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Biomedical subjects

S McKinney

Publications and source records attributed to S McKinney.

At least 19 recordsLinked to original sources

Molecular cloning and characterization of a novel rat activin receptor.

We report the isolation of a full-length rat cDNA for a new activin receptor. The deduced amino acid sequence of this receptor shows 67 percent overall identity with that of a previously identified mouse activin receptor. As predicted for the mouse activin receptor, the amino acid sequence of the rat receptor is consistent with a polypeptide containing an extracellular ligand binding domain, a hydrophobic transmembrane domain, and a serine/threonine kinase intracellular domain. In an expression assay, this new receptor was found to bind I125 radiolabeled activin.

Activin Receptors

Mouse/human chimeric anti-HIV-1 gp120 antibody to the principal neutralizing determinant: tolerability and pharmacokinetics in cynomolgus monkeys, Macaca fascicularis.

In preparing for testing a pharmaceutical grade preparation of chimeric (mouse/human) antibody CGP 47,439 in HIV-1 infected individuals, it was administered to Macaca fascicularis (cynomolgus) monkeys to study tolerability, immunogenicity and pharmacokinetics. Four groups of monkeys, three males and three females per group, received respectively four infusions of 0, 1.43, 4.3, and 14.3 mg of CGP 47,439/kg body weight at one-week intervals. The chimeric antibody induced no fever, was tolerated well throughout the 50-day observation period, elicited no tissue damage and no anti-antibody response. The pharmacokinetic profile was similar at all dose levels with a mean T1/2 alpha of 14.2 h (range 11.8-19.3 h) and a mean T1/2 beta of 172.6 h (range 137.2-220.5h). Following four successive antibody infusions serum concentrations of CGP 47,439 increased without reaching a steady state, and its measured concentrations were comparable to the simulated values. Collectively the study has provided safety and pharmacokinetic data that would allow human studies with this antibody in AIDS patients.

Animals

Making the grade.

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Airway Obstruction

Rescue by phone.

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Aged

Obesity in black adolescent girls: a controlled clinical trial of treatment by diet, behavior modification, and parental support.

Recent findings indicate that nearly 50% of black American women are obese and that adolescence is a critical period for the development of their obesity. This study investigated the efficacy of a behavioral weight control program in 36 black female adolescents with a mean age of 14.0 years, weight of 95.0 kg, and height of 163.2 cm. All subjects participated in the same 16-week program but had different levels of parent participation: (1) child alone with no parent participation; (2) mother and child treated in the same session; and (3) mother and child treated in separate but concurrent session. At the end of the 16-week program, children in the three conditions lost 1.6, 3.7, and 3.1 kg, respectively. Differences among conditions were not statistically significant; however, a secondary analysis revealed that the greater the number of sessions attended by mothers, the greater their daughters' weight losses. Weight reduction was associated with significant improvements in body composition, serum total cholesterol concentrations, and psychological status. Results are discussed in terms of the need to improve the maintenance of weight loss in adolescents and to explore possible differences between black and white females in their preferred body types.

Adolescent

Nutritional factors and growth in children with sickle cell disease.

A study of growth and nutrition was conducted with 20 growth-retarded (GR) and 20 growth-normal (GN) preadolescent children with sickle cell disease (SCD). All children were matched for age, sex, hemoglobin disorder, and hematologic values. Ten normal children served as control subjects. Mean serum levels of retinol, retinol-binding protein, prealbumin, and zinc were significantly lower in the children with SCD than in normal children. Mean serum retinol and prealbumin levels were similar in the GR and GN sickle cell groups. Mean serum retinol-binding protein levels were lower in GR than in GN patients. Serum zinc levels, somatomedin C levels, and bone age were frequently abnormal in the patients with SCD, but these factors did not correlate with growth status. It was not possible to explain the poor growth in patients with SCD in this study solely on the basis of nutritional factors.

Anemia, Sickle Cell

Nutritional and metabolic profile of children with epidermolysis bullosa.

The clinical features of epidermolysis bullosa (EB) include oral, pharyngeal, gastrointestinal, and total-body blistering. This results in the potential for decreased oral intake, malabsorption, anemia, and depressed visceral protein stores, and a multifactorial etiology for the development of malnutrition and growth retardation. Thus, it was the purpose of this study to document the nutritional and metabolic profile of seven children with junctional or recessive dystrophic EB as compared to seven age- and sex-matched controls. Each child underwent a comprehensive nutritional assessment, including evaluation of anthropometric, dietary, and biochemical values and determination of resting energy expenditures. This study demonstrated that subjects with EB are statistically different for all anthropometric values studied and represent a population suffering from the effects of acute and chronic malnutrition. Nutrient deficiencies were reported for zinc, magnesium, calcium, potassium, and iron; vitamines A, D, E, B1, B12, and B6; protein, and calories. Comparison of laboratory values revealed significantly lower values for hemoglobin, hematocrit, and zinc. This research illustrates the magnitude of the growth deficits, and nutrient and biochemical deficiencies present in children with EB. The results provide a strong argument for the value of nutritional assessment and intervention and their potential impact in this population. Optimizing nutritional status may be one viable method of improving the morbidity and mortality associated with the disease and ultimately improving the overall quality of life.

Anthropometry

Who does the public think should perform health care tasks?

The dietitian was identified as the most appropriate provider of such key nutrition services as nutrition assessment, determination of caloric requirements, provision of diet counseling, and prescription of diets. Several tasks fundamental to nutrition services were not viewed as highly suitable tasks for the dietitian, e.g., plan for care at home, monitor client progress, and check laboratory values. Activities that constitute key nutrition services need to be accentuated to clarify the numerous skills and extensive knowledge that dietitians possess. In the health care system of today, the dietetic profession must be associated with a wider range of health-related tasks than the traditional triad of diet, food, and hospital. Public relations and marketing strategies should focus on activities that provide the public with a clearer understanding of how the dietetic profession contributes to patient/client care.

Adult

Human lymphocyte and monocyte lysis of tumor cells mediated by a mouse/human IgG1 chimeric monoclonal antibody.

The mouse monoclonal antibody 17-1A (gamma 2a, kappa) recognizes a tumor-associated antigen expressed on human gastrointestinal malignancies and has been used in Phase I and II clinical trials. Chimeric genetic constructs have been produced using 17-1A variable region genes (VL and VH) and the constant region genes for human kappa light chains and gamma 1 heavy chains (C kappa and gamma 1). The chimeric gene constructs were transfected into mouse myeloma cells for antibody production. The secreted mouse/human chimeric antibody contains the antigen-binding domain of 17-1A and the human (gamma 1, kappa) constant regions. Native mouse 17-1A and the chimeric antibody (chIgG1) were analyzed for binding to two human colon cancer cell lines and for the mediation of cancer cell line antibody-dependent cellular cytotoxicity by normal human peripheral blood lymphocytes and monocytes in 4 h 51Cr-release assays. The 17-1A and chIgG1 gave similar results in these in vitro biologic assays. This study demonstrates the feasibility of using mouse/human chimeric antibodies in human therapeutic applications.

Animals

Characterization of a mouse/human chimeric monoclonal antibody (17-1A) to a colon cancer tumor-associated antigen.

Mouse monoclonal antibody 17-1A is specific for an antigen expressed on cells of human gastrointestinal malignancies and has been used in radioimmune imaging and therapy trials for patients with colon and pancreatic cancer. The cell line SG3/5 was generated by transfection of a nonproducing mouse myeloma line (SP2/0) with a chimeric gene construct composed of variable regions from the mouse 17-1A immunoglobulin (gamma 2a, kappa) and constant regions of human k and gamma 3 immunoglobulin genes. The secreted immunoglobulin was bound by mouse monoclonal antibodies to human IgG(Fc) and IgG3 but not by staphylococcal protein A. Gel filtration HPLC profiles of purified chimeric antibody were similar to normal human IgG3 but quite different from native 17-1A and normal human IgG1, 2, and 4. Native and chimeric 17-1A had similar patterns of reactivity with colon cancer, other adenocarcinoma, and leukemic cell lines. Competitive inhibition documented that native and chimeric 17-1A had identical capacities to inhibit radiolabeled native 17-1A binding to colon cancer cell lines. Thus, the chimeric 17-1A exhibits molecular characteristics of normal human IgG3 but retains the specificity and binding affinity of the native 17-1A murine monoclonal antibody. The native and chimeric 17-1A mediated similar modest degrees of human lymphocyte and monocyte ADCC in a 4-hr 51Cr release assay, and both failed to mediate complement lysis of colon carcinoma cell lines in the presence of human complement. This human/mouse chimeric monoclonal antibody may be a good candidate for use in clinical trials because it retains the tumor antigen specificity and human effector cell recognition of the native 17-1A, would presumably have a fivefold to 10-fold longer circulating half-life in man, and should be considerably less immunogenic as compared with native murine immunoglobulins.

Animals

Human T-cell lymphotropic virus type III (HTLV-III) core antigens: synthesis in Escherichia coli and immunoreactivity with human sera.

Fragments of human T-cell lymphotropic virus type III (HTLV-III) proviral DNA carrying the gene for the core antigen (gag) was cloned in the plasmid REV. Several of the recombinants direct high levels of synthesis of the antigens. One clone, pG1, produced a hybrid protein containing 13 amino acid residues of the carboxyl terminus of the 17 kD virion protein, the entire p24, the major core protein of HTLV-III, and 74 amino acid residues of the amino terminal of the 15 kD core ribonucleoprotein. A second clone, pG2, was similar to pG1 except that it contained no p17 sequences and was missing the amino-terminal 77 amino acid residues of the p24. A third clone, pG3, was similar to pG2, except that all but 56 amino acids of the carboxyl terminus of p24 were removed. All three proteins were found to be strongly immunoreactive with anti-HTLV-III antibodies present in sera from patients with acquired immune deficiency syndrome (AIDS) or AIDS-related complex (ARC). In addition, pG1 and pG2, but not pG3, reacted with a monoclonal antibody (M26) specific for the p24 virion core protein. Whereas all three reacted with an anti-p15 monoclonal antibody, none of the clones reacted with an anti-p17 monoclonal antibody. These results provide direct evidence to support the predicted assignment of the coding region of the gag gene of HTLV-III. The product from pG2 was purified and was found to be potentially useful for the detection of anti-p24 antibodies in sera from patients with AIDS or ARC and from individuals at risk from AIDS.

Acquired Immunodeficiency Syndrome

Expression in Escherichia coli of open reading frame gene segments of HTLV-III.

Human T-cell lymphotropic virus type III (HTLV-III), the causative agent of the acquired immune deficiency syndrome (AIDS), was recently isolated and its genomic structure analyzed by DNA cloning methods. In the studies reported here a combined cloning and expression system was used to identify HTLV-III encoded peptides that react immunologically with antibodies in sera from AIDS patients. Cloned HTLV-III DNA was sheared into approximately 500-base-pair fragments and inserted into an "open reading frame" expression vector, pMR100. The inserted DNA was expressed in Escherichia coli transformants as a polypeptide fused to the lambda CI protein at its amino terminus and to beta-galactosidase at its carboxyl terminus. Sera from AIDS patients containing antibodies to HTLV-III were then used to screen for immunoreactive fusion proteins. Twenty clones, each specifying a fusion protein strongly reactive with AIDS serum, were identified. DNA sequence analysis indicated that the HTLV-III fragments were derived from the open reading frame DNA segments corresponding to the gag and pol gene coding regions and also the large open reading frame region (env-lor) located near the 3' end of the viral genome.

Acquired Immunodeficiency Syndrome

Colony growth and self renewal of plasma cell precursors in multiple myeloma.

Culture conditions that support the growth of multi-and single-lineage hemopoietic colonies are also able to give rise to large myeloma colonies from bone marrow and peripheral blood samples of some patients with multiple myeloma. The culture system was used to determine the frequency of hemopoietic precursors and clonogenic myeloma progenitors in 71 patients with multiple myeloma studied in various clinical phases of the disease. The frequency of normal hemopoietic precursors in patients with benign monoclonal gammopathy and smoldering myeloma were indistinguishable from normal controls. Myeloma colonies were not observed in these subgroups. In contrast, patients with active disease showed significantly reduced hemopoietic colony formation, even before the initiation of therapy. A further reduction was demonstrated for patients with acute phase disease. A correlation between the frequency of hemopoietic colonies and the concentration of plasma cells in the plated sample was not observed. Large myeloma colonies with recloning potential were identified in cultures of specimens derived from 14 of the studied patients. These colonies were most frequently (ten cases) obtained from patients who had entered the acute phase of the disease. These patients manifested marrow failure (pancytopenia) and their marrow had a limited capacity to generate normal hemopoietic colonies. Three of the patients that formed myeloma colonies were studied in chronic phase following chemotherapy and one patient was examined at diagnosis. The myeloma colonies were composed exclusively of cells characterized by the same M protein as the patient. Some of the cells within the colonies retained their ability to self renew extensively, as demonstrated by serial recloning studies. Colonies derived from six of the patients are now propagated in semisolid and liquid medium for as many as nine to 34 generations. Patients that form myeloma colonies under these culture conditions represent a high-risk group with significantly shorter survival than patients not able to give rise to myeloma colonies. A Cox proportional hazards model was fitted to the data to determine the prognostic role of myeloma colony growth in culture after accounting for the influence of other well established risk factors, such as concentration of plasma cells and disease status. The analysis indicated that myeloma colony growth in culture serves as a strong and independent predictive indicator of poor clinical prognosis.

Actuarial Analysis

Typology of food preferences identified by Nutri-Food Sort.

A Q-sort instrument to measure and identify a typology of food preferences was developed and tested. Sixty-eight pictures of food items were used for the Q-sort called the Nutri-Food Sort. Foods chosen were divided evenly among the following categories: low nutrient/high calorie, low nutrient/low calorie, high nutrient/high calorie, and high nutrient/low calorie. Ninety-seven women sorted the pictures on the basis of preference on a 7-point scale from "like a lot" to "dislike a lot." The results were factor analyzed (Q-type), producing four distinct respondent groups or types. The types were labeled: "finicky eaters," "health-conscious dieters," "diverse diners," and "high-calorie traditionalists." The "finicky eaters" favored only 8 foods and disliked 40. "Health-conscious dieters" preferred low-calorie foods. The "diverse diners" preferred a wide variety of foods and were more adventuresome in their choices. The "high-calorie traditionalists" preferred high-calorie foods and "all-American" favorites. The four food preference categories originally predicted were partially accurate descriptions of the resulting four food preference factor groups. Overall, the Nutri-Food Sort appears to be a versatile instrument that has wide applicability in research on food behaviors, attitudes, and preferences.

Adult