Search PubMed⌕ Search

Biomedical subjects

J L Klein

Publications and source records attributed to J L Klein.

At least 37 records · Page 2Linked to original sources
PubMed1998

Mycobacterium kansasii and human immunodeficiency virus co-infection in London.

OBJECTIVES: although Mycobacterium kansasii infection has long been endemic in the U.K., the disease burden and characteristics of infection in the HIV-seropositive population has not been well documented. This study addresses these issues in an inner city population that comprises a quarter of all cases of acquired immunodeficiency syndrome (AIDS) reported in the U.K. METHODS: retrospective review of case notes from two inner London specialist HIV Units. RESULTS: twenty-nine cases of M. kansasii infection were identified, with case notes available for review in 26. Ten had pulmonary disease and nine had disseminated infection: a further seven patients appeared simply to be colonized (two respiratory and five gastrointestinal): M. kansasii was isolated from stool in over a third (nine of 26) of cases. Disseminated M. kansasii infection occurred in 0.44% of AIDS cases seen in our two units and all isolates were resistant to isoniazid ion vitro. A clinical response achieved in 11 of the 13 patients with M. kansasii-related disease who received anti-mycobacterial therapy. All four patients who relapsed following initial clinical response to therapy had received sub-optimal treatment. CONCLUSIONS: the incidence of disseminated M. kansasii infection in HIV-infected individuals in the U.K. is similar to that seen in those from high prevalence regions of the U.S.A., and anti-mycobacterial therapy leads to a clinical response in the majority of patients with HIV and M. kansasii co-infection. The frequent isolation of M. kansasii from the stool suggests that the gastrointestinal tract may be a significant source of disseminated infection.

Adult↗
PubMed1998

A quantitative evaluation of the three dimensional reconstruction of patients' coronary arteries.

BACKGROUND: Through extensive training and experience angiographers learn to mentally reconstruct the three dimensional (3D) relationships of the coronary arterial branches. Graphic computer technology can assist angiographers to more quickly visualize the coronary 3D structure from limited initial views and then help to determine additional helpful views by predicting subsequent angiograms before they are obtained. METHODS: A new computer method for facilitating 3D reconstruction and visualization of human coronary arteries was evaluated by reconstructing biplane left coronary angiograms from 30 patients. The accuracy of the reconstruction was assessed in two ways: 1) by comparing the vessel's centerlines of the actual angiograms with the centerlines of a 2D projection of the 3D model projected into the exact angle of the actual angiogram; and 2) by comparing two 3D models generated by different simultaneous pairs on angiograms. The inter- and intraobserver variability of reconstruction were evaluated by mathematically comparing the 3D model centerlines of repeated reconstructions. RESULTS: The average absolute corrected displacement of 14,662 vessel centerline points in 2D from 30 patients was 1.64 +/- 2.26 mm. The average corrected absolute displacement of 3D models generated from different biplane pairs was 7.08 +/- 3.21 mm. The intraobserver variability of absolute 3D corrected displacement was 5.22 +/- 3.39 mm. The interobserver variability was 6.6 +/- 3.1 mm. CONCLUSIONS: The centerline analyses show that the reconstruction algorithm is mathematically accurate and reproducible. The figures presented in this report put these measurement errors into clinical perspective showing that they yield an accurate representation of the clinically relevant information seen on the actual angiograms. These data show that this technique can be clinically useful by accurately displaying in three dimensions the complex relationships of the branches of the coronary arterial tree.

Adult↗
PubMed1998

The role of protein glycosylation inhibitors in the prevention of metastasis and therapy of cancer.

Oligosaccharide moieties of cell-surface glycoproteins are thought to be involved in recognition events during cancer metastasis and invasion. Swainsonine, an inhibitor of the Golgi alpha-mannosidase II, has been shown to block pulmonary colonization by tumor cells and stimulate components of the immune system. Swainsonine also abrogates much of the toxicity of chemotherapeutic agents and stimulates bone marrow hematopoietic progenitor cells, suggesting additional therapeutic applications. We are currently characterizing the ability of swainsonine to modify cell growth in human and murine bone marrow progenitor cells. Furthermore, we are examining crucial steps in metastasis that depend upon cell surface molecules that play a role in cell-matrix interactions. Our work shows that tumor cell adhesion to collagen IV in vitro is rapidly stimulated by cis-polyunsaturated fatty acids and is dependent on protein kinase C activity. We are investigating the hypothesis that integrins are critical components of this adhesion and are examining potential signal transduction pathways that lead to the modulation of cell adhesion.

Animals↗
PubMed1998

Relationship of tacrolimus (FK506) whole blood concentrations and efficacy and safety after HLA-identical sibling bone marrow transplantation.

A randomized clinical trial comparing tacrolimus with cyclosporine, both with short-course methotrexate, as prophylaxis against graft-vs.-host disease (GVHD) in allogeneic HLA-matched sibling bone marrow transplant patients was conducted. Cyclosporine was dosed to achieve a target concentration range between 150 and 450 ng/mL during the first 8 weeks after transplant. For tacrolimus, the target concentration range was 10-30 ng/mL during the first 8 weeks after transplant. A gradual tapering schedule of 20% per month during months 3-6 was then conducted for patients in both treatment arms. The efficacy of the immunosuppressive regimen was determined by the rate of acute GVHD grades II-IV The toxicity of the immunosuppressive regimen was determined by the occurrence of the creatinine exceeding 2 mg/dL, the creatinine doubling the baseline value, or the necessity for hemodialysis. Correlations between blood concentrations and efficacy and toxicity parameters were assessed. For both tacrolimus and cyclosporine, increasing blood concentrations were associated with greater renal dysfunction. For cyclosporine, there was a nonsignificant trend to an increased incidence of grades II-IV acute GVHD with lower cyclosporine blood concentrations (<300 ng/mL). In contrast, there did not appear to be a relationship between the blood concentrations of tacrolimus and the occurrence of acute GVHD. This suggests that optimization of efficacy while minimizing the risk for nephrotoxicity could be achieved by dosing tacrolimus to a targeted range between 10 and 20 ng/mL.

Adolescent↗
PubMed1998

Radioimmunoscintigraphy of recurrent, metastatic, or occult colorectal cancer with technetium 99m-labeled totally human monoclonal antibody 88BV59: results of pivotal, phase III multicenter studies.

PURPOSE: To assess the performance and potential clinical impact of a totally human monoclonal antibody, 88BV59 (HumaSPECT) (INTRACEL, Corp, Rockville, MD), in 202 assessable presurgical patients with recurrent, metastatic, or occult colorectal cancer. METHODS: 88BV59, labeled with technetium Tc 99m (99mTc) (HumaSPECT-Tc), was injected intravenously, and planar and single photon emission tomography (SPECT) images were obtained 14 to 20 hours postinjection. Surgical and pathologic verification of tumor were used as the standard against which the performance of HumaSPECT-Tc imaging and computed tomography (CT) analysis were evaluated. RESULTS: All patients entered onto the recurrent disease study had at least one tumor site defined on CT. The sensitivity of HumaSPECT-Tc in those CT-positive patients was 87%. The specificity of HumaSPECT-Tc was 57% compared with 17% for CT and the difference was statistically significant (P < .001). The diagnostic information provided by HumaSPECT-Tc significantly (P < .001) improved the accuracy of the identification of resectable and nonresectable disease over that of CT (80% v 62%). HumaSPECT-Tc scans resulted in a significant (P < .001) reduction versus CT in terms of the proportion of patients understaged (27% v 41%) and overstaged (4% v 26%). In patients with occult disease (increasing carcinoembryonic antigen [CEA] titer, negative diagnostic work-up, negative CT), HumaSPECT-Tc correctly identified disease in 15 of 22 (68%) patients. HumaSPECT-Tc images provided additional clinical data that would have affected patient management decisions in 40 of 202 (19.8%) patients. In 365 patients who received 88BV59, only a single detectable human anti-human antibody (HAHA) response (90 ng/mL) at 9 weeks postinfusion was observed. CONCLUSION: HumaSPECT-Tc can provide important and accurate information about the presence and location of disease in patients with a high clinical suspicion of metastatic or recurrent colorectal cancer and either positive (known disease) or negative (occult disease) CT scans.

Adult↗
PubMed1997

Lack of interaction between tacrolimus (FK506) and methotrexate in bone marrow transplant recipients.

Tacrolimus (FK506) is a macrolide lactone effective in the control of graft-versus-host disease (GVHD). An interaction between high-dose methotrexate and a macrolide antibiotic (pristinamycin) leading to prolonged methotrexate exposure has been described. Because a randomized prospective trial comparing tacrolimus with cyclosporine (both in combination with methotrexate) following allogeneic BMT showed the tacrolimus plus methotrexate regimen to be more effective in prevention of GVHD, we assessed methotrexate pharmacokinetics in a subgroup of the participants of this trial to evaluate the possibility that an interaction of FK506 and methotrexate was the explanation for the clinical findings. Mean and median methotrexate levels at various time-points after the day 1 and 6 methotrexate doses were comparable in the tacrolimus and cyclosporine cohorts and were elevated in only three of 70 study patients. Area under the curve (AUC) concentrations were also similar after the day 1 and 6 methotrexate doses. Thus, no significant interaction between tacrolimus and methotrexate is apparent and the differences in efficacy between tacrolimus and cyclosporine are unlikely to be attributable to pharmacologic interactions with methotrexate.

Adolescent↗
PubMed1997

Mobilization of peripheral-blood progenitor cells with high-dose etoposide and granulocyte colony-stimulating factor in patients with breast cancer, non-Hodgkin's lymphoma, and Hodgkin's disease.

PURPOSE: We analyzed the safety and effectiveness of high-dose etoposide (2 g/m2) followed by granulocyte colony-stimulating factor (G-CSF) as a peripheral-blood progenitor cell (PBPC) mobilization regimen and assessed extent of tumor reduction in patients with breast cancer, non-Hodgkin's lymphoma (NHL), and Hodgkin's disease (HD). PATIENTS AND METHODS: One hundred sixty-nine consecutive patients who eventually underwent PBPC transplantation received treatment with high-dose etoposide (2 g/m2) followed by daily G-CSF (5 microg/kg). RESULTS: This mobilization method was effective in nearly all patients. No patients died of mobilization-related complications. A 50% reduction in tumor size was seen in 19% of assessable patients with breast cancer, 44% of those with NHL, and 38% of those with HD. Hematopoietic recovery (HR) following transplantation occurred in all patients. Patients with > or = 4 x 10(6) CD34+ cells/kg engrafted with neutrophils at a median of 9 days after transplant and patients with at least 1.2 x 10(6) CD34+/CD33- cells/kg achieved platelet recovery at a median of 15 days. CONCLUSION: Etoposide plus G-CSF is an effective and safe method for mobilization of PBPCs. Etoposide is an effective agent in tumor reduction in NHL and HD and is less effective in breast cancer. The substantially lower incidence of prior exposure to this agent compared with cyclophosphamide favors its use.

Adolescent↗
PubMed1996

Performance standards and edge detection with computerized quantitative coronary arteriography. The Lovastatin Restenosis Trial Group.

Quantitative coronary angiography (QCA) has become an important tool for evaluating coronary angiograms. Many methodologic factors, such as the choice of frame to analyze, the selection of the "normal," segment and the method of edge detection used may affect the results of QCA. The sequential steps in performing QCA, including a comparison of visual and automated edge-detection methodologies, were evaluated using 12 precision-drilled phantoms and 20 patient films. Normal diameter, minimal lumen diameter, and diameter stenosis were measured. In the phantom studies, the measurements from both visual and automated systems correlated well with the true measurements of the phantoms and between systems (all r values >0.92). To study the difference between methodologies on QCA results as influenced by the choice of frame and normal segment analyzed, the patient films were analyzed independently in 3 separate rounds of interpretation. In round 1, each system's operator individually chose frames and normal segments for analysis. In round 2, both systems analyzed the same preselected frames, but independently chose normal segments. In round 3, both systems analyzed the same preselected normal segments and frames. The intersystem correlations between visual and automatic systems for rounds 1, 2, and 3 were: normal diameter, r = 0.25, r = 0.37, and r = 0.75, respectively; minimal lumen diameter, r = 0.79, r = 0.86, and r = 0.85, respectively; and diameter stenosis, r = 0.65, r = 0.73, and r = 0.87, respectively. The manual edge-detection and automated edge-detection systems used in this study are reasonably accurate and consistent on phantom studies. In patient studies, the nonautomated processes (choice of frame and normal segment for analysis) produced significant differences in the QCA results, thus illustrating that operator-dependent factors other than edge detection are very important in QCA.

Constriction, Pathologic↗
PubMed1996

Herpesvirus saimiri immortalized gamma delta T cell line activated by IL-12.

IL-12 is a novel heterodimeric cytokine important for the regulation and differentiation of lymphocytes and NK cells. Like other cytokines, IL-12 mediates its biologic activity through high-affinity receptors expressed on responsive cells. To date, a large number of receptors for IL-12 have been found only on PBMC following activation with PHA or IL-2. To gain further knowledge of the IL-12R complex and the IL-12 signal transduction pathway in cytotoxic T cells, we studied a number of human T cell lines that had been transformed to permanent growth with Herpesvirus saimiri, an oncogenic virus of nonhuman primates. This paper reports the expression of IL-12R on a human gamma delta T cell line that responds to IL-12 with enhanced cytolytic activity and increased expression of cytolytic effector molecules granzyme B and perforin. Using these T cells as a model of IL-12 signal transduction, we confirmed that these events involve members of the Janus kinase family of nonreceptor tyrosine kinases JAK2, TYK2, and signal transducer and activator of transcription 4.

Cell Line, Transformed↗
PubMed1996

IL-12 expression in AIDS-related lymphoma B cell lines.

IL-12 is a 70-kDa heterodimer formed by the 40-kDa heavy chain (p40) and the 35-kDa light chain (p35). Twenty-five Burkitt's lymphoma cell lines (CL) and seven normal lymphoblastoid B CL were studied. The Burkitt's CL included AIDS-associated B CL (AABCL) (7 EBV+/2 EBV-) and non-AABCL (8 EBV+/8 EBV-). Reverse transcription-PCR detected p40 in EBV+ AABCL (7 of 7), EBV+ non-AABCL (3 of 8), and normal lymphoblastoid B CL (6 of 6) but not in EBV- CL (0 of 10). p35 mRNA was detected in 30 of 30 CL. Constitutive secretion of p40 was found in 7 of 7 EBV+ AABCL (range, 341-18,086 pg/ml) and p70 in 3 of 7 EBV+ AABCL (range, 25-197 pg/ml), but in only 1 of 8 EBV+ non-AABCL and 0 of 7 normal lymphoblastoid CL. PMA stimulated p40 secretion in 7 of 7 EBV+ AABCL and p70 secretion in 5 of 7 EBV+ AABCL. PMA also triggered p40 and p70 secretion in 2 EBV+ non-AABCL and in 3 of 7 normal lymphoblastoid CL. No IL-12 secretion was detected in 10 EBV- CL, including EBV- AABCL. The CL produced IL-10, a known inhibitor of IL-12, but anti-IL-10 Abs did not neutralize IL-12. Similarly, neutralizing anti-IFN gamma Abs or IFN gamma did not affect B cell IL-12. For IL-12R studies, reverse transcription-PCR and 125I-IL-12 binding assays were performed. Although all CL tested showed mRNA accumulation for one of the IL-12R components, IL-12 binding sites were detected in only 1 of 30 CL. Our data suggest that: 1) AABCL constitutively secrete large amounts of IL-12, contrasting with low IL-12 production by HIV-1 infected PBMC; 2) lack of IL-12 expression in EBV- AABCL suggests that in vivo exposure of B cells to HIV-1 only does not induce IL-12 secretion and that both HIV-1 and EBV are required; 3) the autocrine-negative effect of IL-10 on IL-12 in monocytes and the enhancing effect of IFN gamma on IL-12 secretion do not apply to B cells derived from AIDS patients.

Acquired Immunodeficiency Syndrome↗
PubMed1996

Bone marrow engraftment following unrelated donor transplantation utilizing busulfan and cyclophosphamide preparatory chemotherapy.

Two major problems of unrelated donor transplantation have been an increased incidence of GVHD and graft failure. Even with HLA identity by microlymphocytotoxicity assay and non-reactive MLC, URD marrow transplant recipients have a higher incidence of graft rejection and GVHD. The preparative regimen busulfan 16 mg/kg and cyclophosphamide 120 mg/kg (BuCy2) has been shown to be at least as effective in preparation of recipients with CML of HLA-identical sibling grafts as cyclophosphamide and total body irradiation (Cy/TBI). However, concern about a high rejection rate in URD transplants has prevented most centers from using BuCy2 in this setting. From March 1990 to March 1994, 26 patients underwent URD transplantation following preparation with BuCy2. Patients received either standard cyclosporine and methotrexate or cyclosporine and methylprednisolone for GVHD prophylaxis. Two patients died on day 16 and 20 without evidence of hematopoietic engraftment. Of the 24 patients evaluable for engraftment, 23 (96%) had evidence of donor engraftment defined as an ANC > 0.5 x 10(9)/1. No patient who had initial engraftment had late graft failure. Within our study group the risk of graft rejection or graft failure does not appear to be higher than that reported for URD transplants utilizing TBI-containing regimens.

Acute Disease↗
PubMed1995

Radioimmunoscintigraphy of colorectal carcinoma using technetium-99m-labeled, totally human monoclonal antibody 88BV59H21-2.

Radioimmunoscintigraphy (RIS) using human monoclonal antibodies offers the important clinical advantage of repeated imaging over murine monoclonal antibodies by eliminating the cross-species antibody response. This article reports a Phase I-II clinical trial with Tc-99m-labeled, totally human monoclonal antibody 88BV59H21-2 in patients with colorectal carcinoma. The study population consisted of 34 patients with colorectal cancer (20 men and 14 women; age range, 44-81 years). Patients were administered 5-10 mg antibody labeled with 21-41 mCi Tc-99m by the i.v. route and imaged at 3-10 and 16-24 h after infusion using planar and single-photon emission computed tomographic (CT) techniques. Pathological confirmation was obtained in 25 patients who underwent surgery. Human antihuman antibody (HAHA) titers were checked prior to and 1 and 3 months after the infusion. RIS with Tc-99m-labeled 88BV59H21-2 revealed a better detection rate in the abdomen-pelvis region compared with axial CT. The combined use of both modalities increased the sensitivity in both the liver and abdomen-pelvis regions. Ten patients developed mild adverse reactions (chills and fever). No HAHA response was detected in this series. Tc-99m-labeled human monoclonal antibody 88BV59H21-2 RIS shows promise as a useful diagnostic modality in patients with colorectal cancer. RIS alone or in combination with CT is more sensitive than CT in detecting tumor within the abdomen and pelvis. Repeated RIS studies may be possible, due to the lack of a HAHA response.

Adult↗
PubMed1995

Transesophageal dobutamine stress echocardiography in the evaluation of coronary artery disease.

OBJECTIVES: The goal of this study was to determine the feasibility, safety, sensitivity and specificity of transesophageal dobutamine stress echocardiography for the detection of coronary artery disease. BACKGROUND: Dobutamine stress echocardiography has been shown to be an extremely sensitive and specific noninvasive technique for the detection of myocardial ischemia. However, inadequate transthoracic images preclude the use of dobutamine stress echocardiography in a small but significant group of patients. Transesophageal echocardiography provides better resolution than that obtained with routine transthoracic imaging. METHODS: Patients scheduled for routine cardiac catheterization underwent transesophageal dobutamine stress echocardiography. All patients underwent coronary arteriography within 48 h of the study, and lesion severity was determined by quantitative coronary angiography. Significant coronary obstruction was defined as stenosis > 50%. RESULTS: Fifty-one male patients were enrolled in the study; six were excluded for technical reasons. There were no adverse outcomes or complications. Of 27 patients with significant coronary artery disease, 22 had positive study results (sensitivity 82%). Of 13 patients without significant obstructive coronary disease, 1 had a false positive study result (specificity 93%). In patients with a minimal lumen diameter < 1.25 mm, sensitivity was > 80%, and in patients with a minimal lumen diameter > 1.5 mm, sensitivity was < 70%, suggesting that lesions with a minimal lumen diameter < 1.25 mm are more likely to be physiologically significant. CONCLUSIONS: Transesophageal dobutamine stress echocardiography is a feasible, safe and accurate technique for the detection of myocardial ischemia. There are inherent limitations to this technique in that transesophageal echocardiography must be performed. Transesophageal dobutamine stress echocardiography may allow extension of dobutamine stress testing to patients with inadequate transthoracic echocardiographic imaging and may provide an opportunity for further research applications.

Coronary Angiography↗
PubMed1995

Beneficial effects of cholesterol-lowering therapy on the coronary endothelium in patients with coronary artery disease.

BACKGROUND: Impaired endothelium-mediated relaxation contributes to vasospasm and myocardial ischemia in patients with coronary artery disease. We hypothesized that cholesterol-lowering therapy with the 3-hydroxy-3-methylglutaryl-coenzyme A reductase inhibitor lovastatin could improve endothelium-mediated responses in patients with coronary atherosclerosis. METHODS: In a randomized, double-blind, placebo-controlled trial, we studied coronary endothelial responses in 23 patients randomly assigned to either lovastatin (40 mg twice daily; 11 patients) or placebo (12 patients) plus a lipid-lowering diet (American Heart Association Step 1 diet). Patients were studied 12 days after randomization and again at 5 1/2 months. These patients had total cholesterol levels ranging from 160 to 300 mg per deciliter (4.1 to 7.8 mmol per liter) and were undergoing coronary angioplasty. At the initial and follow-up studies, patients received serial intracoronary infusions (in a coronary artery not undergoing angioplasty) of acetylcholine to assess endothelium-mediated vasodilatation. The responses of the coronary vessels were analyzed with quantitative angiography. RESULTS: The patients in the placebo and lovastatin groups had similar responses to acetylcholine at a mean of 12 days of therapy (expressed as the percentage of change in diameter in response to acetylcholine doses of 10(-9) M, 10(-8) M, 10(-7) M, and 10(-6) M). In the placebo group, the respective mean (+/- SE) changes were 1 +/- 2, 0 +/- 2, -2 +/- 4, and -19 +/- 4 percent; in the lovastatin group, they were -2 +/- 2, -4 +/- 4, -12 +/- 5, and -16 +/- 7 percent (P = 0.32). (Coronary-artery constriction is reflected by negative numbers). The responses to acetylcholine in the placebo group after a mean of 5.5 months of therapy were -3 +/- 3, -1 +/- 2, -8 +/- 4, and -18 +/- 5 percent, respectively; there was significant improvement in the lovastatin group, which had responses of 3 +/- 3, 3 +/- 3, 0 +/- 2, and 0 +/- 3 percent (P = 0.004). CONCLUSIONS: Cholesterol lowering with lovastatin significantly improved endothelium-mediated responses in the coronary arteries of patients with atherosclerosis. Such improvement in the local regulation of coronary arterial tone could potentially relieve ischemic symptoms and signal the stabilization of the atherosclerotic plaque.

Acetylcholine↗