[Accuracy of COPD questionnaires in the general health check-up setting].

To evaluate the accuracy of the International Primary Care Airways Group (IPAG)-COPD questionnaire for detection of airflow limitation in the general health check up setting, we conducted a cross-sectional study in 186 subjects who underwent spirometry and filled out COPD questionnaire with a recommended cut-off level of 17 points. The prevalence of airflow limitation defined as FEV1/FVC < 70% was 3.8%. When the subjects were restricted to those 40 years or older, the prevalence was 5.5%. When we used a cut-off level of 17 points to detect airflow limitation, the sensitivity, specificity, positive predictive value (PPV) and positive likelihood ratio (LR+) were 14.3%, 83.2%, 3.2%, and 0.85, respectively. When the cut-off level was changed to 14 points, the sensitivity, specificity, PPV and LR+ were 85.7%, 59.2%, 7.6%, and 2.10, respectively. The questionnaire was useful to find airflow limitations in the general health check-up setting with a cut-off level of 14 points.

Primary hyperparathyroidism presumably caused by chronic parathyroiditis manifesting from hypocalcemia to severe hypercalcemia.

A 67-year-old woman who presented with hypocalcemia compatible with idiopathic hypoparathyroidism gradually changed into a state of primary hyperparathyroidism. The left upper parathyroid gland, which was larger and harder than other glands, was resected. Despite the operation, hypercalcemia and high levels of intact PTH persisted. Six weeks later total parathyroidectomy was done to induce remission. The resected gland in the first operation had clusters of lymphoid follicles with germinal centers indicating a chronic autoimmune inflammation. This case suggests a transition from hypoparathyroidim to hyperparathyroidism associated with chronic parathyroiditis, possibly by a mechanism analogous to that observed in chronic thyroiditis.

A possible role of TARC in antigen-specific Th2-dominant responses in patients with Paragonimiasis westermani.

BACKGROUND: Paragonimiasis westermani (Pw), a common parasitic zoonosis in Asia, is typically associated with eosinophilia. Th2 cytokines seem to have an important role in the clinical manifestations of this disease. Thymus and activation-regulated chemokine (TARC) is a potential key regulator of Th2-mediated inflammation. The purpose of the present study was to evaluate the antigen-specific Th2-dominant responses in patients with Pw. METHODS: The concentrations of cytokines and chemokines in supernatants of peripheral blood mononuclear cell (PBMC) cultures with or without antigen stimulation were measured by enzyme-linked immunosorbent assay (ELISA). TARC levels in serum from Pw patients were also evaluated by ELISA. The number of Th2 cells expressing the CC-chemokine receptor 4 (CCR4) in the peripheral blood was evaluated by flow cytometry. RESULTS: Antigen-stimulation induced production of IL-5 and IL-13, but not IFN-gamma from PBMC cultures in patients with Pw. Pw patients had elevated serum TARC levels and a higher proportion of CCR4-expressing cells among CD4+ T cells in the peripheral blood. There were also higher levels of TARC, but not IP-10, in supernatants of antigen-stimulated PBMC culture compared to unstimulated PBMC culture in patients with Pw. CONCLUSION: Our findings clarify antigen-specific Th2-dominant responses in patients with Pw and suggest a possible role for TARC in Th2-dominant responses.

The expression and functional role of nicotinic acetylcholine receptors in rat adipocytes.

To clarify whether nicotine has a direct effect on the function of adipocytes, we evaluated nicotinic acetylcholine receptor (nAChR) expression in adipocytes by reverse transcriptase-polymerase chain reaction (RT-PCR) and immunocytochemistry and the direct effects of nicotine on the production of adipocytokines by enzyme-linked immunosorbent assay and Western blot analysis. Receptor binding assays were performed using [3H]nicotine. RT-PCR studies revealed that alpha1-7, 9, 10, beta1-4, delta, and epsilon subunit mRNAs are expressed in adipocytes. Immunocytochemical experiments also suggested the presence of alpha7 and beta2 subunits. The receptor binding assay revealed a binding site for nicotine (Kd = 39.2 x 10(-9) M) on adipocytes. Adipocytes incubated with nicotine for 12 and 36 h released tumor necrosis factor-alpha (TNF-alpha), adiponectin, and free fatty acid (FFA) into the medium in a dose-dependent manner with increasing nicotine concentration from 6 x 10(-8) to 6 x 10(-4) M. However, TNF-alpha protein levels in adipocytes incubated for 12 and 36 h decreased in a dose-dependent manner with increasing nicotine concentration from 6 x 10(-8) to 6 x 10(-4) M. These results show that adipocytes have functional nAChRs and suggest that nicotine reduces TNF-alpha protein production in adipocytes through the activation of nAChRs. Nicotine may temporarily lower insulin sensitivity by stimulating the secretion of TNF-alpha and FFA, whereas long-term direct stimulation of nAChRs by nicotine in addition to autonomic nervous system stimulation may contribute to better insulin sensitivity in vivo through a modulated secretion of adipocytokines.

Fasting plasma ghrelin levels in subtypes of anorexia nervosa.

Ghrelin has a role in regulating eating behavior and energy metabolism in the central nervous system, and has been reported to play an important role in the pathophysiology of anorexia nervosa (AN). The aim of the present study was to compare fasting plasma ghrelin levels in different subtypes of untreated AN patients. The subjects included 39 female AN patients and 11 female controls. The patients were then divided into two subtypes as follows: 19 AN patients with restricting (AN-R) and 20 AN patients with binge-eating/purging (AN-BP) form of the illness. Blood samples from subjects after an overnight fast were used to analyze plasma ghrelin concentrations. Plasma ghrelin concentrations in both AN-R and AN-BP were negatively correlated with body mass index (BMI). The mean plasma ghrelin levels in both AN-R and AN-BP were significantly higher than that in controls. The mean ghrelin level in AN-BP was significantly higher than that in AN-R. However, mean BMI and serum potassium in both groups were not significantly different. These results suggest that both BMI and the presence of binge-eating/purging may have some influence on fasting plasma ghrelin levels in patients with AN.

Elevated levels of circulating adhesion molecules in patients with active pulmonary tuberculosis.

OBJECTIVE: Recent studies have indicated the importance of cell adhesion molecules in the pathogenesis of various inflammatory lung diseases. Our study was designed to determine whether five soluble adhesion molecules including soluble L-, E- and P-selectin (sL-, sE- and sP-selectin), intercellular adhesion molecule-1 (sICAM-1), and vascular cell adhesion molecule-1 (sVCAM-1) in serum reflect the severity of active pulmonary tuberculosis (TB), and whether there is a distinct profile of these soluble molecules in this disease. METHODOLOGY: Using enzyme-linked immunosorbent assays, we measured the serum levels of these five soluble adhesion molecules in 31 patients with active TB and 11 healthy volunteers. RESULTS: Serum levels of sE-selectin, sP-selectin and sICAM-1, but not sL-selectin or sVCAM-1, were significantly higher in patients with active TB than in the control subjects (P < 0.001, each). Significant correlations were detected only between serum levels of sE-selectin and sP-selectin, sE-selectin and sICAM-1, and sP-selectin and sICAM-1. There was a significant correlation between the Gaffky scale result (a scale assessing the number of mycobacteria bacilli present) and all of the above adhesion molecules, except for sL-selectin. Serum levels of sE-selectin, sL-selectin and sICAM-1 also correlated with the CXR radiological score. Higher levels of sL-selectin and sICAM-1 were detected in the serum of patients with radiological cavity formation compared to those without. The ESR, C-reactive protein and circulating neutrophil counts all correlated significantly with sE-selectin, sP-selectin, sICAM-1 and sVCAM-1. CONCLUSION: The results suggest that there is a distinct profile of soluble adhesion molecules in active pulmonary TB and that sE-selectin, sP-selectin, and especially sICAM-1 appear to be the most sensitive clinical measures of disease severity.

A role for CD44 in an antigen-induced murine model of pulmonary eosinophilia.

Previous studies established that IL-5-producing CD4(+) T cells play a pivotal role in allergic respiratory inflammation. It was also reported that CD4(+) T cells express higher levels of CD44 in the airway than in peripheral blood of patients with allergic respiratory diseases. We have used experimental pulmonary eosinophilia induced in mice by Ascaris suum (Asc) extract to investigate the role of CD44 in the development of allergic respiratory inflammation. Intraperitoneal administration of anti-CD44 mAb prevented both lymphocyte and eosinophil accumulation in the lung. Anti-CD44 mAb also blocked antigen-induced elevation of Th2 cytokines as well as chemokines (CCL11, CCL17) in bronchoalveolar lavage fluid (BALF). Treatment with anti-CD44 mAb inhibited the increased levels of hyaluronic acid (HA) and leukotriene concentrations in BALF that typically result from antigen challenge. Anti-CD44 mAb also blocked antigen-induced airway hyperresponsiveness. An anti-CD44 mAb (IM7) inhibited the HA-binding ability of splenocytes associated with decreased levels of CD44. Soluble CD44 levels in serum were increased in Asc-challenged IM7-treated mice, but not in KM201-treated mice, compared with Asc-challenged rat IgG-treated mice. Ab's that block CD44-HA binding reduced allergic respiratory inflammation by preventing lymphocyte and eosinophil accumulation in the lung. Thus, CD44 may be critical for development of allergic respiratory inflammation.

Critical role of IL-5 in antigen-induced pulmonary eosinophilia, but not in lymphocyte activation.

Infiltration of antigen-specific CD4+ T cells and production of interleukin (IL)-5 in inflammatory regions play a central role in antigen-induced pulmonary eosinophilia. Genetically IL-5-deficient mice lack antigen-induced airway eosinophilia, but little is known about the role of IL-5 in accumulation and activation of CD4+ T cells in the lung and in airway hyperresponsiveness (AHR). ASCARIS SUUM extract (Asc) has been used to induce airway eosinophilia and analyze airway inflammation in IL-5 receptor alpha-chain-deficient (IL-5RKO) mice. We examined the role of IL-5 in CD4+ T cell activation, cytokine production, and AHR upon Asc sensitization. Pulmonary CD4+ T cells in Asc-immunized mice were activated and produced IL-5 upon local exposure to Asc in both wild-type (WT) and IL-5RKO mice. IL-2, IL-4, IL-5, IL-10 and eotaxin were detected in bronchoalveolar lavage fluid of both WT and IL-5RKO mice following exposure to Asc. Airway eosinophilia and AHR were seen only in WT mice, but not in IL-5RKO mice. We conclude that IL-5 appears to be required for the accumulation of eosinophils and AHR in the inflammatory lung. However, IL-5 does not play a critical role in the accumulation of activated CD4+ T cells in the inflammatory lung.

Ghrelin-induced food intake is mediated via the orexin pathway.

The hypothalamus regulates energy intake by integrating the degree of starvation or satiation with the status of the environment through a variety of neuronal and blood-derived signals. Ghrelin, a peptide produced in the stomach and hypothalamus, stimulates feeding and GH secretion. Centrally administered ghrelin exerts an orexigenic activity through the neuropeptide Y (NPY) and agouti-related protein systems. The interaction between ghrelin and other hypothalamic orexigenic peptides, however, has not been clarified. Here, we investigated the anatomical interactions and functional relationship between ghrelin and two orexigenic peptides, orexin and melanin-concentrating hormone (MCH), present in the lateral hypothalamus. Ghrelin-immunoreactive axonal terminals made direct synaptic contacts with orexin-producing neurons. Intracerebroventricular administration of ghrelin induced Fos expression, a marker of neuronal activation, in orexin-producing neurons but not in MCH-producing neurons. Ghrelin remained competent to induce Fos expression in orexin-producing neurons following pretreatment with anti-NPY IgG. Pretreatment with anti-orexin-A IgG and anti-orexin-B IgG, but not anti-MCH IgG, attenuated ghrelin-induced feeding. Administration of NPY receptor antagonist further attenuated ghrelin-induced feeding in rats treated with anti-orexin-IgGs. Ghrelin-induced feeding was also suppressed in orexin knockout mice. This study identifies a novel hypothalamic pathway that links ghrelin and orexin in the regulation of feeding behavior and energy homeostasis.

Acute eosinophilic pneumonia with fine nodular shadows.

A 19-year-old woman presented with acute onset of cough and dyspnea. She started smoking two weeks before the appearance of symptoms. On admission, arterial blood gas analysis on room air breathing revealed PaO2 55 Torr. Chest roentgenogram and high resolution computed tomograms showed localized fine nodular shadows at the right lower lung field. Bronchoalveolar lavage fluid revealed a high eosinophil count. Eosinophil infiltration was also observed in transbronchial lung biopsy specimens. The final diagnosis was acute eosinophilic pneumonia (AEP). Although few reports have demonstrated diffuse fine nodular shadows in AEP, localized fine nodular shadows on chest roentgenogram and CT may sometimes be the sign of AEP especially in the early phase of the clinical course.

Anti-cachectic effect of ghrelin in nude mice bearing human melanoma cells.

Ghrelin is a novel brain-gut peptide that stimulates food intake and body weight gain. We studied the anabolic effect of ghrelin in a cancer cachexia mouse model. SEKI, a human melanoma cell line, was inoculated into nude mice to examine the effects of ghrelin on food intake and body weight. The intraperitoneal administration of ghrelin twice a day (6 nmol/mice/day) for 6 days suppressed weight loss in SEKI-inoculated mice and increased the rate of weight gain in vehicle-treated nude mice. Ghrelin administration also increased food intake in both SEKI- and vehicle-treated mice. Both the weight of white adipose tissue and the plasma leptin concentration were reduced in tumor-inoculated mice compared with vehicle-treated mice; these factors increased following ghrelin administration. The levels of both ghrelin peptide and mRNA in the stomach were upregulated in tumor-inoculated mice. The anabolic effect of ghrelin efficiently reverses the cachexia in mice bearing SEKI human melanoma. Ghrelin therefore may have a therapeutic ability to ameliorate cancer cachexia.

Habitual binge/purge behavior influences circulating ghrelin levels in eating disorders.

Previous studies have reported that fasting plasma ghrelin concentrations play an important role in the pathophysiology of eating disorders. The purpose of this study was to examine the relationship between plasma ghrelin levels and frequency of abnormal eating behaviors, nutritional parameters in eating disorders. Fasting blood samples were obtained in 40 female anorexia nervosa (AN) patients, 21 restricting type (AN-R) and 19 binge-eating/purging type (AN-BP), in 31 bulimia nervosa (BN) patients, 18 purging type (BN-P) and 13 non-purging type (BN-NP), in 15 female healthy volunteers (control) before the initiation of active treatment. The fasting plasma ghrelin concentrations in all subjects were negatively correlated with nutritional parameters such as body mass index, percent body fat and serum cholinesterase concentration. The mean plasma ghrelin level in BN-P was higher than that in both BN-NP and controls despite similar nutritional parameters. The plasma ghrelin levels in both AN-R and AN-BP did not differ from BN-P despite difference of nutritional parameters. For both AN-BP and BN-P patients with habitual binge/purge behavior, there were significant correlations among plasma ghrelin values, frequencies of binge/purge cycles and serum amylase values. In BN-NP, there were no significant correlations among plasma ghrelin values, frequencies of binge-eating episodes and serum amylase values. These results suggest that habitual binge/purge behavior may have some influence on circulating plasma ghrelin levels in both BN-P and AN-BP. Habitual binge/purge cycles with vomiting as opposed to binge-eating episodes without vomiting may have a greater influence on fasting plasma ghrelin concentration in eating disorders.

Long-term oral nicotine administration reduces insulin resistance in obese rats.

This study aimed to investigate the effect of long-term oral nicotine administration on insulin resistance in an animal model of obesity. Eight-week-old male Zucker fatty rats (ZFRs) were administered nicotine tartrate dihydrate (4.6 mg/kg/day) in the drinking water. The control group was pair-fed. The body weights and food intake over 8 weeks were similar in both groups. Plasma glucose levels at 3, 6, 9, 12, and 15 min after insulin administration (0.5 U/kg) in the nicotine group were significantly lower than those in the control group. The calculated K(ITT) value for the nicotine group was significantly higher than that for the control group. Wet weight of the liver in the nicotine group was significantly lower than that in the control group. Transaminases and histological examination of the liver revealed no alteration by nicotine administration. Glycogen, glycogen synthetase activity and gluconeogenesis in the liver in the nicotine group were significantly lower than those in the control group. Phosphorylase-a activity of the liver in the nicotine group was significantly higher than that in the control group. Glycogen, glycogen synthetase, and phosphorylase-a activity of skeletal muscle were similar in both groups. These results suggest that long-term oral nicotine administration may reduce insulin resistance in obese diabetic rats through a reduced hepatic glucose release and, in part, contribute to lowering blood glucose levels.

[Comparison of bronchoalveolar lavage fluids from nonspecific interstitial pneumonia and from ordinary interstitial pneumonia].

We studied cell findings in the bronchoalveolar lavage fluid (BALF) of 13 patients with nonspecific interstitial pneumonia (NSIP) and 20 with ordinary interstitial pneumonia (UIP). NSIP and UIP were difficult to distinguish by high-resolution CT. Surgical lung biopsies were performed in all patients. We divided the patients with NSIP and UIP into 4 groups, a group of idiopathic NSIP (idiopathic NSIP), a group of NSIP patients associated with collagen vascular disease (CVD NSIP), a group of idiopathic UIP patients (idiopathic UIP) and a group of UIP patients associated with collagen vascular disease (CVD UIP). We then examined the differences in BALF cell findings between these groups. The percentage of lymphocytes in BALF was higher in idiopathic NSIP and CVD NSIP than in the healthy control. The percentage of alveolar macrophages was lower and the percentage of lymphocytes was higher in CVD NSIP than in idiopathic UIP. The CD4/CD8 ratio in BALF of idiopathic NSIP was lower than with idiopathic UIP. It is important that NSIP be distinguished from UIP clinically, and our results suggest that BALF cell findings may be useful for making this distinction.

The role of the gastric afferent vagal nerve in ghrelin-induced feeding and growth hormone secretion in rats.

BACKGROUND & AIMS: Visceral sensory information is transmitted to the brain through the afferent vagus nerve. Ghrelin, a peptide primarily produced in the stomach, stimulates both feeding and growth hormone (GH) secretion. How stomach-derived ghrelin exerts these central actions is still unknown. Here we determined the role of the gastric afferent vagal nerve in ghrelin's functions. METHODS: Food intake and GH secretion were examined after an administration of ghrelin intravenously (IV) to rats with vagotomy or perivagal application of capsaicin, a specific afferent neurotoxin. We investigated Fos expression in neuropeptide Y (NPY)-producing and growth hormone-releasing hormone (GHRH)-producing neurons by immunohistochemistry after administration IV of ghrelin to these rats. The presence of the ghrelin receptor in vagal afferent neurons was assessed by using reverse-transcription polymerase chain reaction and in situ hybridization histochemistry. A binding study on the vagus nerve by (125)I-ghrelin was performed to determine the transport of the ghrelin receptor from vagus afferent neurons to the periphery. We recorded the electric discharge of gastric vagal afferent induced by ghrelin and compared it with that by cholecystokinin (CCK), an anorectic gut peptide. RESULTS: Blockade of the gastric vagal afferent abolished ghrelin-induced feeding, GH secretion, and activation of NPY-producing and GHRH-producing neurons. Ghrelin receptors were synthesized in vagal afferent neurons and transported to the afferent terminals. Ghrelin suppressed firing of the vagal afferent, whereas CCK stimulated it. CONCLUSIONS: This study indicated that the gastric vagal afferent is the major pathway conveying ghrelin's signals for starvation and GH secretion to the brain.

[A case of cortical deafness following bilateral putaminal hemorrhage].

A 59-year-old man had suffered from consciousness disturbance and right hemiplegia in December, 1996. He was diagnosed as left putaminal hemorrhage and his symptoms improved by conservative treatment. After one week since the onset, when he became alert, he noticed deafness. He was admitted in our hospital because of deafness and dysarthria in March, 2001. T 1-weighted MR image of the brain revealed bilateral putaminal hemorrhage and a low signal area in the white matter of right temporal lobe. Single photon emission computed tomography image revealed hypoperfusion in the bilateral temporal lobes. His electrocochleogram and auditory brainstem response were normal. Audiogram revealed increased air and bone conduction thresholds. Therefore, we diagnosed his condition as cortical deafness. He could only recognize loudness as the sound by the electrical promontory test. These results indicate that his cortical deafness might be caused by his bilateral acoustic radiation damage associated with the right partial temporal lobe damage and that some fibers of the acoustic radiation, which were responsible for the recognition of loudness of sound, were spared. Therefore he has a possibility of regaining hearing capability by a cochlear implant.

Increased fasting plasma ghrelin levels in patients with bulimia nervosa.

OBJECTIVE: Fasting plasma ghrelin levels play an important role in the pathophysiology of the eating disorder anorexia nervosa. Bulimia nervosa (BN) also has been associated with abnormal neuroendocrine regulation. Thus, we examined the relationship between body mass index (BMI) and plasma ghrelin concentrations in patients with BN for the first time. METHODS: The subjects included 15 female BN patients and 11 female healthy volunteers (controls). Fasting blood samples were collected from all subjects. RESULTS: The plasma ghrelin concentrations in all subjects demonstrated a significantly negative correlation with BMI. Mean plasma ghrelin level in BN patients was significantly higher than that in the controls, though mean BMIs between the groups were not significantly different. CONCLUSION: These findings suggest that not only BMI but also abnormal eating behaviors with habitual binge eating and purging may have some influence on circulating ghrelin level in BN.

Clinical features and neuropathological findings of familial amyotrophic lateral sclerosis with a His46Arg mutation in Cu/Zn superoxide dismutase.

We examined the characteristic clinical features of one family of familial amyotrophic lateral sclerosis (FALS) with a His46Arg mutation in the enzyme Cu/Zn superoxide dismutase-1 (SOD1). The disease duration for this family was 18.1 +/- 13.2 (mean +/- S.D.) years, with the age at onset being 39.7 +/- 10.5 years old (mean +/- S.D.). The initial sign was distal weakness of the unilateral lower limb, extending to the lower limb of the other side. A wheel chair became necessary at 9.8 +/- 3.2 years after the onset. Upper limb weakness started at 15.5 +/- 8.9 years following from the onset. An autopsy was performed on a 71-year-old woman of the family with the mutation. Her disease duration was 47 years, and she died of pneumonia. She had no clear upper motor neuron involvement. Bulbar sign and respiratory muscle weakness had developed 2 years before her death. Neuropathological findings showed degeneration of corticospinal tracts, anterior/posterior spinocerebellar tracts, posterior columns, and Clarke's columns. There were few anterior horn cells in the lumbar spinal cord and no Lewy body-like hyaline inclusion bodies in these remaining anterior horn neurons. This is the first autopsy report of FALS with a His46Arg mutation in the SOD1 enzyme.

Elevated plasma procoagulant and fibrinolytic markers in patients with chronic obstructive pulmonary disease.

OBJECTIVE: There is clinical and pathological evidence of thrombosis in pulmonary vessels of patients with chronic obstructive pulmonary disease (COPD). The purpose of this study was to investigate the presence of hypercoagulability and determine the extent of this abnormality in COPD patients. PATIENTS AND METHODS: We measured plasma levels of thrombin antithrombin III complex (TAT), fibrinopeptide A (FPA), tissue plasminogen activator-plasminogen activator inhibitor (tPA-PAI): markers of coagulation-fibrinolysis-system, and also beta-thromboglobulin (beta-TG): a marker of platelet activation, in 40 COPD patients and in 20 control subjects. Measurements were also repeated 12 months after entry in all patients. RESULTS: TAT, FPA, tPA-PAI, and beta-TG concentrations were significantly higher in COPD than in control subjects. At 12 months follow-up, deltaA-aDO2 and delta%FEV1 were significantly higher in patients with high TAT or tPA-PAI levels than in patients with low levels and TAT, FPA and tPA-PAI levels remained elevated, although beta-TG levels decreased after domiciliary O2 therapy. CONCLUSION: Our results showed an enhanced prothrombotic process in COPD patients, which could potentially account for the increased thrombosis in pulmonary vessels in these patients.