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Biomedical subjects

D Peckham

Publications and source records attributed to D Peckham.

17 recordsLinked to original sources
PubMed2001

Difference in apoptosis induction between surface IgD and IgM.

In the classic 'two-signal' model for B cell activation, signal 1 through the antigen receptor plus signal 2 through lymphokine receptors and CD40 leads to proliferation, but signal 1 alone leads to tolerance or anergy. In a protocol designed to deliver signal 1 in vitro with anti-delta without signal 2, purified small dense B cells from untreated mice exposed to any of three monoclonal anti-delta antibodies or to polyclonal anti-delta in vitro showed modest S phase entry at 50 microg/ml. In contrast, at low doses (0.1-0.5 microg/ml) of anti-delta, there was no cell cycle entry at 64 h, but apoptosis was accelerated at 16 h. Polyclonal anti-mu and three monoclonal anti-mus did not show this early apoptosis induction. Anti-CD40 and IL-4 inhibited apoptosis in B cells treated with 0.5 microg/ml anti-delta and increased S phase entry at 10 microg/ml anti-delta. Low-dose anti-delta (but not anti-mu) induced increased B7-2 and class II MHC expression on a subset of B cells, many of which were in apoptosis. Larger transient increases in c-Myc and Egr-1 expression were seen with low-dose anti-delta than with anti-mu, followed by an abrupt fall below baseline, a sequence previously linked to apoptosis. There was no change in Bcl-2, Bcl-x(L) or Bax. These data suggest a functional difference between delta and mu cross-linking on resting spleen B cells. A BCR stimulus sufficient for early activation events, but insufficient for full G1 entry, may lead to apoptosis.

Animals↗
PubMed1997

Na+/K+ ATPase in lower airway epithelium from cystic fibrosis and non-cystic-fibrosis lung.

The basolateral Na+/K+ ATPase plays a critical role in sodium reabsorption across airway epithelium. Nasal epithelium shows increased Na+/K+ ATPase activity in cystic fibrosis (CF) but Na+/K+ ATPase has not been characterized in human lung epithelium or compared in CF and normal lung. We measured 3[H] ouabain binding and Na+/K+ ATPase activity in human tracheal epithelium and compared Na/K ATPase activity in bronchial epithelium in CF and control subjects. In tracheal epithelium Na+/K+ ATPase pumps were abundant and of high 3[H] ouabain affinity (Kd 4.7 nM, Bmax 38 pmol/mg) and Na+/K+ ATPase activity was 55 +/- 8 nmol/mg protein/min. Bronchial epithelial Na+/K+ ATPase activity was twofold higher in CF patients than in controls. The increased Na+/K+ ATPase activity may contribute to the increased sodium reabsorption seen in cystic fibrosis.

Adolescent↗
PubMed1997

Serum IgG response to an outer membrane porin protein of Burkholderia cepacia in patients with cystic fibrosis.

Early and accurate diagnosis of Burkholderia cepacia infection is important, particularly if segregation is to prevent patient-to-patient transmission. We have examined the serum response to a B. cepacia-specific 80-kDa outer membrane protein. 21 patients colonised with B. cepacia and Pseudomonas aeruginosa for 2-51 months (mean 11 months) were age- and sex-matched with 21 patients colonised with P. aeruginosa but not B. cepacia. The 80-kDa protein was recovered by electroelution from outer membrane proteins, separated by SDS-PAGE, coated onto ELISA plates, reacted with patient sera diluted 1:200, protein A-peroxidase and chromogenic substrate. We found that 19/24 patients colonised with B. cepacia and P. aeruginosa had high values, 2/24 patients had intermediate values, and 2/24 patients had a low value. 20/21 patients colonised with P. aeruginosa alone had low values and 1/21 had an intermediate value. We found that in the longitudinal serum samples studied from four patients only one patient developed high values after the first isolation of B. cepacia suggesting that seroconversion does not occur immediately after the first sputum culture of B. cepacia. We conclude that an ELISA test using B. cepacia-specific 80-kDa outer membrane protein can distinguish B. cepacia colonised and non-colonised patients and may be useful in the early diagnosis of B. cepacia infection.

Adolescent↗
PubMed1996

Fc receptor off-signal in the B cell involves apoptosis.

By linking surface Ig to the FcR Fc gamma RII on the mouse B lymphocyte surface, whole anti-Ig has been shown to block cell cycle entry and subsequent Ab production, a phenomenon called the "Fc receptor off-signal." IL-4 or blocking Ab to Fc gamma RII, present with whole anti-Ig, restores cell cycle progress to the levels observed with F(ab')2 anti-Ig. The current study demonstrates that under "off-signal" conditions with whole anti-Ig, the early entry of B cells into apoptosis was accelerated relative to medium alone or equimolar F(ab')2 anti-Ig. All reagents tested which opposed the whole-anti-Ig-induced blockade of B cell cycle entry also protected B cells from apoptosis (IL-4, PMA, dextran sulfate, and the monoclonal anti-Fc gamma RII 2.4G2). This protective effect was most evident at 4 to 12 h, waning at later times. Low dose cycloheximide partially protected B cells from whole anti-Ig-induced apoptosis, but acted as a survival factor, failing to advance B cells from G0 phase or stimulate thymidine incorporation. Additive early apoptosis-associated membrane changes were transiently seen when whole anti-Ig was combined with other apoptosis-accelerating agents (trifluoperazine, staurosporine, dexamethasone, ionomycin, high-dose cycloheximide), but hypodiploid nuclei did not show this effect. B cells from bcl-2 transgenic mice showed less apoptosis when cultured with whole anti-Ig, or with any of the other agents tested. At 4 h the bcl-2-associated reduction in hypodiploid nuclei was greater than the reduction in membrane unpacking, but by 16 h this difference was much less. These results suggest that acceleration of apoptosis contributes to the inhibition of proliferation induced by whole anti-Ig.

Animals↗
PubMed1996

Is Burkholderia (Pseudomonas) cepacia disseminated from cystic fibrosis patients during physiotherapy?

Burkholderia cepacia is well recognized as a potential respiratory pathogen in cystic fibrosis (CF) patients and there is increasing concern about nosocomial acquisition. Environmental contamination with B. cepacia before, during and after physiotherapy was studied in eight adult CF patients. Air was sampled using a surface air sampler, and horizontal surfaces and pillows were sampled with moistened swabs and contact plates, respectively. Thirty-nine (40%) of 97 air samples were positive and counts ranged from 1-63 cfu/m3. Forty-four percent of samples taken after physiotherapy were positive. B. cepacia was not recovered from sinks or horizontal surfaces but the pillows of three patients were positive. B. cepacia is disseminated into the immediate environment by adult CF patients receiving physiotherapy. The potential risk of person-to-person transmission during hospitalization justifies the recommendation that B. cepacia-positive patients should be segregated from other CF patients.

Adult↗
PubMed1996

Glutathione S-transferase GSTT1 genotypes and susceptibility to cancer: studies of interactions with GSTM1 in lung, oral, gastric and colorectal cancers.

Allelism in glutathione S-transferase GSTM1 and GSTT1 has been suggested as a risk factor in various cancers. Accordingly, we describe a group of case-control studies carried out to identify associations between GSTT1 genotypes and susceptibility to lung, oral, gastric and colorectal cancers. The frequencies of the putatively high risk GSTT1 null genotype were not increased in the lung, oral or gastric cancer cases compared with controls but the frequency of this genotype was significantly increased (P = 0.0011, odds ratio = 1.88) in the colorectal cancer cases. No significant interactions between the GSTT1 and GSTM1 null genotypes types were identified in the cancer groups studied. Indeed, no significant associations between GSTM1 genotypes and susceptibility were identified though further evidence was obtained that the protective effect of GSTM1*A and GSTM1*B is not equal. The data complement studies showing that GSTT1 null is associated with an increased susceptibility to total ulcerative colitis and suggests that this enzyme is important in the detoxification of unidentified xenobiotics in the large intestine.

Case-Control Studies↗
PubMed1995

Membrane unpacking and the rapid disposal of apoptotic cells.

There is evidence that macrophages can recognize phosphatidylserine (PS) on the surface of apoptotic thymocytes, where PS exposure relates to looser packing ('unpacking') of the polar headgroups of the outer lamina, detectable by lipophilic dyes (Fadok, V.A., Voelker, D.R., Campbell, P.A., Cohen, J.J., Bratton, D.L. and Henson, P.M. (1992) J. Immunol. 148, 2207). We have shown that membrane unpacking also occurs in B cells, where this event actually precedes DNA cleavage (Mower, D.A. Jr., Peckham, D.W., Illera, V.A., Fishbaugh, J.K., Stunz, L.L. and Ashman, R.F. (1994) J. Immunol. 152, 4832). This paper demonstrates that the time interval between membrane unpacking (detected as merocyanine 540 binding) and DNA cleavage (detected by flow cytometry of propidium iodide stained nuclei) also occurs in both T cells and thymocytes. The tight coupling of these two apparently distinct events is emphasized by their co-regulation by a variety of agents which accelerate or inhibit apoptosis. One hypothesis to explain the very low numbers of free apoptotic cells seen in vivo is that macrophages can recognize cells with unpacked membranes and destroy them before they cleave their DNA. In support of this hypothesis, we demonstrated that parenteral cycloheximide triggers a wave of apoptosis in the spleen detected by merocyanine 540 as well as by hypodiploid nuclei. Significantly, both parameters returned from peak values at 2 h virtually to normal by 4 h, testifying to the existence of a rapid disposal mechanism in vivo for cells with unpacked membranes as well as hypodiploid nuclei.

Animals↗
PubMed1994

Familial translocation t(10;14) (q26.1;q32.3): report of three offspring with 10q deletion and 14q duplication.

We describe two brothers and a cousin with common clinical features, including mild mental retardation, motor delays, hypotonia with truncal ataxia, esotropia, and mild facial and hand dysmorphia. The initial routine chromosome study failed to detect any abnormality in the proband. Based on a high index of clinical suspicion, high-resolution chromosome studies were performed on the proband's parents. A small reciprocal translocation t(10;14) (q26.1;q32.3) was detected in the father. The breakpoint on the derivative chromosome 14 was further placed telomeric to the immunoglobulin heavy-chain gene cluster at the band q32.33 by fluorescence in situ hybridization. Studies of the proband and two affected paternal cousins revealed that each had inherited the same derivative chromosome 10 from their carrier parents. This unbalanced karyotype resulted from an adjacent-1 segregation of the 10;14 translocation.

Abnormalities, Multiple↗
PubMed1994

Airborne dissemination of Burkholderia (Pseudomonas) cepacia from adult patients with cystic fibrosis.

BACKGROUND: Burkholderia (Pseudomonas) cepacia is an increasingly important pathogen in patients with cystic fibrosis but it is unclear how it spreads from patient to patient. A study was undertaken to determine whether B cepacia could be recovered from room air occupied by colonised adult patients with cystic fibrosis. METHODS: Air samples were obtained consecutively from an enclosed room or isolation cubicle before, during, and after occupation by six patients on nine occasions using a surface air sampler incorporating contact plates with selective medium. Settle plates were also used and sputum from five patients was cultured. RESULTS: B cepacia was recovered from room air during occupation by five of six patients, the number of bacteria ranging from 1 to 158 cfu/m3 (mean 32 cfu/m3). The number of bacteria isolated was greater when patients were coughing. B cepacia persisted in room air on four occasions after the patient left the room, on one occasion for up to 45 minutes. CONCLUSIONS: The isolation of B cepacia from the air of rooms occupied by colonised patients suggests that dissemination might occur by aerosol as well as by direct physical contact with patients or contaminated environmental sites.

Adult↗
PubMed1994

Effect of antibiotic treatment on inflammatory markers and lung function in cystic fibrosis patients with Pseudomonas cepacia.

BACKGROUND: The acquisition of Pseudomonas cepacia in patients with cystic fibrosis is associated with increasing deterioration in lung function and more frequent hospital admissions. Pseudomonas cepacia is usually resistant to several antibiotics in vitro, but the response of patients colonised with the organism has not been extensively studied in vivo. METHODS: A three month prospective study was performed to investigate the response of 14 Ps cepacia positive patients and 10 Ps cepacia negative patients to a two week course of intravenous antibiotics. All those who were Ps cepacia negative and six of the 14 Ps cepacia positive patients had Ps aeruginosa in their sputum which was sensitive to the prescribed therapy. The inflammatory markers C-reactive protein, white blood cell count, serum lactoferrin, neutrophil elastase/alpha 1-antitrypsin complex, and tumour necrosis factor alpha were measured at the start and end of each antibiotic course. RESULTS: The median (range) % improvement in baseline FEV1 and FVC following treatment in the group as a whole was 15.2% (-23.5% to 156.3%) and 23.9% (-36.8% to 232.7%) respectively. There was no statistical difference in improvement in lung function, body weight, or inflammatory markers between individuals who were Ps cepacia positive and those who were Ps cepacia negative. CONCLUSIONS: Patients who are Ps cepacia positive appear to respond as well to intravenous antibiotics as those who are Ps cepacia negative, despite having lower lung function and a bacterium in their sputum which is resistant in vitro to the antibiotics used.

Adult↗
PubMed1993

Regulation of apoptosis in vitro in mature murine spleen T cells.

Previously it has been shown that thymocytes undergo apoptosis, a form of programmed cell death, in response to glucocorticoids. This classic form of apoptosis is prevented by inhibition of protein synthesis. The current paper demonstrates that mature T cells also undergo apoptosis, but that the regulation of apoptosis in spleen T cells differs from that of thymocytes. Mature mouse spleen T cells were shown to die by apoptosis, not necrosis, when cultured without an added stimulus. Assays for apoptosis included internucleosomal DNA cleavage by gel electrophoresis, percent fragmentation of DNA by the diphenylamine method, and percent of cells with hypodiploid DNA by flow cytometry. The percent of apoptotic cells was 2% in fresh spleen T cells, and increased at least until 16 h, when 21% were apoptotic. Dexamethasone caused apoptosis in both thymus and spleen T cells, but only thymocytes showed a requirement for protein synthesis in dexamethasone-induced death. Cycloheximide increased apoptosis in spleen T cells, indicating that apoptosis was controlled by newly synthesized protective proteins. Spontaneous apoptosis was decreased in spleen T cells by protein kinase C activation, and was increased by H7 and staurosporine, which inhibits protein kinases, in contrast with the behavior of thymocytes. The protein kinase A/G inhibitor HA1004 also decreased spleen T cell apoptosis. The contrasting effects of cycloheximide on thymocytes and spleen T cells occurred over the same concentration range, and the same was true for PMA. The dexamethasone dose-response curves were similar, except that a greater proportion of spleen T cells were dexamethasone-resistant. These data support the hypothesis that the apoptosis program in T cells undergoes a transition during their maturation, such that apoptosis in mature T cells is regulated more like that of mature B cells than that of thymocytes.

Animals↗