Long-term anticoagulation therapy for atrial fibrillation in elderly patients: efficacy, risk, and current patterns of use.
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Aged↗
Biomedical subjects
D McCormick
Publications and source records attributed to D McCormick.
Loss-of-function mutations in the cathepsin C gene result in periodontal disease and palmoplantar keratosis.
Papillon-Lefèvre syndrome, or keratosis palmoplantaris with periodontopathia (PLS, MIM 245000), is an autosomal recessive disorder that is mainly ascertained by dentists because of the severe periodontitis that afflicts patients. Both the deciduous and permanent dentitions are affected, resulting in premature tooth loss. Palmoplantar keratosis, varying from mild psoriasiform scaly skin to overt hyperkeratosis, typically develops within the first three years of life. Keratosis also affects other sites such as elbows and knees. Most PLS patients display both periodontitis and hyperkeratosis. Some patients have only palmoplantar keratosis or periodontitis, and in rare individuals the periodontitis is mild and of late onset. The PLS locus has been mapped to chromosome 11q14-q21 (refs 7, 8, 9). Using homozygosity mapping in eight small consanguineous families, we have narrowed the candidate region to a 1.2-cM interval between D11S4082 and D11S931. The gene (CTSC) encoding the lysosomal protease cathepsin C (or dipeptidyl aminopeptidase I) lies within this interval. We defined the genomic structure of CTSC and found mutations in all eight families. In two of these families we used a functional assay to demonstrate an almost total loss of cathepsin C activity in PLS patients and reduced activity in obligate carriers.
Aggressive Periodontitis↗
Differences in discharge medication after acute myocardial infarction in patients with HMO and fee-for-service medical insurance.
OBJECTIVE: To assess the impact of fee-for-service (FFS) versus HMO medical insurance coverage on receipt of aspirin, beta-blockers, and calcium channel blockers at the time of hospital discharge following an acute myocardial infarction. DESIGN: Prospective, population-based study. SETTING: All 16 community and tertiary care hospitals in the metropolitan area of Worcester, Massachusetts. PATIENTS: The study population consisted of patients under 65 years of age hospitalized with a validated acute myocardial infarction in all hospitals in the Worcester (Massachusetts) Standard Metropolitan Statistical Area (1990 census estimate, 437,000) during 1986, 1988, 1990, 1991, and 1993. MEASUREMENTS AND MAIN RESULTS: After adjustment for demographic and clinical variables as well as study year, the odds ratios for receipt of each medication for patients with HMO insurance compared with FFS were 1.05 (95% confidence interval [CI] 0.77, 1.44) for aspirin, 1.32 (95% CI 0.98, 1.76) for beta-blockers, and 0.72 (95% CI 0.54, 0.96) for calcium channel blockers. Examination of temporal trends in utilization of these agents suggests that observed decreases in use of calcium channel blockers and increases in use of beta-blockers over the period under study occurred more rapidly for HMO than for FFS patients. CONCLUSIONS: Overall, use of aspirin and beta-blockers was comparable among HMO and FFS patients and use of calcium channel blockers (deemed less effective or ineffective for secondary prevention) was lower among HMO patients. Differential adoption, over time, of evidence-based prescribing practices for medications between HMO and FFS patients who have had a myocardial infarction warrants further study.
Adrenergic beta-Antagonists↗
Superficial angiomyxoma: clinicopathologic analysis of a series of distinctive but poorly recognized cutaneous tumors with tendency for recurrence.
Despite being first described in 1988, superficial angiomyxoma is still a poorly recognized cutaneous tumor. Although its histologic features are distinctive, its existence seems not to be widely accepted. We analyzed the clinicopathologic and immunohistochemical features in a series of 39 cases. Twenty-five patients were males; age range was birth to 82 years (median, 45.5 years). Most cases presented as cutaneous papules, nodules, or polypoid lesions. Seventeen tumors arose on the trunk, 14 on the head and neck, and seven on the lower limbs. All cases were treated by local excision, and eight recurred locally. In four of the latter cases, there were two recurrences. Histologically, the lesions were dermal with variable involvement of the subcutis. Tumors were poorly circumscribed, but a focal lobular outline was always identified. Distinctive histologic features included extensive myxoid stroma, numerous small blood vessels, varying cellularity, acellular mucin pools, stellate or bipolar fibroblastic cells, muciphages, a sparse, mixed inflammatory cell infiltrate with notable neutrophils, and occasional plumper cells with eosinophilic cytoplasm. Cytologic atypia was mild at most, and mitotic figures were rare. In approximately 20% of cases, the primary lesion or its recurrence contained epithelial structures, including epidermoid cysts, thin strands of squamous epithelium, and small buds of basaloid cells. Immunohistochemically, tumor cells were negative for S-100 protein, smooth muscle actin, and pan-keratin. We support the concept of superficial angiomyxoma as a distinctive clinicopathologic entity that should be included in the differential diagnosis of other myxoid cutaneous tumors, including dermal nerve sheath myxoma, trichodiscoma and trichofolliculoma, and low-grade myxofibrosarcoma.
Adolescent↗
Adult smoking in the home environment and children's IQ.
In a sample of 3- and 5-yr.-old children, smoking in the home was found to be significantly and inversely related to IQ. Children of normal birth weight and without neurological impairment had been enrolled in a longitudinal study of child development. Analyses were conducted with sex, ethnicity, socioeconomic status, educational stimulation in the home, day care, and mother's intelligence controlled. Significant results were obtained for scores on the Peabody Picture Vocabulary Test-Revised at age three years and on the major Stanford-Binet Fourth Edition scales at ages three and five years. All effects were for the mother, not the father, smoking in the home.
Adult↗
Cutaneous T-lymphocyte infiltrate associated with B-cell chronic lymphocytic leukaemia.
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Antigens, CD↗
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↗