A new ethic for medicine?
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Conflict of Interest↗
Biomedical subjects
M A Hall
Publications and source records attributed to M A Hall.
Ethical practice in managed care: a dose of realism.
This article examines the ethics of medical practice under managed care from a pragmatic perspective that gives physicians more useful guidance than do existing ethical statements. The article begins with a framework for constructing a realistic set of ethical principles, namely, that medical ethics derives from physicians' role as healers; that ethical statements are primarily aspirational, not regulatory; and that preserving patient trust is the primary objective. The following concrete ethical guidelines are presented: Financial incentives should influence physicians to maximize the health of the group of patients under their care; physicians should not enter into incentive arrangements that they are embarrassed to describe accurately to their patients; physicians should treat each patient impartially without regard to source of payment, consistent with the physician's own treatment style; if physicians depart from this ideal, they should inform their patients honestly; and it is desirable, although not mandatory, to differentiate medical treatment recommendations from insurance coverage decisions by clearly assigning authority over these different roles and by physicians advocating for recommended treatment that is not covered.
Disclosure↗
Important immunoregulatory role of interleukin-11 in the inflammatory process in rheumatoid arthritis.
OBJECTIVE: To investigate the possible immunoregulatory role of interleukin-11 (IL-11) in rheumatoid arthritis (RA). METHODS: IL-11 protein was assayed in RA tissue, and the effect of exogenous IL-11 on neutralization of endogenous IL-11 was investigated with respect to tumor necrosis factor alpha (TNFalpha), matrix metalloproteinase (MMP), and tissue inhibitor of metalloproteinases (TIMP) production. RESULTS: IL-11 was found in RA synovial membranes, synovial fluids, and blood sera. Blockade of endogenous IL-11 resulted in a 2-fold increase in TNFalpha levels, which increased to 22-fold if endogenous IL-10 was also blocked. Addition of exogenous IL-11 inhibited spontaneous TNFalpha production in RA synovium only in the presence of soluble IL-11 receptor. However, exogenous IL-11 directly inhibited spontaneous MMP-1 and MMP-3 production, and up-regulated TIMP-1 in RA synovial tissue. CONCLUSION: IL-11 has important endogenous immunoregulatory effects in RA synovium, which suggests that exogenous IL-11 may have therapeutic activity in RA.
Adjuvants, Immunologic↗
Ulnar lengthening in juvenile chronic arthritis.
Ten wrists in eight children with severe destructive changes in the wrist due to juvenile chronic arthritis underwent distraction lengthening of the ulna between 1983 and 1996 in an attempt to restore wrist alignment, which had not been preserved by previous splinting. Eight wrists in six patients (four female and two male) were evaluated. The average age at the time of operation was 13.8 years (range, 12-15.5). The average follow-up period was 70 months (range, 12-152). The average ulna minus deformity was between 8 and 9 mm. It was found that ulnar lengthening can be done safely and the procedure seems to stabilize the carpus, is likely to improve appearance, may improve function and in the majority of cases does eliminate the use of an external splint. Results seem to be stable for at least 3 to 5 years.
Adolescent↗
The distribution of human TCR junctional region lengths shifts with age in both CD4 and CD8 T cells.
Several normal and pathological antigen-driven immune responses are associated with limited TCR usage. CDR3 sequence and to some extent length represent clonal markers which can be used to follow the course of an immune response. We investigated whether differences exist in the CDR3 length distribution in the CD4 versus CD8 populations which might reflect the HLA class restriction of the T cell subpopulation. We showed that the range is similar in both the CD4 and CD8 populations for most BV families. Differences exist between CDR3 length distributions of adult versus cord blood CD4 and CD8 T cells. The percentage expressing CDR3 of 10 amino acids or more across all BV families was significantly lower in the cord blood T cells compared to the adults for both CD4 and CD8 populations. This is likely to reflect either differences in the development of the T cell population such as increased N region length post-partum or may be the result of foreign antigen exposure. To address this issue, samples of TCRBV sequences from cord and adult T cell populations were compared. No significant differences were found in either exonucleolytic removal or N region addition between the adult and cord blood samples suggesting that the population shift is the result of antigen exposure. No spectratype distortions existed for any BV family in the adult or cord blood CD4 populations; however, distortions were seen in CD8 populations from all the adults and much less frequently in the cord blood T cells. We investigated the ability to detect clonality at frequencies that one would expect to find antigen-specific T cells in the peripheral repertoire. It was possible to identify a clone at a frequency of 0.1% in a polyclonal CD4 population. This frequency corresponds to that of some individual clones after antigen-driven T cell expansion and establishes parameters within which T cell immune responses may be tracked ex vivo.
Adult↗
The use of intravenous pulsed methylprednisolone in the treatment of systemic-onset juvenile chronic arthritis.
An open prospective study using i.v. methylprednisolone in children with juvenile chronic arthritis (JCA) who had had a systemic exacerbation of disease is described. Eighteen children aged from 3 to 14 yr and 9 months (mean 9.7 yr) were treated. Ten patients (55%) had a loss of all systemic features 1 month after the pulse, and eight (45%) had a reduction in the active joint count. At this time, five of the patients on oral prednisolone had achieved a reduction in dosage. Also at 1 month, a reduction in erythrocyte sedimentation rate was observed in 11 patients (61%) and of C-reactive protein in 11 of 16 (72%). Altogether, 13 patients (72%) had a good response, while a further three (16%) went into remission. Our conclusions are that pulse methylprednisolone provides good short-term benefit in patients with systemic-onset JCA; no serious side-effects were noted. Further long-term studies are warranted.
Adolescent↗
When courts review medical appropriateness.
OBJECTIVES: The authors examined how the courts have responded to public and private insurers' use of medical appropriateness criteria to establish coverage and payment policies. METHODS: A structured review of all federal and state court health insurance cases decided between 1960 and June 1994 that involved a dispute involving medical appropriateness was performed. A total of 3,215 published court decisions were analyzed, of which 203 met the criteria of relevance and 124 explicitly mentioned medical appropriateness criteria. The main outcome variable was whether the court ordered the insurer to provide coverage. RESULTS: In 185 cases, a definitive decision was rendered, and the insurer was required to pay in 57% of the decisions. Whether the insurer relied on an assessment or not, whether the assessment process was formal or informal, and who conducted the assessment did not appear to influence courts' decisions, nor did the specificity of the coverage exclusion. Significant predictors of courts ordering coverage were court jurisdiction, contract language assigning discretion to the insurer, severity of patient's condition, and whether the treatment appeared to work for the particular patient. CONCLUSIONS: For practice guidelines to be accepted by the courts, it is more important to focus on how insurance contracts are written than on how medical assessments are performed.
Eligibility Determination↗
T cell receptor V beta gene usage in Guillain-Barré syndrome.
We set out to determine whether the T cell receptor (TCR) V beta gene usage in acute inflammatory demyelinating polyradiculoneuropathy (AIDP) is restricted. We separated activated from non-activated peripheral blood T cells with anti-IL2 receptor (anti-CD25) antibody-labelled magnetic beads from four AIDP patients and four normal control (NC) subjects. The TCR V beta gene usage of circulating activated and non-activated T cells was heterogeneous in all the patients and controls, but the activated T cells of all four of the AIDP patients showed a more limited usage of V beta genes and enhanced V beta 15 usage, as compared to the non-activated T cells. This was not seen in the healthy controls. The activated and non-activated T cells from a patient with acute motor and sensory axonal neuropathy (AMSAN) showed a similar V beta gene usage to that of the controls. From a further patient with AIDP, we studied the V beta gene usage of short-term T cell lines reactive to the peripheral nerve myelin proteins P2, P0 and the P0 peptide amino acid sequence 194-208. The V beta gene usage of the lines was heterogeneous, with enhanced usage of V beta 15 in the cell line responsive to the Pzero peptide. We conclude that T cells activated during the immune response associated with AIDP preferentially used V beta 15, which may indicate a restricted response to a common antigen, or a role for an as yet undefined superantigen in the pathogenesis of AIDP.
Adult↗
T cell receptor alpha-chain and beta-chain junctional region homology in clonal CD3+, CD8+ T lymphocyte expansions in Felty's syndrome.
OBJECTIVE: Up to 42% of patients with Felty's syndrome (FS) have peripheral blood expansions of CD3+,CD8+ large granular lymphocytes (LGLs). The aim of this study was to determine whether the T cell receptor (TCR) alpha- and beta-chain sequences of these expansions from different patients have features in common that would support the hypothesis of an antigen-driven process. METHODS: Extraction of RNA from peripheral blood lymphocytes followed by synthesis of complementary DNA, inverse polymerase chain reaction (PCR) with TCR-specific primers, bacteriophage transformation, and sequencing of PCR products. RESULTS: Structural analysis of TCR beta-chain usage in such patients demonstrated a junctional region motif comprising the amino acids -LG- or -RG- in 7 of 14 clonal sequences and the motif -GXG- in 8 of 14. A biased alpha-chain junctional region usage of a hydrophobic and/or basic amino acid at position 2 was seen in 5 of 8 expanded sequences. These features differed significantly from control sequences. CONCLUSION: Given current models of TCR-peptide-major histocompatibility complex interaction, these observations are consistent with an antigen-driven, rather than a superantigen-driven, process in at least a subgroup of patients with FS.
Aged↗
Detection of alprazolam in three cases of methadone/benzodiazepine overdose.
Benzodiazepine abuse is common among clients at methadone maintenance clinics. Diazepam and lorazepam are readily detected by immunological screening methods and confirmed by GC/MS. Alprazolam has been relatively difficult to confirm. We recently reported a modification of an existing serum HPLC procedure which allows us to analyze whole blood. We report here three cases of fatal drug overdose caused by co-ingestion of methadone and alprazolam. In all three cases, alprazolam was detected by HPLC and could not be identified by alkaline extraction GC/MS. Postmortem blood concentrations of methadone were at the lower range or below the concentrations previously identified in methadone overdose fatalities, suggesting an increased risk from co-ingestion of methadone and alprazolam.
Adult↗
Multiple T cell expansions are found in the blood and synovial fluid of patients with reactive arthritis.
OBJECTIVE: To look for evidence of T lymphocyte expansions in the blood and synovial fluid (SF) of patients with reactive arthritis (ReA). METHODS: Paired peripheral blood and synovial samples from 10 patients with ReA were studied by dual color flow cytometry using T cell receptor (TCR) V beta specific and CD4 or CD8 specific antibodies. Two synovial CD8 expansions were studied by 3 color flow cytometry. Peripheral blood samples from 13 healthy, age matched individuals were studied as controls. RESULTS: Statistically significant expansions were observed in all patients, occurring in blood and SF CD4 and CD8 compartments, but were most common in the synovial CD8 compartment. Expansions studied in further detail displayed an activated "memory" phenotype. A synovial BV22S1/CD8 expansion was seen in 5/6 patients with sexually acquired ReA. CONCLUSION: Multiple T lymphocyte expansions are found in both the blood and SF of patients with ReA. Expansions were most commonly found in the synovial CD8 compartment, where they appeared to express both activation and memory markers. This indicates that T lymphocytes (and in particular cytotoxic T cells) may play a pathogenic role in ReA. These findings are consistent with either an antigen or a superantigen driven response.
Adolescent↗
Two differentially expressed interleukin-11 receptor genes in the mouse genome.
Interleukin-11 (IL-11) is a multifunctional cytokine involved in the regulation of cell proliferation and differentiation in a variety of cell types and tissues in vitro and in vivo. The effects of IL-11 were shown to be mediated by the IL-11 receptor (hereafter referred to as IL-11 R alpha), which is a ligand-binding subunit and provides ligand specificity in a functional multimeric signal-transduction complex with gp130. Here we show that the mouse genome contains a second gene encoding an IL-11-binding protein, referred to as IL-11R beta. The structure of the IL-11R beta gene is highly similar to that of IL-11R alpha, and IL-11R beta exhibits 99% sequence identity with IL-11R alpha at the amino acid level. IL-11R beta is co-expressed with IL-11R alpha, albeit at lower levels, in embryos and in various adult tissues. IL-11R beta transcripts are abundant in testis, and, in contrast with IL-11R alpha, absent from skeletal muscle. IL-11R beta expressed in vitro binds IL-11 with high affinity, suggesting that the mouse genome contains a second functional IL-11R.
Amino Acid Sequence↗
Mediation of interleukin-11-dependent biological responses by a soluble form of the interleukin-11 receptor.
Interleukin-11 (IL-11) is a polyfunctional cytokine whose biological actions require a specific IL-11 receptor (IL-11R) and the transmembrane transducer gp130. Here we report the production of a soluble form of the murine IL-11R and demonstrate that it interacts with IL-11 ligand with high affinity. The affinity of IL-11 alone for gp130 is below the level of detection, but a complex of IL-11 and soluble IL-11R interacts with gp130 with high affinity. The addition of soluble IL-11R potentiates the effects of exogenous IL-11 in cells that are normally responsive to IL-11. A biological response to IL-11 can be reconstituted in BAF cells transfected with gp130 by addition of IL-11 and soluble IL-11R. These findings show that the cytoplasmic domain of the IL-11R is not required for the biological effects of IL-11 and that a complex of IL-11 and IL-11R mediates signalling by association with gp130.
Animals↗
The public's preference for bedside rationing.
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Disclosure↗
HLA class II region genes and susceptibility to dermatitis herpetiformis: DPB1 and TAP2 associations are secondary to those of the DQ subregion.
Classical dermatitis herpetiformis (DH) is associated with similar HLA class I, II and III polymorphisms to coeliac disease (CD). The two diseases share distinctive pathological changes to the small intestinal mucosa which reverse on withdrawal of dietary gluten. In order to determine the locus primarily associated with DH, and to examine whether there is a common genetic link predisposing to the enteropathy seen in both DH and coeliac disease, HLA-DR, DQ and DP subregion associations were investigated by HLA genotyping in 23 DH patients and 64 healthy controls. We also studied polymorphisms of the TAP2 locus, which is located between the DP and DQ subregions. Genotyping was carried out by PCR of genomic DNA with allelic assignment by sequence-specific oligonucleotide (SSO) hybridization or amplification refractory mutation system (ARMS). The strongest associations in the patient group were with HLA DRB1*0301 (91% vs 22% of controls), HLA DQB1*02 (100% vs 32% of controls) and DPB1*0101 (39% and 14%). These associations are similar to those described for CD. 100% of DH patients were positive for the DQA1*0501/DQB1*02 dimer in cis or trans and, by analogy with CD, this is probably responsible for presenting gliadin peptide implicated in the disease process. Homozygosity for DQ2 was significantly increased in the CD patient group compared to the DH patient group (65% versus 39%), and so differences in dosage of HLA class II genotypes between DH and CD may be responsible for the milder gastrointestinal symptoms characteristic of DH.
ATP Binding Cassette Transporter, Subfamily B, Mem↗
Long term follow-up of children with mixed connective tissue disease.
Mixed connective tissue disease (MCTD) is characterized by features of more than one of the rheumatic disorders with antinuclear antibodies in a speckled pattern and with antibodies to nuclear ribonucleoprotein (nRNP). MCTD is uncommon in children and long-term follow-up studies in children are infrequently reported. A retrospective review of clinical experience at five pediatric rheumatology centers provided 11 patients who met the following inclusion criteria: (1) Kasukawa's criteria for MCTD1; (2) presentation younger than 18th birthday; (3) greater than five years of follow-up; (4) completion of data collection form. The widely varying outcomes of these 11 children with MCTD on long-term follow-up may lend doubt that this is a unique and distinctive rheumatologic disorder.
Adolescent↗
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↗
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↗