The synthesis and structure–activity-relationship (SAR) for a series of N-substituted piperazinyl carbamoyl 7—15 and piperazinyl acetyl 18—26 derivatives of tetrahydropapaverine have been carried out. The general synthetic methods of carbamoyl tetrahydropapaverine analogues involve N-substituted piperazines and carbamoyl imidazole tetrahydropapaverine as starting materials. Another route for synthesizing these compounds, involving the formation of carbamoyl imidazole piperazine has also been explored. Acylation of tetrahydropapaverine followed by substitution with various piperazinyl moities afforded the acetyl tetrahydropapaverine derivatives. Variously substituted piperazines have been used to monitor the effect of electron releasing and electron withdrawing substituents upon the antispasmodic activity of the molecules. Effect of varying electron densities on the antispasmodic activity, by altering the position of these groups on the benzene ring has also been monitored. Pharmacological methods involve the in vitro antispasmodic activity studies on a freshly removed guinea pig ileum using a force displacement transducer amplifier connected to a physiograph. Among the analogues synthesized in the present study, a promising compound 7, a potent muscle relaxant as compared to papaverine has been obtained.

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This paper describes development of a rule-based expert system for the diagnosis of main diseases (like powdery mildew, anthracnose, black spot etc, their causing agent and remedy) of Indian mango tree. The objective is to provide computer-based support for agricultural specialist or farmer in fruiticulture. The proposed expert system makes diagnosis on the basis of response/responses of the user made against queries related to particular disease symptoms. The system has been developed in Borland's Turbo-prolog 2.0 environment. The knowledge base of the system contains knowledge about symptoms of 14 diseases of Indian mango tree appearing during fruiting season or in non-fruiting season. The result given by the system has been found to be sound and consistent.

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Auditory brain stem responses were recorded in five patients with cerebello-pontine angle tumor (2 meningionas and 3 acoustic neurinomas). The data were compaired with the results of in animal experiments, and the pssbility of the topographical differential diagnosis for the central lesions by were studied.
The results were as follows.
1) Three cases out of five showed indistinguishable patterns of wave II to wave V.
2) These patterns were considered as the typical in cerebello-pontine angle tumors.
3) In the case of disturbances of cerebello-pontine angle, the decrease of amplitudes and the increase of latencies could be observed in the conponents after wave I.
4) The pattern was coincident with that of destruction of cochlear nucleus in animal studies.

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Occupational noise has been recognized as hazardous for the human beings. A high noise level in forging shops is considered to lower the labour productivity and cause illness however occupational noise is being accepted as an integral part of the job. The present study has been carried out in 5 small scale hand tool forging units (SSI) of different sizes in Northern India in Punjab. Noise levels at various sections were measured. OSHA norms for hearing conservation has been incorporated which includes an exchange rate of 5 dB (A), criterion level at 90dB (A), criterion time of 8 h, threshold level=80dB (A), upper limit=140 dB (A) and with F/S response rate. Equivalent sound pressure level (L_eq) has been measured in various sections of these plants. Noise at various sections like hammer section, cutting presses, punching, grinding and barrelling process was found to be >90 dB (A), which is greater than OSHA norms. A cross-sectional study on the basis of questionnaire has been carried out. The results of which revealed that 68% of the workers are not wearing ear protective equipments out of these 50% were not provided with PPE by the company. About 95% of the workers were suffering speech interference though high noise annoyance was reported by only 20%. It has been established that the maximum noise exposure is being taken by the workers as they are working more than 8h a day for six days per week. More than 90% workers are working 12 to 24 h over time per week which lead to very high noise exposure i.e. 50 to 80% per week higher than exposure time/week in USA or European countries^{15, 16)}.

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ICH S1

(1)ガイドラインが、10年を超える国際共同前向き研究の末、令和4年8月に成立し、ICHウェブサイト公開された。本改定においてPart Ⅱ として追加された補遺は、証拠の重み付け（weight of evidence：WoE）に基づいて、2年間ラットがん原性試験の実施がヒト発がんリスク評価に価値を付与すると考えられるか否かを判断する統合的なアプローチを導入し、2年間ラットがん原性試験を実施することなく、ヒトへの発がんリスクを評価することに道を開くものである。本補遺は、がん原性試験を必要とするすべての医薬品に適用され、ヒト発がんリスク評価において 2年間ラットがん原性試験実施の価値を判断するにあたり、1)標的の生物学的特性、2)副次的薬理作用、3)慢性毒性試験の病理組織学的データ、4)ホルモン作用、5)遺伝毒性、6)免疫調節を考慮すべき主要な要素とし、WoEによって明らかとなった懸念に対応する非臨床試験及び臨床データを含む探索的アプローチを加えて包括的に評価することとしている。

米国ではすでに令和4年11月2日に発出されStep 5の実装に至っている。日本でも、令和5年3月10日に厚生労働省から通知文書が発出された。また、欧州でも、ほぼ同時期の令和5年3月16日に実装となり、国内外で本補遺に基づくがん原性評価が開始されている。

本補遺の成立から約1年、三極での実装から3か月が経過し、改めて補遺の要点を整理すると共に、WoEアプローチによる評価の実施状況について、情報共有することが必要と考えられる。本シンポジウムでは、S1

(1)の要点、実際の実装状況、及び今後の運用におけるポイントなどについて情報提供し、適切な利用に向けて議論する機会としたい。

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The test-retest reliability and the threshold differences among the responses of action potential (AP), brain stem response (), middle latency response (MLR), and slow vertex response (SVR) in the same individual are still uncertain. This is partly due to the fact that each response has not been obtained in the same condition.
The response wave form might be affected by spontaneous EEG or various artifacts during the test period. Then, it must be one of the important things that these responses should be obtained during the same recording period. From this standpoint of view, a new device is developped, that is, so-called simultaneous recording of various kinds of responses (AP, , MLR, and SVR).
A single click and click train composed of 30 clicks are generated alternatively at the interval of about 3 seconds. The SVR to single click is averaged by one averaging computor. Other responses (AP, , MLR) to click train are averaged by another computor with different analysis time. One series are composed of 50 click train and 50 single clicks. So, there are 50 samples for SVR and 1500 samples for AP, and MLR.
In the trial on 5 adults with normal hearing, it was noticed that the distribution of artifacts was almost equal among these responses. Thus, the comparative study of these responses would be possible by this recording technique.

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Burkholderia glumae causes bacterial seedling rot (

) and bacterial grain rot (BGR) in rice (Oryza sativa), both of which are important diseases in Japan. We previously evaluated major Japanese cultivars for BGR resistance and selected standard cultivars for resistance assessments. Here, we assessed the occurrence rate in cultivars from the World Rice Collection (WRC) and other sources and found wide variation in resistance. Next, we evaluated major Japanese cultivars for resistance and found that two Japanese landraces, ‘Kujuu’ and ‘Aikoku’, showed “strong” resistance; most others were categorized as “medium” or “medium to weak”. We previously developed a near-isogenic line (RBG1-NIL) by introducing the genomic region containing RBG1, a quantitative trait locus (QTL) for resistance, from ‘Nona Bokra’ (indica) into ‘Koshihikari’ (temperate japonica). The resistance level of RBG1-NIL was “strong”, indicating the effectiveness of RBG1 against . The correlation between and BGR resistance scores was low, indicating that it is necessary to introduce QTLs for resistance from different sources to develop cultivars resistant to both and BGR. On the basis of the screening results, we selected standard cultivars for resistance to cover a range of resistance levels.

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The S1BR1 addendum expanded the evaluation process for assessing the human carcinogenic risk of pharmaceuticals. The addendum introduced a weight-of-evidence (WoE) approach to determine if a 2 year rat study would add value to an assessment based on an integrated review of drug target pharmacology and compound-specific toxicology. Successful implementation of this approach would ideally shift focus toward more mechanism-based carcinogenicity assessments and reduce the use of animals, while continuing to promote the safe development of new pharmaceuticals. The WoE document should include a comprehensive description of key factors outlined in the S1BR1 guidance. These WoE documents are complex and require scientific judgement which can lead to different conclusions on whether data from a 2yr rat study is necessary for an adequate assessment of carcinogenic risk. These differences may occur between a sponsor and the regulatory agency and also differ across regulatory regions. The S1BR1 was implemented in the United States following publication in the Federal Register (Nov 2022). To support successful implementation, the FDA arranged a review forum comprised of core reviewers and leadership staff and members of the Executive Carcinogenicity Assessment Committee to discuss and provide recommendations on sponsor’s WoE submissions. This approach increases familiarity with these submissions, fosters consistency in review and regulatory decision making, and allows for tracking decisions and lessons learned from each submission. Initial experience with S1BR1 WoE submissions indicates variable quality of assessments with higher quality documents coming from sponsors that participated in the prospective study conducted during the S1B revision process. Key strengths and deficiencies of the WoE submissions submitted to US FDA will be presented.

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Two types of recombinant plasmids containing 600 bp Nde I fragments that coded the gene in opposite directions were obtaind. Nucleotide sequencing shows that the encodes a 140 amino acid protein with a putative molecular weight of 15560, the same as that of purified blasticidin S (BS)-deaminase (), on sodium dodecyl sulfate-polyacrylamide gel electrophoresis (SDS-PAGE) (15500). Upstream of the open reading frame, a Shine-Dalgarno (SD) sequence, frequent inverted repeats, and the σ^A and σ^B promoter sequences are observed. The tarnscriptional start point was determined to be the A located 7 bases downstream from the putative σ^A promoter (⁹¹TTGATC and ¹¹³TAAAAT) by the primer estension method and site directed mutagenesis at the -10 or -35 promoter region.A comparison of the amino acid sequence of with that of BS-deaminase from Aspergillus terreus (BSD) showed 27.2% homology. Low degrees of homology were also observed with cytidine deaminase and deoxy cytidine monophosphate (CMP) deaminase. Four conserved amino acid motifs were observed, VGAx₆ G, C(orH)AEx₆A, SPCGxCR, and Gx₈ELIP (x_n indicates a nonspecific residue and its position). It is possible that the three Cys residues and the Glu in the conserved motifs comprise the active center. Site-directed mutagenesis of the Cys residues supports this possibility.

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Auditory brain stem responses () were studied in five cases including 2 acoustic neurinomas, degenerative type of myoclonus epilepsy, pontine glioma and the 4-th ventricle tumor.
They showed typical suspecting of brain stem lesions, and the patterns were compared with those of animal experiments for discussion of the topographical differential diagnosis. In two patients with acoustic neurinoma, nothing but wave I was recognized at the pathologic side, and normal was recorded at the healthy side. The was similar to that of a cat destructed ipsilateral cochlear nucleus.
In the patient with degenerative type of myoclonus epilepsy, wave I was reconized only in both sides.
In the patient with pontine glioma, wave 1, 2 and 3 at the right side and wave 1 and 2 at the left side were recognized, but the following components were obscured in both sides. The right side response was considered similar to of a cat destructed bilat. inf. colliculus, and the left side one was similar to that of a cat with destruction of bilat. Sup. olivery nucleus complex.
In the patient with the 4-th ventricle tumor, wave 1, 2, 3 and 4 were recognized in both sides, and probably wave 5 was depressed in both sides. was considered similar to that of a cat with destruction of contralateral inf. colliculus or contralateral sup. olivery nucleus complex. It was considered that the pattern was suggestive of a medial lesion of the upper portion of the brain stem.
The data of animal experiments could not be applied to the clinical use, but it could be very useful for topographical differential diagnosis of the brain stem lesions.

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Die Botelho'sche Reaktion (. . ), die beim Serum des Krebskranken positiv ist, zeigt dasselbe Verhalten beim Phthisiker. Wir untersuchten bei ca.100 Patienten . . und erlangten zu folgenden Schlüssen:
1) Das Resultat der . . entspricht häufig nicht der Stadienteilung nach Turban Gerhardt, weil erstere auf die Hypalbuminose des Krankenserums zurückzuführen ist, die andere nur auf lokalen Veränderungen beruht.
2) Jc stärker positiv . . ist, desto besorgniserrcgcnder wird der Allgemein zustand des Patienten, desto ernster die Prognose der Krankheit.
3) Eine negative oder schwach positive . . zeigt eine stationäre oder zur Heilung neigende oder eine inaktive glattwandig cavernöse Form der Phthise an.

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