Beyond Our Pages
Authors: Burton Zweiman, Marc E. Rothenberg
Journal: Journal of Allergy and Clinical Immunology (2002)

Articles of note…Editor's Note: The following 2 articles deal with the therapy of acute sinusitis, a subject of considerable interest to those treating individuals with allergic respiratory diseases.Principles of appropriate antibiotic use for acute rhinosinusitis in adultsThis report is from a committee of representatives from the American Academy of Family Physicians, the American College of Physicians–American Society of Internal Medicine, the Centers for Disease Control, and the Infectious Diseases Society of America. It discusses appropriate approaches to acute maxillary and ethmoid rhinosinusitis in adults who are not immunocompromised. The authors point out that most cases of acute rhinosinusitis seen in ambulatory practice are of nonbacterial origin yet are difficult to differentiate from acute bacterial rhinosinusitis on purely clinical grounds. The diagnosis of acute bacterial rhinosinusitis should be reserved for episodes of more than 7 days' duration with acute pain in the maxillary region/teeth and with purulent nasal secretions (particularly if unilateral). Occasionally, patients with acute bacterial rhinosinusitis present with dramatic symptoms of severe unilateral maxillary pain, swelling, and fever of less than 7 days' duration. Sinus radiography is not recommended for diagnosis in routine cases. Most cases of acute sinusitis resolve without antibiotic therapy. Antibiotic therapy should be reserved for patients with moderately severe symptoms who meet the criteria for the clinical diagnosis of acute bacterial rhinosinusitis and for those with severe rhinosinusitis symptoms—especially those with unilateral facial pain—regardless of duration of illness. If antibiotics are used, initial treatment should consist of relatively narrow-spectrum agents effective against Streptococcus pneumoniae and Hemophilus influenza , the most common offenders in uncomplicated acute bacterial rhinosinusitis. This report did not discuss treatment when there was an underlying chronic obstructive nasal airway disease.(Hickner et al. Ann Intern Med 2001;134:498-505) MEDLINEImpact of first-line vs second-line antibiotics for the treatment of acute uncomplicated sinusitisPrevious studies have suggested little additional benefit in the relief of acute sinusitis symptoms from the use of newer and more expensive (second-line) antibiotics instead of older and less expensive (first-line) antibiotics. However, such studies have failed to include development of complications and the total cost of sinusitis treatment in their analyses. This report described a retrospective cohort study using a pharmaceutical database in 29,102 adults with a diagnosis of acute sinusitis receiving initial antibiotic treatment over a 1-year period. Measures of effective antibiotic treatment of the acute sinusitis episode were absence of sinusitis complications and no requests for a second antibiotic treatment within the next 28 days. In approximately 60% of the patients, an older (first-line) antibiotic was used; the success rate was 90.1%. In the remaining 40% of the patients, a second-line antibiotic was used; the success rate was 90.8%. There was a serious sinusitis complication in 1 patient in each treatment group. The mean cost of therapy was significantly greater with the second-line antibiotics than with the first-line antibiotics ($135 vs $69; P < .001), the difference being due almost entirely to the greater costs of the second-line antibiotics. The authors conclude that the very small differences in clinical outcome did not warrant use of the more expensive second-line antibiotics. However, it is unclear from this database review how many of the patients in each group had acute sinusitis of nonbacterial origin, the course of which would be unaffected by any of the antibiotics used.(Piccirillo et al. JAMA 2001;286:1849-56) MEDLINEIdentification of a gene for familial cold urticariaFamilial cold autoinflammatory syndrome (FCAS), also known as familial cold urticaria , is an autosomal dominant systemic disorder characterized by episodic urticaria, arthralgias, fever, and conjunctivitis after exposure to cold. The syndrome was previously mapped to a region on chromosome 1q44, which also maps to Muckle-Wells syndrome (MWS), an autosomal dominant periodic fever syndrome. The phenotype of MWS is similar to that of FCAS, except that the former is not precipitated by cold exposure and sensorineural hearing loss is frequent. To identify the genes for these syndromes, 80 exons lying in this genomic region were directly sequenced. Four different missense mutations were identified in exon 3 of a gene that the investigators called cryopyrin . A 4-generation family with FCAS was identified with a de novo mutation in the first generation. Two other families with FCAS and MWS were shown to have other de novo mutations in this exon. These missense mutations were not found in unaffected individuals or in random North American blood bank samples. The cryopyrin gene is preferentially expressed in peripheral blood leukocytes and contains several motifs suggestive of a role in signaling, inflammation, and apoptosis. Importantly, cyropyrin contained an internal pyrin domain and belonged to the same family of proteins that caused other episodic autoinflammatory syndromes, such as familial Mediterranean fever. In addition, cyropyrin contains significant homology to Nod2, which has been implicated in Crohn's disease. Functional analysis of cryopyrin will likely further elucidate the mechanisms of inflammation and the molecular basis for cold-sensitive phenotypes, and there is hope that it will provide further insight into the pathogenesis of other inherited disorders characterized by urticaria.(Hoffman HM et al. Nat Genet 2001;29:301-5) MEDLINEIdentification of critical chromosome 5q23 asthma gene?Asthma is a complex trait that arises from environmentally induced allergic pulmonary responses in genetically susceptible individuals. Genome-wide searches have identified more than 20 loci that might account for asthma susceptibility. Of these, chromosome 5q23-25 has received the most attention because it contains a large number of candidate genes, including those for TH2 cytokines (IL-4, IL-5, IL-9, IL-13), IL-12p40, and the β-adrenergic receptor. However, the fact that the region on chromosome 5q that is associated with asthma is quite large (containing hundreds of genes) has prohibited identification of the dominant gene in this locus. In a recent article, investigators studied congenic mouse strains and mapped the critical gene that appears to be responsible for the asthma phenotype in this locus. These congenic strains were derived from asthma-resistant (DBA/2) and susceptible (Balb/C) strains of mice. A series of mice with distinct regions of chromosome 11 (the 5q23 syntenic region) were generated. This approach allowed the identification of a congenic line that had reduced TH2 responses, termed Tapr (for T-cell airway phenotype regulator ). Importantly, the Tapr was distinct from the region on human chromosome 5q that contained other known asthma candidate genes. Traditional cloning of the Tapr identified a new gene family referred to as Tim (T cell, immunoglobulin domain, and mucin domain). Three Tim family members were cloned from activated T cells; all demonstrated common structural motifs, including a signal peptide, immuno-globulin domains, mucin domains, and a transmembrane domain with an intracellular tail containing consensus tyrosine phosphorylation sites. Tim-1 and Tim-3 were found to cosegregate with asthma susceptibility; importantly, major polymorphisms were identified in the loci for Tim-1 and Tim-2 that correlated with asthma susceptibility in the congenic mouse lines. Interestingly, the human homolog of Tim-1 is the hepatitis A virus cellular receptor. This is relevant because studies have shown that exposure to hepatitis A is associated with protection from asthma, consistent with the hygiene hypothesis. Taken together, these studies identify a new family of genes that are likely to play a major role in TH1/TH2 differentiation and susceptibility to asthma and other immune-mediated diseases. Although the mechanism by which the Tim gene affects cytokine production has not been determined, the finding that Tim-1 is the hepatitis A virus receptor offers suggestive evidence that this will likely turn out to be a critical pathway involved in the pathogenesis of asthma and other immune disorders.(McIntire et al. Nature Immunol 2001;2:1109-16) MEDLINEOthers articles of interest•Armentia et al. Asthma caused by a cathedral wall. N Engl J Med 2001;345:1068-9. This case report describes an asthmatic reaction following inhalation of egg protein that was present in a protective surface coating on the stone walls of an ancient cathedral when an egg-allergic individual was involved in the removal of surface material from the cathedral walls. This interesting case highlights the persistence of allergenic egg components on stone surfaces for many years. MEDLINE•Neer et al. Effect of parathyroid hormone (1-34) on fractures and bone mineral density in postmenopausal women with osteoporosis. N Engl J Med 2001;344:1434-41. Agents currently used to retard osteoporosis in postmenopausal women (eg, estrogens, selective estrogen-receptor modulators, bisphosphonates, calcitonin) might retard bone resorption with variable effects on vertebral fracture rate and generally no stimulation of new bone formation. In this study, it was found that daily subcutaneous injections of parathyroid hormone led to a significantly decreased vertebral fracture rate as well as increased bone density in postmenopausal women, probably by stimulating bone formation. This approach might be of considerable value in treating older individuals who require chronic corticosteroid therapy. MEDLINE•Huang Q et al. The plasticity of dendritic cell responses to pathogens and their components. Science 2001;294:870-5. Oligonucleotide microarray chips were used to determine gene expression profiles of dendritic cells in response to Escherichia coli , Candida albicans , and influenza viruses as well as their molecular components. Interestingly, although all pathogens induced a significant number of genes that overlapped, there were pathogen-specific genetic programs. For example, E coli induced 685 genes, of which 305 were shared with the genes induced by influenza. These results reveal that dendritic cells can elicit pathogen-specific immune responses. MEDLINE Articles of note…Editor's Note: The following 2 articles deal with the therapy of acute sinusitis, a subject of considerable interest to those treating individuals with allergic respiratory diseases.Principles of appropriate antibiotic use for acute rhinosinusitis in adultsThis report is from a committee of representatives from the American Academy of Family Physicians, the American College of Physicians–American Society of Internal Medicine, the Centers for Disease Control, and the Infectious Diseases Society of America. It discusses appropriate approaches to acute maxillary and ethmoid rhinosinusitis in adults who are not immunocompromised. The authors point out that most cases of acute rhinosinusitis seen in ambulatory practice are of nonbacterial origin yet are difficult to differentiate from acute bacterial rhinosinusitis on purely clinical grounds. The diagnosis of acute bacterial rhinosinusitis should be reserved for episodes of more than 7 days' duration with acute pain in the maxillary region/teeth and with purulent nasal secretions (particularly if unilateral). Occasionally, patients with acute bacterial rhinosinusitis present with dramatic symptoms of severe unilateral maxillary pain, swelling, and fever of less than 7 days' duration. Sinus radiography is not recommended for diagnosis in routine cases. Most cases of acute sinusitis resolve without antibiotic therapy. Antibiotic therapy should be reserved for patients with moderately severe symptoms who meet the criteria for the clinical diagnosis of acute bacterial rhinosinusitis and for those with severe rhinosinusitis symptoms—especially those with unilateral facial pain—regardless of duration of illness. If antibiotics are used, initial treatment should consist of relatively narrow-spectrum agents effective against Streptococcus pneumoniae and Hemophilus influenza , the most common offenders in uncomplicated acute bacterial rhinosinusitis. This report did not discuss treatment when there was an underlying chronic obstructive nasal airway disease.(Hickner et al. Ann Intern Med 2001;134:498-505) MEDLINEImpact of first-line vs second-line antibiotics for the treatment of acute uncomplicated sinusitisPrevious studies have suggested little additional benefit in the relief of acute sinusitis symptoms from the use of newer and more expensive (second-line) antibiotics instead of older and less expensive (first-line) antibiotics. However, such studies have failed to include development of complications and the total cost of sinusitis treatment in their analyses. This report described a retrospective cohort study using a pharmaceutical database in 29,102 adults with a diagnosis of acute sinusitis receiving initial antibiotic treatment over a 1-year period. Measures of effective antibiotic treatment of the acute sinusitis episode were absence of sinusitis complications and no requests for a second antibiotic treatment within the next 28 days. In approximately 60% of the patients, an older (first-line) antibiotic was used; the success rate was 90.1%. In the remaining 40% of the patients, a second-line antibiotic was used; the success rate was 90.8%. There was a serious sinusitis complication in 1 patient in each treatment group. The mean cost of therapy was significantly greater with the second-line antibiotics than with the first-line antibiotics ($135 vs $69; P < .001), the difference being due almost entirely to the greater costs of the second-line antibiotics. The authors conclude that the very small differences in clinical outcome did not warrant use of the more expensive second-line antibiotics. However, it is unclear from this database review how many of the patients in each group had acute sinusitis of nonbacterial origin, the course of which would be unaffected by any of the antibiotics used.(Piccirillo et al. JAMA 2001;286:1849-56) MEDLINEIdentification of a gene for familial cold urticariaFamilial cold autoinflammatory syndrome (FCAS), also known as familial cold urticaria , is an autosomal dominant systemic disorder characterized by episodic urticaria, arthralgias, fever, and conjunctivitis after exposure to cold. The syndrome was previously mapped to a region on chromosome 1q44, which also maps to Muckle-Wells syndrome (MWS), an autosomal dominant periodic fever syndrome. The phenotype of MWS is similar to that of FCAS, except that the former is not precipitated by cold exposure and sensorineural hearing loss is frequent. To identify the genes for these syndromes, 80 exons lying in this genomic region were directly sequenced. Four different missense mutations were identified in exon 3 of a gene that the investigators called cryopyrin . A 4-generation family with FCAS was identified with a de novo mutation in the first generation. Two other families with FCAS and MWS were shown to have other de novo mutations in this exon. These missense mutations were not found in unaffected individuals or in random North American blood bank samples. The cryopyrin gene is preferentially expressed in peripheral blood leukocytes and contains several motifs suggestive of a role in signaling, inflammation, and apoptosis. Importantly, cyropyrin contained an internal pyrin domain and belonged to the same family of proteins that caused other episodic autoinflammatory syndromes, such as familial Mediterranean fever. In addition, cyropyrin contains significant homology to Nod2, which has been implicated in Crohn's disease. Functional analysis of cryopyrin will likely further elucidate the mechanisms of inflammation and the molecular basis for cold-sensitive phenotypes, and there is hope that it will provide further insight into the pathogenesis of other inherited disorders characterized by urticaria.(Hoffman HM et al. Nat Genet 2001;29:301-5) MEDLINEIdentification of critical chromosome 5q23 asthma gene?Asthma is a complex trait that arises from environmentally induced allergic pulmonary responses in genetically susceptible individuals. Genome-wide searches have identified more than 20 loci that might account for asthma susceptibility. Of these, chromosome 5q23-25 has received the most attention because it contains a large number of candidate genes, including those for TH2 cytokines (IL-4, IL-5, IL-9, IL-13), IL-12p40, and the β-adrenergic receptor. However, the fact that the region on chromosome 5q that is associated with asthma is quite large (containing hundreds of genes) has prohibited identification of the dominant gene in this locus. In a recent article, investigators studied congenic mouse strains and mapped the critical gene that appears to be responsible for the asthma phenotype in this locus. These congenic strains were derived from asthma-resistant (DBA/2) and susceptible (Balb/C) strains of mice. A series of mice with distinct regions of chromosome 11 (the 5q23 syntenic region) were generated. This approach allowed the identification of a congenic line that had reduced TH2 responses, termed Tapr (for T-cell airway phenotype regulator ). Importantly, the Tapr was distinct from the region on human chromosome 5q that contained other known asthma candidate genes. Traditional cloning of the Tapr identified a new gene family referred to as Tim (T cell, immunoglobulin domain, and mucin domain). Three Tim family members were cloned from activated T cells; all demonstrated common structural motifs, including a signal peptide, immuno-globulin domains, mucin domains, and a transmembrane domain with an intracellular tail containing consensus tyrosine phosphorylation sites. Tim-1 and Tim-3 were found to cosegregate with asthma susceptibility; importantly, major polymorphisms were identified in the loci for Tim-1 and Tim-2 that correlated with asthma susceptibility in the congenic mouse lines. Interestingly, the human homolog of Tim-1 is the hepatitis A virus cellular receptor. This is relevant because studies have shown that exposure to hepatitis A is associated with protection from asthma, consistent with the hygiene hypothesis. Taken together, these studies identify a new family of genes that are likely to play a major role in TH1/TH2 differentiation and susceptibility to asthma and other immune-mediated diseases. Although the mechanism by which the Tim gene affects cytokine production has not been determined, the finding that Tim-1 is the hepatitis A virus receptor offers suggestive evidence that this will likely turn out to be a critical pathway involved in the pathogenesis of asthma and other immune disorders.(McIntire et al. Nature Immunol 2001;2:1109-16) MEDLINE Editor's Note: The following 2 articles deal with the therapy of acute sinusitis, a subject of considerable interest to those treating individuals with allergic respiratory diseases. Principles of appropriate antibiotic use for acute rhinosinusitis in adultsThis report is from a committee of representatives from the American Academy of Family Physicians, the American College of Physicians–American Society of Internal Medicine, the Centers for Disease Control, and the Infectious Diseases Society of America. It discusses appropriate approaches to acute maxillary and ethmoid rhinosinusitis in adults who are not immunocompromised. The authors point out that most cases of acute rhinosinusitis seen in ambulatory practice are of nonbacterial origin yet are difficult to differentiate from acute bacterial rhinosinusitis on purely clinical grounds. The diagnosis of acute bacterial rhinosinusitis should be reserved for episodes of more than 7 days' duration with acute pain in the maxillary region/teeth and with purulent nasal secretions (particularly if unilateral). Occasionally, patients with acute bacterial rhinosinusitis present with dramatic symptoms of severe unilateral maxillary pain, swelling, and fever of less than 7 days' duration. Sinus radiography is not recommended for diagnosis in routine cases. Most cases of acute sinusitis resolve without antibiotic therapy. Antibiotic therapy should be reserved for patients with moderately severe symptoms who meet the criteria for the clinical diagnosis of acute bacterial rhinosinusitis and for those with severe rhinosinusitis symptoms—especially those with unilateral facial pain—regardless of duration of illness. If antibiotics are used, initial treatment should consist of relatively narrow-spectrum agents effective against Streptococcus pneumoniae and Hemophilus influenza , the most common offenders in uncomplicated acute bacterial rhinosinusitis. This report did not discuss treatment when there was an underlying chronic obstructive nasal airway disease.(Hickner et al. Ann Intern Med 2001;134:498-505) MEDLINE This report is from a committee of representatives from the American Academy of Family Physicians, the American College of Physicians–American Society of Internal Medicine, the Centers for Disease Control, and the Infectious Diseases Society of America. It discusses appropriate approaches to acute maxillary and ethmoid rhinosinusitis in adults who are not immunocompromised. The authors point out that most cases of acute rhinosinusitis seen in ambulatory practice are of nonbacterial origin yet are difficult to differentiate from acute bacterial rhinosinusitis on purely clinical grounds. The diagnosis of acute bacterial rhinosinusitis should be reserved for episodes of more than 7 days' duration with acute pain in the maxillary region/teeth and with purulent nasal secretions (particularly if unilateral). Occasionally, patients with acute bacterial rhinosinusitis present with dramatic symptoms of severe unilateral maxillary pain, swelling, and fever of less than 7 days' duration. Sinus radiography is not recommended for diagnosis in routine cases. Most cases of acute sinusitis resolve without antibiotic therapy. Antibiotic therapy should be reserved for patients with moderately severe symptoms who meet the criteria for the clinical diagnosis of acute bacterial rhinosinusitis and for those with severe rhinosinusitis symptoms—especially those with unilateral facial pain—regardless of duration of illness. If antibiotics are used, initial treatment should consist of relatively narrow-spectrum agents effective against Streptococcus pneumoniae and Hemophilus influenza , the most common offenders in uncomplicated acute bacterial rhinosinusitis. This report did not discuss treatment when there was an underlying chronic obstructive nasal airway disease. (Hickner et al. Ann Intern Med 2001;134:498-505) MEDLINE Impact of first-line vs second-line antibiotics for the treatment of acute uncomplicated sinusitisPrevious studies have suggested little additional benefit in the relief of acute sinusitis symptoms from the use of newer and more expensive (second-line) antibiotics instead of older and less expensive (first-line) antibiotics. However, such studies have failed to include development of complications and the total cost of sinusitis treatment in their analyses. This report described a retrospective cohort study using a pharmaceutical database in 29,102 adults with a diagnosis of acute sinusitis receiving initial antibiotic treatment over a 1-year period. Measures of effective antibiotic treatment of the acute sinusitis episode were absence of sinusitis complications and no requests for a second antibiotic treatment within the next 28 days. In approximately 60% of the patients, an older (first-line) antibiotic was used; the success rate was 90.1%. In the remaining 40% of the patients, a second-line antibiotic was used; the success rate was 90.8%. There was a serious sinusitis complication in 1 patient in each treatment group. The mean cost of therapy was significantly greater with the second-line antibiotics than with the first-line antibiotics ($135 vs $69; P < .001), the difference being due almost entirely to the greater costs of the second-line antibiotics. The authors conclude that the very small differences in clinical outcome did not warrant use of the more expensive second-line antibiotics. However, it is unclear from this database review how many of the patients in each group had acute sinusitis of nonbacterial origin, the course of which would be unaffected by any of the antibiotics used.(Piccirillo et al. JAMA 2001;286:1849-56) MEDLINE Previous studies have suggested little additional benefit in the relief of acute sinusitis symptoms from the use of newer and more expensive (second-line) antibiotics instead of older and less expensive (first-line) antibiotics. However, such studies have failed to include development of complications and the total cost of sinusitis treatment in their analyses. This report described a retrospective cohort study using a pharmaceutical database in 29,102 adults with a diagnosis of acute sinusitis receiving initial antibiotic treatment over a 1-year period. Measures of effective antibiotic treatment of the acute sinusitis episode were absence of sinusitis complications and no requests for a second antibiotic treatment within the next 28 days. In approximately 60% of the patients, an older (first-line) antibiotic was used; the success rate was 90.1%. In the remaining 40% of the patients, a second-line antibiotic was used; the success rate was 90.8%. There was a serious sinusitis complication in 1 patient in each treatment group. The mean cost of therapy was significantly greater with the second-line antibiotics than with the first-line antibiotics ($135 vs $69; P < .001), the difference being due almost entirely to the greater costs of the second-line antibiotics. The authors conclude that the very small differences in clinical outcome did not warrant use of the more expensive second-line antibiotics. However, it is unclear from this database review how many of the patients in each group had acute sinusitis of nonbacterial origin, the course of which would be unaffected by any of the antibiotics used. (Piccirillo et al. JAMA 2001;286:1849-56) MEDLINE Identification of a gene for familial cold urticariaFamilial cold autoinflammatory syndrome (FCAS), also known as familial cold urticaria , is an autosomal dominant systemic disorder characterized by episodic urticaria, arthralgias, fever, and conjunctivitis after exposure to cold. The syndrome was previously mapped to a region on chromosome 1q44, which also maps to Muckle-Wells syndrome (MWS), an autosomal dominant periodic fever syndrome. The phenotype of MWS is similar to that of FCAS, except that the former is not precipitated by cold exposure and sensorineural hearing loss is frequent. To identify the genes for these syndromes, 80 exons lying in this genomic region were directly sequenced. Four different missense mutations were identified in exon 3 of a gene that the investigators called cryopyrin . A 4-generation family with FCAS was identified with a de novo mutation in the first generation. Two other families with FCAS and MWS were shown to have other de novo mutations in this exon. These missense mutations were not found in unaffected individuals or in random North American blood bank samples. The cryopyrin gene is preferentially expressed in peripheral blood leukocytes and contains several motifs suggestive of a role in signaling, inflammation, and apoptosis. Importantly, cyropyrin contained an internal pyrin domain and belonged to the same family of proteins that caused other episodic autoinflammatory syndromes, such as familial Mediterranean fever. In addition, cyropyrin contains significant homology to Nod2, which has been implicated in Crohn's disease. Functional analysis of cryopyrin will likely further elucidate the mechanisms of inflammation and the molecular basis for cold-sensitive phenotypes, and there is hope that it will provide further insight into the pathogenesis of other inherited disorders characterized by urticaria.(Hoffman HM et al. Nat Genet 2001;29:301-5) MEDLINE Familial cold autoinflammatory syndrome (FCAS), also known as familial cold urticaria , is an autosomal dominant systemic disorder characterized by episodic urticaria, arthralgias, fever, and conjunctivitis after exposure to cold. The syndrome was previously mapped to a region on chromosome 1q44, which also maps to Muckle-Wells syndrome (MWS), an autosomal dominant periodic fever syndrome. The phenotype of MWS is similar to that of FCAS, except that the former is not precipitated by cold exposure and sensorineural hearing loss is frequent. To identify the genes for these syndromes, 80 exons lying in this genomic region were directly sequenced. Four different missense mutations were identified in exon 3 of a gene that the investigators called cryopyrin . A 4-generation family with FCAS was identified with a de novo mutation in the first generation. Two other families with FCAS and MWS were shown to have other de novo mutations in this exon. These missense mutations were not found in unaffected individuals or in random North American blood bank samples. The cryopyrin gene is preferentially expressed in peripheral blood leukocytes and contains several motifs suggestive of a role in signaling, inflammation, and apoptosis. Importantly, cyropyrin contained an internal pyrin domain and belonged to the same family of proteins that caused other episodic autoinflammatory syndromes, such as familial Mediterranean fever. In addition, cyropyrin contains significant homology to Nod2, which has been implicated in Crohn's disease. Functional analysis of cryopyrin will likely further elucidate the mechanisms of inflammation and the molecular basis for cold-sensitive phenotypes, and there is hope that it will provide further insight into the pathogenesis of other inherited disorders characterized by urticaria. (Hoffman HM et al. Nat Genet 2001;29:301-5) MEDLINE Identification of critical chromosome 5q23 asthma gene?Asthma is a complex trait that arises from environmentally induced allergic pulmonary responses in genetically susceptible individuals. Genome-wide searches have identified more than 20 loci that might account for asthma susceptibility. Of these, chromosome 5q23-25 has received the most attention because it contains a large number of candidate genes, including those for TH2 cytokines (IL-4, IL-5, IL-9, IL-13), IL-12p40, and the β-adrenergic receptor. However, the fact that the region on chromosome 5q that is associated with asthma is quite large (containing hundreds of genes) has prohibited identification of the dominant gene in this locus. In a recent article, investigators studied congenic mouse strains and mapped the critical gene that appears to be responsible for the asthma phenotype in this locus. These congenic strains were derived from asthma-resistant (DBA/2) and susceptible (Balb/C) strains of mice. A series of mice with distinct regions of chromosome 11 (the 5q23 syntenic region) were generated. This approach allowed the identification of a congenic line that had reduced TH2 responses, termed Tapr (for T-cell airway phenotype regulator ). Importantly, the Tapr was distinct from the region on human chromosome 5q that contained other known asthma candidate genes. Traditional cloning of the Tapr identified a new gene family referred to as Tim (T cell, immunoglobulin domain, and mucin domain). Three Tim family members were cloned from activated T cells; all demonstrated common structural motifs, including a signal peptide, immuno-globulin domains, mucin domains, and a transmembrane domain with an intracellular tail containing consensus tyrosine phosphorylation sites. Tim-1 and Tim-3 were found to cosegregate with asthma susceptibility; importantly, major polymorphisms were identified in the loci for Tim-1 and Tim-2 that correlated with asthma susceptibility in the congenic mouse lines. Interestingly, the human homolog of Tim-1 is the hepatitis A virus cellular receptor. This is relevant because studies have shown that exposure to hepatitis A is associated with protection from asthma, consistent with the hygiene hypothesis. Taken together, these studies identify a new family of genes that are likely to play a major role in TH1/TH2 differentiation and susceptibility to asthma and other immune-mediated diseases. Although the mechanism by which the Tim gene affects cytokine production has not been determined, the finding that Tim-1 is the hepatitis A virus receptor offers suggestive evidence that this will likely turn out to be a critical pathway involved in the pathogenesis of asthma and other immune disorders.(McIntire et al. Nature Immunol 2001;2:1109-16) MEDLINE Asthma is a complex trait that arises from environmentally induced allergic pulmonary responses in genetically susceptible individuals. Genome-wide searches have identified more than 20 loci that might account for asthma susceptibility. Of these, chromosome 5q23-25 has received the most attention because it contains a large number of candidate genes, including those for TH2 cytokines (IL-4, IL-5, IL-9, IL-13), IL-12p40, and the β-adrenergic receptor. However, the fact that the region on chromosome 5q that is associated with asthma is quite large (containing hundreds of genes) has prohibited identification of the dominant gene in this locus. In a recent article, investigators studied congenic mouse strains and mapped the critical gene that appears to be responsible for the asthma phenotype in this locus. These congenic strains were derived from asthma-resistant (DBA/2) and susceptible (Balb/C) strains of mice. A series of mice with distinct regions of chromosome 11 (the 5q23 syntenic region) were generated. This approach allowed the identification of a congenic line that had reduced TH2 responses, termed Tapr (for T-cell airway phenotype regulator ). Importantly, the Tapr was distinct from the region on human chromosome 5q that contained other known asthma candidate genes. Traditional cloning of the Tapr identified a new gene family referred to as Tim (T cell, immunoglobulin domain, and mucin domain). Three Tim family members were cloned from activated T cells; all demonstrated common structural motifs, including a signal peptide, immuno-globulin domains, mucin domains, and a transmembrane domain with an intracellular tail containing consensus tyrosine phosphorylation sites. Tim-1 and Tim-3 were found to cosegregate with asthma susceptibility; importantly, major polymorphisms were identified in the loci for Tim-1 and Tim-2 that correlated with asthma susceptibility in the congenic mouse lines. Interestingly, the human homolog of Tim-1 is the hepatitis A virus cellular receptor. This is relevant because studies have shown that exposure to hepatitis A is associated with protection from asthma, consistent with the hygiene hypothesis. Taken together, these studies identify a new family of genes that are likely to play a major role in TH1/TH2 differentiation and susceptibility to asthma and other immune-mediated diseases. Although the mechanism by which the Tim gene affects cytokine production has not been determined, the finding that Tim-1 is the hepatitis A virus receptor offers suggestive evidence that this will likely turn out to be a critical pathway involved in the pathogenesis of asthma and other immune disorders. (McIntire et al. Nature Immunol 2001;2:1109-16) MEDLINE Others articles of interest•Armentia et al. Asthma caused by a cathedral wall. N Engl J Med 2001;345:1068-9. This case report describes an asthmatic reaction following inhalation of egg protein that was present in a protective surface coating on the stone walls of an ancient cathedral when an egg-allergic individual was involved in the removal of surface material from the cathedral walls. This interesting case highlights the persistence of allergenic egg components on stone surfaces for many years. MEDLINE•Neer et al. Effect of parathyroid hormone (1-34) on fractures and bone mineral density in postmenopausal women with osteoporosis. N Engl J Med 2001;344:1434-41. Agents currently used to retard osteoporosis in postmenopausal women (eg, estrogens, selective estrogen-receptor modulators, bisphosphonates, calcitonin) might retard bone resorption with variable effects on vertebral fracture rate and generally no stimulation of new bone formation. In this study, it was found that daily subcutaneous injections of parathyroid hormone led to a significantly decreased vertebral fracture rate as well as increased bone density in postmenopausal women, probably by stimulating bone formation. This approach might be of considerable value in treating older individuals who require chronic corticosteroid therapy. MEDLINE•Huang Q et al. The plasticity of dendritic cell responses to pathogens and their components. Science 2001;294:870-5. Oligonucleotide microarray chips were used to determine gene expression profiles of dendritic cells in response to Escherichia coli , Candida albicans , and influenza viruses as well as their molecular components. Interestingly, although all pathogens induced a significant number of genes that overlapped, there were pathogen-specific genetic programs. For example, E coli induced 685 genes, of which 305 were shared with the genes induced by influenza. These results reveal that dendritic cells can elicit pathogen-specific immune responses. MEDLINE •Armentia et al. Asthma caused by a cathedral wall. N Engl J Med 2001;345:1068-9. This case report describes an asthmatic reaction following inhalation of egg protein that was present in a protective surface coating on the stone walls of an ancient cathedral when an egg-allergic individual was involved in the removal of surface material from the cathedral walls. This interesting case highlights the persistence of allergenic egg components on stone surfaces for many years. MEDLINE•Neer et al. Effect of parathyroid hormone (1-34) on fractures and bone mineral density in postmenopausal women with osteoporosis. N Engl J Med 2001;344:1434-41. Agents currently used to retard osteoporosis in postmenopausal women (eg, estrogens, selective estrogen-receptor modulators, bisphosphonates, calcitonin) might retard bone resorption with variable effects on vertebral fracture rate and generally no stimulation of new bone formation. In this study, it was found that daily subcutaneous injections of parathyroid hormone led to a significantly decreased vertebral fracture rate as well as increased bone density in postmenopausal women, probably by stimulating bone formation. This approach might be of considerable value in treating older individuals who require chronic corticosteroid therapy. MEDLINE•Huang Q et al. The plasticity of dendritic cell responses to pathogens and their components. Science 2001;294:870-5. Oligonucleotide microarray chips were used to determine gene expression profiles of dendritic cells in response to Escherichia coli , Candida albicans , and influenza viruses as well as their molecular components. Interestingly, although all pathogens induced a significant number of genes that overlapped, there were pathogen-specific genetic programs. For example, E coli induced 685 genes, of which 305 were shared with the genes induced by influenza. These results reveal that dendritic cells can elicit pathogen-specific immune responses. MEDLINE