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Biomedical subjects

M Clay

Publications and source records attributed to M Clay.

At least 19 recordsLinked to original sources
PubMed1999

Effects of granulocyte-colony-stimulating factor on potential normal granulocyte donors.

BACKGROUND: The use of granulocyte-colony-stimulating factor (G-CSF) to increase the granulocyte count and the yield from leukapheresis in normal donors is leading to renewed interest in granulocyte transfusion. Therefore, it is important to understand the side effects of G-CSF. STUDY DESIGN AND METHODS: We studied the effect of G-CSF on peripheral blood counts and recorded the side effects experienced 24 hours after an injection of G-CSF in normal subjects donating peripheral blood progenitor cells for research. RESULTS: Following administration of G-CSF to 261 donors, the neutrophil count increased to 20.6 to 24.5 x 10(9) per microL depending on the dose of G-CSF. This represented a 6.2 to 7.4-fold increase over the neutrophil count before G-CSF administration. Of all donors, 69 percent experienced one or more side effects. The most common effects were: muscle and bone pain, headache, fatigue, and nausea. There was a relationship between the dose of G-CSF and the likelihood of experiencing a side effect. Most side effects were mild, but about 75 percent of donors took analgesics because of them. CONCLUSIONS: In a granulocyte donation program involving G-CSF stimulation, about two-thirds of donors would experience one or more side effects, but these would usually be mild and well tolerated.

Adolescent↗
PubMed1999

Rats with hypothalamic obesity are insensitive to central leptin injections.

Genetically determined obesities, involving leptin- and melanocortin-signaling pathways, have focused attention on the four medial hypothalamic nuclei as primary sources of feeding- and metabolically-based obesity. All four medial cell groups contain leptin receptors. To determine which of these cell groups normally mediates the effects of leptin on food intake and body weight gain, we injected colchicine bilaterally into each nucleus and determined the pathophysiological effects of disruption and responsivity to leptin injected intracerebroventricularly. Intracerebroventricular injections of leptin in sham-lesioned rats decreased food intake during the dark period, but not during the light period. Lesions of the arcuate (ARC), paraventricular (PVN), and ventromedial (VMN) nuclei all resulted in leptin insensitivity; by contrast, lesions of the dorsomedial nuclei (DMN) augmented sensitivity to leptin on feeding and body weight gain. Although rats with ARC and PVN lesions were obese, they were still capable of reducing caloric efficiency over the 5 days of study and increasing uncoupling protein content in interscapular brown adipose tissue. Caloric efficiency and uncoupling protein content were unchanged in rats with VMN and DMN lesions. Finally, the slope of the relationship between leptin and mesenteric white adipose tissue was increased in rats with VMN lesions and abolished in rats with ARC lesions. Thus, lesions of the ARC, PVN, and VMN produced obesity via separate pathways. We conclude that the medial hypothalamic cell groups, each with a different role in energy balance, are all necessary for normal leptin responsiveness.

Animals↗
PubMed1997

Characterization of a new alloantigen (SH) on the human neutrophil Fc gamma receptor IIIb.

Polymorphic structures of the neutrophil Fc gamma receptor IIIb (Fc gamma RIIIb) result in alloantibody formation that causes alloimmune neonatal neutropenia and transfusion reactions. Alloantigens located on Fc gamma RIIIb include the antigens NA1 and NA2. In four cases of alloimmune neonatal neutropenia, granulocyte-specific alloantibodies directed against a thus far unknown antigen were detected by granulocyte agglutination and immunofluorescence tests in the maternal sera. By the use of the monoclonal antibody-specific immobilization of granulocyte antigens (MAIGA) assay, the new antigen, termed SH, was located on the Fc gamma RIIIb. Nucleotide sequence analysis of the Fc gamma RIIIb coding region from a SH(+) individual showed a single-base C-->A mutation at position 266, which results in an Ala78Asp amino acid substitution. A family study confirmed that this nucleotide difference is inherited, and corresponds to the SH phenotype. Serologic typing of 309 randomly selected individuals showed an antigen frequency of 5% in the white population. The same frequency was found by genotyping, for which a technique based on polymerase chain reaction (PCR) using sequence-specific primers (PCR-SSP) was developed. Typing of all SH(+) individuals for NA1 and NA2, and PCR-restriction fragment length polymorphism analysis of the NA-specific PCR products from five SH(+) individuals using the SH-specific endonuclease SfaN 1 showed that SH antigen is very probably the result of an additional mutational event in the NA2 form of the Fc gamma RIIIB gene. Immunochemical studies also demonstrated that the SH determinants reside on the 65- to 80-kD NA2 isoform of the Fc gamma RIIIb. Our findings show the existence of an additional polymorphism of the Fc gamma RIIIb, which can result in alloantibody formation causing alloimmune neonatal neutropenia.

Adult↗
PubMed1996

Molecular characterization of antigenic polymorphisms (Ond(a) and Mart(a)) of the beta 2 family recognized by human leukocyte alloantisera.

We show that the previously described alloantisera Ond and Mart, which recognize the alloantigens Ond(a) and Mart(a), react with polymorphic variants of alpha L and alpha M subunits of the beta 2 integrin family (CD11a and CD11b molecules). This was shown by testing the alloantisera in a monoclonal antibody-specific immobilization of leukocyte antigens, immunoprecipitation, and immunofluorescence assay against cells from normal donors and from patients with leukocyte adhesion deficiency (beta 2 intergrin deficient). To elucidate the molecular basis of the Ond(a) and Mart(a) alloantigens, RNA was isolated from mononuclear leukocytes derived from individuals of known serologic phenotype. Reverse transcriptase-polymerase chain reaction (RT-PCR) was performed to amplify the entire coding region of the alpha L and alpha M mRNAs. The Ond(a) antigen was found to be due to a G2466C substitution in the DNA coding for the alpha L subunit, which predicts an Arg766Thr amino-acid polymorphism. The Mart(a) antigen was also found to be due to a single nucleotide substitution (G302A) in the DNA coding for the alpha M subunit, which predicts an Arg61His amino acid polymorphism. Using allele-specific restriction enzyme analysis, the association between point mutations and phenotypes was confirmed. The localization of these alloantigens on integrin molecules further illustrates the polymorphic nature of this class of proteins. Whether the polymorphisms influence the adhesive capacity of the leukocyte integrins remains to be investigated.

Alleles↗
PubMed1994

Granulocyte transfusions: efficacy in treating fungal infections in neutropenic patients following bone marrow transplantation.

BACKGROUND: A retrospective study was conducted to evaluate the efficacy of granulocyte transfusions in neutropenic patients with fungal infections following bone marrow transplantation. STUDY DESIGN AND METHODS: Systemic fungal infection was detected in 87 patients during the first 100 days following bone marrow transplantation; 50 received granulocytes in addition to appropriate antifungal agents. The median age was 17 years in the transfused patients (range, 1.5-57) and 35 years in the nontransfused patients (range, 0.8-50). Granulocyte transfusions were given on a daily to twice-daily basis. To evaluate their responses, patients were categorized by infection type (candidal [n = 38] vs. noncandidal [n = 49]) and site (fungemia alone [n = 30] vs. invasive infection [n = 57]). Resolution of infection was defined as the resolution of signs and symptoms and negative cultures and/or histopathology. RESULTS: No benefit of granulocyte transfusions could be shown in the resolution of infection in patients with either invasive noncandidal infection (29% in the transfused patients vs. 23% in the nontransfused patients, p > 0.1) or candidal sepsis (56% vs. 50%, p > 0.1). Among patients with delayed marrow recovery, no difference was seen in the resolution of infection in the transfused (25.9%) and nontransfused (50%) patients (p > 0.1); nor was any difference between the transfused and nontransfused patients evident in the duration of febrile episode associated with the fungal infection. Granulocyte transfusions were well tolerated, with the only complications being fever in 12 patients (24%), chills in 10 (20%), and respiratory distress in 2 (4%). Despite attempts to stratify by infection type, invasiveness, and marrow recovery, it was not possible to show any benefit of granulocyte transfusions in this group. CONCLUSIONS: It is likely that only through a prospective randomized trial can the question of the efficacy of granulocyte transfusions in treating fungal infections be conclusively answered.

Adolescent↗
PubMed1991

Aerosol delivery in neonatal ventilator circuits: a rabbit lung model.

The benefits of inhaled therapy in ventilated neonates are recognized, but the reliability of drug delivery in nebulizer-ventilator circuits is uncertain. We quantified the effect of changing variables. Twenty-three freshly killed rabbits (1.15-1.9 kg) were ventilated via a tracheostomy by a pressure-limited, time-cycled ventilator (Neovent). A radioaerosol of 99Tcm pertechnetate from an Ultravent nebulizer (Mallinkrodt) was fed into the proximal ventilator tubing. Two 3-minute nebulizations at "standard settings" were followed by 2 at altered pressure, frequency, gas flow, I:E ratio, or position of the nebulizer in the circuit. Each nebulization was followed by a 3-minute gamma camera image and total deposited radioactivity was measured in excised lungs and trachea. Images demonstrated good peripheral aerosol deposition. At standard settings, lung deposition averaged 2.8% of the aerosol released. This was decreased markedly by reducing tidal volume (ventilator pressures) and residence time of aerosol (I:E ratio). Reduced gas flow decreased deposition slightly, presumably by increased particle size and marginally reduced tidal volume. Deposition did not change with increased frequency; increased minute ventilation was offset by decreased residence time of the aerosol. We conclude that the Ultravent nebulizer can be used to nebulize drugs in a standard neonatal circuit, although the dose delivered is small. Tidal volume and aerosol residence time are important determinants of aerosol delivery.

Animals↗
PubMed1990

Evaluation of nebulizers for use in neonatal ventilator circuits.

The use of nebulizers in neonatal ventilator circuits offers a new and relatively uncharted route of therapy for infants in respiratory failure. We used a model lung to investigate and compare different nebulizer types and therapeutic agents and to make practical observations. Five different nebulizers (Ultravent, Acorn, MAD2, Small Particle Aerosol Generator, and Pulmosonic) were compared for efficiency of delivery of an amino-phylline aerosol to the model lung, and the particle size of aerosol produced by them was measured. A Nebulizer Efficiency Index (NEI) was created, representing the deposition rate of the original solution as aerosol upon the model lung filter. The Acorn (2.8.10(3) ml/min) and MAD2 (2.4.10(-3) scored highest NEI. When a suspension of budesonide was nebulized, minimal amounts of drug were recovered from the filter when the nebulizer producing the smallest particle size (Ultravent) was studied, suggesting that suspensions of drugs behave differently from solutions. Significant changes need to be made to a conventional circuit when jet nebulizers are used; most of these are obviated by the use of an ultrasonic nebulizer, which also avoids the potential problem of marked cooling of the gas flow produced by jet nebulizers.

Aerosols↗
PubMed1987

Granulocyte antigens and antibodies.

Granulocyte-specific antigens defined by human alloantisera are clinically important in neonatal neutropenia, autoimmune neutropenia, transfusion reactions, drug-induced immune neutropenia, and poor response to granulocyte transfusions. Many different antigens have been defined by human alloantisera using different assays. Only antigens of the N system of Lalezari are commonly studied today. The composition and location of these antigens within the granulocyte membrane are not known, but work is now proceeding on those issues. It also appears that these antigens may have some structural or functional role in the granulocyte. Although many myeloid MoAbs have been developed, there are very few reports to establish whether these identify structures that are related to the N series of granulocyte antigens. However, these MoAbs can serve as excellent reagents for better understanding the granulocyte membrane. It appears that studies during the next several years will provide exciting information about the structure-function relationships in the granulocyte membrane.

Antibodies↗
PubMed1987

Protective effect of methylxanthines against carbachol-induced bronchoconstriction in normal subjects.

The bronchoprotective effect of bioequivalent doses of theophylline (TH; 234 mg) and a combination of TH, proxyphylline (PPH) and diprophylline (DPH) in the proportion 2:3:3 (Neo-Biphyllin, NB; 600 mg) against carbachol-induced bronchoconstriction was studied in 10 healthy non-smokers in a randomised controlled double-blind cross-over trial. The subjects were on a methylxanthine-free diet 4 days prior to and during each study day. Bronchial provocation tests were conducted in the morning and afternoon of the three separate study days--control and two medication days--using a standardised technique. On the control day, the dose of carbachol required to reduce the partial expiratory flow volume at 25% of vital capacity (V25p) by at least 25% was established. A significant protective effect was achieved with both TH (p less than 0.05) and NB (p less than 0.001) as measured by V25p. Bronchoprotection was achieved with low maintenance serum levels of TH.

Adult↗
PubMed1986

Three sera defining a new granulocyte-monocyte-T-lymphocyte antigen.

Three sera containing antibodies recognizing a previously undescribed antigen on granulocytes were found during testing of sera from multiparous donors. All of the antibody producers were in good health. None had a history of transfusion. Using the granulocyte agglutination assay the sera recognize a single antigen which is not associated with the neutrophil antigens NA1, NA2, NB1, NC1, ND1, NE1, 5a, 5b, 9a, nor common red blood cell or HLA antigens. The three sera did not react with autologous cells or with the cells of the other antibody producers. Granulocytes from one antibody producer did not absorb antibody activity from any of the three sera. The antigen was found in large quantities on granulocytes and monocytes, in smaller quantities on T lymphocytes, and not on B lymphocytes, red cells, and platelets. The sera reacted with 340 of 343 random donors (99.1%) and were negative with the same donor cells. Family studies showed autosomal dominant inheritance of the antigen. Five of 12 sibs in three families lacked this antigen (not statistically different from the expected ratio). The calculated gene frequency for the gene controlling the production of this antigen is 0.906. There appeared to be no association to the HLA, NA or Rh loci or to the X or Y chromosomes. None of the infants of these three women showed clinical signs of alloimmune neonatal neutropenia.

Adult↗
PubMed1986

Effect of leukocyte antibodies and HLA matching on the intravascular recovery, survival, and tissue localization of 111-indium granulocytes.

The effect of leukocyte antibodies detected under different conditions on the fate in vivo of granulocytes was studied using 111-indium-labeled granulocytes. Sera from patients were tested by granulocyte agglutination (GA), granulocytotoxicity (GC), granulocyte immunofluorescence (GIF), lymphocytotoxicity (LC), and antibody-dependent lymphocyte-mediated granulocytotoxicity. Granulocytes from donors to be studied were labeled with 111-indium and injected. Then the intravascular recovery and survival or tissue localization was determined in 93 studies. Antibodies detected by granulocyte agglutination were associated with a significant reduction in recovery (6.7% v 30.8% in controls; P less than .001) and t1/2 (0.3 hours v 5.6 hours in controls; P = .002). When all possible combinations of serum reactivity were considered, reactivity in the GA plus GIF assays had the best correlation with decreased recovery (R2 = .49; P less than .001) and t1/2 (R2 = .73; P less than .001). When the relationship between the strength of antibody reactivity and the recovery and t1/2 were analyzed, the best relationship was between the combination of LC and GIF with recovery (R2 = .62; P = .001). Because of the general availability of the HLA (LC) testing, the role of LC reactivity was investigated in other ways. There was a strong relationship between sera highly reactive by LC and those reactive by GIF. These highly reactive sera were also associated with reduced recovery and t1/2. The influence of specific HLA antigen mismatches was also studied. When donor and recipient were mismatched for the HLA-A2, B8, or BW44 antigens, there was a significant reduction in either recovery, t1/2, or both. Tissue localization was studied by body scans in patients with and without known sites of inflammation. Antibodies detected by a combination of GA and GIF caused abnormal pulmonary sequestration of granulocytes (three cases) and failure of granulocytes to localize at known sites of inflammation (three cases). HLA (LC) antibodies did not alter tissue localization despite the presence of the corresponding HLA antigens on granulocytes. It appears that GA, GIF, or a combination of these tests is the most effective predictor of altered in vivo fate of granulocytes. However, sera highly reactive by LC and GIF probably define a group of highly immunized patients in whom granulocyte recovery and t1/2 are also reduced. Mismatching for certain HLA antigens is also associated with reduced granulocyte recovery and survival. At present, GA, with or without the immunofluorescence assay, is the most effective predictor of altered in vivo granulocyte activity.(ABSTRACT TRUNCATED AT 400 WORDS)

Antibodies↗
PubMed1985

Leptospiral exposure in Detroit rodent control workers.

Antibody levels to L. icterohemorrhagiae of rodent control workers and two control groups were compared with antibodies against five other leptospiral serotypes carried predominantly by species other than rats. Rodent control workers contact urban rats, 77 per cent of which are carriers of leptospiral organisms. Rodent control workers had higher antibody levels against L. icterohemorrhagiae than control groups (OR 4.37, 99 per cent CI = 3.0, 6.3 and OR 11.08, 99 per cent CI = 5.6, 22). Antibodies against the other five serotypes were almost non-existent in the study group.

Adult↗
PubMed1984

Severe pulmonary hypersensitivity associated with passive transfusion of a neutrophil-specific antibody.

A life-threatening pulmonary hypersensitivity reaction accompanied by profound leucopenia and transient hypocomplementaemia developed in a 73-year-old man after repair of an abdominal aortic aneurysm. A neutrophil-specific antibody, anti-NA2) was demonstrated by granulocyte immunofluorescence and microagglutination in one of the transfused donor units. In addition, activated complement component C5a was generated in vitro by incubation of the patient's serum with the aortic graft material. This severe clinical reaction may have resulted from the interaction of the transfused anti-NA2 antibody with complement activation induced by the aortic graft material.

Aged↗