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Biomedical subjects

Michael F McDermott

Publications and source records attributed to Michael F McDermott.

At least 19 recordsLinked to original sources
PubMed2006

Hereditary auto-inflammatory disorders and biologics.

The term auto-inflammatory disorders has been coined to describe a group of conditions characterized by spontaneously relapsing and remitting bouts of systemic inflammation without apparent involvement of antigen-specific T cells or significant production of auto-antibodies. The hereditary periodic fever syndromes are considered as the prototypic auto-inflammatory diseases, and genetic studies have yielded important new insights into innate immunity. DNA analysis has greatly enhanced the clinical characterization of these conditions, and elucidation of their molecular aetiopathogenesis has suggested that therapies may be aimed at specific targets within the immune cascade. The availability of biologic response modifiers such as inhibitors of tumour necrosis factor (TNF) and interleukin-1beta has greatly improved the outlook for some of these disorders, although effective therapies remain elusive in patients with certain conditions, including hyperimmunoglobulinaemia-D with periodic fever syndrome (HIDS) and a proportion of those with TNF-receptor associated periodic syndrome (TRAPS). Indeed, outstanding challenges and the unique potential to further elucidate molecular mechanisms in innate immunity are illustrated by the dashed early hope that TNF blockade would be a panacea for TRAPS: not only is etanercept (Enbrel) ineffective in some cases, but there are anecdotal reports of this condition being greatly exacerbated by infliximab (Remicade).

Acne Vulgaris↗
PubMed2006

Adequacy of medical chart review to characterize emergency care for asthma: findings from the Illinois Emergency Department Asthma Collaborative.

OBJECTIVES: To assess the intermethod reliability of medical chart review compared with directly observed care in patients presenting to emergency departments (EDs) for asthma care. METHODS: ED care practices for persons with asthma were evaluated by comparing chart review with trained observers. Fifty-one patients from five EDs participating in the Illinois Emergency Department Asthma Collaborative were studied. Practices in assessment, treatment, education, and referral were measured. Eighteen elements of care were assessed. Concordance between chart and observation was measured by using the kappa statistic. RESULTS: Of 51 subjects studied, nine were children. Kappa values varied depending on content. Kappa values ranged from 0.22 to 0.91 for items reflecting asthma assessment. Good concordances (kappa = 0.50 to 0.82) were found for items reflecting treatment practices. The lowest concordances were for items assessing educational activities (kappa = 0.04 to 0.34). Referral practices had fair to moderate concordances (kappa = 0.21 to 0.45). CONCLUSIONS: Intermethod reliability of medical chart review and directly observed care varied depending on the element of care being measured. The use of chart review to measure quality of ED-based asthma care may only be appropriate for a limited number of care processes that are reliably and validly captured from chart review.

Adolescent↗
PubMed2006

Improving pediatric asthma care through surveillance: the Illinois Emergency Department Asthma Collaborative.

OBJECTIVES: To better understand and improve the care of asthma patients who require emergency department (ED) care, the Illinois Emergency Department Asthma Collaborative (IEDAC) was created to develop, test, and disseminate an ED-based surveillance system. This report describes the development and testing of the pediatric IEDAC surveillance instruments and demonstrates how these instruments can be used to describe the health status, healthcare delivery, and outcome of children using ED services. METHODS: A convenience sample of 128 children presenting to 5 EDs in Illinois for asthma care was the study base. Data were collected on monthly samples of children aged 2 through 17 years who presented to these EDs from May to November 2003. Three instruments were used to collect data regarding the children's pre-ED, ED, and post-ED experience. RESULTS: At the ED visit, 73.4% of children met national guideline criteria for persistent-level asthma symptoms. Among this group, 53.2% were using inhaled corticosteroid (ICS) medications. At 1 month follow-up, 66.6% of the children met the criteria for persistent-level asthma symptoms, which was statistically unchanged from the ED visit. Among the latter group, 64.2% were using ICS medications, again statistically unchanged compared with the ED visit. At follow-up, 24.5% of children were reported to have returned to an ED or were subsequently hospitalized. The majority of children were noted at follow-up to have limitation of at least some activity. CONCLUSIONS: Children who presented to IEDAC EDs were found to have a high level of asthma burden that continued at follow-up despite treatment. Moreover, a substantial proportion of children had returned to an ED or were subsequently hospitalized. Encouraging trends in medication use were observed, although suboptimal medication use was also observed.

Adolescent↗
PubMed2005

The tumour necrosis factor receptor-associated periodic syndrome: current concepts.

The tumour necrosis factor receptor (TNFR)-associated periodic syndrome (TRAPS) is an autosomal dominant, multisystemic, autoinflammatory disorder caused by mutations in the TNFR1 gene ( TNFRSF1A ). Traps seems to be the most common hereditary periodic fever (HPF) syndrome in some western populations, and the second most prevalent HPF worldwide, behind familial mediterranean fever (FMF). The proteins involved in susceptibility to TRAPS (TNFRSF1A) and FMF (pyrin) are both members of the death-domain-fold superfamily. Mutations affecting these proteins might cause dysregulation of innate immune responses, with a propensity to autoinflammation. Most TRAPS patients have reduced blood levels of soluble TNFRSF1A between attacks, with an inappropriately small increase during bouts of fever. The pathogenesis of the 'hyperinflammatory state' in TRAPS has been variously ascribed to a shedding defect of TNFRSF1A from the cell surface resulting in increased TNF inflammatory signalling, or impaired TNF apoptotic signalling. Some low-penetrance TNFRSF1A variants also contribute to the clinical phenotype in individuals carrying other HPF-associated mutations, and have been reported in several disorders such as Behçet's disease and systemic lupus erythematosus. Synthetic anti-TNF agents provide a rational form of therapy for TRAPS, and have been shown to delay or indeed prevent development of systemic amyloidosis (AA type), a life-threatening complication in this condition.

Animals↗
PubMed2005

Tumor necrosis factor receptor I from patients with tumor necrosis factor receptor-associated periodic syndrome interacts with wild-type tumor necrosis factor receptor I and induces ligand-independent NF-kappaB activation.

OBJECTIVE: To investigate the molecular consequences of expressing mutated forms of tumor necrosis factor receptor I (TNFRI) as found in patients with TNFR-associated periodic syndrome (TRAPS). METHODS: We cloned and expressed full-length wild-type (WT) and T50K and P46L variants of TNFRI using a new tightly regulated doxycycline-dependent expression system. This system enabled the study of molecular interactions between these receptors at both physiologic and pathophysiologic levels of expression. RESULTS: We used chemical crosslinking on the cell surface to show that WT and mutant forms of TNFRI, derived from TRAPS patients, interact in the absence of TNF ligand. Doxycycline-controlled up-regulation of one TNFRI allele, either WT or mutant, caused down-regulation of the other allele, indicating dynamic control of cell surface assembly. We also demonstrated that increased expression of mutant TNFRI (T50K) was associated with a parallel increase in NF-kappaB p65 (RelA) subunit activation, which did not occur with increased expression of WT TNFRI. CONCLUSION: The T50K TRAPS-related variant is capable of sustaining inappropriate NF-kappaB activation, resulting in persistent auto-inflammation in target organs such as skin, synovial membrane, and the central nervous system. We conclude that some of the inflammatory processes seen in TRAPS do not involve direct interaction of TNF with its receptors, but that other proinflammatory mechanisms capable of up-regulating TNFRI expression may cause cellular activation through the NF-kappaB signaling pathway.

Cloning, Molecular↗
PubMed2004

Spectrum of clinical features in Muckle-Wells syndrome and response to anakinra.

OBJECTIVE: Mutations in the NALP3/CIAS1/PYPAF1 gene are associated with the autoinflammatory diseases Muckle-Wells syndrome (MWS), familial cold autoinflammatory syndrome (FCAS), and neonatal-onset multisystem inflammatory disease (NOMID), which is also known as chronic infantile neurologic, cutaneous, articular (CINCA) syndrome. Molecular studies suggest that NALP3 is involved in the processing of interleukin-1beta (IL-1beta), prompting us to investigate whether IL-1 blockade may be therapeutic in patients with MWS. METHODS: We reviewed the clinical features of 3 members of a family, all of whom had MWS associated with the NALP3 variant V200M (also designated V198M), and evaluated the response of their inflammatory disease to treatment with the recombinant human IL-1 receptor antagonist anakinra. The subjects kept a diary of symptoms and underwent fortnightly clinical and laboratory assessments, including measurement of the serum amyloid A protein concentration. RESULTS: Each subject had fever, rashes, arthralgia, conjunctivitis, sensorineural deafness, and an intense acute-phase response characteristic of MWS. However, additional features were identified, including exacerbation of their disease by cold and neurologic manifestations, that have hitherto been described only in FCAS and NOMID, respectively. Clinical and serologic evidence of active inflammatory disease resolved rapidly and completely during treatment with anakinra. CONCLUSION: The remarkable response of MWS to anakinra suggests that IL-1beta has a fundamental role in the pathogenesis of inflammation associated with mutations in the NALP3 gene, and supports study of IL-1 inhibition in patients with NOMID/CINCA syndrome or FCAS. The clinical features of the various syndromes associated with mutations in the NALP3 gene may overlap to a greater extent than has previously been recognized.

Acute-Phase Reaction↗
PubMed2004

A common pathway in periodic fever syndromes.

Familial Mediterranean fever (FMF) is an autosomal recessive disease due to mutations in pyrin, which normally inhibits pro-interleukin-1beta (IL-1beta) cytokine processing to the active form. A novel role for pyrin has been proposed by Shoham et al., who studied patients with an autosomal dominant disease called pyogenic arthritis, pyoderma gangrenosum, and acne (PAPA) syndrome. They demonstrated an interaction between pyrin and proline serine threonine phosphatase-interacting protein 1 (PSTPIP1), the protein involved in PAPA, and thus revealed a biochemical pathway common to both FMF and PAPA.

Adaptor Proteins, Signal Transducing↗
PubMed2004

NALP3 forms an IL-1beta-processing inflammasome with increased activity in Muckle-Wells autoinflammatory disorder.

Mutations within the NALP3/cryopyrin/CIAS1 gene are responsible for three autoinflammatory disorders: Muckle-Wells syndrome, familial cold autoinflammatory syndrome, and CINCA. The NALP3 protein is homologous to NALP1, which is a component of the inflammasome, a molecular platform that activates the proinflammatory caspases-1 and -5. NALP3 (and other members of the NALP family) lacks the C-terminal, CARD-containing sequence of NALP1, and its role in caspase activation is unclear. Here, we report that NALP2 and NALP3 associate with ASC, the CARD-containing protein Cardinal, and caspase-1 (but not caspase-5), thereby forming an inflammasome with high proIL-1beta-processing activity. Macrophages from Muckle-Wells patients spontaneously secrete active IL-1beta. Increased inflammasome activity is therefore likely to be the molecular basis of the symptoms associated with NALP3-dependent autoinflammatory disorders.

Adaptor Proteins, Signal Transducing↗
PubMed2004

The major histocompatibility complex origin.

The present review focuses on the history of genes involved in the major histocompatibility complex (MHC), with a special emphasis on class I function in peptide presentation. The MHC class II story is covered in less detail, as it does not have a major impact on the general understanding of the MHC evolution. We first redefine the MHC as the definition evolved over time. We then use phylogenetic analysis to investigate the history of genes involved in the MHC class I process. As not all the genes involved in this process have been phylogenetically analyzed and because new sequences have been recently released in biological databases, we have re-investigated this matter. In the light of the phylogenetic analysis, the functions of the orthologs of the genes involved in MHC processes are examined in species not having an MHC system. We then demonstrate that the emergence of this new function is due to various levels of co-option.

Animals↗
PubMed2003

Heterogeneity among patients with tumor necrosis factor receptor-associated periodic syndrome phenotypes.

OBJECTIVE: To investigate the prevalence of tumor necrosis factor receptor-associated periodic syndrome (TRAPS) among outpatients presenting with recurrent fevers and clinical features consistent with TRAPS. METHODS: Mutational screening was performed in affected members of 18 families in which multiple members had symptoms compatible with TRAPS and in 176 consecutive subjects with sporadic (nonfamilial) "TRAPS-like" symptoms. Plasma concentrations of soluble tumor necrosis factor receptor superfamily 1A (sTNFRSF1A) were measured, and fluorescence-activated cell sorter analysis was used to measure TNFRSF1A shedding from monocytes. RESULTS: Eight novel and 3 previously reported TNFRSF1A missense mutations were identified, including an amino acid deletion (Delta D42) in a Northern Irish family and a C70S mutation in a Japanese family, both reported for the first time. Only 3 TNFRSF1A variants were found in patients with sporadic TRAPS (4 of 176 patients). Evidence for nonallelic heterogeneity in TRAPS-like conditions was found: 3 members of the "prototype familial Hibernian fever" family did not possess C33Y, present in 9 other affected members. Plasma sTNFRSF1A levels were low in TRAPS patients in whom renal amyloidosis had not developed, but also in mutation-negative symptomatic subjects in 4 families, and in 14 patients (8%) with sporadic TRAPS. Reduced shedding of TNFRSF1A from monocytes was demonstrated in vitro in patients with the T50M and T50K variants, but not in those with other variants. CONCLUSION: The presence of TNFRSF1A shedding defects and low sTNFRSF1A levels in 3 families without a TNFRSF1A mutation indicates that the genetic basis among patients with "TRAPS-like" features is heterogeneous. TNFRSF1A mutations are not commonly associated with nonfamilial recurrent fevers of unknown etiology.

Antigens, CD↗
PubMed2003

BMS-561392. Bristol-Myers Squibb.

Bristol-Myers Squibb Pharma Co is developing the tumor necrosis factor-alpha (TNF alpha) converting enzyme inhibitor BMS-561392 (DPC-333) for the potential treatment of diseases characterized by overproduction of TNF alpha, such as rheumatoid arthritis (RA). A phase IIa trial in RA patients had commenced by April 2001, and by October 2002, BMS-561392 was also under investigation for the potential treatment of inflammatory bowel disease.

ADAM Proteins↗
PubMed2002

SPINK1 is a susceptibility gene for fibrocalculous pancreatic diabetes in subjects from the Indian subcontinent.

Fibrocalculous pancreatic diabetes (FCPD) is a secondary cause of diabetes due to chronic pancreatitis. Since the N34S variant of the SPINK1 trypsin inhibitor gene has been found to partially account for genetic susceptibility to chronic pancreatitis, we used a family-based and case-control approach in two separate ethnic groups from the Indian subcontinent, to determine whether N34S was associated with susceptibility to FCPD. Clear excess transmission of SPINK1 N34S to the probands with FCPD in 69 Bangladeshi families was observed (P<.0001; 20 transmissions and 2 nontransmissions). In the total study group (Bangladeshi and southern Indian) the N34S variant was present in 33% of 180 subjects with FCPD, 4.4% of 861 nondiabetic subjects (odds ratio 10.8; P<.0001 compared with FCPD), 3.7% of 219 subjects with type 2 diabetes, and 10.6% of 354 subjects with early-onset diabetes (aged <30 years) (P=.02 compared with the ethnically matched control group). These results suggest that the N34S variant of SPINK1 is a susceptibility gene for FCPD in the Indian subcontinent, although, by itself, it is not sufficient to cause disease.

Chronic Disease↗
PubMed2002

An Israeli Arab patient with a de novo TNFRSF1A mutation causing tumor necrosis factor receptor-associated periodic syndrome.

OBJECTIVE: To investigate genetic susceptibility to recurrent fevers, generalized severe myalgia, and migratory erythema in an Israeli Arab child with no family history of similar disease. METHODS: DNA sequencing of exons 1-6 of the TNFRSF1A gene (formerly TNFR1) was performed in the patient and his parents to determine the presence of the autosomal-dominant tumor necrosis factor receptor-associated periodic syndrome (TRAPS); informative markers spanning the TNFRSF1A locus were used to genotype all available members of the patient's family. The TNFRSF1A gene was subsequently screened in 69 healthy Arab controls and 96 Caucasian controls. Formal forensic paternity testing was performed on the child. RESULTS: We found a de novo missense mutation in exon 3 of the TNFRSF1A gene, involving a novel C-->T transition encoding a Cys70Arg (C70R) variant, in the Israeli Arab patient. Eight of the common familial Mediterranean fever (FMF) gene MEFV mutations were excluded. This mutation was not present in the parents or siblings, or among the 69 healthy Arab controls. However, another TNFRSF1A variant, Pro46Lys (P46L), was present in 1 of the Arab controls. CONCLUSION: We have identified a TNFRSF1A mutation associated with periodic fever in an Arab patient, and a TNFRSF1A variant, which is variably pathogenic in Caucasians, in an Arab control. This is the first report of a de novo mutation in periodic fevers in general, and also of TRAPS in the Arab population. These findings demonstrate the need to include TRAPS in the differential diagnosis of recurrent fevers in this population.

Adolescent↗
PubMed2002

A novel mutation in the third extracellular domain of the tumor necrosis factor receptor 1 in a Finnish family with autosomal-dominant recurrent fever.

OBJECTIVE: To investigate the presence of TRAPS (tumor necrosis factor receptor-associated periodic syndrome), which is a recently defined, dominantly inherited autoinflammatory syndrome caused by mutations in the tumor necrosis factor receptor superfamily 1A gene (TNFRSF1A, CD120a), in a Finnish family with recurrent fever. METHODS: The TNFRSF1A gene was sequenced in both affected and unaffected family members. Flow cytometry and enzyme-linked immunosorbent assay analyses were used to assess membrane expression and serum levels of the TNFRSF1A protein, respectively. RESULTS: A missense mutation in exon 4, located in the third extracellular domain of TNFRSF1A and resulting in an amino acid substitution (F112I) close to a conserved cysteine, was found in all 4 affected family members and in 1 asymptomatic individual. The mutation was clearly associated with low levels of soluble TNFRSF1A as well as with the clinical symptoms of recurrent fever and abdominal pain. Impaired shedding of TNFRSF1A after phorbol myristate acetate stimulation was detected in blood granulocytes and monocytes from the 3 adult family members with the mutation, but in the child bearing the mutation and showing clinical symptoms of recent onset, the shedding defect was less marked. CONCLUSION: TRAPS should be suspected in any patient who presents with a history of intermittent fever accompanied by unexplained abdominal pain, arthritis, or skin rash, particularly in the presence of a family history of such symptoms. Screening for low serum levels of soluble TNFRSF1A identifies individuals who are likely to have TNFRSF1A mutations.

Adult↗
PubMed2002

Association of mutations in the NALP3/CIAS1/PYPAF1 gene with a broad phenotype including recurrent fever, cold sensitivity, sensorineural deafness, and AA amyloidosis.

OBJECTIVE: Familial cold urticaria (FCU) and Muckle-Wells syndrome (MWS) are dominantly inherited autoinflammatory disorders that cause rashes, fever, arthralgia, and in some subjects, AA amyloidosis, and have been mapped to chromosome 1q44. Sensorineural deafness in MWS, and provocation of symptoms by cold in FCU, are distinctive features. This study was undertaken to characterize the genetic basis of FCU, MWS, and an overlapping disorder in French Canadian, British, and Indian families, respectively. METHODS: Mutations in the candidate gene NALP3, which has also been named CIAS1 and PYPAF1, were sought in the study families, in a British/Spanish patient with apparent sporadic MWS, and in matched population controls. Identified variants were sought in 50 European subjects with uncharacterized, apparently sporadic periodic fever syndromes, 48 subjects with rheumatoid arthritis (RA), and 19 subjects with juvenile idiopathic arthritis (JIA). RESULTS: Point mutations, encoding putative protein variants R262W and L307P, were present in all affected members of the Indian and French Canadian families, respectively, but not in controls. The R262W variant was also present in the subject with sporadic MWS. The V200M variant was present in all affected members of the British family with MWS, in 2 of the 50 subjects with uncharacterized periodic fevers, and in 1 of 130 Caucasian and 2 of 48 Indian healthy controls. No mutations were identified among the subjects with RA or JIA. CONCLUSION: These findings confirm that mutations in the NALP3/CIAS1/PYPAF1 gene are associated with FCU and MWS, and that disease severity and clinical features may differ substantially within and between families. Analysis of this gene will improve classification of patients with inherited or apparently sporadic periodic fever syndromes.

Adult↗