Radiological aggravations during and afterchemotherapy were reported.
Aggravations were divided into three groups.The first group is called as“Schub” that newfoci appeared on the lungfield, where no fociwere previously observed. The second groupcontains enlargement of foci or cavities. Thethird is the group which contains two aggrava- tions together described above. Cavities wererecorded as aggravations by extention of external diameter. Size of foci were divided into 6groups by diameter, i. e. 1-4mm, 5-7mm, 8-10mm, 11-15mm, 16-20mm, 21mm or more.Enlargement was recorded by size of foci beforeand after enlargement.
Results were as follows:
Rate of aggravation during chemotherapy was
3.3 per cent in the primarily treated group, and
3.7 per cent in the retreated group.
Aggravation rate after chemotherapy of theprimary treatment and of the retreatment was
9.9 per cent and 13.8 per cent, respectively.
As to the type of aggravation during chemotherapy, the rates of “Schub” and enlargementwere almost equally observed. However, in theaggravation cases after chemotherapy, “Schub”was more frequently observed than enlargement.
I. Aggravation during chemotherapy

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Except infants, bacteriological examinationwas made on all persons, to whom precise examinations were required according to the resultsof miniature X-ray findings and tuberculin reaction.
Among the specimens examined, about 15 %were sputa and the remained 85 % were laryngeal swabs. These specimens were kept in anicebox and each of them was cultured on threeOgawa's egg slants after pretreatment with 4 %NaOH on the same day. Then, the slants werekept in an incubator at 37°C and observed for8 weeks.
All of the acid-fast bacilli, which developedlater than one week of incubation, were investigated on their biological characteristics precisely.Drug resistance was tested by the indirect testmethod on the strains which were identified ashuman type tubercle bacilli. The results obtained were as follows;
1) Bacteriological examination was made on827 cases, which comprises about 85 % of thecases requiring precise examination and in 67cases tubercle bacilli were positive. The proportion of the cases who received bacteriologicalexamination was 30% of the pulmonary pathology and 75.8 % of the cases requiring medicalinstruction, respectively.
2) That the proportion of sputum was only15.7 % of total specimens examined would indicate the indispensability of laryngeal swab examination for the bacteriological examination intuberculosis mass survey.
3) Positive rate in the bacteriological examination in every type of pulmonary tuberculosiswas 92.2 % in Type I, 30.5 % in Type II, 12.6 % in Type III, 5.9 % in Type IV and 1.1%in Tipe V, respectively. On the other hand, in no case of extrapulmonary tuberculosis andof that with or without any X-ray findingsother than tuberculosis was bacilli positive.
The fact that bacilli positive cases were foundalso in Type TV and y of pulmonary tuberculo sis, shows the difficulties in reading of X-rayfilms and the necessity of paying caution in determining each type of pulmonary tuberculosis.From these results, it is clear that bacteriological examination is necessary at least for allcases of Type IV and some of Type V of pulmonary tuberculosis.
4) Among the strains of tubercle bacilli isolated 28.1 % were drug resistant and the majority of them were streptomycin resistant. However, no case was found to be infected withresistant tubercle bacilli.
5) Contamination of saprophytic bacilli ormolds were found in 1.6 % of total slants used,
6) Ten strains among the acid-fast bacilliother than human type tubercle bacilli wereexamined and the results revealed that one washuman type-like, seven were non-photochromogen-like and the remained two were saprophyticmycobacteria.

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We have found that tubercle bacilli do notgrow homogenously in the whole tube of Kirchner's medium containing 0.25% agar, but ingeneral, growth occurs only at the top layer ofthe tube to form a disc of colonies. When theculture was carried out in oxygen environmentor when the culture was maintained with INH solution on the top of the medium, the disc ofcolonies submerged below the surface, the distances between the surface of the medium andthe submerged disc varied in relation to theconcentration of INH solution which was placedon the top of the medium, furthermore in relation to the grade of INH-resistance of the tubercle bacilli. Measuring the distances whichappear in tubes of medium with INH containingplasma on the top of the medium, and comparingwith the control, one may titrate the INH concentration in the plasma.
We measured the plasma concentration of activeINH after administration of INH in 188 cases ofpulmonary tuberculosis by the following method: 4 mg per kg of INH was orally given at 8: 00a. m., and blood sample was taken at 12: 00 a.m.and 2: 00 p.m.
The tube containing 0.25% agar Kirchner'smedium, homogenously inoculated with 0.5% ofDubos' liquid medium in which INH-susceptiblestrains of the tubercle bacilli were cultured for2-3 weeks at 37.0°C, was used. As the tuberclebacilli grow into a visible colony usually in 5-6days in the Kirchner's medium, the titrationmay be conducted at this period.
It has been known that the plasma level ofactive INH after administration of INH variesfrom case to case. All the cases were classifiedinto three groups, rapid inactivators, intermediate inactivators, and slow inactivators.
Rapid inactivator: The case Whose concentration of active INH was less than 0.2 γ per mlat 6 hour after administration of INH 4 mg perkg.
Intermediate inactivator: The case whose concentration of active INH ranged from 0.2-0.8γ per ml.
Slow inactivator: The case whose concentration of active INH was over than 0.8 γ per ml.
Results obtained are as follows:
1) In each investigated case, the 6-hour levelof active INH was lower than the 4-hour level.
2) The 6-hour levels of active INH of the allcases showed a trimodal curve. 16.6% of allcases were slow inactivators, 48.9% were intermediate inactivators, and 35.1 % were rapidinactivators.
3) The plasma levels of active INH in femalecases were generally lower than those in malecases.
4) It was found that the group of slow inactivators often had highly INH-resistant tuberclebacilli.
5) It was found that the group of rapid inactivators often had INH-sensitive or INH-lowerlyresistant tubercle bacilli.
6) The rate of highly INH-resistant tuberclebacilli became definitely higher in the casestreated by INH for more than one year in thegroup of slow inactivators.

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Nitrate reduction activity was tested on thestock cultures of various Mycobacteria. For thequantitative measurement of nitrite, three reagents were used following Shinn's method: one to two dilution of HC1, 0.2% sulfanilamide solution and 0.1% N (1-Naphthyl) ethylendiaminedihydrochloride solution. As NaNO₂ solutionshows a lineality between the concentrations from10^-6M to 6×10^-6M, the reaction was read quan titatively by the use of photometer.
All strains tested were subcultured on 1% Ogawa's medium and the growth was used forthe test. One to hundred mole solution of NaNO₃ in 1/40 M phosphate buffer (pH 7.0) was autoclaved at 120°C for 20 minutes and stored atroom temperature. Thirty ml of NaNO₃ solutionthus prepared was put into a test tube and 60mg of bacillary mass of each strains was addedaseptically into it. After every 2, 4, 6 and 24 hoursof incubation at 37°C, the amount of NaNO₂produced was measured quantitatively.
Stock cultures tested were as follows: 11strains of Mycobacterium tuberculosis including8 drug resistant strains, 3 strains of M. bovis, 8 substrains of BCG, 8 strains of M. avium, 6saprophytic and 17 unclassified acid-fast bacilli.Among these unclassified Mycobacteria, 5 werePhotochromogens, 6 Scotochromogens, 6 Nonphotochromogens according to Runyon's Classification.
In accordance with their type and group, theseMycobacteria have shown various degrees of activity in reducing nitrate.
Both drug sensitive and drug resistant strainsof M. tuberculosis have shown strong activity.
Contrary to this, M. bovis could not show theactivity in reducing nitrate after 6 hours of incubation. Among 8 BCG strains, however, somehave shown strong and others weak activities inreducing nitrate.
Among 8 strains of M. avium, 7 strains couldnot reduce nitrate at all even after 24 hours ofincubation, while only one (Flamingo) has shownweak positive reaction.
Den-Cho strain, which was originally isolatedfrom chicken and maintained for a long periodof time as an avian strain, has to be identifiedas a saprophytic strain not only with its strongactivity in reducing nitrate but also with otherbiological properties.
The strong positive reaction was observed inthe strains of M. phlei and M. smegmatis. M.fortuitum was also able to reduce nitrate relatively strong, but M. ranae was able to do soonly weakly.
Among the unclassified Mycobacteria, Photochromogenic strains alone have shown strongactivity, whereas both Scotochromogenic and Nonphotochromogenic strains very weak activity.
From these results, it is concluded that nitratereduction test seems to be available in the dailylaboratory testing as one of the methods in differentiating qualitatevely the type or the groupof Mycobacteria to be examined.

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There are many studies dealing with the mechanism of action of isoniazid; (1) pyridoxalcoenzyme inhibition; (2) TCA cycle inhibition; (3) dehydrogenase inhibition; (4) inhibition ofporphyrin metabolism; (5) inhibition due toperoxide production. However, there is no decisive elucidation to account for different observations presented. This study has been designedto present some findings through radioisotopeincorporation studies.
Mycobacterium “Jucho” growing in Sauton.medium was washed in saline and used for experiments. Fractionation was conducted according to the procedure of Schneider. Concentration of isoniazid used was 10μg/ml throughoutthe experiments.
1) Incorporation of P³²-orthophosphate intonucleic acid and protein fractions, especiallyinto the former, were inhibited significantly inthe presence of isoniazid. This inhibition increased after 3 hours of incubation (figures 1and 2 and tables 1 and 2). Since, as shownlater, incorporation of S³⁵-sulfate was not inhibited and, in addition, the inhibition of the P³² incorporation was most significant not in allfractions but in the nucleic acid fraction, theinhibition of the p³² incorporation observed doesnot appear to be derived from an unspecific inhibition due to the general cease of cell function. It seems likely that the inhibition ofnucleic acid synthesis and protein synthesismay be a secondary effect due to an inhibitionof transaminase activity. Since a direct inhibition of transaminase by the drug requires toomuch amount of isoniazid to account for theantibacterial action of this drug, it appearsrather possible that disfunction of transaminaseis derived from a substitution of pyridoxalphosphate or pyridoxamine by isoniazid. Thispossibility remains to be studied in the future.
2) When P³²-labeled cells were exposed toa P³²-free phosphate solution, a considerableamount of P³² was released from cells. Declineof P³² compounds in the presence of isoniazidoccurred most significantly in the nucleic acidfraction (table 5). This finding shows thatphosphorus compounds incorporated into thenucleic acid fraction are not stabilized in thepresence of isoniazid.
3) Incorporation of S³⁵-sulfate into differentcellular fractions were increased in the presenceof isoniazid. This suggests that an increase ofpermeability in cell membrane may be present (table 3). However, incorporation of S³⁵ wasreduced in the presence of isoniazid after 22hours of incubation. The delayed decrease ofincorporation may be due to a general inactivation of cell functions.
4) Incorporation of Fe⁵⁹C1₃ was inhibitedby the presence of isoniazid. However, theratio of distribution of Fe⁵⁹ in cellular fractionsremained unchanged (table 4). Therefore, it islikely that the inhibition remains unspecific andis derived from a general inactivation of cellactivity.
In summary: Incorporation of P³²-phosphateinto the nucleic acid fraction and the proteinfraction, especially into the former, were inhibited by the presence of isoniazid (10μg/ml) Accordingly, it is conceivable that inhibition ofnucleic acid synthesis and protein synthesistake place in the presence of isoniazid. Thisinhibition does not appear to be an unspecificphenomenon derived from a general inactivationof cells. Incorporation of S³⁵-sulfate is increased by the presence of isoniazid, suggesting thepresence of a change in permeability (changeof permeability seems to be some selective one, because incorporation of S³⁵ is increased andthat of P³² is not increased).

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In September, 1953, a healthy 4 years and 11 months old female received BCG vaccinationon the left upper arm. Three weeks latter, a dark brownish edematous swelling with papules appeared at the site of vaccination, followed by ulceration after 3 more weeks. Herfirst visit to this clinic was in April, 1955, 19months after vaccination, and the examinationsat that time revealed the following findings.Erythrocyte sedimentation rate was 16mm/hour. Tuberculin reaction (1: 2, 000 tuberculin) was positive. T. B. culture of gastric aspirateswas negative. A chest roentgenogram showedno evidence of pulmonary disease. The cutaneous lesion was confined to the left upper armand it showed scar formation accompanied withelevated ulcerations as well as lupus nodules bydiascope. Besides, scattered brownish-red papules were noticed over the upper arms, extending bilaterally to the trunk. A strain ofacid-fast bacilli was isolated from the specimensof the ulcerated parts.
From these findings, lupus vulgaris followingBCG vaccination (BCG-lupus) associated withlichen scrophulosorum was suspected.
As a reference, 43 cases of BCG-lupus reported up to this time were reviewed.

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The relationship between cancer and tuberculosisis still obscure inspite of many effortsabout this problem. In this report we performedseveral experiments as follows:
1) A: The living tubercle bacilli were directlyinjected into the subcutaneous solid tumorsof mice in order to know the direct effect oftubercle bacilli for Ehrlich's ascites tumor cells, but we could not find any special direct effect.
B: First, the living tubercle bacilli wereintraperitoneally injected to Ehrlich's ascitestumor bearing mice. Then these tumor cellswere collected three days aftar tubercle dacilliinjection, and these collected cells were subcutaneouslyinoculated to the other mice. However, we could not find any difference in size oftumors between the tubercle bacilli pre-treatedgroup and the control group. Because of this, it does not seem that tubercle bacilli have anydirect effect for the Ehrlich's ascites tumorcells.
2) The living H₃₇Rv were intravenously injectedbeforehand to the miceW and, two weeksafter, Ehrlich's ascites tumor cells were subcutaneouslyinoculated to these mice. Theinoculated tumor cells increased and made asubcutaneous solid tumor up to thirty daysafter inoculation, but after that the size of solidtumors in the H₃₇Rv injected group graduallydecrease and finally became indetectable. Itseems to us that some anti-cancerous responseor ability will be produced in vivo due to preinoculationwith living tubercle bacilli to themice. However in the experiments using heatkilledH₃₇Rv, H₃₇Ra, BCG and ATM No.8 wecould not observe such a specific effect like theliving H₃₇Rv experiment. This discrepancy aboutexperiment might be derived from the differencesof experimental methods and conditions.
3) The living H₃₇Rv were intravenously injectedto the mice and, two weeks after, Ehrlich's ascites tumors cells were intraperitoneallyinoculated to these pre-treated mice. The survival time of the treated mice wasdefinitely prolonged as compared to the nontreatedcontrol animals. In this case, we hadto use about 1/100 tumor cells of solid tumorexperiment in order to know the definite prolongationof survival time. Therefore, it is theobvious matter that the living tubercle bacilli H₃₇Rv have some indirect anti-cancerous effecton transplanted solid and ascites tumors in themice.
4) No relationship was observed betweennumbers of tubercle bacilli colonies in the miceorgans by culture and, the sizes or weights ofsolid tumors and spleens.
5) It is still obscure that the indirect anticancerouseffect of tubercle bacilli will be dueto the enhanced activity of reticulo-endothelialsystem or the enhanced capacity for antibodyproduction. Experiments about this are now in progress.

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Concerning the non-specific resistance to tuberculosis, extensive studies were made by Nukadain Japan with his idea of “heterogenous resistance”. Also recently Dubos and others reportedthat heterologous bacterial infection markedlyenhanced this resistance in mice.
The establishment of the method of determiningthe function of reticulo-endothelial system (RES) by measuring the rate of clearance ofcarbon particles from the blood stream, hasmade it possible to study the relation betweenthe function of RES and the resistance to infectiousdiseases. In this connection, the authorsformerly reported a simplified method of measuringthe function of RES by use of Idia ink, which will be described as follows: Mice wereinjected intravenously with a does of 16mg ofcarbon particles per 100 gr of body weight.After 20 minutes o. 4 ml of blood was taken bycutting the axillary vessel, diluted with thesame amount of 3.8 % sodium citrate solution, and was subjected to the centrifugation. Thesupernatant fluid was further diluted with fivefoldvolume of distilled water. The amount ofcarbon contained in this sample was measuredelectrophotometrically. From this reading thelog of the true concentration of carbon particleswas calculated, of which the absolute value wasnamed “the phagocytic index of carbon particle”of RES.

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