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Viral mediated gene therapy has progressed after overcoming early failures, and gene therapy has now been approved for several conditions in Europe and the USA. Glycogen storage disease (GSD) type Ia, caused by a deficiency of glucose-6-phosphatase-α, has been viewed as an outstanding candidate for gene therapy. This follow-up report describes the long-term outcome for the naturally occurring GSD-Ia dogs treated with rAAV-GPE-hG6PC-mediated gene therapy. A total of seven dogs were treated with rAAV-GPE-hG6PC-mediated gene therapy. The first four dogs were treated at birth, and three dogs were treated between 2 and 6 months of age to assess the efficacy and safety in animals with mature livers. Blood and urine samples, radiographic studies, histological evaluation, and biodistribution were assessed. Gene therapy improved survival in the GSD-Ia dogs. With treatment, the biochemical studies normalized for the duration of the study (up to 7 years). None of the rAAV-GPE-hG6PC-treated dogs had focal hepatic lesions or renal abnormalities. Dogs treated at birth required a second dose of rAAV after 2–4 months; gene therapy after hepatic maturation resulted in improved efficacy after a single dose. rAAV-GPE-hG6PC treatment in GSD-Ia dogs was found to be safe and efficacious. GSD-Ia is an attractive target for human gene therapy since it is a monogenic disorder with limited tissue involvement. Blood glucose and lactate monitoring can be used to assess effectiveness and as a biomarker of success. GSD-Ia can also serve as a model for other hepatic monogenic disorders.

Mutations in the liver glycogen phosphorylase (Pygl) gene are associated with the diagnosis of glycogen storage disease type VI (GSD-VI). To understand the pathogenesis of GSD-VI, we generated a mouse model with Pygl deficiency (Pygl -/-). Pygl -/- mice exhibit hepatomegaly, excessive hepatic glycogen accumulation, and low hepatic free glucose along with lower fasting blood glucose levels and elevated blood ketone bodies. Hepatic glycogen accumulation in Pygl -/- mice increases with age. Masson's trichrome and picrosirius red staining revealed minimal to mild collagen deposition in periportal, subcapsular, and/or perisinusoidal areas in the livers of old Pygl -/- mice (>40 weeks). Consistently, immunohistochemical analysis showed the number of cells positive for alpha smooth muscle actin (α-SMA), a marker of activated hepatic stellate cells, was increased in the livers of old Pygl -/- mice compared with those of age-matched wild-type (WT) mice. Furthermore, old Pygl -/- mice had inflammatory infiltrates associated with hepatic vessels in their livers along with up-regulated hepatic messenger RNA levels of C-C chemokine ligand 5 (Ccl5/Rantes) and monocyte chemoattractant protein 1 (Mcp-1), indicating inflammation, while age-matched WT mice did not. Serum levels of aspartate aminotransferase and alanine aminotransferase were elevated in old Pygl -/- mice, indicating liver damage. Conclusion: Pygl deficiency results in progressive accumulation of hepatic glycogen with age and liver damage, inflammation, and collagen deposition, which can increase the risk of liver fibrosis. Collectively, the Pygl-deficient mouse recapitulates clinical features in patients with GSD-VI and provides a model to elucidate the mechanisms underlying hepatic complications associated with defective glycogen metabolism.

Background This study evaluated the impact of lymph node-related factors on the risk of and site of recurrence in patients who had papillary thyroid carcinoma with lymph node metastasis in the lateral compartment (classified as pN1b). Methods Patients underwent total thyroidectomy with unilateral modified radical neck dissection for classical papillary thyroid carcinoma. Risk factors for recurrence were evaluated according to the pattern of recurrence. Results A total of 324 patients were included in the study. The median follow-up was 63 (range 14–181) months. Recurrence was detected in 47 patients (14·5 per cent). In the multivariable analysis, a maximum diameter of metastatic lymph nodes larger than 2·0 cm (hazard ratio (HR) 1·15, 95 per cent c.i. 1·06 to 1·25; P = 0·033) and a central compartment metastatic lymph node ratio of more than 0·42 (HR 3·35, 1·65 to 6·79; P < 0·001) were identified as independent risk factors for locoregional recurrence. Age 45 years or older (HR 5·69, 1·24 to 26·12; P = 0·025) and extranodal extension of metastasis (HR 12·71, 1·64 to 98·25; P = 0·015) were risk factors for distant metastasis. In subgroup analysis of locoregional recurrence, several lymph node-related factors affected the risk of recurrence according to the specific site of metastasis. Conclusion Lymph node-related factors are of importance for the risk of recurrence in patients with classical papillary thyroid carcinoma classified as pN1b.

Glycogen storage disease type Ia (GSD-Ia), characterized by impaired glucose homeostasis and chronic risk of hepatocellular adenoma (HCA), is caused by a deficiency in glucose-6-phosphatase-α (G6Pase-α or G6PC) activity. In a previous 70–90 week-study, we showed that a recombinant adeno-associated virus (rAAV) vector-mediated gene transfer that restores more than 3% of wild-type hepatic G6Pase-α activity in G6pc−/− mice corrects hepatic G6Pase-α deficiency with no evidence of HCA. We now examine the minimal hepatic G6Pase-α activity required to confer therapeutic efficacy. We show that rAAV-treated G6pc−/− mice expressing 0.2% of wild-type hepatic G6Pase-α activity suffered from frequent hypoglycemic seizures at age 63–65 weeks but mice expressing 0.5–1.3% of wild-type hepatic G6Pase-α activity (AAV-LL mice) sustain 4–6 h of fast and grow normally to age 75–90 weeks. Despite marked increases in hepatic glycogen accumulation, the AAV-LL mice display no evidence of hepatic abnormalities, hepatic steatosis, or HCA. Interprandial glucose homeostasis is maintained by the G6Pase-α/glucose-6-phosphate transporter (G6PT) complex, and G6PT-mediated microsomal G6P uptake is the rate-limiting step in endogenous glucose production. We show that hepatic G6PT activity is increased in AAV-LL mice. These findings are encouraging for clinical studies of G6Pase-α gene-based therapy for GSD-Ia., Highlights • Establish the minimal hepatic G6Pase-α activity restoration required to provide a blood glucose level that enables GSD-Ia mice grow to old age (75–90 weeks). • Establish the minimal hepatic G6Pase-α activity restoration required that enables GSD-Ia mice grow to old age (75-90 weeks). • Define the lowest dose for G6Pase-α gene therapy that provides efficacy in mice, which informs a phase I/II clinical trial design in human GSD-Ia.

Glycogen storage disease type-Ib (GSD-Ib), deficient in the glucose-6-phosphate transporter (G6PT), is characterized by impaired glucose homeostasis, myeloid dysfunction, and long-term risk of hepatocellular adenoma (HCA). We examined the efficacy of G6PT gene therapy in G6pt-/- mice using recombinant adeno-associated virus (rAAV) vectors, directed by either the G6PC or the G6PT promoter/enhancer. Both vectors corrected hepatic G6PT deficiency in murine GSD-Ib but the G6PC promoter/enhancer was more efficacious. Over a 78-week study, using dose titration of the rAAV vectors, we showed that G6pt-/- mice expressing 3-62% of normal hepatic G6PT activity exhibited a normalized liver phenotype. Two of the 12 mice expressing

Glycogen storage disease type Ia (GSD-Ia), characterized by impaired glucose homeostasis and chronic risk of hepatocellular adenoma (HCA) and carcinoma (HCC), is caused by a deficiency in glucose-6-phosphatase-α (G6Pase-α or G6PC). We have previously shown that G6pc−/− mice receiving gene transfer mediated by rAAV-G6PC, a recombinant adeno-associated virus (rAAV) vector expressing G6Pase-α, and expressing 3–63% of normal hepatic G6Pase-α activity maintain glucose homeostasis and do not develop HCA/HCC. However, the threshold of hepatic G6Pase-α activity required to prevent tumor formation remained unknown. In this study, we constructed rAAV-co-G6PC, a rAAV vector expressing a codon-optimized (co) G6Pase-α and showed that rAAV-co-G6PC was more efficacious than rAAV-G6PC in directing hepatic G6Pase-α expression. Over an 88-week study, we showed that both rAAV-G6PC- and rAAV-co-G6PC-treated G6pc−/− mice expressing 3–33% of normal hepatic G6Pase-α activity (AAV mice) maintained glucose homeostasis, lacked HCA/HCC, and were protected against age-related obesity and insulin resistance. Of the eleven rAAV-G6PC/rAAV-co-G6PC-treated G6pc−/− mice harboring 0.9–2.4% of normal hepatic G6Pase-α activity (AAV-low mice), 3 expressing 0.9–1.3% of normal hepatic G6Pase-α activity developed HCA/HCC, while 8 did not (AAV-low-NT). Finally, we showed that the AAV-low-NT mice exhibited a phenotype indistinguishable from that of AAV mice expressing ≥ 3% of normal hepatic G6Pase-α activity. The results establish the threshold of hepatic G6Pase-α activity required to prevent HCA/HCC and show that GSD-Ia mice harboring less than 2% of normal hepatic G6Pase-α activity are at risk of tumor development.

A canine model of Glycogen storage disease type Ia (GSDIa) is described. Affected dogs are homozygous for a previously described M121I mutation resulting in a deficiency of glucose-6-phosphatase-α. Metabolic, clinicopathologic, pathologic, and clinical manifestations of GSDIa observed in this model are described and compared to those observed in humans. The canine model shows more complete recapitulation of the clinical manifestations seen in humans including “lactic acidosis”, larger size, and longer lifespan compared to other animal models. Use of this model in preclinical trials of gene therapy is described and briefly compared to the murine model. Although the canine model offers a number of advantages for evaluating potential therapies for GSDIa, there are also some significant challenges involved in its use. Despite these challenges, the canine model of GSDIa should continue to provide valuable information about the potential for generating curative therapies for GSDIa as well as other genetic hepatic diseases.

Chronic cough is common in the community and causes significant morbidity. Several factors may underlie this problem, but comorbid conditions located at sensory nerve endings that regulate the cough reflex, including rhinitis, rhinosinusitis, asthma, eosinophilic bronchitis, and gastroesophageal reflux disease, are considered important. However, chronic cough is frequently non-specific and accompanied by not easily identifiable causes during the initial evaluation. Therefore, there are unmet needs for developing empirical treatment and practical diagnostic approaches that can be applied in primary clinics. Meanwhile, in referral clinics, a considerable proportion of adult patients with chronic cough are unexplained or refractory to conventional treatment. The present clinical practice guidelines aim to address major clinical questions regarding empirical treatment, practical diagnostic tools for non-specific chronic cough, and available therapeutic options for chronic wet cough in children and unexplained chronic cough in adults in Korea.

Glycogen storage disease type-Ia (GSD-Ia) is caused by a lack of glucose-6-phosphatase-α (G6Pase-α or G6PC) activity. We have shown that gene therapy mediated by a recombinant adeno-associated virus (rAAV) vector expressing human G6Pase-α normalizes blood glucose homeostasis in the global G6pc knockout (G6pc(-/-)) mice for 70-90 weeks. The treated G6pc(-/-) mice expressing 3-63% of normal hepatic G6Pase-α activity (AAV mice) produce endogenous hepatic glucose levels 61-68% of wild-type littermates, have a leaner phenotype and exhibit fasting blood insulin levels more typical of young adult mice. We now show that unlike wild-type mice, the lean AAV mice have increased caloric intake and do not develop age-related obesity or insulin resistance. Pathway analysis shows that signaling by hepatic carbohydrate response element binding protein that improves glucose tolerance and insulin signaling is activated in AAV mice. In addition, several longevity factors in the calorie restriction pathway, including the NADH shuttle systems, NAD(+) concentrations and the AMP-activated protein kinase/sirtuin 1/peroxisome proliferator-activated receptor-γ coactivator 1α pathway are upregulated in the livers of AAV mice. The finding that partial restoration of hepatic G6Pase-α activity in GSD-Ia mice not only attenuates the phenotype of hepatic G6Pase-α deficiency but also prevents the development of age-related obesity and insulin resistance seen in wild-type mice may suggest relevance of the G6Pase-α enzyme to obesity and diabetes.

In this study, we proposed a testis-mediated germline chimera production system based on the transplantation of testicular cells directly into heterologous testes. The testicular cells of juvenile (4-wk-old) or adult (24-wk-old) Korean Ogol chickens with a recessive pigmentation inhibitory gene, with or without prior culture, were injected (2 x 10(7) cells/head) into the seminiferous tubules of juvenile or adult recipients with White Leghorn with a dominant pigmentation inhibitory gene in a 2 x 2 factorial arrangement. The localization of transplanted cells into the inner space of the seminiferous tubules was confirmed within 24 h after injection. Subsequent testcross analyses showed that 7.8% (5/64) of the recipients had chimeric status in their testes. The periods of time from transfer to hatching of the first progeny with black feathers were 38 and 45 days for adult cells transplanted into an adult recipient, 188 days for adult cells into a juvenile recipient, and 137 days for juvenile cells into a juvenile recipient. Culture of the testicular cells derived both colony-forming and monolayer-forming cells. The colony-forming cells were stained positively for periodic acid Schiff solution, and further reacted with anti-SSEA-1, anti-SSEA-3, and anti-SSEA-4 antibodies both before and after culture for 15 days. In conclusion, it may be possible to develop the testis-mediated germline chimera production technique, which extends the feasibility of genetic manipulations in avian species.

Landau-Kleffner syndrome is characterized by epileptic aphasia associated with electrical status epilepticus of slow wave sleep. A 5-year-old female, who had manifested normal developmental progress, was referred with principal complaints of fluctuating sensory aphasia and bizarre behavior during the preceding 4 months. Landau-Kleffner syndrome was confirmed by clinical and electroencephalographic features; in addition, the patient's mitochondrial respiratory chain-complex I deficiency was confirmed by fibroblast culture with the evidence of energy metabolism disorder. This patient's seizures were intractable to many antiepileptic drugs, adrenocorticotrophic hormone, and intravenous immunoglobulin, with catastrophic cognitive and behavioral decline, but the seizures were successfully controlled by ketogenic diet with supplementary mitochondrial cocktail including coenzyme Q10, riboflavin, L-carnitine, and high-dose multivitamins. The patient finally regained fully normal cognitive functioning. Landau-Kleffner syndrome with mitochondrial respiratory chain-complex I deficiency was controlled in this case by ketogenic diet and supplementary mitochondrial cocktail therapy.

The possibility of producing quail germline chimeras by the transfer of gonadal primordial germ cells (gPGCs) into recipient embryos was investigated. Japanese quail of the black (D: homozygous for the autosomal incomplete dominant gene D) and wild-type plumage (WP: d+/d+) strains were used as donors and recipients, respectively. Gonadal cells were retrieved from the gonads of 5-day-old D embryos, and gPGCs were enriched by magnetism-activated cell sorting. Fresh (noncultured) gPGCs or those isolated after culture for 3 days with gonadal stromal cells present in the mixed cell population were introduced into the dorsal aorta of 2-day-old recipient WP embryos. Hatchability of the recipient embryos was 23.7% (31/131) and 34.4% (31/90) for those transfused with cultured or noncultured gPGCs, respectively. Of the hatched quail, 28 acquired sexual maturity; among these animals, 7.1% (1/14) and 21.4% (3/14) of those that received cultured or noncultured gPGCs, respectively, were proved to be germline chimeras. The percentage of germline transmission to the donor-derived gametes in the chimeras that received cultured and noncultured gPGCs were 1.9 and 2.2-4.7%, respectively. In conclusion, quail gPGCs retrieved from 5-day-old embryos were thus transmitted in the germline after their transfer to quail embryos of a different strain. This property of the gPGCs was not adversely affected by culture for up to 3 days.

Study objectives: Extensive airway inflammation and excessive mucus production are implicated in deaths from asthma. High-resolution CT (HRCT) can be used to image both large and small airway abnormalities in asthmatics. The aims of this study were to clarify the distinction of HRCT features between near-fatal asthma (NFA) and non-NFA, and to evaluate serial follow-up HRCT scans of patients with NFA. Patients and design: Abnormalities of the large airway (bronchial wall thickness) and small airways (prominence of centrilobular structures and air trapping) were measured semiquantitatively on HRCT scans of 24 non-NFA, 16 NFA, and 16 control subjects. In addition, these abnormalities were reevaluated after intensive and relatively long-term (> 6 months) treatment with inhaled corticosteroids. Results: Prominence of centrilobular structures was observed in 36% of mild asthma cases, in 70% of moderate-to-severe asthma cases, and in 100% of NFA cases. Prominence of centrilobular structures, but neither bronchial wall thickness nor the area of air trapping, was significantly increased in NFA, as compared with mild or moderate-to-severe asthma (p < 0.05). In the seven non-NFA and five NFA patients who underwent follow-up HRCT scans, only bronchial wall thickness was decreased significantly in the NFA cases (p < 0.05), while bronchial wall thickness and the prominence of centrilobular structures were significantly decreased in the non-NFA cases. These small airway abnormalities were partially reversible in the both groups. Residual prominence of centrilobular structures after long-term inhaled corticosteroid treatment was significantly higher in NFA than non-NFA patients. Conclusions: The results of our study indicate that extensive small airway abnormalities may be associated with NFA, and that these abnormalities are partially reversible after the successful control of asthma symptoms. (CHEST 2004; 126:1840–1848)

Study objectives Eosinophilic bronchitis (EB) presents as a chronic cough and sputum eosinophilia without airflow limitation or bronchial hyperreactivity. Its long-term clinical course remains unknown. This study evaluated how frequently EB recurs and whether it develops chronic airway obstruction. Design This study was a prospective analysis. Methods Cough severity, FEV 1 , provocative concentration of methacholine causing a 20% fall in FEV 1 , and sputum eosinophil percentages were serially measured in 36 subjects for up to 48 months. All subjects inhaled corticosteroids until cough subsided. Results Five of the twenty four follow-up subjects (21%) had a recurrent episode of EB 4 to 6 months after disappearance of the first episode of EB (recurrent eosinophilic bronchitis). Progressive FEV 1 reduction > 20% was observed in three of the subjects, including a subject with asthma developing at the ninth month. Nineteen subjects had no recurrence of cough (nonrecurrent eosinophilic bronchitis) and no progressive FEV 1 reduction > 20%. However, sputum eosinophilia recurred between 4 months and 24 months in 10 subjects. Mean values of FEV 1 at the ninth and 12th months of the study were significantly lower in the recurrent eosinophilic bronchitis group than in the nonrecurrent eosinophilic bronchitis group (p Conclusion These results suggest that repeated episode of EB is associated with the development of chronic airflow obstruction, including asthma.

Glycogen storage disease type Ib (GSD-Ib) deficient in the glucose-6-phosphate transporter (G6PT or SLC37A4) is characterized impaired glucose homeostasis, myeloid dysfunction, and long-term complication of hepatocellular adenoma (HCA). We have shown that gene therapy mediated by a recombinant (r) AAV8 vector expressing G6PT directed by the chicken β-actin promoter/CMV enhancer enabled the G6pt-/- mice lived to over 51 weeks but all 5 transduced G6pt-/- mice expressed only low levels of hepatic G6PT activity and two developed multiple HCAs with one undergoing malignant transformation. We now examined the safety and efficacy of rAAV8-GPE-G6PT, a rAAV8 vector expressing G6PT directed by the gluconeogenic tissue-specific human G6PC promoter/enhancer (GPE). Of the fifteen rAAV8-GPE-G6PT-treated G6pt-/- mice that lived over age 60 weeks expressed 2-62% of wild-type hepatic G6PT activity with only one developed HCA. The treated mice, including the HCA-bearing mouse exhibit a leaner phenotype along with normal blood metabolite, display normal glucose tolerance profiles, maintain normoglycemia over a 24-hour fast, and retain insulin sensitivity. We further show that activation of hepatic ChREBP signaling that improves glucose tolerance and insulin sensitivity is one mechanism that protects the rAAV-GPE-G6PT-treated G6pt-/- mice against age-related obesity and insulin resistance.

Allergic rhinitis (AR) is one of the most common chronic allergic respiratory diseases worldwide. Various practical guidelines for AR have been developed and updated to improve the care of AR patients; however, up to 40% patients remain symptomatic. The unmet need for AR care is one of the greatest public health problems in the world. The gaps between guideline and real-world practice, and differences according to the region, culture, and medical environments may be the causes of unmet needs for AR care. Because there is no evidence-based AR practical guideline reflecting the Korean particularity, various needs are increasing. The purpose of the study was to evaluate whether existing guidelines are sufficient for AR patient management in real practice and whether development of regional guidelines to reflect regional differences is needed in Korea. A total of 99 primary physicians comprising internists, pediatricians, and otolaryngologists (n=33 for each) were surveyed by a questionnaire relating to unmet needs for AR care between June 2 and June 16 of 2014. Among 39 question items, participants strongly agreed on 15 items that existing guidelines were highly insufficient and needed new guidelines. However, there was some disagreement according to specialties for another 24 items. In conclusion, the survey results demonstrated that many physicians did not agree with the current AR guideline, and a new guideline reflecting Korean particularity was needed.

Glycogen storage disease type Ib (GSD-Ib) is an autosomal-recessive syndrome characterized by neutropenia and impaired glucose homeostasis resulting from a deficiency in the glucose-6-phosphate (G6P) transporter (G6PT). The underlying cause of GSD-Ib neutropenia is an enhanced neutrophil apoptosis, but patients also manifest neutrophil dysfunction of unknown etiology. Previously, we showed G6PT interacts with the enzyme glucose-6-phosphatase-β (G6Pase-β) to regulate the availability of G6P/glucose in neutrophils. A deficiency in G6Pase-β activity in neutrophils impairs both their energy homeostasis and function. We now show that G6PT-deficient neutrophils from GSD-Ib patients are similarly impaired. Their energy impairment is characterized by decreased glucose uptake and reduced levels of intracellular G6P, lactate, adenosine triphosphate, and reduced NAD phosphate, whereas functional impairment is reflected in reduced neutrophil respiratory burst, chemotaxis, and calcium mobilization. We further show that the mechanism of neutrophil dysfunction in GSD-Ib arises from activation of the hypoxia-inducible factor-1α/peroxisome-proliferators–activated receptor-γ pathway.

Depression is an important comorbidity of asthma. However, little information is available about depression and its potential impact on asthma control in Korean adult asthma patients. We aimed to estimate the prevalence and risk factors for depression in Korean adults with persistent asthma. The 127 non-elderly (20-64 yr) and 75 elderly (≥65 yr) patients with asthma were recruited. Demographic and clinical data were extracted, and the patients completed the Asthma Specific Quality of Life (AQOL) questionnaire and asthma control test (ACT). Depression status was defined using the Korean version of the Patient Health Questionnaire-9 (PHQ-9). Depression was more prevalent in non-elderly (18.9%) than in elderly patients with asthma (13.3%). Patients with depression were significantly younger, had lower economic status, shorter disease duration, poorer asthma control, and worse AQOL scores (P

Summary Xylitol has many uses, such as in dentistry and as a sweetening agent, and is synthesized from fungus by fermentation. According to some publications, xylitol has no adverse effects on the lungs in either healthy people or patients with cystic fibrosis, but no studies have examined the effects of long-term exposure. Here, we report a patient who developed occupational asthma due to xylitol as confirmed with provocation tests.

Summary We report a case of bulla formation in usual interstitial pneumonia (UIP) after a 5-year follow-up, proven by open lung biopsy, in a 35-year-old Korean man with dermatomyositis. Chest computed tomography showed marked bulla formation and bilateral hydrothorax. To our knowledge, the end result of UIP is honeycombing, respiratory failure, and infection. We postulate that if patients show good compliance in dealing with their UIP, the next form of honeycombing is bulla formation. This is the first report of bulla formation in UIP with dermatomyositis after long-term follow-up.

Glycogen storage disease type Ia (GSD-Ia), which is characterized by impaired glucose homeostasis and chronic risk of hepatocellular adenoma (HCA), is caused by deficiencies in the endoplasmic reticulum (ER)-associated glucose-6-phosphatase-α (G6Pase-α or G6PC) that hydrolyzes glucose-6-phosphate (G6P) to glucose. G6Pase-α activity depends on the G6P transporter (G6PT) that translocates G6P from the cytoplasm into the ER lumen. The functional coupling of G6Pase-α and G6PT maintains interprandial glucose homeostasis. We have shown previously that gene therapy mediated by AAV-GPE, an adeno-associated virus (AAV) vector expressing G6Pase-α directed by the human G6PC promoter/enhancer (GPE), completely normalizes hepatic G6Pase-α deficiency in GSD-Ia (G6pc−/−) mice for at least 24 weeks. However, a recent study showed that within 78 weeks of gene deletion, all mice lacking G6Pase-α in the liver develop HCA. We now show that gene therapy mediated by AAV-GPE maintains efficacy for at least 70-90 weeks for mice expressing more than 3% of wild-type hepatic G6Pase-α activity. The treated mice displayed normal hepatic fat storage, had normal blood metabolite and glucose tolerance profiles, had reduced fasting blood insulin levels, maintained normoglycemia over a 24-hour fast, and had no evidence of hepatic abnormalities. After a 24-hour fast, hepatic G6PT messenger RNA levels in G6pc−/− mice receiving gene therapy were markedly increased. Because G6PT transport is the rate-limiting step in microsomal G6P metabolism, this may explain why the treated G6pc−/− mice could sustain prolonged fasts. The low fasting blood insulin levels and lack of hepatic steatosis may explain the absence of HCA. Conclusion: These results confirm that AAV-GPE–mediated gene transfer corrects hepatic G6Pase-α deficiency in murine GSD-Ia and prevents chronic HCA formation. (HEPATOLOGY 2012;56:1719–1729)

Glycogen storage disease type Ia (GSD-Ia) patients deficient in glucose-6-phosphatase-alpha (G6Pase-alpha or G6PC) manifest disturbed glucose homeostasis. We examined the efficacy of liver G6Pase-alpha delivery mediated by AAV-GPE, an adeno-associated virus (AAV) serotype 8 vector expressing human G6Pase-alpha directed by the human G6PC promoter/enhancer (GPE), and compared it to AAV-CBA, that directed murine G6Pase-alpha expression using a hybrid chicken beta-actin (CBA) promoter/cytomegalovirus (CMV) enhancer. The AAV-GPE directed hepatic G6Pase-alpha expression in the infused G6pc(-/-) mice declined 12-fold from age 2 to 6 weeks but stabilized at wild-type levels from age 6 to 24 weeks. In contrast, the expression directed by AAV-CBA declined 95-fold over 24 weeks, demonstrating that the GPE is more effective in directing persistent in vivo hepatic transgene expression. We further show that the rapid decline in transgene expression directed by AAV-CBA results from an inflammatory immune response elicited by the AAV-CBA vector. The AAV-GPE-treated G6pc(-/-) mice exhibit normal levels of blood glucose, blood metabolites, hepatic glycogen, and hepatic fat. Moreover, the mice maintained normal blood glucose levels even after 6 hours of fasting. The complete normalization of hepatic G6Pase-alpha deficiency by the G6PC promoter/enhancer holds promise for the future of gene therapy in human GSD-Ia patients.

Object The authors propose that anterior callosotomy—thought to have some advantages over total callosotomy—is not superior to total callosotomy for prevention of seizure propagation or other complications. Methods The study comprised 34 patients in whom generalized epilepsy syndrome or frontal lobe seizures with a secondary generalization were diagnosed. Preoperatively, all patients suffered from disabling drop attacks or intense head-drop seizures, and some patients also experienced other types of seizures. The male/female ratio was 22:12, and patients ranged in age between 1 to 19 years (mean 8.7 years). The follow-up period ranged from 1.08 to 5.0 years (mean 2.58 years). Seizure outcome, parental assessment of daily function, and parental satisfaction with the outcome was assessed postoperatively. Results After undergoing 1-stage total callosotomy, drop attacks disappeared completely in 25 patients during the follow-up period, and in 6 patients the frequency of drop attacks decreased to < 10% of baseline. With regard to other types of seizures, seizures resolved completely in 12 patients, and in another 18 seizure frequency decreased. Two patients experienced a transient disconnection syndrome for 2 and 4 weeks. One patient experienced ataxic hemiparesis for 3 weeks before it completely abated. The overall daily function of the patients improved, and all parents were satisfied with the surgical outcome. Conclusions For pediatric generalized epilepsy syndrome, 1-stage total callosotomy will be the first choice in treatment for controlling generalized seizures.

Glycogen storage disease type Ib (GSD-Ib) is an autosomal recessive disorder caused by deficiencies in a glucose-6-phosphate (G6P) transporter (G6PT) that transloacates G6P from the cytoplasm into the lumen of the endoplasmic reticulum where it is hydrolyzed to glucose and phosphate by the glucose-6-phosphatase-α (G6Pase-α or G6PC) enzyme. The functional coupling of G6PT and G6Pase-α maintains interprandial blood glucose homeostasis. GSD-Ib patients manifest impaired glucose homeostasis characterized by fasting hypoglycemia, hepatomegaly, nephromegaly, hyperlipidemia, hyperuricemia, lactic acidemia, and growth retardation. The current dietary therapies enable patients to maintain normoglycemia but the underlying pathological processes remain uncorrected and long-term complications, including hepatocellular adenoma (HCA), are common. In this study, we examined the efficacy of liver G6PT delivery mediated by two human G6PT-expressing recombinant adeno-associated virus (AAV) pseudotype 2/8 (rAAV8) vectors. One is a single-stranded vector containing a 2864-bp of the human G6PC promoter/enhancer (rAAV8-GPE-G6PT) and the other is a double-stranded vector containing the minimal human G6PT promoter/enhancer (rAAV8-miGT-G6PT). GSD-Ib mice were infused with either vector neonatally, then at age 4 weeks, and metabolic profiles of the infused animals were monitored at age 12 weeks. We show that the rAAV8-GPE-G6PT vector directed significantly higher levels of hepatic G6PT expression, achieved greater reduction in hepatomegaly, and led to a better toleration of fasting in GSD-Ib mice than the rAAV8-miGT-G6PT vector. Our results suggest that the rAAV8-GPE-G6PT vector is an efficacious vector in correcting metabolic abnormalities in murine GSD-Ib.

Boda Nam, MD, Jung Hwa Hwang, MD*, Young Mok Lee, MD, Jai Soung Park, MD, Sung Shick Jou, MD, Youngbae Kim, MD 1Department of Radiology, Soonchunhyang University Hospital, Seoul, Korea 2Bangbae GF Allergy Clinic, Seoul, Korea 3Department of Radiology, Soonchunhyang University Bucheon Hospital, Bucheon, Korea 4Department of Radiology, Soonchunhyang University Cheonan Hospital, Cheonan, Korea 5Department of Preventive Medicine, Soonchunhyang University College of Medicine, Cheonan, Korea

Background: Airway hyperresponsiveness in asthmatics is considered to be one of the major consequences of airway inflammation and remodelling. Airway responsiveness is normal in patients with eosinophilic bronchitis (EB), despite eosinophilic inflammation of the airways comparable to that which occurs in asthmatics. Comparisons between asthma and EB should clarify the changes in airway morphology that are related specifically to AHR in asthmatics. Methods: Eighteen asthmatic patients, 15 patients with EB, and 11 healthy subjects were recruited. Airway wall area percentage (WA%), centrilobular prominence, and air trapping were compared using thin slice section computed tomography. Results: WA% was significantly greater in asthmatics than in patients with EB (72 (3.1)% v 54 (2.1)%, p = 0.032) and was similar in EB patients and controls (54 (2.1)% v 57 (1.8)%, p>0.05). Centrilobular prominence and air trapping were similar in EB patients and asthmatics and were significantly greater than in controls. Conclusion: WA% rather than air trapping or centrilobular prominence may be associated with the airway hyperresponsiveness that occurs in asthmatics but not in patients with EB.

Inhaled glucocorticoids (GCs) are the most effective control therapy for asthma. Although the clinical effects of inhaled GCs vary, there are few data on the differences in the responsiveness of individuals to inhaled GCs. The purpose of this study was to identify those factors that are associated with responsiveness to high-dose inhaled GCs in patients with moderate-to-severe asthma.This study was a prospective analysis.Outpatient clinics of tertiary hospitals.Eighty-six adult outpatients with moderate-to-severe asthma.Eighty-six patients with asthma who had initial FEV1 values of80% predicted after they had received inhaled GCs (fluticasone propionate, 1,000 microg/d) for 4 weeks. The primary end points were FEV1, FEV1/FVC ratio, forced expiratory flow (midexpiratory phase), and the score at presentation in the asthma-related quality-of-life questionnaire (AQLQ).The inhalation of GCs for 4 weeks had significant improvements in the FEV1% predicted and in the AQLQ score compared with the baseline values. Asthmatic patients with responses of12% (n = 46, 53.4%) in the change in FEV1 (deltaFEV1 = [FEV1 at 4 weeks--baseline FEV1]/baseline FEV1 x 100) also had significantly higher proportions of blood eosinophils and lower FEV1 values (in liters) prior to treatment. The change in FEV1 values correlated with the number of sputum eosinophils prior to GC inhalation (r = 0.242; p0.05) and correlated inversely with the FEV1 percent predicted values prior to GC inhalation (r = -0.462; p0.001).The FEV1 percent predicted and the blood and sputum eosinophil levels prior to GC inhalation are associated with the responsiveness to inhaled GCs in patients with moderate-to-severe asthma.

To investigate the pathogenic mechanism of late asthmatic response in comparison to early asthmatic response, changes of serum neutrophil chemotactic activity (NCA) using the Boyden chamber method and histamine level using the automated fluorometric analyzer were observed in 13 aspirin (ASA)-sensitive asthma subjects (group I: 7 early responders and group II: 6 dual responders) during lysine aspirin bronchoprovocation test (L-ASA BPT). Sera were collected before, and 30 min and 240 min after L-ASA BPT. Serum NCA increased significantly after 30 min (p=0.02) and decreased significantly at 240 min (p=0.02) in group I, while serum NCA of group II increased significantly at 30 min (p=0.04), tending to increase further up to 240 min with no statistical significance. NCA at 240 min in group II subjects was significantly higher than baseline NCA (p=0.02). The serum NCAs collected before and 240 min were significantly higher in group II than in group I (p

1 , Jong Won Park, M.D. Background: The rising prevalence of asthma worldwide may be associated with the rising prevalence of obesity in developed nations. Although several studies have suggested a relationship between asthma and obesity, controversy still remains. The aim of this study was to examine the relationship between obesity and asthmatic factors such as atopy, eosinophilia, serum total Ig E and bronchial hyperresponsiveness in chronic cough patients. Methods: This study was a retrospective, observational study in two centers done between January 2007 and June 2008. The subjects included individuals who had a chronic cough. We examined body mass index (BMI) to measure obesity and pulmonary function. We did a metacholine provocation test for airway hyperresponsiveness (AHR), a skin prick test for atopy, and tests for blood eosinophils and serum IgE. Results: A total of 1022 subjects were included. Airway hyperresponsiveness was not related with obesity (p=0.06), and atopy incidence was significant higher in non obese patients (p=0.00). There was no significant difference in serum IgE and blood eosinophil counts between obese and non obese patients. Forced expiratory volue in one second (FEV 1)/forced vital capacity (FVC) was significantly reduced in obese patients (p=0.03), but FEV1 and FVC were no significant difference between obese and non obese patients. Conclusion: There is no relationship between obesity and bronchial hyperresponsiveness. The nonobese group appears to have more atopy. The relationship between obesity and bronchial hyperresponsiveness and atopy need further investigation.

Methods: Fifty patients with COPD were enrolled in this study. Their subjective dyspnea score (modified Borg scale dyspnea index), spirometry, and lung volume were measured. Simultaneous hyperinflations of chest x-ray score ("chest score") and degree of emphysema of HRCT ("HRCT score") were measured. The "chest score" were composed of lung length, retrosternal space width, and height of the arc of the diaphragm and "HRCT score" were composed of severity and extent of emphysema. Results: The mean age of patients was 69 years old and their mean FEV1 was 51.7%. The Borg score significantly correlated with parameters of spirometry and lung volume, including FVC, FEV1, FEV1/FVC, RV, RV/TLC, and DLCO. The Borg score correlated well with "HRCT score", but did not correlate with "chest score". Also, the Borg scale correlates inversely with body mass index. Conclusion: The quantity of emphysema on chest HRCT may serve as an objective marker of dyspnea in patients with COPD.

Churg-Strauss syndrome (CSS) or allergic granulomatous angiitis is a rare syndrome that is characterized by hypereosinophilic systemic necrotizing vasculitis affecting small- to medium-sized arteries and veins. In gen-eral, it occurs in individuals with pre-existing allergic asthm a. When CSS appears in patients, it has the follow-ing characteristics: eosinophilia of more than 10% in peripheral blood, paranasal sinusitis, pulmonary in-filtrates, histological proof of vasculitis with extravascular eosinophils, and mononeuritis multiplex or polyneuropathy. Therapeutic trials dedicated to Churg-Strauss syndrome have been limited due to the rarity of this disorder and the difficulty in making a histological diagnosis. Proper treatment of patients with CSS is not widely known. In this case study, we report on our experience with an unusual patient case, charac-terized by purpura and a perforation of the small intestine after inadequate steroid therapy.Key Words: Churg-Strauss syndrome, Asthma, Intestinal perforation, Eosinophilic infiltration

Bronchogenic cyst arises from anomalous budding of the primitive foregut during embryonic development and it represents a part of the spectrum of bronchopulmonary foregut malformations. Approximately two-thirds of the malformations are found within the mediastinum, and one-third are found in the lung parenchyma. The prevalence of bronchogenic cyst is unknown, presumably because most patients are asymptomatic. Incidentally detected bronchogenic cysts are usually removed at the time of diagnosis. We do not know how and why bronchogenic cysts grow. We recently experienced a case of rapidly growing mediastinal mass in a young adult, and this presented as a huge mass that had newly developed within one year. This mass was pathologically confirmed to be a bronchogenic cyst. We report on this case of a rapidly growing bronchogenic cyst, which is a rare characteristic of this type of cyst.

Reexpansion pulmonary edema is not a common phenomenon after chest tube insertion but some reports from 0% to 14%. There are various resulting complications, including acute respiratory distress syndrome. We report a case of focal reexpansion pulmonary edema after chest tube insertion. A 49-year-old male came to the hospital due to ongoing dyspnea and left chest pain for 3 days. On chest X-ray, the patient had a left pneumothrax. We planned to insert a chest tube for symptom relief. To determine whether or not the chest had expanded as a result of the chest tube insertion, the patient underwent repeated chest X-rays the following day. The patient experienced brief respiratory symptoms upon initial suction; a chest PA showed patchy consolidated infiltration at the inserted site. After 5 days of conservative management, the recovered completely.

The mechanism and cause of acute eosinophilic pneumonia are largely unknown. Many factors including the smoking of cigarettes have been suggested, but none have been proven to directly cause acute eosinophilic pneumonia. The authors report a case of acute eosinophilic pneumonia in a young Asian male who recently started smoking. The diagnosis was made based on his clinical course and results of chest radiography, lung spirometry, bronchoalveolar lavage, and transbronchial lung biopsies. After administration of methylprednisolone, his clinical course rapidly improved. A provocation test was designed to establish a connection between cigarette smoking and the development of acute eosinophilic pneumonia. After the provocation test, the patient showed identical symptoms, increase in sputum eosinophils, and worsening of pulmonary function. The results of the provocation test suggest that smoking may directly cause acute eosinophilic pneumonia, and support previous reports of cigarette smoking-induced acute eosinophilic pneumonia.

Neurilemmomas are benign nerve sheath tumors derived from Schwann cells that rarely occur in the chest wall. Neurilemmomas of the chest wall are usually solitary lesions th at bulge toward the pleural cavity. Neurilemmomas are confirmed histologically based on the presence of Verocay bodies, Antoni A and Antoni B tissue patterns and S-100 protein. Bilateral neurilemmomas in the chest wall are extremely rare, as are those that grow in the subcutaneous tissue but not the pleural area. We report here a case of bilateral chest wall neurilemmomas in which the tumors bulged out to the skin and were palpable. (Tuberc Respir Dis 2008;65:318-322)Key Words: Bilateral neurilemmomas, Chest wall

Tracheomegaly is a distinctive condition that presents with marked dilation of the trachea. Spontaneous pneumomediastinum is the result of alveolar rupture with dissection of the airway along the bronchus and into the mediastinum. Tracheomegaly and recurrent spontaneous pneumomediastinum are rare complications of pulmonary fibrosis when combined with rheumatoid arthritis. We present a case of tracheomegaly and recurrent spontaneous pneumomediastinum that was precipitated by repeated respiratory infection and chronic cough in a patient with pulmonary fibrosis that was associated with rheumatoid arthritis.

A bronchial artery aneurysm is a rare condition, which needs optimal treatment due to the possibility of a life-threatening hemorrhage by rupture. The surgical removal of the aneurysm is the standard treatment. However, there are a few reports of coil embolization with a transcatheter. A 69 year-old man was referred for a further evaluation of a mass in the right hilum on chest radiography. He denied any respiratory symptoms. A chest CT scan showed a 3 × 3 × 4.5 cm sized vascular mass with strong contrast enhancement on the right hilar area that originated from the bronchial artery. On the angiogram, the bronchial artery originated from the descending thoracic aorta at the T8 level. A bronchial artery aneurysm was catheterized selectively. and embolized successfully with a coil. After coil embolization, the selective bronchial arteriography confirmed complete occlusion. We report this case of bronchial aneurysm that was treated successfully with coil embolization. (Tuberc Respir Dis 2007; 62: 62-66)

A 29-year-old female patient presented with exertional dyspnea that she had suffered with for 2 months. The chest X-ray displayed right pleural effusion that was diagnosed as chyle, according to the level of cholesterol and triglyceride in the pleural fluid. VATS (video assisted thoracic surgery) of the right lung was performed on the 7th day of hospitalization for obtaining a lung biopsy and to control the of pneumochylothorax. On the 11th hospitalization day, VATS of left lung was also performed to control the recurrent pneumothorax via pleurodesis. The lung biopsy showed moderate amounts of spindle-shaped and rounded cells (so-called LAM cells), which were reactive to actin and HMB45 (on immunohistochemical stains). We report here on a rare case of lymphangioleiomyomatosis combined with chylothorax and bilateral pneumothroraces.

A 29-year-old male patient was admitted due to his general weak ness and poor oral intake for several months. He was diagnosed as having Crohn disease 16 years ago and total colect omy was performed 10 years ago. On the 3rd day after admission, gross hematuria and sudden hemoptysis combined with diffuse infiltration were noted on chest X-ray. His symptoms and the diffusely increased lung opacities improved wi th administering high-dose steroid therapy. Later, anti-GBM antibody was found to be positive on the laboratory fi ndings. We report here on a rare case of Goodpsture syndrome combined with prolonged Crohn disease along with a review of literature. (Tuberc Respir Dis 2006; 61: 384-388)Key word: Goodpsture syndrome, Crohn disease, anti-GBM antibody Address for correspondence : Soo-taek Uh, M.D. Department of Internal Medicine, Soonchunhyang University, School of Medicine, 657, Hannam-Dong, Yougsan-Ku, Seoul 140-743, KoreaPhone: +82-2-709-9482, Fax: +82-2-709-9554E-mail: uhs@hosp.sch.ac.krReceived : May. 18. 2006Accepted : Aug. 14. 2006

Background : A pulmonary embolism often presents with nonspecific symptoms and signs. However, a delayed diagnosis can result in catastrophic outcome. The majority of preventable deaths associated with a pulmonary embolism can be ascribed to a missed diagnosis rather than to the failure of existing treatments. Therefore, accurate and rapid diagnostic methods are essential for the management of a pulmonary embolism. The recent generation of multidetector-row spiral CT scanners appears to outperform other imaging modalities in detecting a central and peripheral pulmonary embolism. However, there are some variations in the interpretations of the findings between observers. This study examined the inter-observer differences of the diagnoses in patients with a pulmonary embolism. Method : 64 patients who were diagnosed with a pulmonary embolism either clinically or with spiral chest CT from 2002 to 2004, were included. Two thoracic radiologists interpreted the multidetector-row spiral CT in terms of the diagnosis of a pulmonary embolism and the location of the thrombus independently. Among 64 patients, 14 patients were excluded because there was no evidence of a pulmonary embolism or there was different interpretation of the pulmonary embolism between radiologists. A clinical diagnosis was based on "Rules for predicting the probability of embolism". Results : The mean score of the patients according to the Wells method was (0-9). The accordance of the radiologists was 95% in the main, 85% in the lobar, 91.2% in the segmental, and 96% in the sub-segmental pulmonary arteries. After excluding the negative interpretation from both radiologists, their agreement was 76.2%( 0.83) in the main, 57.6%( 0.63) in the lobar, 51.5%( 0.63) in the segmental, and 34.6%( 0.49) in the sub-segmental pulmonary arteries. Conclusion : Chest CT has been recently applied to patients suspected of having a pulmonary embolism. It was found that spiral CT is a rapid test for diagnosing a thrombus, and there was reliable accordance between the observers from the area of the large pulmonary arteries. However, there was a lack of agreement between the observers in diagnosing thrombi located distal to the sub-segmental arteries.

Background : Diagnosing a pulmonary embolism is difficult because its presenting symptoms are nonspecific and there are limitations with all of the objective tests. The D-dimer is known to be a marker of the lysis of intravascular cross-linked fibrin as a result of the activation of the endogenous fibrinolytic pathways, and the D-dimer assay is these an objective method for diagnosing a pulmonary embolism. This study assessed the benefits of the D-dimer test for diagnosing a pulmonary embolism using semiquantitative latex agglutination. Methods : The latex agglutination results of 185 patients were retrospectively reviewed. The D-dimer test was performed at the time a pulmonary embolism was suspected. Ninety patients(group I) were diagnosis with PE through spiral chest CT or a chest CT angiogram, perfusion/ventilation scans, and/or pulmonary angiogram. Ninety-five patients (group II) were found not to have a pulmonary embolism through the above tests. Results : The male to female ratio and mean age in groups I and II was 37:55, and 57 years old to 50:45 and 52 years old, respectively. When the cut off value for a positive D-dimer assay was set to , the sensitivity, positive predictive value, negative predictive value and specificity was 86.7%, 61.4%, 79.3%, and 48.4%, respectively. Conclusion : The semiquantitative latex agglutination method in the D-dimer test has a lower sensitivity and negative predictive value than the well known ELISA test particularly for small emboli. Therefore, this test is not a suitable screening test for excluding a pulmonary embolism.

Aspergillus fumigatus causes a variety clinical syndrome in lung including aspergilloma, chronic necrotizing aspergillosis, invasive pulmonary aspergillosis, and allergic bronchopulmonary aspergillosis. Aspergilloma develops by a colonization and growing of Aspergillus inside lung cavities with underlying lung disease. There is a few report of endobronchial aspergilloma without lung parenchymal lesion. We experienced a case of endobronchial aspergilloma did not fit any category of Aspergillus-induced lesion, who show minimal fibrostreaky denstities on chest PA and chest CT. Massive hemoptysis was improved by a removal of the aspergilloma in this patient. Here, we report a rare case of endobronchial aspergilloma showing massive hemoptysis with review of literatures. (Tuberc Respir Dis 2004; 57:589-593)

Background : A tracheobronchial obstruction in lung cancer is associated with significant morbidity and mortality due to dyspnea, cough, hemoptysis, and recurrent respiratory infection. It is well known that one of standard treatments is photodynamic therapy (PDT) in tracheobronchial obstruction after radiotherapy, chemotherapy, and/or surgery. We reported here the role of PDT in airway obstruction in patients advanced lung cancer. Method : Pre-treatment protocol consisted of clinical, radiologic, and bronchoscopic examination, pulmonary function test, and assessment of Karnofsky performance status. A 2 mg/kg of porfimer sodium was injected intravenously, and then followed by cylindrical and/or interstitial irradiation with 630 nm of laser after 48 hours. The repeated bronchoscopy for debridement of necrotic tissue and re-illumination was performed after 48 hours. Result : Improved airway obstruction and selective tumor necrosis were achieved by photodynamic therapy in all cases. Dyspnea and performance status were improved in three cases. A purulent sputum, fever and hemoptysis were improved in one of five cases. After PDT, all patients showed temporarily aggravation of dyspnea, two of five showed febrile reaction for a few days and nobody presented photosensitivity reaction, hemoptysis and respiratory failure. Conclusion : Our experiences of PDT are effective in palliation of inoperable advanced lung cancer in terms of tracheobronchial obstruction. (Tuberc Respir Dis 2004; 57:72-77)

Eosinophil and mast cell infiltrations are consistent findings in nasal polyp tissue. Previous studies have shown that matrix metalloproteinases (MMPs) may be involved in eosinophil infiltration in airway mucosa of asthmatic patients, and that transforming growth factor-beta1 (TGF-beta1) induces extracellular matrix deposition in nasal polyp tissue. The aim of this study was to evaluate the role of MMPs and tissue-inhibitor of metalloproteinase-1 (TIMP-1) in association with TGF-beta1, eosinophils and mast cell activation in nasal polyp tissue. Nasal polyp tissues from 20 patients who underwent polypectomies were collected and prepared into tissue homogenate. Eosinophil cationic protein (ECP) and tryptase levels were measured by CAP system (Pharmacia, Sweden). MMP-2, MMP-9, TIMP-1 and TGF-beta1 levels were measured by enzyme-liked immunosorbent assay. MMP-2 was the predominant form of MMPs, followed by MMP-9 and TIMP-1. There were significant correlations between ECP, and MMP-9, MMP-2, TGF-beta1 and tryptase, but not with TIMP-1. Significant correlations were noted between tryptase, and MMP-2, MMP-9, and TGF-beta1, but not with TIMP-1. Close correlations were noted between TGF-beta1, and MMP-9 and MMP-2, but not with TIMP-1. MMP-2, MMP-9, and TGF-beta1 may contribute to eosinophil and mast cell migrations into nasal polyp tissue.

Background : Usual interstitial pneumonia (UIP) is a progressive fibrous lung disease with occasional fatal outcomes. However, the extent and rate of progression varies markedly from one patient to another. As a result, it is difficult to determine the time of the initial treatment and assess the disease activity and course. Fibroblast foci (FF) is well known to synthesize collagen actively by their myofibroblasts component. However, the prognostic value of the FF have not been evaluated in patients with VIP. Therefore this study was undertaken to determine how the number of fibroblastic foci can reflect the disease activity and progression. Methods: Twenty patients with UIP(M : F=13 : 7), who were diagnosed by a surgical lung biopsy. The number of fibroblastic foci was analyzed in terms of its correlation with the clinical manifostations, pulmonary function test, arterial blood gas analysis, and a bronchoalveolar lavage(BAL). Results : The number of fibroblastic foci did not correlate with the various lung function tests and the other clinical parameters. Interestingly, the percentage of neutrophils in the bronchoalveolar lavage fluid did correlate with the quantity of the normalized Vv of FF(r=0.60, p

Background: TNF-alpha is related to the generation of lung fibrosis in patients with UIP. The precise mechanism leading to lung fibrosis by TNF-alpha is unknown. However, the activation of a transcription factor like AP-1(down stream of c-jun N-terminal kinase, JNK) by TNF-alpha may be related to the induction of fibrogenic cytokines like PDGF or IGF-I. Furthermore, JNK was reported to be activated in the radiation-induced lung fibrosis model. This study examined JNK activity in patients with UIP. Methods : The expression of phosphorous JNK(p-JNK), macrophage/monocyte specific markers, CD68, and cytokeratin was evaluated by immunohistochemical(IHC) staining of lung tissues from patients with UIP and lung cancer. An in vitro kinase assay was performed with alveolar macrophages obtained by a bronchol-avleolar lavage from patients with UIP and healthy persons as the control. Results : The IHC stain showed that p-JNK is expressed in the almost all of the alveolar macrophages and smooth muscle cells in patients with UIP. In case of the normal areas of the lung from patients with lung cancer, the alveolar macrophages showed little p-JNK expression. Interestingly, increased JNK activity was not found in the in vitro kinase assay of the alveolar macrophages obtained from both patients with UIP and healthy persons as the control. Furthermore, 10 ng/mL of TNF-alpha failed to increase the JNK activity of the alveolar macrophages in both patients with UIP and healthy people. Conclusion : The JNK was activated constitutionally in patients with UIP. However, the role of JNK in the pathogenesis of lung fibrosis needs to be clarified.

Purpose : An anthracofibrosis(AF), dark multiple anthracotic pigmentations combined with narrowing and obstruction of bronchi, was reported to be strongly related with past and active pulmonary tuberculosis. This study was performed to determine whether anti-tuberculous regiemens would be helpful in patients with anthracofibrosis who failed to demonstrate the evidences of pulmonary tuberculosis. Methods : Twenty-two patients with multiple anthracotic pigmentations in bronchial mucosa with luminal narrowing were enrolled in this study. The bacteriological and histological findings for Mycobacterium tuberculosis was reviwed in each patients. They are composed of 8 males and 14 females ranging from 55 to 85 years old in age. Results: The most common symptoms were coughing(73%, 16/22), followed by sputum(41%, 9/22), dyspnea on exertion(32%, 7/22), and hemoptysis(27%, 6/22). The evidence of pulmonary tuberculosis, defined by positive AFB smear or culture of Mycobacterium tuberculosis from sputum or bronchial washing fluid or histological findings of granuloma with caseous necrosis, were found in eleven patients(50%) and the others has showed no evidences. Among 11 patients without pulmonary tuberculosis, only one patient showed the evidences of pulmonary tuberculosis after 16 months, and the 8 patients still showed no evidence of pulmonary tuberculosis during follow-up periods of ranging from 8 months to 60 months. Conclusions : Beause the anthracofibrosis is closely related to tuberculosis, it needs to find out extensively the evidences of tuberculosis in patients with anthracofibrosis. Chemotherapy for tuberculosis should be administrated only with confirmation of tuberculosis on bacteriologic study.