Search PubMed⌕ Search

Biomedical subjects

M A Hall

Publications and source records attributed to M A Hall.

At least 19 recordsLinked to original sources
PubMed1995

Isolation of small, primitive human hematopoietic stem cells: distribution of cell surface cytokine receptors and growth in SCID-Hu mice.

Human CD34+ cells were subfractionated into three size classes using counterflow centrifugal elutriation followed by immunoadsorption to polystyrene cell separation devices. The three CD34+ cell fractions (Fr), Fr 25/29, Fr 33/37, and Fr RO, had mean sizes of 8.5, 9.3 and 13.5 microns, respectively. The majority of cells in the large Fr RO CD34+ cell population expressed the committed stage antigens CD33, CD19, CD38, or HLA-DR and contained the majority of granulocyte-macrophage colony-forming units (CFU-GM), burst-forming units-erythroid (BFU-E), and CFU-mixed lineage (GEMM). In contrast, the small Fr 25/29 CD34+ cells were devoid of committed cell surface antigens and lacked colony-forming activity. When seeded to allogeneic stroma, Fr RO CD34+ cells produced few CFU-GM at week 5, whereas cells from the Fr 25/29 CD34+ cell population showed a 30- to 55-fold expansion of myeloid progenitors at this same time point. Furthermore, CD34+ cells from each size fraction supported ontogeny of T cells in human thymus/liver grafts in severe combined immunodeficient (SCID) mice. Upon cell cycle analyses, greater than 97% of the Fr 25/29 CD34+ cells were in G0/G1 phase, whereas greater proportions of the two larger CD34+ cell fractions were in active cell cycle. Binding of the cytokines interleukin (IL)-1 alpha, IL-3, IL-6, stem cell factor (SCF), macrophage inhibitory protein (MIP)-1 alpha, granulocyte colony-stimulating factor (G-CSF), and granulocyte-macrophage (GM)-CSF to these CD34+ cell populations was also analyzed by flow cytometry. As compared with the larger CD34+ cell fractions, cells in the small Fr 25/29 CD34+ cell population possessed the highest numbers of receptors for SCF, MIP1 alpha, and IL-1 alpha. Collectively, these results indicate that the Fr 25/29 CD34+ cell is a very primitive, quiescent progenitor cell population possessing a high number of receptors for SCF and MIP1 alpha and capable of yielding both myeloid and lymphoid lineages when placed in appropriate in vitro or in vivo culture conditions.

Animals↗
PubMed1995

HLA-DRB, -DQA, and -DQB polymorphism in celiac disease and enteropathy-associated T-cell lymphoma. Common features and additional risk factors for malignancy.

CD is a gluten-sensitive enteropathy, strongly associated with expression of the DQA1*0501, DQB1*0201 genotype. CD patients have an increased risk of malignancy, particularly EATCL. However, it is controversial as to whether adults with EATCL represent a subgroup of patients with CD or should be regarded as a distinct entity. To investigate the genetic relationship between CD and EATCL, HLA class II DRB1, DQA1, and DQB1 typing of peripheral blood, frozen or paraffin-embedded biopsy tissue obtained from Caucasian patients with CD (n = 91) or EATCL (n = 47) was performed by PCR-SSOP typing. Genotype frequencies were compared with those observed in 151 unrelated control individuals. A total of 83 (91%) of 91 CD patients were of DQA1*0501, DQB1*0201 genotype (pc < 10(-6), RR = 522.2), compared with 40 (93%) of 43 EATCL patients (pc < 10(-6), RR = 44.2) with amplifiable DNA versus 35 (23%) of 151 controls. DRB1*03 frequencies were also elevated in both patient groups (79 of 91 in CD [87%; pc < 10(-6), RR = 24.5] and 38 of 40 in EATCL [95%; pc < 10(-6), RR = 70.7]) compared with controls (32 of 151, 21%). These results confirm previous studies of HLA associations in CD and also suggest that EATCL arises in individuals with the DQA1*0501, DQB1*0201 CD-predisposing genotype. However, the frequency of DRB1*03,04 heterozygotes was significantly increased in the EATCL group (16 of 40, 40%) compared with both control individuals (3 of 151, 2%; pc < 10(-6), RR = 32.9) and uncomplicated CD patients (6 of 91, 7%; pc = 0.04, RR = 9.4).(ABSTRACT TRUNCATED AT 250 WORDS)

Adolescent↗
PubMed1995

Healthy human T-cell receptor beta-chain repertoire. Quantitative analysis and evidence for J beta-related effects on CDR3 structure and diversity.

Analysis of TCR repertoire usage and clonality is of potential value in understanding the pathogenesis of a number of human immune-mediated diseases. In diseases that are likely to be dependent on antigen-driven T cells, it has been suggested that particular TCR junctional region or CDR3 sequences may be critical. Rigorous methods for TCR analysis which are both quantitative and qualitative are therefore required. Of those commonly available, only anchor and inverse PCR are capable of giving high-quality information on V, D, N, and J region usage, but it has not been established whether both methods are quantitatively or analytically equivalent. We show here that both methods detected considerable variability in the usage of V beta and J beta segments in the peripheral blood repertoire of a normal individual. No preferential V-J pairing could be demonstrated. An excess usage of J beta 2 family members was indicated by both methods, although the relative usage of different J beta 2 families differed between the two techniques. The predominantly used V beta usage showed that for some families, estimates of their frequency in the repertoire differed significantly between the anchor and inverse libraries. When sampling relatively few clones the variation between V beta families estimated using the two methods can be considerable. This is likely to be a result of sampling error from a large gene family. Large-scale screening of several thousand clones is recommended to confirm the absolute values obtained from sequencing. Variation in CDR3 length appeared to be normally distributed, suggesting that a statistically optimal junctional region length may have been selected for contact with antigen. CDR3 length distribution differs significantly between receptors, which have rearranged to J beta 1 versus J beta 2 families, with the J beta 2-associated CDR3 on average between 0.5 and 1.2 of an amino acid longer. Thus the TCR beta junctional region repertoire of humans is subject to structural constraints associated with J beta usage. It will be important to establish whether variation in CDR3 length and J beta usage exists between subsets of human T cells in order to interpret TCR repertoire data from disease and control tissues.

Adult↗
PubMed1995

T cell receptor usage in rheumatoid arthritis.

The structure of alpha beta T cell receptors (TCR) is restricted in a number of rodent and human antigen responses. In several rodent EAE models of multiple sclerosis a limited range of T cell receptors are expressed by T cells which respond to the inciting antigen and are capable of transferring the disease to naive animals. These observations have raised the question of whether in rheumatoid arthritis (RA), a particular T cell receptor structural signature can be identified among T cells derived from the synovium compared to autologous peripheral blood. The parameters which are usually measured are TCR variable region usage, oligoclonality and/or limited junctional region usage. A large number of studies have been carried out and results are variable with some authors claiming evidence for the effect of uncharacterised superantigens expanding or deleting T cells with particular V beta regions while others have suggested that observations of restricted V region usage and limited junctional regions imply that clones of cells have been expanded by antigen. So far none of these studies have led to the identification of an antigen or superantigen which plays a role in RA pathogenesis.

Animals↗
PubMed1995

Urinary tract candidiasis in neonates and infants.

OBJECTIVE: To examine the range of disease caused by invasive Candida infection in neonates and infants and to discuss the available treatment options, particularly surgery and drug therapy. PATIENTS AND METHODS: Five consecutive infants with invasive urinary tract Candida infection presenting over an 18-month period were reviewed. Treatment protocols included a combination of surgery and treatment with amphotericin, flucytosine and fluconazole. RESULTS: The range of disease severity from simple Candida urinary tract infection to overwhelming multi-organ sepsis was demonstrated. Urinary tract obstruction was identified as a predisposing factor in three of the five cases. In all cases, infection was cleared by the treatment protocol. Two cases with bilateral renal pelvic fungal balls showed resolution with no surgery in three kidneys and showed no advantage of pyelotomy and perfusion. CONCLUSION: The results question the role of surgery, which may be limited to the relief of primary urological obstruction. We advocate the use of oral fluconazole to prevent or treat early systemic infection and, for severe systemic infections, a prolonged course of fluconazole in combination with flucytosine should be considered as an alternative to amphotericin, which is toxic and can only be given intravenously.

Amphotericin B↗
PubMed1995

Neonatal chest drain insertion--an animal model.

Trainees rarely see a neonatal pneumothorax because of the combination of decreased doctors' hours, the use of surfactant, and modern ventilator techniques. An animal model, using a dead rabbit, is described that could be used to train doctors and others in the management of this serious complication of neonatal care.

Animals↗
PubMed1994

Association of TAP2 polymorphism with rheumatoid arthritis is secondary to allelic association with HLA-DRB1.

OBJECTIVE: To study polymorphisms of the newly described TAP2 locus in rheumatoid arthritis (RA) and to analyze their relationship with HLA-DRB1 alleles previously implicated in the development of the disease. METHODS: TAP2 polymorphic residues at 3 sites, Val/Ile-379, Ala/Thr-565, and Ala/Thr-665, were characterized by amplification refractory mutation system polymerase chain reaction in 185 RA patients and 48 HLA-DR4 positive healthy controls. HLA-DR4 subtypes were determined by sequence-specific priming and oligonucleotide hybridization. RESULTS: The frequencies of Ile-379, Thr-565, and Thr-665 were significantly increased in DR4 positive versus DR4 negative RA patients. TAP2 genotype distributions also differed between the patient groups stratified by DR4 status. However, no significant differences in TAP2 polymorphisms were observed between DR4 positive RA patients and DR4 positive controls, although relationships between specific DR4 subtypes and TAP2 variants were identified. CONCLUSION: Particular TAP2 polymorphisms are associated with distinct HLA-DR specificities in both normal and RA populations. Thus, the prevalence of specific TAP2 residues and genotypes in RA appears to be secondary to the HLA-DR frequencies and genotypic combinations that are typical of RA.

Adult↗
PubMed1994

The large granular lymphocyte syndrome with rheumatoid arthritis. Immunogenetic evidence for a broader definition of Felty's syndrome.

OBJECTIVE: To assess whether the HLA-DR4 association found in rheumatoid arthritis (RA) is also seen in the large granular lymphocyte (LGL) syndrome. METHODS: HLA-DR genotyping was performed using restriction fragment length polymorphism and polymerase chain reaction analysis. RESULTS: LGL syndrome patients with RA showed the same HLA-DR4 association seen in RA/Felty's syndrome (FS), while LGL syndrome patients without arthritis did not. CONCLUSION: It is proposed that FS and the LGL syndrome represent different variants of a broader syndrome comprising RA, neutropenia, LGL expansions, HLA-DR4 positivity, and splenomegaly.

Adult↗
PubMed1994

Associations between alleles of the major histocompatibility complex-encoded ABC transporter gene TAP2, HLA class II alleles, and celiac disease susceptibility.

The study of celiac disease among Southern European populations has confirmed the hypothesis from Northern Europe that a close association exists between disease susceptibility and a combination of polymorphic alleles at the HLA-DQ loci (DQA1*0501-DQB1*0201) arranged either in a cis- or a trans-configuration. Attempts to identify additional genetic influences have been inconclusive, although many studies have raised possibilities of further major histocompatibility complex (MHC)-linked susceptibility genes. This study examines the disease associations of polymorphisms of a recently discovered gene located close to the DQ loci, TAP2, whose products are thought to be involved in the transport of antigen peptides across the endoplasmic reticulum for binding to HLA class I molecules. Like the products of the DQ loci, the product of TAP2 forms part of a heterodimeric molecule with products of a second genetic locus, TAP1, which is located centromerically to TAP2. The populations studied were central Italians from Rome and Ashkenazi Jews from Rehovot, Israel. HLA studies demonstrate that the Roman celiac group has a high proportion of people with DR3-negative celiac disease in whom the combination DR5/7 is frequently found. In Israel, 20% of celiac patients lack the DQ susceptibility markers but are DR4 positive. The polymorphic substitutions of TAP2 studied encode amino acid changes in the trans-membrane region (position 379) and the ATP-binding cassette region (positions 565 and 665) of the protein. No TAP2-specific disease associations were found in any HLA subgroup.(ABSTRACT TRUNCATED AT 250 WORDS)

ATP Binding Cassette Transporter, Subfamily B, Mem↗
PubMed1994

Complement and antibody in neutrophil-mediated killing of type V group B streptococcus.

Serious infections caused by type V group B streptococci (GBS) are increasing. The requirements for antibody, complement, and neutrophil receptors in the killing of 12 clinical type V GBS isolates were investigated. When tested at concentrations of 33%, 5% and 1%, a human serum pool promoted neutrophil-mediated killing of the 12 isolates at a mean of 83% +/- 9%, 77% +/- 17%, and 14% +/- 28%, respectively. Addition of heated immune rabbit serum to the 5% or 1% pool increased killing significantly (97% +/- 2% or 80% +/- 15%, respectively, P < .01). With hypogammaglobulinemic serum, complement-mediated killing ranged from 74% +/- 2% for a strain designated resistant to 98% +/- 1% for a strain designated sensitive. Neutrophil-mediated killing was not altered by use of human sera deficient in C4 or C7 but was reduced significantly with C3-deficient serum (P < .05). Maximal inhibition of neutrophil-mediated killing was observed by monoclonal antibody blockade of complement receptor (CR) 3 alone or in combination with CR1 or Fc receptor III. Thus, C3 is required and specific antibody promotes neutrophil-mediated killing of type V GBS. Neutrophil CR3 and either CR1 or Fc receptor III optimize phagocytosis. A number of host responses function in concert to effect optimal neutrophil-mediated killing of clinical isolates of type V GBS.

Animals↗
PubMed1994

The problems with rule-based rationing.

Centralized, democratic rules are often asserted as a superior basis for rationing than individualized physician discretion. This article counters this prevailing wisdom by exploring the deficiencies of rule-based rationing. Rules are too imprecise to accurately reflect all the nuances of physical and mental impairment and the complexity of medical science, particularly considering the widely varying personal values that different patients attach to medical risk and benefit. Rule-based rationing also suffers from the biasing effects of interest group pressure on political processes and the tendency to absolve physicians from any moral responsibility for the rationing decisions they implement. Internalizing cost constraints is a more socially and professionally acceptable means of rationing and, in any event, it is inevitable since even a preponderance of rule-based rationing will leave considerable areas of discretion for physician judgment in the implementation and interpretation of the rules. As a consequence, despite the flaws of bedside rationing, it is foolhardy to dispense with it entirely in favor of an exclusively rule-based system.

Cultural Diversity↗
PubMed1994

Surfactant phosphatidylcholine composition during dexamethasone treatment in chronic lung disease.

OBJECTIVES: To determine whether dexamethasone 'matures' the phosphatidylcholine (PC) composition of broncheoalveolar fluid in infants at high risk of neonatal chronic lung disease (CLD), either by increasing the proportion of dipalmitoylphosphatidylcholine (DPPC), expressed as a percentage of total PC (%DPPC), or by increasing the ratio of DPPC to palmitoyloleoylphosphatidylcholine (DPPC:POPC ratio). DESIGN: Double blind, placebo controlled. SETTING AND PATIENTS: Sixteen infants < 32 weeks' gestation, < 1250 g birth weight who were dependent on mechanical ventilation and requiring a fractional inspired oxygen of > 0.30 at 12 days of chronological age. INTERVENTION: Randomisation to receive a two week reducing course of dexamethasone base at an initial dose of 0.2 mg/kg three times a day, or equivalent volumes of normal saline, starting at 14 days. Eight infants were randomised into each group. Broncheoalveolar lavage was performed serially throughout the study period or until extubation. PC composition of the fluid was analysed by high performance liquid chromatography. OUTCOME MEASURES: The %DPPC and the DPPC:POPC ratios were calculated for individual infants for days -1 and 0 combined, days 1 and 3 combined, and days 5 and 7 combined. Analysis of covariance was used to analyse the results. RESULTS: The DPPC:POPC ratio was significantly less in the treated group than the placebo group on days 1 and 3, and not greater as the hypothesis stated. Three out of five infants treated with dexamethasone and for whom data were available showed a substantial rise in DPPC:POPC ratio on days 5/7, compared with the placebo group, but overall these changes were not statistically significant. CONCLUSIONS: The data do not support the hypothesis that dexamethasone's action in producing a clinical improvement within the first 72 hours of treatment for neonatal CLD is by the 'maturation' of pulmonary surfactant PC.

1,2-Dipalmitoylphosphatidylcholine↗