Cutaneous T-lymphocyte infiltrate associated with B-cell chronic lymphocytic leukaemia.
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Antigens, CD↗
Biomedical subjects
D McCormick
Publications and source records attributed to D McCormick.
Age-related trends in short- and long-term survival after acute myocardial infarction: a 20-year population-based perspective (1975-1995).
This study examines age-related differences and temporal trends in hospital and long-term survival after acute myocardial infarction (AMI) over a 2-decade-long (1975 to 1995) experience. A total of 8,070 patients with validated AMI hospitalized in all acute care hospitals in the Worcester, Massachusetts, metropolitan area (1990 census population 437,000) were studied over 10 one-year periods between 1975 and 1995. This population included 1,326 patients aged <55 years (16.4%), 1,768 patients aged 55 to 64 years (21.9%), 2,325 patients aged 65 to 74 years (28.8%), 1,880 patients aged 75 to 84 years (23.3%), and 771 patients aged > or = 85 years (9.6%). Compared with patients <55 years, patients 55 to 64 years were 2.2 times more likely to die during hospitalization for AMI, whereas patients 65 to 74, 75 to 84, and > or = 85 years were at 4.2, 7.8, and 10.2 times greater risk of dying, respectively. Similar age disparities in the risk of dying were seen when controlling for additional prognostic factors. Despite the adverse impact of increasing age on hospital survival after AMI, declining in-hospital death rates were seen in each of the age groups under study, with declining magnitude of these trends with advancing age. Among discharged hospital patients, increasing age was related to a significantly poorer long-term prognosis. Trends toward improving long-term prognosis were seen in patients discharged in the mid-1990s compared with those discharged in the mid- to late 1970s for patients aged <85 years. The present results demonstrate the marked impact of advancing age on survival after AMI. Despite the adverse impact of age on prognosis, encouraging trends in prognosis were observed in all age groups, although to a lesser extent in the oldest elderly patients. These findings emphasize the low death rates in middle-aged patients with AMI and the need for targeted secondary prevention efforts in elderly patients with AMI.
Age Distribution↗
Evaluation of devices for skin prick testing.
BACKGROUND: Previous comparisons of devices for percutaneous skin testing have revealed statistically and clinically significant differences, from one device to another, in the size of reactions to histamine and allergen extracts and at negative control sites. OBJECTIVE: The objective of this study was to compare the performance of several skin test devices which are either new, modified, or used with a modified technique. METHODS: Twenty subjects were tested five to eight times with each of the devices both to glycerol-saline and to 10 mg/ml histamine base. The devices tested were the MultiTest II, Duo Tip-Test (prick and scarification), Quintest, DermaPik (prick and scarification), and small pox needle. RESULTS: There were highly significant differences among the devices for the size of the reaction to histamine (mean wheal diameter 4.28 to 8.59 mm, p < 0.0001), the standard errors of the wheals to histamine (0.82 to 1.45 mm, p < 0.05) and in the mean wheal size with glycerol-saline (0.00 to 2.48 mm, p < 0.0001). CONCLUSIONS: Devices for performing skin prick testing vary greatly in several characteristics, including the size of reactions at both positive and negative test sites. Each skin test technician should be tested with the device used in that skin testing laboratory to establish criteria for positive and negative tests.
Adult↗
Benefits of high-dose i.v. immunoglobulin in patients with severe steroid-dependent asthma.
STUDY OBJECTIVE: To determine the efficacy of IV immunoglobulin (IVIg) in severe asthma to reduce steroid requirements. DESIGN: Pre- and posttreatment measurements were analyzed using Dunnett's multiple comparison procedure. SETTING: Hospital clinical research center. PATIENTS: Eleven adolescents and adults with severe, steroid-dependent asthma enrolled over a 14-month period. INTERVENTIONS: IVIg was administered at a dose of 2 g/kg every 4 weeks for a total of seven infusions. MEASUREMENTS AND RESULTS: Steroid requirements, pulmonary function including lung volumes, symptom scores, bone densitometry, and airway reactivity monitored by methacholine challenge were followed over the course of 7 months. A significant decrease in steroid usage was achieved. Despite substantial steroid reduction, the patients demonstrated improvement in their pulmonary function and symptom scores. The responses to methacholine challenge were unaffected by IVIg treatment. CONCLUSIONS: IVIg provides a potentially important adjunctive therapy in severe asthma, reducing oral steroid requirements and steroid side effects without deterioration of lung function.
Administration, Oral↗
Glioma invasion in vitro is mediated by CD44-hyaluronan interactions.
Invasion is a clinically important problem contributing to mortality and morbidity in patients with gliomas, but the mechanism(s) by which glioma cells invade surrounding brain structures is poorly understood. Various experimental models have been used in attempts to elucidate the process of glioma invasion. An in vitro model which is increasingly being employed involves measurement of the rate of invasion of tumour cells through Matrigel-a complex mixture of extracellular matrix components derived from the Engelbroth-Holm-Swarm (EHS) sarcoma. This model has been used to examine the possibility that extracellular hyaluronan (HA) might facilitate the invasive behaviour of human glioma cells. The major component of Matrigel is laminin, with smaller amounts of collagen IV, heparan sulphate proteoglycans, entactin, and nidogen but it lacks HA. In our experiments, we have incorporated HA into Matrigel and have measured its effect on the rate of invasion of human glioma cells in a modified Boyden chamber assay system. The incorporation of HA (50-800 mg/cm2) resulted in a dose-dependent increase in invasion. Invasion was enhanced by up to 70 per cent in comparison with HA-free Matrigel. Since CD44 is a major HA receptor expressed on gliomas, it might have a role in the HA-mediated facilitation of invasion. This was tested by blocking CD44 with specific antibody, which resulted in a 43 per cent reduction in invasion rate. We conclude that in an in vitro model system, HA enhances invasion of glioma cells and that the mechanism involves a CD44-HA interaction.
Biocompatible Materials↗
Characterization of the antigenic structure of human type II collagen.
A series of 101 peptides each 20 amino acids in length (10-residue overlap) spanning the helical portion of the mature alpha-chain of human type II collagen (CII) was synthesized. DBA/1 (H-2q) mice were immunized with individual peptides, and draining lymph node cells were challenged in vitro. Strong responses were measured to three peptides: peptide I (residues 74-93), peptide 14 (residues 254-273), and peptide 81 (residues 924-943). B10.Q (H-2q) mice were responsive to peptides I and 81 but not to peptide 14. B10.RIII (H-2r) mice, which are resistant to arthritis induction following immunization with human CII, were unresponsive to peptides I, 14, and 81. Using single amino acid truncated peptides, we determined minimal immunostimulatory lengths for peptides I and 81. Residues critical to antigenicity were identified by introducing alanine and glycine substitutions into minimal length immunostimulatory peptides. The determinants within peptides I and 81 are 100% homologous to mouse CII and are autoantigens. Peptide 81 has homology to viral proteins. Peptide 14 is 90% homologous to mouse CII and has homology to heat shock proteins.
Adjuvants, Immunologic↗
T cell tolerance and activation to a transgene-encoded tumor antigen.
Much has been learned in recent years concerning the nature of tumor antigens recognized by T cells. To apply this knowledge clinically, the nature of the host response to individual and multiple tumor antigens has to be characterized. This will help to define the efficacy of immune surveillance and the immune status of the host following exposure to tumor antigens expressed on pre-neoplastic tissue. To approach these questions, we have developed a transgenic mouse which expresses the tumor-specific antigen P91A. The single amino acid substitution in P91A results in the expression of a new MHC class I (H-2Ld)-binding peptide. In transgenic tissue, the H-2Ld/P91A complex is expressed in isolation from other tumor-associated antigens, allowing definition of the immune response to a single defined tumor antigen, a situation closely analogous to events during tumorigenesis. We show that CD8+ T cell immune surveillance of P91A is ineffective without the introduction of a helper determinant operating through stimulation of CD4+ T cells. Recognition of the isolated P91A tumor antigen on normal tissue by CD8+ T cells is a tolerogenic process. Induction of T cell tolerance suggests tumor antigen-T cell interactions occurring during tumorigenesis may elicit T cell tolerance and hence confound some immunotherapeutic approaches.
Animals↗
Major histocompatibility complex and T cell receptor interaction of the P91A tum- peptide.
The P91A antigen was identified following mutation of P1 mastocytoma cells. The peptide epitope is encoded by a mutant form of the S3 subunit of the PA700 proteasome regulatory complex. P91A stimulates a strong CD8+ T cell response when expressed on tumor cells or normal tissue and P91A-specific T cells express a restricted range of T cell receptors. Although it is a strong Ld-binding peptide, P91A does not conform to the established motif for this major histocompatibility complex (MHC) molecule and this has hampered elucidation of the precise epitope. Ld predominantly associates with nonamer peptides; however, using a variety of complementary approaches, the P91A epitope is identified as the octamer QNHRALDL. In the absence of the Ld motif residue proline at position 2, residues 5-7 are primarily involved in MHC interaction. P91A is thus atypical in its interaction with Ld. Residues 1, 3, and 4 are found to influence T cell recognition of P91A. Definition of the P91A peptide will allow studies on P91A processing and interactions of the P91A peptide/MHC complex with T cell receptors of differing avidity to establish the basis for restricted T cell receptor usage. The basis for the failure of the P91A tum+ peptide (QNRRALDL) to bind to Ld is addressed by molecular modeling.
Amino Acids↗
Multiple translation initiation factor Sui1 related sequences in mammalian genomes.
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Amino Acid Sequence↗
Epitopes for human CD4+ cells on diphtheria toxin: structural features of sequence segments forming epitopes recognized by most subjects.
The sequence regions of diphtheria toxin (DTX) recognized by CD4+ T cells of seven healthy humans of different major histocompatibility complex haplotypes were identified. Overlapping synthetic peptides, screening the DTX sequence, were used to test in proliferation assays unselected blood CD4+ cells, or DTX-specific CD4+ lines propagated by stimulation with DTX of blood mononuclear cells. Blood CD4+ cells and DTX-specific CD4+ lines gave consistent results. Although each subject had an individual pattern of peptide recognition, six peptide sequences (residues 271-290, 321-340, 331-350, 351-370, 411-430 and 431-450) were recognized by all subjects. In the native DTX molecule, these sequence regions are flanked by sequence loops exposed on the DTX surface. They overlap uncharged segments of the DTX sequence. These structural properties may be general requirements for immunodominance in CD4+ cell sensitization in humans.
Adult↗
Urinary N1-acetylspermidine and N8-acetylspermidine excretion in normal humans and in patients with colorectal cancer.
Urinary N1-acetylspermidine (N1SPD) and N8-acetylspermidine (N8SPD) were measured in 24-hr urine specimens from 42 patients with colon adenocarcinoma and 29 healthy controls to assess their use as markers for colon cancer screening. Serial spot urines in four controls demonstrated significant fluctuations in these polyamine levels throughout the day without a distinct circadian pattern and therefore all subsequent analyses were performed on 24-hr collections. Both N1SPD and N8SPD were significantly increased in colon cancer patients compared to controls. Neither test correlated with tumor stage or location, but N8SPD was elevated in patients with poorly differentiated adenocarcinoma when compared to moderate or well-differentiated tumors. Using receiver operator characteristic (ROC) analysis, N1SPD had a higher information content than N8SPD, N1SPD + N8SPD, or the ratio of N1SPD/N8SPD and at a normal cut-off value of 4.0 nmol/mg creatinine, yielded a 95% specificity and 50% sensitivity for colon cancer.
Adenocarcinoma↗
Value of granulocyte colony stimulating factor in radiotherapy induced neutropenia: clinical and laboratory studies.
We report the effect of granulocyte colony stimulating factor (G-CSF) on neutropenia occurring during extended field radiotherapy in two groups of patients. The first group comprised 8 patients receiving craniospinal irradiation for a variety of central nervous system (CNS) neoplasms. None of these patients received cytotoxic chemotherapy. G-CSF was administered when the absolute neutrophil count (ANC) approached 1.5 x 10(9)/l. Neutropenia was promptly corrected in all cases, thereby avoiding unscheduled interruptions in radiotherapy. Following each G-CSF administration, ANC reached a peak on the following day and then declined steadily. Mean ANC rose from 1.33 x 10(9)/l on the day of G-CSF treatment to 7.07 x 10(9)/l the next day. Patients received 2-6 G-CSF injections during radiotherapy. Experiments were carried out in vitro to assess the risk of G-CSF causing increased CNS tumour cell proliferation. 11 human CNS tumour cultures (2 medulloblastomas, 2 primitive neuroectodermal tumours and 7 astrocytic tumours) were cultured in the presence of G-CSF at a range of concentrations up to 100 ng/ml. Their proliferation was compared with that of a G-CSF dependent murine leukemia cell line (NFS-60). None of the human tumour cultures demonstrated a significant increase in proliferation in response to G-CSF. 4 patients undergoing "mantle" type radiotherapy for Hodgkin's Disease or Non-Hodgkin's Lymphoma also received G-CSF treatment for neutropenia. All 4 had previously received cytotoxic chemotherapy. The number of G-CSF injections given per patient during radiotherapy ranged from 3-6. Mean ANC rose from 1.76 x 10(9)/l to 10.8 x 10(9)/l the next day. These results suggest that G-CSF is a reliable treatment for radiotherapy induced neutropenia and that an intermittent dosage schedule is effective.
Adult↗
Myasthenia gravis. Residues of the alpha and gamma subunits of muscle acetylcholine receptor involved in formation of immunodominant CD4+ epitopes.
We propagated from myasthenia gravis (MG) patients by stimulation in vitro with synthetic sequences (alpha 48-67, alpha 304-322, gamma 75-94 and gamma 321-340) of the human muscle acetylcholine receptor (AChR), CD4+ lines against four 20-residue sequence regions of the AChR alpha and gamma subunits that are recognized by Th cells of most MG patients. Most lines secreted IL-2 and not IL-4, suggesting that they comprise Th1 cells. For three lines we verified that, as reported previously, AChR epitopes are presented by DR molecules: their response to the relevant peptide was abolished by anti-DR Abs. The DR molecules presenting AChR epitopes were identified by testing the response of the lines to the relevant peptide, using APC from donors homozygous for the different DR alleles of the line. We tested the lines with single residue-substituted analogues of the epitope sequence. The results of these experiments indicated that the lines were polyclonal and recognized overlapping epitopes. Their response was abolished by some substitutions, identifying residues common to all epitopes within a given region, whereas other substitutions reduced but did not obliterate the response, indicating residues included in some but not all epitopes recognized by the line. Comparison of the residues involved in epitope formation for different lines supported the conclusion that within the 20-residue immunodominant regions investigated here, the same sequence segment is involved in formation of epitopes, even in DR-discordant patients.
Adult↗
Dual skin testing with Mycobacterium avium sensitin and purified protein derivative: an open study of patients with M. avium complex infection or tuberculosis.
The sensitivity and specificity of dual mycobacterial skin testing were assessed in an unblinded study of 22 patients with culture-confirmed Mycobacterium avium complex (MAC) infection and 20 patients with culture-confirmed Mycobacterium tuberculosis infection. Intradermal skin tests were performed with 0.1 mL of M. avium sensitin, 0.1 mL of PPD (purified protein derivative), and two control antigens (mumps and Candida). All patients with M. tuberculosis infection reacted to the skin tests; the mean reaction size was 19.7 +/- 1.4 mm when PPD was administered and 10.3 +/- 1.5 mm when M. avium sensitin was administered. Four patients with MAC were anergic; for the remaining 18, mean reactions of 15.2 +/- 1.4 mm to M. avium sensitin and 4.3 +/- 1.3 to PPD were noted. A skin test was defined as M. avium-dominant or PPD (M. tuberculosis)-dominant if there was a minimum reaction size of > or = 5 mm to the given species, and the reaction to the given species was > or = 3 mm greater than the reaction to the heterologous species. Dominant skin test reactions were present in 18 (90%) of 20 patients with M. tuberculosis and 15 (83%) of 18 nonanergic patients with MAC. The specificity of dominant skin tests was 100% for infection with M. tuberculosis and 100% for infection with MAC. M. avium-dominant skin tests identify subjects with prior MAC infection and distinguish them from patients with M. tuberculosis infection.
Adult↗
Dedifferentiated liposarcoma. Clinicopathologic analysis of 32 cases suggesting a better prognostic subgroup among pleomorphic sarcomas.
Dedifferentiated liposarcoma is uncommon, and only a small number of cases have been documented. We describe the clinicopathologic features in a series of 32 cases. All patients were adults (age range, 37-83 years; median, 67 years); 20 were men and 12 were women. Commonest site was the retroperitoneum (fifteen cases); six cases arose in the limbs, four in the paratesticular region, three in the peritoneal cavity, two on the trunk, and one each in the buttock and larynx. One primary tumor was subcutaneous. Thirty tumors arose de novo (i.e., combined with well-differentiated tumor in the primary lesion), while two developed in recurrences of a previously well-differentiated liposarcoma. The well-differentiated component was most often lipoma-like and typically there was a histologically abrupt transition to spindle celled nonlipogenic tumor. The dedifferentiated component most often resembled either storiform "malignant fibrous histiocytoma" ("MFH") with limited pleomorphism or myxofibrosarcoma (myxoid "MFH"); the latter pattern is rarely otherwise seen in the retroperitoneum. A small number of cases showed appearances reminiscent of myxoid embryonal rhabdomyosarcoma. An unusual feature in three cases was the occurrence of a discontinuous micronodular pattern of dedifferentiation. Average follow-up of 5.6 years (range, 3 months to 33 years) in 27 cases have revealed local recurrence in 14 patients and systemic metastases in only four patients. The primary sites of the metastasising cases were upper back, thigh, retroperitoneum, and paratesticular region. There have been only seven tumor-related deaths. Good prognosis in de novo dedifferentiated liposarcomas seems unrelated to the extent or morphologic pattern of dedifferentiation. However, high mitotic activity in the dedifferentiated component was associated with a more aggressive clinical course. Our study underlines that dedifferentiation in peripherally located or even subcutaneous liposarcomas does occur, albeit rarely, and that dedifferentiated liposarcomas of the limbs may metastasize. The results suggest that dedifferentiated liposarcomas, as a subgroup among the "MFH-like" sarcomas, have a better prognosis than pleomorphic sarcomas as a whole.
Adult↗
CD44 plays a role in adhesive interactions between glioma cells and extracellular matrix components.
Glioma invasion is a complex process involving interactions of tumour cells with host cells and extracellular matrix (ECM). The initial event in the process is recognition and attachment of glioma cells to specific ECM molecules prior to migration into proteolytically modified matrix. In comparison with other tissues, brain ECM is a relatively amorphous matrix which contains glycosaminoglycans including hyaluronan (HA). Recently CD44 which is a transmembrane adhesion molecule found on a wide variety of cells, has been suggested as the principal cell surface receptor for HA. In the present in vitro investigation we have analysed the role of CD44 in adhesive interactions between human gliomas and ECM. Our experimental procedures included immunocytochemistry, immunoblotting, in vitro adhesion assay and flow cytometry. CD44 was expressed on the surface of all gliomas analysed (9) and the level of expression showed no correlation with tumour grade. Eighty, 95 and 120 kDa isoforms were demonstrated by immunoblotting. In an adhesion blocking assay it was found that ligation of CD44 with specific antibody resulted in reduced adhesion to hyaluronan, chondroitin sulphate, fibronectin, laminin, collagen IV and Matrigel. We conclude that CD44 is involved in adhesion of glioma cells to a wide range of ECM components.
Brain Neoplasms↗
A window of opportunity.
Still in shock from sepsis, biotechnology now has to face healthcare Clinton-style. But research in biotechnology is on the increase as its products surge towards the markets.
Biotechnology↗
Use of recombinant granulocyte-colony stimulating factor to treat neutropenia occurring during craniospinal irradiation.
PURPOSE: To investigate the effectiveness of recombinant human Granulocyte-Colony Stimulating Factor, a hematopoietic growth factor which stimulates neutrophil production, in the treatment of neutropenia caused by Craniospinal Irradiation. METHODS AND MATERIALS: Four consecutive patients who developed neutropenia (neutrophils less than 1.5 X 10(9)/l in peripheral blood) during craniospinal irradiation for primary intracranial tumors received intermittent subcutaneous injections of Granulocyte-Colony Stimulating Factor. Two of the patients had medulloblastoma, one had a primitive neuroectodermal tumor and the other a pinealocytoma. No patient received prior or concurrent chemotherapy. RESULTS: In all cases peripheral blood neutrophil counts returned rapidly to normal levels following Granulocyte-Colony Stimulating Factor injections and treatment delays were therefore avoided. Platelet counts were unaffected by Granulocyte Colony Stimulating Factor treatment. In one case, slight elevation of peripheral blood monocyte and lymphocyte counts occurred after each Granulocyte-Colony Stimulating Factor injection. No toxicity was encountered. CONCLUSION: Our results suggest that Granulocyte-Colony Stimulating Factor is a safe and effective treatment for neutropenia caused by extended field radiotherapy.
Adult↗