound, and migrated lymphocytes, the CD4/CD8 ratio and the lymphocytic expression of activation markers and adhesion molecules were analysed by fluorocytometry. RESULTS: 13 (SD 12)% of the SSc PBMC migrated compared with only 5 (5)% HC PBMC (p<0.0002); this increase was primarily due to the migration of CD3+ T lymphocytes and mainly to a larger proportion of CD4+ cells within this CD3+ fraction (71 (SD 14)% for SSc v 56 (14)% for HC, p<0.03), leading to an increased CD4/CD8 ratio among migrated SSc lymphocytes in comparison with controls (3.3 (1.5) v 1.62 (0.93), p<0.006). Among migrated SSc CD4+ T lymphocytes, the frequency of HLA-DR+ cells was increased; migrated lymphocytes highly expressed the adhesion molecules CD11a, CD49d, CD29, and CD44. CONCLUSION: Transendothelial migration of CD4+ T lymphocytes is enhanced in SSc, and migrating cells exhibit an activated phenotype. The data suggest that activated CD3+CD4+ lymphocytes as found in SSc peripheral blood are prone to transvascular migration, thus contributing to the formation of typical perivascular lymphocytic infiltrates.

CD3 Complex↗
PubMed2003

Extracorporeal photochemoimmunotherapy in cutaneous T-cell lymphoma.

Extracorporeal photochemotherapy was originally conceived for the treatment of cutaneous T-cell lymphoma (CTCL) and as well as other T-cell mediated diseases. Evidence collected in the past 17 years has demonstrated that this treatment modality can have a very significant effect on the course of a subset of CTCL patients. The evidence available is positive but for a variety of reasons has been controversial within the medical community. A number of very well-designed multi-center trials which have been lacking since the first publication by Edelson et al. are being carried out so that hopefully a number of open questions will be resolved with greater clarity in the coming years. The fact remains that this innovative approach for the treatment of CTCL and T-cell mediated diseases has certainly opened new avenues of therapy and thought in photoimmunology and photomedicine. Clearly the very low side effect profile of this therapy has made it more attractive than the chemotherapeutic and immunosuppressive substances that are presently available or in experimental protocols. If and when the mechanisms of action are fully understood and appropriate studies investigating different treatment schedules and different combination therapies and modifications of its present form are performed the place of photopheresis in the therapeutics of CTCL as well as other T-cell mediated diseases and oncology will be better placed.

Combined Modality Therapy↗
PubMed2002

EORTC cutaneous lymphoma task force. European Organisation for Research and Treatment of Cancer.

The Cutaneous Lymphoma Task Force has represented the European Organisation for Research and Treatment of Cancer (EORTC) over the last two decades and has received worldwide acceptance and the highest respect. The group has been able to bring together the world's experts in this field to try to solve the basic problems associated with primary lymphomas of the skin and to create a productive scientific research basis. The definition and the classification of the disease per se has been a major controversial problem and the development of an EORTC classification for primary cutaneous lymphoma has been one of the main goals of the group. The purpose of this paper is to highlight and to provide a historical perspective regarding the contribution of the EORTC Cutaneous Lymphoma Group to the development of consensus guidelines for securing uniform diagnosis, classification and management of the heterogeneous group of primary cutaneous lymphomas. Some future perspectives and strategies of the group are also presented.

Achievement↗
PubMed2001

Increased differentiation of intracranial white matter lesions by multispectral 3D-tissue segmentation: preliminary results.

MRI is a very sensitive imaging modality, however with relatively low specificity. The aim of this work was to determine the potential of image post-processing using 3D-tissue segmentation technique for identification and quantitative characterization of intracranial lesions primarily in the white matter. Forty subjects participated in this study: 28 patients with brain multiple sclerosis (MS), 6 patients with subcortical ischemic vascular dementia (SIVD), and 6 patients with lacunar white matter infarcts (LI). In routine MR imaging these pathologies may be almost indistinguishable. The 3D-tissue segmentation technique used in this study was based on three input MR images (T(1), T(2)-weighted, and proton density). A modified k-Nearest-Neighbor (k-NN) algorithm optimized for maximum computation speed and high quality segmentation was utilized. In MS lesions, two very distinct subsets were classified using this procedure. Based on the results of segmentation one subset probably represent gliosis, and the other edema and demyelination. In SIVD, the segmented images demonstrated homogeneity, which differentiates SIVD from the heterogeneity observed in MS. This homogeneity was in agreement with the general histological findings. The LI changes pathophysiologically from subacute to chronic. The segmented images closely correlated with these changes, showing a central area of necrosis with cyst formation surrounded by an area that appears like reactive gliosis. In the chronic state, the cyst intensity was similar to that of CSF, while in the subacute stage, the peripheral rim was more prominent. Regional brain lesion load were also obtained on one MS patient to demonstrate the potential use of this technique for lesion load measurements. The majority of lesions were identified in the parietal and occipital lobes. The follow-up study showed qualitatively and quantitatively that the calculated MS load increase was associated with brain atrophy represented by an increase in CSF volume as well as decrease in "normal" brain tissue volumes. Importantly, these results were consistent with the patient's clinical evolution of the disease after a six-month period. In conclusion, these results show there is a potential application for a 3D tissue segmentation technique to characterize white matter lesions with similar intensities on T(2)-weighted MR images. The proposed methodology warrants further clinical investigation and evaluation in a large patient population.

Adult↗
PubMed2001

Extracorporeal photochemotherapy in patients with steroid-dependent Crohn's disease: a prospective pilot study.

BACKGROUND: Extracorporeal photochemotherapy has been proven effective in selected T-cell mediated diseases. AIM: To evaluate the safety and efficacy of extracorporeal photochemotherapy in patients with steroid-dependent Crohn's disease by an open, monocentric trial in three phases of 24 weeks each. METHODS: In phase 1 standardized steroid tapering was initiated in patients with a history of steroid-dependent Crohn's disease. Those with a prospectively evaluated maintenance dose of at least 10 mg/day prednisolone continued steroid-withdrawal under the application of extracorporeal photochemotherapy in phase 2. The duration of remission or response was followed during phase 3. Colonic tissue bioptically obtained before and after extracorporeal photochemotherapy was studied by immunofluorescence microscopy for the presence of photoadduct positive cells. RESULTS: Out of 24 patients included in phase 1, 10 entered phase 2 for extracorporeal photochemotherapy. Four subjects achieved remission and four others response. Significant reductions in serum C-reactive protein levels and intestinal permeability were measured, as well as increases in quality of life and plasma adrenocorticotropic hormone levels. No major side-effects were observed. Remission remained stable in three out of four patients during phase 3. In three patients, positive nuclear stainings of photoadducts were detected in colonic mononuclear cells after extracorporeal photochemotherapy. CONCLUSIONS: Extracorporeal photochemotherapy represents a safe steroid-sparing approach in patients with Crohn's disease and is associated with intestinal homing of photopheresed cells.

Adult↗
PubMed2001

Treatment of peripheral blood mononuclear cells with 8-methoxypsoralen plus ultraviolet A radiation induces a shift in cytokine expression from a Th1 to a Th2 response.

Treatment with 8-methoxypsoralen plus ultraviolet A radiation and extracorporeal photochemotherapy (photopheresis) are widely used for the treatment of psoriasis and other inflammatory skin diseases, graft-versus-host disease, and mycosis fungoides. As the ratio of Th1 and Th2 cells appears to be critical for pathogenesis and progression of these disorders the effect of psoralen plus ultraviolet A on Th1 and Th2 cytokine production by CD4+ lymphocytes was investigated. Human peripheral blood lymphocytes were incubated in the presence of anti-CD3, rh-IL2, and rh-IL4 for 48 h. After subsequent stimulation with rh-IL2 and rh-IL4 for 72 h cells were treated with 8-methoxypsoralen (100, 500, 1000 ng per ml) plus ultraviolet A (2 J per cm2) and incubated for a further period of 5 h in the presence of ionomycine, phorbol-12-myristate acetate and monensin. Fluorescence-activated cell sorter analysis revealed a significant reduction of interleukin-2- and interferon-gamma-producing CD4+ cells upon psoralen plus ultraviolet A treatment depending on the concentration of 8-methoxypsoralen. In contrast, interleukin-4-producing CD4+ cells were increased, indicating a shift from Th1 to a Th2 cell cytokine profile upon psoralen plus ultraviolet A treatment. These results indicate that 8-methoxypsoralen photochemotherapy of lymphocytes is able to modulate their Th1/Th2 distribution. Inhibition of Th1 cytokine expression by psoralen plus ultraviolet A might help to explain its beneficial effects in the treatment of Th1 dominated skin diseases.

Cells, Cultured↗
PubMed2001

Extracorporeal photochemoimmunotherapy in cutaneous T cell lymphomas.

Extracorporeal photochemotherapy (ECP), or photopheresis, is a widely used treatment for cutaneous T cell lymphoma (CTCL) and other T cell-mediated disorders, having been administered in more than 150 centers worldwide more than 200,000 times. Consistent with the theme of this conference--that is, highlighting the potentially most productive investigative avenues for unraveling the mysteries of CTCL in the next decade--ECP has been futuristic since its inception in the early 1980s. In 1988, the treatment was the first FDA-approved selective immunotherapy for any type of cancer. Yet, the mechanism by which it could suppress a clone of CTCL cells or inactivate multiple autoreactive T cell clones in graft-versus-host disease (GVHD) or allograft rejection remained obscure until quite recently. In fact, the scientific principles necessary to begin to comprehend the basis of ECP's efficacy were not available when the treatment was first introduced in 1982. In the intervening years, necessary detailed knowledge of the structure and function of the clonotypic T cell receptors, of class I major histocompatibility complex (MHC) presentation of tumor antigens, of CTCL tumor-specific antigens, of dendritic antigen presenting cell (DC) biology, and of 8-methoxypsoralen immunopharmacology has been attained. Although much remains to be learned, we now appreciate that ECP simultaneously and efficiently induces both apoptosis of disease-causing T cells and conversion of monocytes to functional DCs. By processing and presenting the unique antigenic determinants of pathogenic T cell clones, the DCs can either initiate a clinically relevant anti-CTCL cytotoxic response or suppress the activity of autoreactive T cell clones. This paper will review clinical trials of ECP in CTCL and evolving scientific understanding of ECP's mechanism in the context of exciting future directions.

Antigen Presentation↗
PubMed2000

Derangement of apoptosis-related lymphocyte homeostasis in systemic sclerosis.

OBJECTIVES: Both increased and decreased apoptosis may be involved in generating autoimmunity. This study addressed the question of whether apoptosis and apoptosis-regulating proteins are altered in systemic sclerosis (SSc). Patients and methods. Peripheral lymphocytes of 39 SSc patients and 47 healthy control persons were studied for apoptosis, Bcl-2 and Bax levels, expression of Fas (CD95) and activation markers (CD25, HLA-DR) as determined by fluorocytometry. Serum Fas and Fas ligand were measured by ELISA. RESULTS: SSc lymphocytes (mainly CD4(+)) expressed increased amounts of Bcl-2, while Bax was not elevated. Apoptosis rates of SSc lymphocytes were increased in unsupplemented medium, but returned to normal in the presence of autologous plasma. SSc patients had increased percentages of activated and CD95(+) lymphocytes and elevated soluble Fas and soluble FasL levels in serum. Activating anti-CD95 antibodies further increased the apoptosis rate. CONCLUSIONS: Increased in vitro apoptosis, elevated lymphocytic Bcl-2 content and the increased number of Fas-positive T cells are not specific for peripheral blood from SSc patients, but indicate deregulation of lymphocyte homeostasis in this disease.

Adult↗
PubMed2000

Extracorporeal photochemotherapy--present and future.

Extracorporeal photochemotherapy (ECP) was introduced by Edelson and co-workers in 1985. Since then the therapy, though still controversial in specific indications, has received wide acceptance and is presently been used in over 160 centers in Europe and the U.S.A. for a number of important dermatological and non-dermatological indications. Convincing data in the past few years has documented that ECP is associated with a very low side-effect profile. As of 2000 ECP continues to be used in the treatment of cutaneous T-cell lymphoma, alone or in combination with other treatment modalities, and increasingly in the management of additional T-cell mediated diseases, acute as well as chronic Graft versus Host Disease (GvHD) after allogeneic bone marrow transplantation in particular. ECP has also been shown to play an important role in the treatment of acute as well as chronic allograft rejection, in renal, lung, and cardiac transplant recipients and lately steroid refractory inflammatory bowel disease. A number of mechanisms for its efficacy have been proposed whereby at present induction of anticlonotypic immunity directed against pathogenic clones of T lymphocytes may be an important concept. Treatment related apoptotic death of involved T cells and concurrent activation of antigen presenting cells may also closely relate to mechanisms associated with this therapy.

Animals↗
PubMed1999

Fast tissue segmentation based on a 4D feature map in characterization of intracranial lesions.

The aim of this work was to develop a fast and accurate method for tissue segmentation in magnetic resonance imaging (MRI) based on a four-dimensional (4D) feature map and compare it with that derived from a 3D feature map. High-resolution MRI was performed in 5 normal individuals, in 12 patients with brain multiple sclerosis (MS), and 9 patients with malignant brain tumors. Three inputs (proton-density, T2-weighted fast spin-echo, and T1-weighted spin-echo MR images) were routinely utilized. As a fourth input, either magnetization transfer MRT was used or T1-weighted post-contrast MRI (in patients only). A modified k-nearest neighbor segmentation algorithm was optimized for maximum computation speed and high-quality segmentation. In that regard, we a) discarded the redundant seed points; b) discarded the points within 0.5 standard deviation from the cluster center that were non-overlapping with other tissue; and c) removed outlying seed points outside 5 times the standard deviation from the cluster center of each tissue class. After segmentation, a stack of color-coded segmented images was created. Our new technique utilizing all four MRI inputs provided better segmentation than that based on three inputs (P < 0.001 for MS and P < 0.001 for tumors). The tissues were smoother due to the reduction of statistical noise, and the delineation of the tissues became sharper. Details that were previously blurred or invisible now became apparent. In normal persons a detailed depiction of deep gray matter nuclei was obtained. In malignant tumors, up to five abnormal tissue types were identified: 1) solid tumor core, 2) cyst, 3) edema in white matter 4) edema in gray matter, and 5) necrosis. Delineation of MS plaque in different stages of demyelination became much sharper. In conclusion, the proposed methodology warrants further development and clinical evaluation.

Brain↗
PubMed1999

Diabetic neuropathic foot ulcer: successful treatment by low-intensity laser therapy.

OBJECTIVE: To evaluate the efficacy of low-intensity laser irradiation for the induction of wound healing of a diabetic neuropathic foot ulcer. CASE: We report a case of a man with insulin-dependent diabetes mellitus, sensory neuropathy, macroangiopathy and microangiopathy who had been suffering from an ulcer of his first left toe accompanied by osteomyelitis for 6 weeks. RESULTS: After a total of 16 sessions of low-intensity laser therapy using a 670-nm diode laser administered within a 4-week period the ulcer healed completely. During a follow-up period of 9 months, there was no recurrence of the ulcer even though the patient's metabolic condition remained unstable. CONCLUSIONS: Although laser therapy was not applied as a monotherapy, the present observation suggests that it might constitute a useful side-effect-free alternative treatment modality for the induction of wound healing of neuropathic ulcers in diabetic patients. Therefore large properly controlled randomized studies seem justified.

Aged↗
PubMed1998

Low-intensity laser irradiation improves skin circulation in patients with diabetic microangiopathy.

OBJECTIVE: Diabetic foot problems due to angiopathy and neuropathy account for 50% of all nontraumatic amputations and constitute a significant economic burden to society. Low-intensity laser irradiation has been shown to induce wound healing in conditions of reduced microcirculation. We investigated the influence of low-intensity laser irradiation by means of infrared thermography on skin blood circulation in diabetic patients with diabetic microangiopathy. RESEARCH DESIGN AND METHODS: Thirty consecutive patients with diabetic ulcers or gangrenes and elevated levels of glycosylated hemoglobin were randomized by blocks of two to receive either a single low-intensity laser irradiation with an energy density of 30 J/cm2 or a sham irradiation over both forefoot regions in a double-blind placebo-controlled clinical study. Skin blood circulation as indicated by temperature recordings over the forefoot region was detected by infrared thermography. RESULTS: After a single transcutaneous low-intensity laser irradiation, a statistically significant rise in skin temperature was noted (P < 0.001 by ANOVA for repeated measurements), whereas in the sham-irradiated control group, a slight but significant drop in temperature (P < 0.001) was found. Subsequently performed contrasts for comparison of measurements before and after irradiation revealed significant temperature increases at 20 min of irradiation time (P < 0.001), at the end of the irradiation (P < 0.001), and 15 min after stopping the irradiation (P < 0.001). In the sham-irradiated feet, the drop in local skin temperature was not significant at 20 min (P = 0.1), but reached significance at the end of the sham-irradiation procedure (P < 0.001) and 15 min after the end of sham irradiation (P < 0.001). CONCLUSIONS: The data from this first randomized double-blind placebo-controlled clinical trial demonstrate an increase in skin microcirculation due to athermic laser irradiation in patients with diabetic microangiopathy.

Analysis of Variance↗