Haloperidol treatment induces tissue- and sex-specific changes in DNA methylation: a control study using rats

BACKGROUND: We previously found that there is a subtle difference in the global methylation state of blood leukocyte DNA between male subjects with and without schizophrenia. The aim of the current study was to determine whether this difference was a primary effect of the disease state, or a secondary effect of antipsychotics administered to these patients. METHODS: We examined the methyl cytosine (mC) content of DNA from the leukocytes, brain, and liver of rats using high performance liquid chromatography. A total of 40 male and female rats received for 21 days daily injection of haloperidol or vehicle solution alone. RESULTS: In control rats injected with buffer only, there was a sex-dependent difference in mC content in leukocyte DNA (male > female; P = 0.028, n = 10), similar to our previous observations in human peripheral leukocytes. No difference in mC content between the sexes was observed in the brain or liver in buffer-treated animals. Haloperidol treatment slightly decreased the mC content of leukocytes in male rats, but unexpectedly, increased the mC content of leukocytes in females. We observed a trend toward a higher level of mC in the liver in both sexes following haloperidol treatment, compared to buffer-treated animals. In contrast, haloperidol treatment resulted in a decrease in mC content in the brain in females, and this difference was statistically significant (P = 0.026). CONCLUSION: These results indicate that haloperidol can affect DNA methylation states in the brain, as well as in certain other tissues, and raise the possibility that antipsychotic drugs play a role in the observed disparity in mC content in male subjects with and without schizophrenia

カンジダ特異的IgG(4)抗体と気管支喘息

Serum levels of Candida-specific IgG(4) antibodies were examined in 66 patients with bronchial asthma, relating to patient age and asthma severity. 1. The levels of Candida-specific IgG(4) antibodies were the highest in patients with 60+years of age, compared to the levels in cases with 0-39 and 40-59 years of age. 2. In cases with 40-59 years of age, the levels of Candida-specific IgG(4) were significantly higher in cases with long-term steroid therapy (severe intractable asthma) than in cases without steroid regimen. The results suggest that increased levels of Candida-specific IgG(4) were observed in relation to patient age and asthma severity.66例の気管支喘息症例を対象に，血清中カンジダ特異的lgG(4)抗体を測定し，その血中レベルと年齢および喘息の重症度との関連について検討を加えた。1．血清カンジダ特異的IgG(4)値は，0～39才，40～59才の年齢層にくらべ，60才以上の年齢層において高く，年齢によりその値が変動することが 示唆された。2．40～59才の年齢層では，血清カンジダ特異的IgG(4)は，ステロイド非使用例にくらべ，ステロイド依存性重症難治性喘息症例で有意の高値を示し，この年齢層では，カンジダ特異的IgG(4)抗体がその発症病態に関連している可能性が示唆された。以上，カンジダ特異的IgG(4)抗体の上昇は，高年齢層の症例（60才以上）では全般的に，また40～59才の年齢層で重症型喘息症例において観察されることが明らかにされた

気管支喘息患者における細胞性免疫,ガンジダ抗原に対する遅延型反応の抑制

Delayed cutaneous hypersensitivity towards Candida albicans was examined　in 200 patients with bronchial asthma in relation to patient age and the level of　total IgE. 1. Delayed skin reactivity towards C.albicans was depressed in the patients between the ages of 10 and 20 and in those over the age of 61. A significant difference was present in delayed skin reactivity between the groups of 10-20 and 41-50 years old. 2. The frequency of the patients with positive delayed skin reactivity towards C.albicans was the highest in those with low levels of total IgE (0 -100 IU/ml) and the low est in those with high levels of total IgE (over than 1001 IU/ml). The results suggest that cell-mediated immunity towards C.albicans is depressed re lating to atopics in the patients between 10 and 20 and to aging in the patients over 61.気管支喘息200例を対象にカンジダに対する即時型および遅延型皮膚反応を観察し,これらの皮膚反応と年令,血清IgE値との関連について検討を加えた｡1. カンジダに対する遅延型皮膚反応は,10～20才の年齢層および61才以上の年齢層の症例において,その陽性率の低下が観察された｡そして,10～20才の年齢層と41～50才の年齢層の症例では,両者間で陽性率の有意の差が見られた(p<0.001)。2. カンジダに対する遅延型皮膚反応の陽性率は,血清IgE値が低い(0～100 IU/ml)症例において最も高く,一方血清IgE値が高い(1001IU/ml以上)症例において最も低いという傾向が見られた｡これらの結果は,カンジダに対する細胞性免疫は,10～20才の年齢層ではアトピーと,また61才以上の年齢層では加齢と関連して抑制されることを示唆するものと考えられる

気管支喘息の発症における加齢の影響について

Skin tests, serum total IgE levels, specific IgE antibodies against each allergen, bronchial reactions provoked by allergens and histamine release from basophils are well known as prameters of immediate allergic reactions. The incidence of positive immediate skin reaction to allergens such as house dust, ragweed, Aspergillus Alternaria, Cladosporium and Broncasma decreased with aging. On the other hand, the incidence of positive skin reaction to Candida albicans was higher in cases between the age of 41 and 50 and cases over the age of 61 compared to that in the other groups classified by age. Serum IgE levels was highest in cases aged between 0 and 30. The levels of serum IgE decreased with aging. The incidence of positive RAST scores (more than 2+) and positive bronchial reaction to house dust were highest in cases between 0 and 30, and decreased with aging. However, the positive ratio of these tests against C. albicans were highest in cases between 41 and 50. The degree of histamine release from basophils of asthmatics induced by anti-IgE was consistently high without any correlation to aging when their serum IgE levels were more than 501 IU/ml. In the cases with serum IgE levels of less than 300 IU/ml, basophil reactivity to anti-IgE decreasd with aging. Basophil reactivity to house dust was generally dependent on the levels of specific IgE antibodies against the allergen. Although basophil reactivity to C. albicans was also high in cases with positive RAST scores, some cases with a RAST score of 0+ or 1+ showed high or moderate basophil reactivity. Moderate or high reactivity of basophils was frequently observed in cases between 41 and 50 and cases over age 61.気管支喘息の発症機序の一つとして,IgE抗体にmediateされる即時型アレルギー反応や好塩基球の反応性の関与が明らかにされている｡本論文では,即時型アレルギー反応や抗ヒトIgEや特異抗原に対する好塩基球の反応性が加齢によりどのような影響を受けるかについて検討を加えた｡ハウスダスト,ブタクサ,アスペルギルス,アルテルナリア,クラドスポリウム,ブロンカスマ などによる皮内反応の陽性率は,加齢とともに低下する傾向を示した｡一方カンジダによる皮内反応の陽性率は,41～50歳および61歳以上の年齢層で高度であった｡血清IgE値は加齢とともに低下する傾向がみられた｡ハウスダスト特異的IgE抗体,吸入誘発試験の陽性率は,加齢とともに低下する傾向を示した｡一方カンジダでは特異的IgE抗体,吸入誘発試験いずれも41～50歳および61歳以上の年齢層で比較的高い陽性率が観察された｡抗ヒトIgEに対する好塩基球の反応性は,血清IgEが高値(501IU/ml以上)の場合は年齢と関係なくIgE依存性であったが,血清IgE値の低い症例(301IU/ml以下)では年齢が高い群でその反応性が低い症例の比率が大きかった｡ハウスダストに対する好塩基球の反応性は,抗ヒトIgE同様年齢が高い群ほど反応性が低い症例の比率が大きかった｡カンジダに対する好塩基球の反応性は,41～50歳および61歳以上の年齢層の症例でより高度であった

気管支喘息における気道内への好酸球の出現とその意義. 過分泌と関連して.

A correlation between the proportion of eosinophils in bronochoalveolar lavage (BAL) fluid and amount of expectoration was examined in patients with atopic asthma. The subjects were divided into two groups : cases with high proportion (20% of more) (group A) and low proportion (less than 5%) (group B) of eosinophils in the BAL fluid. Any significant difference was not paesent in the value of each ventilatory parameter between the two groups. The amount of expectoration/day was significantly higher in group A compared with group B (p<0.001). These results suggest that eosinophilia in BAL fluid correlates to mucus hypersecretion in the airways of patients with atopic asthma.アトピー型気管支喘息のなかから,気管支肺胞洗浄液(BALF)中の好酸球の出現頻度が20%以上の症例(グループA)と5%以下の症例(グループB)の2群を選び出し,それぞれの換気機能および喀痰量を比較検討した｡その結果,換気機能には両群間に有意の差は見られなかったが,1日喀痰量は,BALF中好酸球の著明増多を示すグループAにおいて有意に多い傾向が見られた｡これらの結果は,BALF中好酸球増多と過分泌との間にはある程度の関連があることを示しているものと考えられた

抗原および抗ヒトIgEに対する抗塩基球の反応性. 3.Ca2(+)の細胞内流入およびヒスタミン遊離

The release mechanism of chemical mediators from basophils and mast cells was discussed when these cells were stimulated by different antigens and anti-IgE. 1. Ca(2+) influx into mast cells increased after stimulation by antigen. The increased Ca(2+) uptake by mast cells was inhibited by antiallergic agents, disodium cromoglycate (DSCG) and tranilast, and calcium antagonists, nifedipine and nicardipine. 2. The dose-response curve of histamine release by antigen was different from that by anti-IgE. The maximum release of histamine by house dust was, however, similar to that by anti-IgE. House dust- and anti-IgE-induced release of histamine increased with higher- serum IgE levels. On the contrary, the release of histamine by Candida albicans was not releated to serum IgE levels, and the release by C. albicans did not parallel therelease by anti-IgE.ハウスダスト,カンジダなどの抗原および抗ヒトIgE刺激時の,抗塩基球および肥満細胞からの化学伝達物質遊離機序について,若干の検討を行った｡1.肥満細胞へのCa(2+)の流入は,抗原刺激後に増加する傾向を示した｡この肥満細胞のCa(2+)取り込みの増加は,抗アレルギー剤であるクロモリン(DSCG)やトラニラストやCa(2+)拮抗剤であるニフェジピンやニカルジピンによって抑制された｡2.抗原(ハウスダスト)によるヒスタミン遊離の濃度依存性カーブは,抗ヒトIgEによるカーブとは異なっていた｡しかし,ハウスダストが抗原である症例では,抗原による最高ヒスタミン遊離値は,抗ヒトIgEによる遊離値とある程度の相関を示した｡そして,抗原(ハウスダスト)および抗ヒトIgEによる好塩基球からのヒスタミン遊離は,血清IgE値が上昇するにつれて,増加する傾向が見られた｡一方,カンジダによるヒスタミン遊離は,血清IgE値との相関は無く,また,抗ヒトIgEによるヒスタミン遊離との間にも関連は見られなかった

臨床所見および検査成績からのスコアーによる喘息分類の特徴

Twenty six patients with bronchial asthma was classified by clinical symptoms and singns (clinical diagnosis), and the classification by clinical diagnosis was compared with the classification by a score calculated from clinical findings and examinations (score diagnosis). 1. Of 12 subjects with type Ia classified by clinical diagnosis, 8 cases with 0 to 49 ml/day of expectoration were evaluated as type Ia by score diagnosis. While four type Ia cases with 50 to 99ml/day of expectoration were calssified as type Ib by score diagnosis. The increased incidence of eosinophils in bronchoalveolar lavage fluid (BALF) of these four cases was similar to the incidence in type Ib cases with hypersecretion. 2. All of 6 subjects with type Ib by clinical diagnosis were estimated as type Ib by score diagnosis. 3. Of 8 cases with type II by clinical diagnosis, 7 cases were assessed as type II by score diagnosis. One case with type II by clinical diagnosis and with the score of 10 points was evaluated as questionable type II by score diagnosis.気管支喘息36例を対象に,臨床病態による喘息の分類（臨床診断）を試み,この分類と臨床所見および臨床検査より求めたスコアーによる分類（スコアー分類）との比較検討を行った｡1.臨床分類でIa.単純性気管支攣縮型と診断された12症例のうち,1日喀痰量0-49mlの8症例は,スコアー分類では同様にIa.型と分類された｡一方,1日喀痰量50-99mlの4症例はスコアー分類ではIb.型（気管支攣縮+過分泌型）と分類された｡これら4症例のBALF中好酸球増多はIb.型に類似した病態であった｡2.臨床診断によりIb.型に分類された6症例はいずれもスコアー診断でもIb.型と分類された｡3.臨床診断によりII.型（細気管支閉塞型）と分類された8症例のうち,7症例はスコアー診断でもII.型と分類されたが,1症例はスコアー10でII.型の診断基準に合わず,questionable II.型と診断された

Production of a macromomycin (MCR)-monoclonal antibody conjugate and its biological activity.

Macromomycin (MCR), an unique membrane-reactive anticancer antibiotic, was incubated with murine monoclonal anti-HLA IgG1 antibody (H-1) in the presence of carbodiimide. The resulting mixture was fractionated with a Sephadex G-200 column. The first and second fractions were shown to contain MCR-(H-1) conjugate by the elution profile, as well as by the Sarcina lutea growth inhibition assay and Ouchterlony double-diffusion method. A membrane immunofluorescence test with anti-MCR and anti-mouse IgG antibodies demonstrated specific localization of MCR-(H-1) on the surface of HLA-bearing NALL -1 cells. MCR-(H-1) inhibited the growth of HLA-lacking NS-1 cells statistically less effectively than MCR alone (p less than 0.01). On the other hand, the conjugate and free MCR equally inhibited the growth and 3H-TdR incorporation of HLA-bearing NALL -1 cells. These results indicate that the antibody-bound MCR retained both MCR and antibody activities, and thus exerted antibody-targeting MCR cytotoxicity in vitro.</p

Possible participation of viral infection in the onset mechanisms of bronchial asthma

ウイルスなどの気道感染により，気管支喘息症状が発症したり，あるいは増悪したりすることが知られている。自験例は65歳の女性で，上気道炎症状に引き続いて，気管支喘息が発症した。臨床症状の軽快とともに気道過敏性・IgE値は低下し，感染による気道過敏性の亢進，IgE型アレルギー反応の機序が関与していると考えられた。これらの結果は喘息患者は気道感染（特にウイルス感染）の予防が必要であり，感染した場合には抗喘息剤とともに抗炎症剤の使用が有用である可能性を示している。It is well known that respiratory infection induces asthma attacks. In this paper one case showing possible participation of viral infection in the onset mechanisms of bronchial asthma was reported. A 65-year-old woman was admitted to Misasa Hospital because of moderate asthma attacks. The attacks appeared after upper respiratory infection. Bronchial hyperactivity were increased when she admitted at the hospital, and decreased with the improvement of the asthma symptoms. It is suggested from her clinical course that repiratory infection (especially by virus) may affect the bronchial hyperactivity and IgE synthesis

A case of rheumatoid arthritis with hypoproteinemia probably induced by diseasemodifying antirheumatic drug, D-Penicillamine

症例は52歳女性で，慢性関節リウマチ（RA）はclassical，stageIV，　class 2であった。症状は進行性で加療を行うも改善がみられなかった。平成元年11月RA症状の増悪のための再入院後，Penicillamine 100～200　mg，Sulfasalazine 500mgを合せて投与を行ったところ，血沈，CRP等の検査所見は改善傾向を示したが入院時には正常値であった血清蛋白量がその後5.1g／dlまで低下し，下肢浮腫が出現，その後さらに血清蛋白量は4.1g／dlにまで減少した。治療により蛋白量は5.8g／dlにまで回復したが，低蛋白血症の原因としてはD－Penicillamineの関与が疑われた。A patient with classical rheumatoid arthritis was treated with D-Penicillamine and other drugs. In the course of treatment, the episodes of hypoproteinemia were found twice. The first hypoproteinemia was improved almostly by supportive therapy and withdrawl of administration of medicines, including D-Penicillamine. The second hypoproteinemia was severe and resistant to the treatment. It was suggested that the agent eliciting hypoproteinemia in this case might be D-Penicillamine