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Abstract

Articles of note…The human genome projectVery recently, 2 independent efforts have resulted in initial sequencing and analysis of the human genome. In one of these efforts, an international program originally conceived in the 1980s involved the United States, the United Kingdom, Japan, France, China, and Germany. In the other effort, a private company (Celera) produced a sequence of the human genome. Both approaches were based on a “shotgun” cloning strategy that involved directly sequencing random segments of the genome. Amazingly, the majority of the sequencing was done over a very short period of time (<1 year), reflecting the large number of people involved in this work and, importantly, the efficiency of the high-throughput automated sequencing. The resulting sequences were “assembled” by sophisticated computer analysis (informatics) and covered >94% of the genome. The DNA was derived from multiple individuals (5 in the case of Celera), and this allowed identification of >1.4 million single nucleotide polymorphisms (SNPs). A summary of some of the interesting combined features of the human genome derived from 2 articles that spanned more than 100 journal pages in Science and Nature includes the following: •The human genome contains a smaller number of genes—30,000 to 40,000—than originally estimated, and this represents only twice the number of genes in the fly or worm.•One half of the human genome appears to be derived from ancestral transposable elements (transposons), apparently derived from elements similar to retroviruses. Related to this, >50% of the genome is composed of repetitive sequences.•The genomic landscape contains marked variation in the distribution of its features, including density of genes, GC content, GpC islands, and recombination rates.•Males have a mutation rate twice as high as the rate seen in females.•Most of the identified genes have an unknown function, indicating that the analysis of the genome is just beginning.•The polymorphism rate is approximately 1/1250 base pairs. However, only a very small proportion of SNPs potentially impact protein function.•Protein coding regions represent only about 1.25% of the genome.•The diversity of specific families of molecules was greater than expected. For example, the immunoglobulin superfamily has the largest representation in the genome (approximately 750 genes); there are 30 genes for fibroblast growth factors and 42 genes for transforming growth factors-βs.The distinguishing feature of the human genome, in comparison with other sequenced eukaryotic genomes (fly, worm, yeast, plant), is the expansion of genes involved in (1) acquired immunity, (2) neural development, (3) signaling pathways, (4) hemostasis, and (5) apoptosis. Examples of expanded genes in the immune system include the following: 22 class I and 22 class II major histocompatibility genes; 21 genes that appear to encode for proteins with homology to the B7 family of costimulatory molecules; a large number of cytokines and chemokines (which are vertebrate-specific proteins); and genes involved in cytokine receptor signal transduction, such as signal transducers and activators of transcription (STATs), the suppressors of cytokine signaling, and protein inhibitors of activated STATs. Some components of innate immunity are numerous and have been selectively expanded in the human genome (eg, there are 24 C1q domain–containing genes in the human genome, but not in the fly or worm), whereas other innate immunity genes do not appear to be significantly expanded in the human genome (eg, there are 10 Toll receptor genes in human beings and 6 in flies). Interestingly, the only enzyme family that was specific to vertebrates is the eosinophil-associated ribonucleases (eosinophil cationic protein and eosinophil-derived neurotoxin), indicating that these enzymes evolved rapidly, possibly to combat vertebrate pathogens. This strongly implicates eosinophils in the protective arm of the immune system.Although we are at the very early stage of our analysis of the human genome, the implications of these recent breakthroughs with respect to understanding and improving health and disease are enormous.(Lander et al. Nature 2001;409:860-921. MEDLINE Venter et al. Science 2001;291:1304-51.) MEDLINEAcute anti-inflammatory effects of inhaled corticosteroids in asthmaSome studies have shown improvement in airway function and bronchial hyperreactivity in asthmatics starting within 6 hours after initiation of inhaled corticosteroid (ICS) therapy. This study investigated possible anti-inflammatory mechanisms for these acute effects of ICSs. Adults with stable asthma (n = 41) ceased ICS treatment for 4 days. Those with >7% eosinophils in a subsequent induced sputum were randomized to inhale a single dose of 2400 μg of budesonide or placebo on 2 separate days and then evaluated 6 hours later. There was a significantly lower percentage of eosinophils in an induced sputum 6 hours after ICS than after placebo treatment (P < .05). There was also a 2.2-fold reduction in airway responsiveness to inhaled hypertonic saline solution after ICS in comparison with placebo treatment. No significant differences were seen in symptoms, lung function, or the frequency of sputum mast cells or apoptotic eosinophils after the ICS vs placebo treatments. These findings suggest that early effects of ICS on the accumulation of eosinophils in the airway might contribute to the initiation of clinical improvement after ICS therapy in asthma. However, the very large single ICS dose used and the relatively stable nature of the asthma in the study subjects do not mimic the usual clinical situation in the treatment of acute, symptomatic asthma. A recent study reviewed in this Beyond Our Pages section found that oral steroids led to significant improvement earlier than ICS treatment in acute symptomatic asthma.(Gibson et al. Am J Respir Crit Care Med 2001; 163:32-36) MEDLINEPredictive markers of asthma exacerbation during stepwise dose reduction of inhaled corticosteroidsAlthough most experts recommend reduction of the daily dosage of inhaled corticosteroids (ICS) to the lowest amount that will control chronic asthma, it has been difficult to predict which patients will manifest a flare in asthma with such dosage reduction. In this study, 50 adults with asthma well controlled on a median dose of 1000 μg of ICS daily underwent baseline pulmonary function studies, assessment for airway hyperresponsiveness (AHR) to histamine, mannitol bronchial challenges, and sputum cytology studies. The ICS doses in individual patients were then reduced by 50% every 8 weeks after repetition of the studies described above. There was an asthma exacerbation in 39 of the patients, whereas ICS could be withdrawn completely without asthma flares in 7 patients. Asthma flares occurred more commonly in older patients and those with greater AHR during baseline and subsequent sequential bronchial challenge studies. AHR and sputum eosinophilia were greater in assessments shortly before asthma flares than when the asthma continued under good control. However, there was no significantly greater worsening in symptoms, pulmonary function, or expired nitric oxide level in the last assessment before an asthma flare. These findings concur with those in another recent study, which found that the relative frequency of eosinophils in the sputum while patients were on ICS therapy was a good predictor of asthma flaring in such individuals after ICS withdrawal.(Leuppi et al. Am J Respir Crit Care Med 2001;163: 406-12) MEDLINEOther articles of interest•Samuelsson et al. Anti-inflammatory activity of IVIG mediated through the inhibitory Fc receptor. Science 2001;291:484-6. The molecular basis of the beneficial role of IVIG in inflammatory and autoimmune disease is presented. IVIG is demonstrated to promote negative signaling through the inhibitory IgG receptor (FcγRIIB) in mice. MEDLINE•King et al. Interleukin-4 acts at the locus of the antigen-presenting dendritic cell to counter-regulate cytotoxic CD8+ T-cell responses. Nat Med 2001;7:206-14. The mechanism underlying suppression of immune responses by IL-4 has remained unexplained. This report shows that the antigen-presenting dendritic cell (DC) is central to counter-regulation of autoimmune disease by IL-4. Usually, antigen-pulsed DC with increased expression of the costimulatory molecules B7.1 and B7.2 stimulate precursors to exhibit cytotoxic activity. This differentiation into functionally active cytotoxic cells is blocked by IL-4 through its influence on DC effects on the precursor cells. MEDLINE•Sano et al. Extracellular signal-regulated kinase 1/2-mediated phosphorylation of cytosolic phospholipase A(2) is essential for human eosinophil adhesion to fibronectin. J Immunol 2001;166:3515-21. Some mitogen-activated kinases are thought to play a role in the activation of eosinophil adhesion to fibronectin. In this study, it was found that one of the mitogen-activated protein kinase isoforms, extracellular signal-regulated kinase mediating activation of cytosolic phospholipase A(2), was essential for such eosinophil adhesion. These findings might help our understanding of the mechanisms involved in eosinophil migration in extracellular tissues during allergic inflammatory reactions. MEDLINE Articles of note…The human genome projectVery recently, 2 independent efforts have resulted in initial sequencing and analysis of the human genome. In one of these efforts, an international program originally conceived in the 1980s involved the United States, the United Kingdom, Japan, France, China, and Germany. In the other effort, a private company (Celera) produced a sequence of the human genome. Both approaches were based on a “shotgun” cloning strategy that involved directly sequencing random segments of the genome. Amazingly, the majority of the sequencing was done over a very short period of time (<1 year), reflecting the large number of people involved in this work and, importantly, the efficiency of the high-throughput automated sequencing. The resulting sequences were “assembled” by sophisticated computer analysis (informatics) and covered >94% of the genome. The DNA was derived from multiple individuals (5 in the case of Celera), and this allowed identification of >1.4 million single nucleotide polymorphisms (SNPs). A summary of some of the interesting combined features of the human genome derived from 2 articles that spanned more than 100 journal pages in Science and Nature includes the following: •The human genome contains a smaller number of genes—30,000 to 40,000—than originally estimated, and this represents only twice the number of genes in the fly or worm.•One half of the human genome appears to be derived from ancestral transposable elements (transposons), apparently derived from elements similar to retroviruses. Related to this, >50% of the genome is composed of repetitive sequences.•The genomic landscape contains marked variation in the distribution of its features, including density of genes, GC content, GpC islands, and recombination rates.•Males have a mutation rate twice as high as the rate seen in females.•Most of the identified genes have an unknown function, indicating that the analysis of the genome is just beginning.•The polymorphism rate is approximately 1/1250 base pairs. However, only a very small proportion of SNPs potentially impact protein function.•Protein coding regions represent only about 1.25% of the genome.•The diversity of specific families of molecules was greater than expected. For example, the immunoglobulin superfamily has the largest representation in the genome (approximately 750 genes); there are 30 genes for fibroblast growth factors and 42 genes for transforming growth factors-βs.The distinguishing feature of the human genome, in comparison with other sequenced eukaryotic genomes (fly, worm, yeast, plant), is the expansion of genes involved in (1) acquired immunity, (2) neural development, (3) signaling pathways, (4) hemostasis, and (5) apoptosis. Examples of expanded genes in the immune system include the following: 22 class I and 22 class II major histocompatibility genes; 21 genes that appear to encode for proteins with homology to the B7 family of costimulatory molecules; a large number of cytokines and chemokines (which are vertebrate-specific proteins); and genes involved in cytokine receptor signal transduction, such as signal transducers and activators of transcription (STATs), the suppressors of cytokine signaling, and protein inhibitors of activated STATs. Some components of innate immunity are numerous and have been selectively expanded in the human genome (eg, there are 24 C1q domain–containing genes in the human genome, but not in the fly or worm), whereas other innate immunity genes do not appear to be significantly expanded in the human genome (eg, there are 10 Toll receptor genes in human beings and 6 in flies). Interestingly, the only enzyme family that was specific to vertebrates is the eosinophil-associated ribonucleases (eosinophil cationic protein and eosinophil-derived neurotoxin), indicating that these enzymes evolved rapidly, possibly to combat vertebrate pathogens. This strongly implicates eosinophils in the protective arm of the immune system.Although we are at the very early stage of our analysis of the human genome, the implications of these recent breakthroughs with respect to understanding and improving health and disease are enormous.(Lander et al. Nature 2001;409:860-921. MEDLINE Venter et al. Science 2001;291:1304-51.) MEDLINEAcute anti-inflammatory effects of inhaled corticosteroids in asthmaSome studies have shown improvement in airway function and bronchial hyperreactivity in asthmatics starting within 6 hours after initiation of inhaled corticosteroid (ICS) therapy. This study investigated possible anti-inflammatory mechanisms for these acute effects of ICSs. Adults with stable asthma (n = 41) ceased ICS treatment for 4 days. Those with >7% eosinophils in a subsequent induced sputum were randomized to inhale a single dose of 2400 μg of budesonide or placebo on 2 separate days and then evaluated 6 hours later. There was a significantly lower percentage of eosinophils in an induced sputum 6 hours after ICS than after placebo treatment (P < .05). There was also a 2.2-fold reduction in airway responsiveness to inhaled hypertonic saline solution after ICS in comparison with placebo treatment. No significant differences were seen in symptoms, lung function, or the frequency of sputum mast cells or apoptotic eosinophils after the ICS vs placebo treatments. These findings suggest that early effects of ICS on the accumulation of eosinophils in the airway might contribute to the initiation of clinical improvement after ICS therapy in asthma. However, the very large single ICS dose used and the relatively stable nature of the asthma in the study subjects do not mimic the usual clinical situation in the treatment of acute, symptomatic asthma. A recent study reviewed in this Beyond Our Pages section found that oral steroids led to significant improvement earlier than ICS treatment in acute symptomatic asthma.(Gibson et al. Am J Respir Crit Care Med 2001; 163:32-36) MEDLINEPredictive markers of asthma exacerbation during stepwise dose reduction of inhaled corticosteroidsAlthough most experts recommend reduction of the daily dosage of inhaled corticosteroids (ICS) to the lowest amount that will control chronic asthma, it has been difficult to predict which patients will manifest a flare in asthma with such dosage reduction. In this study, 50 adults with asthma well controlled on a median dose of 1000 μg of ICS daily underwent baseline pulmonary function studies, assessment for airway hyperresponsiveness (AHR) to histamine, mannitol bronchial challenges, and sputum cytology studies. The ICS doses in individual patients were then reduced by 50% every 8 weeks after repetition of the studies described above. There was an asthma exacerbation in 39 of the patients, whereas ICS could be withdrawn completely without asthma flares in 7 patients. Asthma flares occurred more commonly in older patients and those with greater AHR during baseline and subsequent sequential bronchial challenge studies. AHR and sputum eosinophilia were greater in assessments shortly before asthma flares than when the asthma continued under good control. However, there was no significantly greater worsening in symptoms, pulmonary function, or expired nitric oxide level in the last assessment before an asthma flare. These findings concur with those in another recent study, which found that the relative frequency of eosinophils in the sputum while patients were on ICS therapy was a good predictor of asthma flaring in such individuals after ICS withdrawal.(Leuppi et al. Am J Respir Crit Care Med 2001;163: 406-12) MEDLINE The human genome projectVery recently, 2 independent efforts have resulted in initial sequencing and analysis of the human genome. In one of these efforts, an international program originally conceived in the 1980s involved the United States, the United Kingdom, Japan, France, China, and Germany. In the other effort, a private company (Celera) produced a sequence of the human genome. Both approaches were based on a “shotgun” cloning strategy that involved directly sequencing random segments of the genome. Amazingly, the majority of the sequencing was done over a very short period of time (<1 year), reflecting the large number of people involved in this work and, importantly, the efficiency of the high-throughput automated sequencing. The resulting sequences were “assembled” by sophisticated computer analysis (informatics) and covered >94% of the genome. The DNA was derived from multiple individuals (5 in the case of Celera), and this allowed identification of >1.4 million single nucleotide polymorphisms (SNPs). A summary of some of the interesting combined features of the human genome derived from 2 articles that spanned more than 100 journal pages in Science and Nature includes the following: •The human genome contains a smaller number of genes—30,000 to 40,000—than originally estimated, and this represents only twice the number of genes in the fly or worm.•One half of the human genome appears to be derived from ancestral transposable elements (transposons), apparently derived from elements similar to retroviruses. Related to this, >50% of the genome is composed of repetitive sequences.•The genomic landscape contains marked variation in the distribution of its features, including density of genes, GC content, GpC islands, and recombination rates.•Males have a mutation rate twice as high as the rate seen in females.•Most of the identified genes have an unknown function, indicating that the analysis of the genome is just beginning.•The polymorphism rate is approximately 1/1250 base pairs. However, only a very small proportion of SNPs potentially impact protein function.•Protein coding regions represent only about 1.25% of the genome.•The diversity of specific families of molecules was greater than expected. For example, the immunoglobulin superfamily has the largest representation in the genome (approximately 750 genes); there are 30 genes for fibroblast growth factors and 42 genes for transforming growth factors-βs.The distinguishing feature of the human genome, in comparison with other sequenced eukaryotic genomes (fly, worm, yeast, plant), is the expansion of genes involved in (1) acquired immunity, (2) neural development, (3) signaling pathways, (4) hemostasis, and (5) apoptosis. Examples of expanded genes in the immune system include the following: 22 class I and 22 class II major histocompatibility genes; 21 genes that appear to encode for proteins with homology to the B7 family of costimulatory molecules; a large number of cytokines and chemokines (which are vertebrate-specific proteins); and genes involved in cytokine receptor signal transduction, such as signal transducers and activators of transcription (STATs), the suppressors of cytokine signaling, and protein inhibitors of activated STATs. Some components of innate immunity are numerous and have been selectively expanded in the human genome (eg, there are 24 C1q domain–containing genes in the human genome, but not in the fly or worm), whereas other innate immunity genes do not appear to be significantly expanded in the human genome (eg, there are 10 Toll receptor genes in human beings and 6 in flies). Interestingly, the only enzyme family that was specific to vertebrates is the eosinophil-associated ribonucleases (eosinophil cationic protein and eosinophil-derived neurotoxin), indicating that these enzymes evolved rapidly, possibly to combat vertebrate pathogens. This strongly implicates eosinophils in the protective arm of the immune system.Although we are at the very early stage of our analysis of the human genome, the implications of these recent breakthroughs with respect to understanding and improving health and disease are enormous.(Lander et al. Nature 2001;409:860-921. MEDLINE Venter et al. Science 2001;291:1304-51.) MEDLINE Very recently, 2 independent efforts have resulted in initial sequencing and analysis of the human genome. In one of these efforts, an international program originally conceived in the 1980s involved the United States, the United Kingdom, Japan, France, China, and Germany. In the other effort, a private company (Celera) produced a sequence of the human genome. Both approaches were based on a “shotgun” cloning strategy that involved directly sequencing random segments of the genome. Amazingly, the majority of the sequencing was done over a very short period of time (<1 year), reflecting the large number of people involved in this work and, importantly, the efficiency of the high-throughput automated sequencing. The resulting sequences were “assembled” by sophisticated computer analysis (informatics) and covered >94% of the genome. The DNA was derived from multiple individuals (5 in the case of Celera), and this allowed identification of >1.4 million single nucleotide polymorphisms (SNPs). A summary of some of the interesting combined features of the human genome derived from 2 articles that spanned more than 100 journal pages in Science and Nature includes the following: •The human genome contains a smaller number of genes—30,000 to 40,000—than originally estimated, and this represents only twice the number of genes in the fly or worm.•One half of the human genome appears to be derived from ancestral transposable elements (transposons), apparently derived from elements similar to retroviruses. Related to this, >50% of the genome is composed of repetitive sequences.•The genomic landscape contains marked variation in the distribution of its features, including density of genes, GC content, GpC islands, and recombination rates.•Males have a mutation rate twice as high as the rate seen in females.•Most of the identified genes have an unknown function, indicating that the analysis of the genome is just beginning.•The polymorphism rate is approximately 1/1250 base pairs. However, only a very small proportion of SNPs potentially impact protein function.•Protein coding regions represent only about 1.25% of the genome.•The diversity of specific families of molecules was greater than expected. For example, the immunoglobulin superfamily has the largest representation in the genome (approximately 750 genes); there are 30 genes for fibroblast growth factors and 42 genes for transforming growth factors-βs. The distinguishing feature of the human genome, in comparison with other sequenced eukaryotic genomes (fly, worm, yeast, plant), is the expansion of genes involved in (1) acquired immunity, (2) neural development, (3) signaling pathways, (4) hemostasis, and (5) apoptosis. Examples of expanded genes in the immune system include the following: 22 class I and 22 class II major histocompatibility genes; 21 genes that appear to encode for proteins with homology to the B7 family of costimulatory molecules; a large number of cytokines and chemokines (which are vertebrate-specific proteins); and genes involved in cytokine receptor signal transduction, such as signal transducers and activators of transcription (STATs), the suppressors of cytokine signaling, and protein inhibitors of activated STATs. Some components of innate immunity are numerous and have been selectively expanded in the human genome (eg, there are 24 C1q domain–containing genes in the human genome, but not in the fly or worm), whereas other innate immunity genes do not appear to be significantly expanded in the human genome (eg, there are 10 Toll receptor genes in human beings and 6 in flies). Interestingly, the only enzyme family that was specific to vertebrates is the eosinophil-associated ribonucleases (eosinophil cationic protein and eosinophil-derived neurotoxin), indicating that these enzymes evolved rapidly, possibly to combat vertebrate pathogens. This strongly implicates eosinophils in the protective arm of the immune system. Although we are at the very early stage of our analysis of the human genome, the implications of these recent breakthroughs with respect to understanding and improving health and disease are enormous. (Lander et al. Nature 2001;409:860-921. MEDLINE Venter et al. Science 2001;291:1304-51.) MEDLINE Acute anti-inflammatory effects of inhaled corticosteroids in asthmaSome studies have shown improvement in airway function and bronchial hyperreactivity in asthmatics starting within 6 hours after initiation of inhaled corticosteroid (ICS) therapy. This study investigated possible anti-inflammatory mechanisms for these acute effects of ICSs. Adults with stable asthma (n = 41) ceased ICS treatment for 4 days. Those with >7% eosinophils in a subsequent induced sputum were randomized to inhale a single dose of 2400 μg of budesonide or placebo on 2 separate days and then evaluated 6 hours later. There was a significantly lower percentage of eosinophils in an induced sputum 6 hours after ICS than after placebo treatment (P < .05). There was also a 2.2-fold reduction in airway responsiveness to inhaled hypertonic saline solution after ICS in comparison with placebo treatment. No significant differences were seen in symptoms, lung function, or the frequency of sputum mast cells or apoptotic eosinophils after the ICS vs placebo treatments. These findings suggest that early effects of ICS on the accumulation of eosinophils in the airway might contribute to the initiation of clinical improvement after ICS therapy in asthma. However, the very large single ICS dose used and the relatively stable nature of the asthma in the study subjects do not mimic the usual clinical situation in the treatment of acute, symptomatic asthma. A recent study reviewed in this Beyond Our Pages section found that oral steroids led to significant improvement earlier than ICS treatment in acute symptomatic asthma.(Gibson et al. Am J Respir Crit Care Med 2001; 163:32-36) MEDLINE Some studies have shown improvement in airway function and bronchial hyperreactivity in asthmatics starting within 6 hours after initiation of inhaled corticosteroid (ICS) therapy. This study investigated possible anti-inflammatory mechanisms for these acute effects of ICSs. Adults with stable asthma (n = 41) ceased ICS treatment for 4 days. Those with >7% eosinophils in a subsequent induced sputum were randomized to inhale a single dose of 2400 μg of budesonide or placebo on 2 separate days and then evaluated 6 hours later. There was a significantly lower percentage of eosinophils in an induced sputum 6 hours after ICS than after placebo treatment (P < .05). There was also a 2.2-fold reduction in airway responsiveness to inhaled hypertonic saline solution after ICS in comparison with placebo treatment. No significant differences were seen in symptoms, lung function, or the frequency of sputum mast cells or apoptotic eosinophils after the ICS vs placebo treatments. These findings suggest that early effects of ICS on the accumulation of eosinophils in the airway might contribute to the initiation of clinical improvement after ICS therapy in asthma. However, the very large single ICS dose used and the relatively stable nature of the asthma in the study subjects do not mimic the usual clinical situation in the treatment of acute, symptomatic asthma. A recent study reviewed in this Beyond Our Pages section found that oral steroids led to significant improvement earlier than ICS treatment in acute symptomatic asthma. (Gibson et al. Am J Respir Crit Care Med 2001; 163:32-36) MEDLINE Predictive markers of asthma exacerbation during stepwise dose reduction of inhaled corticosteroidsAlthough most experts recommend reduction of the daily dosage of inhaled corticosteroids (ICS) to the lowest amount that will control chronic asthma, it has been difficult to predict which patients will manifest a flare in asthma with such dosage reduction. In this study, 50 adults with asthma well controlled on a median dose of 1000 μg of ICS daily underwent baseline pulmonary function studies, assessment for airway hyperresponsiveness (AHR) to histamine, mannitol bronchial challenges, and sputum cytology studies. The ICS doses in individual patients were then reduced by 50% every 8 weeks after repetition of the studies described above. There was an asthma exacerbation in 39 of the patients, whereas ICS could be withdrawn completely without asthma flares in 7 patients. Asthma flares occurred more commonly in older patients and those with greater AHR during baseline and subsequent sequential bronchial challenge studies. AHR and sputum eosinophilia were greater in assessments shortly before asthma flares than when the asthma continued under good control. However, there was no significantly greater worsening in symptoms, pulmonary function, or expired nitric oxide level in the last assessment before an asthma flare. These findings concur with those in another recent study, which found that the relative frequency of eosinophils in the sputum while patients were on ICS therapy was a good predictor of asthma flaring in such individuals after ICS withdrawal.(Leuppi et al. Am J Respir Crit Care Med 2001;163: 406-12) MEDLINE Although most experts recommend reduction of the daily dosage of inhaled corticosteroids (ICS) to the lowest amount that will control chronic asthma, it has been difficult to predict which patients will manifest a flare in asthma with such dosage reduction. In this study, 50 adults with asthma well controlled on a median dose of 1000 μg of ICS daily underwent baseline pulmonary function studies, assessment for airway hyperresponsiveness (AHR) to histamine, mannitol bronchial challenges, and sputum cytology studies. The ICS doses in individual patients were then reduced by 50% every 8 weeks after repetition of the studies described above. There was an asthma exacerbation in 39 of the patients, whereas ICS could be withdrawn completely without asthma flares in 7 patients. Asthma flares occurred more commonly in older patients and those with greater AHR during baseline and subsequent sequential bronchial challenge studies. AHR and sputum eosinophilia were greater in assessments shortly before asthma flares than when the asthma continued under good control. However, there was no significantly greater worsening in symptoms, pulmonary function, or expired nitric oxide level in the last assessment before an asthma flare. These findings concur with those in another recent study, which found that the relative frequency of eosinophils in the sputum while patients were on ICS therapy was a good predictor of asthma flaring in such individuals after ICS withdrawal. (Leuppi et al. Am J Respir Crit Care Med 2001;163: 406-12) MEDLINE Other articles of interest•Samuelsson et al. Anti-inflammatory activity of IVIG mediated through the inhibitory Fc receptor. Science 2001;291:484-6. The molecular basis of the beneficial role of IVIG in inflammatory and autoimmune disease is presented. IVIG is demonstrated to promote negative signaling through the inhibitory IgG receptor (FcγRIIB) in mice. MEDLINE•King et al. Interleukin-4 acts at the locus of the antigen-presenting dendritic cell to counter-regulate cytotoxic CD8+ T-cell responses. Nat Med 2001;7:206-14. The mechanism underlying suppression of immune responses by IL-4 has remained unexplained. This report shows that the antigen-presenting dendritic cell (DC) is central to counter-regulation of autoimmune disease by IL-4. Usually, antigen-pulsed DC with increased expression of the costimulatory molecules B7.1 and B7.2 stimulate precursors to exhibit cytotoxic activity. This differentiation into functionally active cytotoxic cells is blocked by IL-4 through its influence on DC effects on the precursor cells. MEDLINE•Sano et al. Extracellular signal-regulated kinase 1/2-mediated phosphorylation of cytosolic phospholipase A(2) is essential for human eosinophil adhesion to fibronectin. J Immunol 2001;166:3515-21. Some mitogen-activated kinases are thought to play a role in the activation of eosinophil adhesion to fibronectin. In this study, it was found that one of the mitogen-activated protein kinase isoforms, extracellular signal-regulated kinase mediating activation of cytosolic phospholipase A(2), was essential for such eosinophil adhesion. These findings might help our understanding of the mechanisms involved in eosinophil migration in extracellular tissues during allergic inflammatory reactions. MEDLINE •Samuelsson et al. Anti-inflammatory activity of IVIG mediated through the inhibitory Fc receptor. Science 2001;291:484-6. The molecular basis of the beneficial role of IVIG in inflammatory and autoimmune disease is presented. IVIG is demonstrated to promote negative signaling through the inhibitory IgG receptor (FcγRIIB) in mice. MEDLINE•King et al. Interleukin-4 acts at the locus of the antigen-presenting dendritic cell to counter-regulate cytotoxic CD8+ T-cell responses. Nat Med 2001;7:206-14. The mechanism underlying suppression of immune responses by IL-4 has remained unexplained. This report shows that the antigen-presenting dendritic cell (DC) is central to counter-regulation of autoimmune disease by IL-4. Usually, antigen-pulsed DC with increased expression of the costimulatory molecules B7.1 and B7.2 stimulate precursors to exhibit cytotoxic activity. This differentiation into functionally active cytotoxic cells is blocked by IL-4 through its influence on DC effects on the precursor cells. MEDLINE•Sano et al. Extracellular signal-regulated kinase 1/2-mediated phosphorylation of cytosolic phospholipase A(2) is essential for human eosinophil adhesion to fibronectin. J Immunol 2001;166:3515-21. Some mitogen-activated kinases are thought to play a role in the activation of eosinophil adhesion to fibronectin. In this study, it was found that one of the mitogen-activated protein kinase isoforms, extracellular signal-regulated kinase mediating activation of cytosolic phospholipase A(2), was essential for such eosinophil adhesion. These findings might help our understanding of the mechanisms involved in eosinophil migration in extracellular tissues during allergic inflammatory reactions. MEDLINE