Central site of the hypertensive action of bradykinin. The intraventricular injection of 1 mug of bradykinin (BK) in rats anesthetized with urethane (1.5 g/kg i.p.) caused an increase in mean arterial blood pressure with little or no change in pulse pressure or heart rate. A similar hypertensive response followed the local administration of 0.5 mug of BK at the pars ventralis of the lateral septal area, whereas local application at other subcortical regions, known to be involved in cardiovascular regulation, caused no effect. Injections of 0.5 or 1 mug of synthetic substance P or 1 mug of 9-desarginine-bradykinin at the pars ventralis of the lateral septal area caused no change in blood pressure. In addition, bilateral electrolytical lesions placed in the lateral septal area either markedly reduced or completely blocked the pressor response to intraventricular BK. These results suggest that the pars ventralis of the lateral septal area is involved in the pressor action of BK in the central nervous system. They also indicate that this brain region responds fairly specifically to BK and that local vascular changes are unlikely to be involved in the mediation of the central action of BK.


The cardiovascular actions of dopamine and the effects of central and peripheral catecholaminergic receptor blocking drugs. The cardiovascular effects of dopamine (DA) were studied in anesthetized dogs with special attention to the susceptibility of these effects to inhibition by catecholaminergic receptor blocking drugs. Dopamine given by rapid i.v. injection at 1 and 3 mug/kg produced depressor responses whereas doses from 9 to 81 mug/kg produced pressor resposes and increases in cardiac contractile force. Propranolol inhibited the increases in cardiac contractility whereas phenoxybenzamine potentiated the depressor effect of low doses of DA and reversed the pressor effect of high doses. Bulbocapnine blocked the depressor effect of DA in both phenoxybenzamine and propranolol-treated dogs. Pimozide, however, had no effect on the depressor response to DA. In hemodynamic studies, DA reduced blood pressure, total peripheral resistance and renal vascular resistance. Cardiac output and renal blood flow were increased. Bulbocapnine, but not pimozide, abolished the effects of DA on blood pressure, vascular resistance and renal blood flow. In conscious dogs, pimozide abolished apomorphine-induced emesis (an effect mediated by DA receptors in the central nervous system) whereas bulbocapnine had no effect. Therefore, the peripheral vascular and central dopamine receptors may be pharmacologically distinct.


Studies concerning the mechanism of suppression of renin secretion by clonidine. Two series of experiments were performed in anesthetized dogs to test the hypothesis that the suppression of renin secretion by clonidine results from a centrally mediated decrease in the activity in the renal sympathetic nerves. In the first series, clonidine (1 mug/kg) was administered directly into the third ventricle of a group of dogs in which renal perfusion pressure was controlled by adjusting an aortic clamp. In these animals, clonidine produced hypotension and bradycardia and suppressed plasma renin activity to 39 percent of the control value. These changes in blood pressure and plasma renin activity were closely correlated. Intraventricular clonidine produced similar alterations in blood pressure and heart rate in another group of dogs in which renal perfusion pressure was not controlled, but failed to suppress plasma renin activity. In the second series of experiments, clonidine was administered intravenously in a dose of 30 mug/kg. Intravenous clonidine produced a transient hypertension followed by hypotension, decreased heart rate and suppressed plasma renin activity to 49 percent of the control value. Renal denervation reduced renin secretion and prevented the suppression of renin secretion produced by intravenous clonidine. Thus, these data are consistent with the hypothesis that the suppression of renin secretion by clonidine results from a centrally mediated decrease in renal sympathetic neural tone. This suppression may be overcome by large falls in renal perfusion pressure.


Distal conformation of thyroid hormones. Crystal and molecular structure of 3,5,3'-triiodo-L-thyronine methyl ester. In the crystal structure of 3,5,3'-triiodo-L-thyronine methyl ester, the 3' -iodine is distal, i.e., away from the alanine bearing ring, and the overall conformation is cisoid, that is, the alanine moiety and the outer phenyl ring lie on the same side of the inner phenyl ring plane. This conformation, reported here, for the first time, is in contrast to the transoid conformation previously observed for thyroid hormone structures. The torsional angles between the diphenyl either linkages (theta and theta') are -108 and 33 degrees, respectively, while the C-O-C angle is 117 degrees. The value of chi1, which describes the amino acid backbone conformation, is 308 degrees. The structure crystallizes in the tetragonal space group P41 with a = 8.225 (5) and c = 28.42 (1) A. The final R index is 0.06.


Synthesis and properties of new bradykinin potentiating peptides. In a study of the relationship between structure and activity of bradykinin potentiating peptides (BPP), six analogs and homologs of peptides occurring in the venoms of Bothrops jararaca and Agkistrodon halys blomhoffii were synthesized and assayed in the isolated guinea pig ileum and rat uterus. None of the peptides had bradykinin-like activity and their bradykinin potentiating activity was much greater in the guinea pig ileum than in the uterus. The following observations were made with the guinea pig ileum. The introduction of Gln as the eigth residue in potentiator B (pGlu-Gly-Leu-Pro-Pro-Arg-Pro-Lys-Ile-Pro-Pro) and potentiator C (pGlu-Gly-Leu-Pro-Pro-Gly-Pro-Pro-Ile-Pro-Pro) produced a small increase in their bradykinin potentiating activity. Removal of the two N-terminal residues of [Gln8]-potentiator B and [Gln8]-potentiator C led to alterations in activity that paralleled those described earlier for the parent compounds (potentiators B and C). The peptide with the sequence pGlu-Trp-Pro-Ary-Pro-Lys-Trp-Ala-Pro was seven times as active as BPP5a, while the most potent natural BPP, a nonapeptide from B. jararaca venom, is reported to be only four times as active as BPP5a. An analog of the above-mentioned nonapeptide containing Pro8 instead of Ala8 was only as active as BPPa. For all of the peptides, as well as for potentiatrs B and C and BPP5a, the concentration vs. potentiating activity curves had similar shapes, with a plateau at twofold potentiation and a maximum potentiation of 10- to 11-fold. A direct action on the bradykinin receptors may be responsible for the effects observed at lower BPP concentration while the effects at higher concentrations may be due to kininase inhibition. The potentiating activities of potentiator B and its Gln8 analog persisted after the peptides were removed from the medium. This "sensitizing activity" was not observed with any of the other peptides.


Norepinephrine uptake sites in cardiac tissue. Lack of affinity of 6-hydroxynorepinephrine and related compounds. The effects of a series of phenethylamines and the corresponding phenethanolamines on (i) rate of uptake of radioactive norepinephrine into cardiac tissue in vivo and (ii) the rate of efflux of radioactive norepinephrine from prelabeled cardiac storage sites have been determined. The results indicate that m- and p-hydroxuphenethylamines and the corresponding phenethanolamines have high affinities for uptake into cytoplasm and storage vesicles of noradrenergic terminals in the heart. o-Hydroxyphenethylamines such as 2-hydroxyphenethylamine and 2,4,5-trihydroxyphenethylamine (6-hydroxydopamine) also have moderate to high activity as inhibitors of norepinephrine uptake and as releasing agents for norepinephrine, but o-hydroxyphenethanolamines such as 2-hydroxyphenethanolamine, 2,5-dihydroxyphenethanolamine, and 2,4,5-trihydroxyphenethanolamine (6-hyproxynorepinephrine) have little or no activity as inhibitors of uptake or as releasing agents. 2,6-Dihydroxyphenethylamines have little or no activity as inhibitors of uptake or as releasing agents. The results are consonant with significant binding of the gauche conformers of 2-hydroxyphenethylamines to uptake sites. Such conformers would be preferred because of stabilization by hydrogen bonding between nitrogen and phenolic oxygen. Apparently a hydrophobic region of the site prevents binding of such stabilized gauche conformers of 2-hydroxyphenethanolamines and 2,6-dihydroxyphenetylamines.


Antiarrhythmic agents. 2-, 3-, And 4-substituted benzylamines. The synthesis of a series of 2-, 3-, and 4-substituted benzylamine derivatives is described. These compounds were studied for their effect on experimental cardiac arrhythmias. Many of the derivatives, but in particular 2-(p-methoxyphenylethynyl)benzylamine (3d), alpha,alpha-dimethyl-4y(phenylethynyl)benzylamine (7a), and alpha,alpha-dimethyl-4-phenethylbenzylamine (12g), showed good antiarrhythmic activity.


Catechol O-methyltransferase. 6. Affinity labeling with N-haloacetyl-3,5-dimethoxy-4-hydroxyphenylalkylamines. Several N-acyl-3,5-dimethoxy-4-hydroxyphenylalkylamines have been synthesized and evaluated for their ability to inactive catechol 9-methyltransferase (COMT). N-iodoacetyl-3,5-dimethoxy-4-hydroxyphenylethylamine was found to rapidly and irreversibly inactivate this enzyme. The corresponding N-bromoacetyl derivative also produced inactivation of COMT but at a slower rate than the N-iodoacetyl derivative. The N-acetyl and N-fumaryl derivatives were completely inactive. The inactivation of COMT by these reagents appears to proceed by a unimolecular reaction within a dissociable complex rather than by a nonspecific bimolecular reaction. The proximity of the amino acid residue being modified relative to the site which binds the aromatic portion of these inhibitors was determined using N-iodoacetylphenylakylamines of varying chain length. The number of methylene carbons separating the aromatic ring and the iodoacetamide moiety in these inhibitors did not greatly influence the binding to COMT nor did it affect how rapidly the enzyme was inactivated. From these observations it was concluded that the amino acid moiety being modified by this class of affinity labeling reagents must be relatively close to or part of the site which binds the aromatic region of these inhibitors.


Synthesis and biological evaluation of xanthine oxidase inhibitors. Pyrazolo(3,4-d)pyrimidines and pyrazolo(3,4-b)pyridines. 1-, 3-, and 5-substituted pyrazolo[3,4-d]pyrimidines and pyrazolo[3,4-b]pyridines related to allopurinol were synthesized and evaluated as xanthine oxidase inhibitors. Among these compounds, 4-hydroxypyrazolo[3,4-b]pyridine-5-carboxylic acids 12 were found to possess potency in the same order of allopurinol. The influence of the substitutions on the enzyme inhibitory effect and the bulk tolerance of the enzyme-inhibitor complex are discussed.


Synthesis and biological activity of some ethers of testosterone. Implications concerning the biological activity of esters of testosterone. The benzyl (2), allyl (4), propyl (10), 3-hydroxypropyl (12), 2,3-dihydroxypropyl (11), 4 pentenyl (7), and pentyl (8) ethers of testosterone were synthesized. Compounds 2, 4, 7, 8, 10, and 12 were found to be almost devoid of anabolic or androgenic activity in a modified Hershberger Assay, but 2,4,10, and 12 were found to be effective inhibitors of testosterone 5alpha-reductase from human skin. These findings suggest that esters of testosterone and of 19-nortestosterone must hydrolyze before interacting with the hormonal receptors, but that the esters may competitively compete with the parent alchohols for interaction with enzymes. The latter effect may shift the distribution of metabolites of the esters relative to the alchohols and thus influence the pharmacological effect of these compounds.


Substituted pyrazolo corticoids as topical antiinflammatory agents. The synthesis of a series of substituted pyrazolo corticoids is described. Of these 11beta,17alpha,21-trihydroxy-6,16alpha-dimethyl-4,6-pregnadieno[3,2-c]-2'-(4-pyridly)pyrazole (21) shows an excellent separation of systemic to local activity in the model animal test. Compound 21 exhibits high vasoconstriction activity in human volunteers and is clinically effective in the treatment of psoriasis.


Chemistry and antiinflammatory activities of prodolic-acid and related 1,3,4,9-tetrahydropyrano[3,4-b]indole-1-alkanoic acids. 1. The synthesis and antiinflammatory activities of a series of 23 novel 1,3,4,9-tetrahydropyrano[3,4-b]indole-1-alkanoic acids are described and some relationships between structure and activity are discussed. One of these compounds, 1,3,4,9-tetrahydro-1-propylpyrano[3,4-b]indole-1-acetic acid (prodolic acid, USAN), has been selected for further studies.


Synthesis of thieno[2,3-b]azepin-4-ones as potential antineoplastic agents. In view of the antitumor activity reported for 7,8-dimethylbenzo[b]azepine-2,5-dione, new isosteric thieno[2,3-b]-azepin-4-ones have been prepared by a Dieckmann ring closure reaction. Substituted 2-amino-3-carbethoxythiophenes were tosylated, or benzoylated, and the corresponding sodium salt was alkylated with ethyl 4-bromobutyrate. The resulting product was cyclized in the presence of sodium hydride, and the azepinones were detosylated with 40% sulfuric acid-acetic acid solution. Preliminary biological data do not indicate any siginificant antineoplastic activity.


Synthfsis of bis(aziridinyl)phosphinyl-N-hydroxyurethane derivatives as antineoplastic agents. Several new "dual antagonists" were synthesized in which the 2,2-dimethyl (or ring C unsubstituted) aziridine phosphinyl function is linked to N-hydroxyurethane rather than the urethane moiety. Three of the new compounds showed very high activities against leukemia L1210 in mice.


Vulpinic acids as potential antiinflammatory agents. 1. Vulpinic acids with substituents in the aromatic rings. The preparation of a series of vulpinic acids, substituted in either or both of the aromatic rings, is described. The compounds were found to be active in the adjuvant arthritis test in rats. High activity combined with an acceptable therapeutic ratio was confined to analogs with electron-withdrawing substituents in the meta positions of the rings.


1,5-ethano-2,3,4,5-tetrahydro-1H-3-benzazepines. 1,5-Ethano-2,3,4,5-tetrahydro-1H-3-benzazepine, from the LiA1H4 reduction of 2-benzyloxy-1,5-ethano-4-oxo-2,3,4,5-tetrahydro-1H-3-benzazepine, was converted to N-alkyl, aralkyl, cycloalkyl, and alkenyl derivatives which were inactive as morphine type analgetics in mice. The LiA1H4 reduction of 2-benzyloxy-1,5-etheno-4-oxo-2,3,4,5-tetrahydro-1H-3-benzazepine gave unstable products from which only the skeletally rearranged dihydro- and tetrahydrobenzo[e]isoindolines, were isolated.


Correlation of psychotomimetic activity of phenethylamines and amphetamines with 1-octanol-water partition coefficients. In an attempt to relate the hallucinogenic potencies in man of some biologically important amphetamines and phenethylamines, the 1-octanol-water partition coefficients for 11 amphetamines were determined. Using these values and published Hansch pi constants, the log P for 17 additional amines was estimated. It was found that lipophilicity, as measured by the log of the partition coefficient, may be a significant determinant of the level of hallucinogenic potency. The study also suggests that an ideal log P value for psychotomimetric activity in man may be from 2.89 to 3.72.


Hashish. Importance of the phenolic hydroxyl group in tetrahydrocannabinols. Optically active delta-3- and delta-8-tetrahydrocannabinols (THC's), cannabidiol and racemic delta-9-cis-THC, and their corresponding analogs (1b yields 4b) in which the positions of the phenolic hydroxyl group and the n-C5 side chain have been interchanged are compared in selected pharmacological tests in mice. the results indicate that the phenolic hydroxyl group in the 1 position in THC's is very important for eliciting activity and that cannabidiol and delta-9-cis-THC possess weak CNS depressant properties.


Synthesis and biological properties of 17 alpha-furylestradiol and dihydroequilin derivatives. A series of 17alpha-furylestradiol and dihydroequilin derivatives was synthesized by reacting the appropriate 3-substituted estrone and equilin with 2- or 3-furyllithium. The oral estrogenic activity of the compounds was compared with that of mestranol. In the Allen-Doisy test, the 17alpha-(3-furyl) analogs were 4-19 times as potent orally as the standard in rats but they were less active in mice. Acetylation of the 17-alcohol or replacement of the 3-furyl by a 2-furyl group produced a decrease in activity. In the mouse uterotrophic assay in mice the compounds were less effective than mestranol and exhibited very shallow dose-response curves.


Synthesis and estrogenic properties of 7 alpha,8 alpha-epoxy- and 7 alpha, 8 alpha-methyleneestradiols. A series of 7alpha,8alpha-expoxyestradiol derivatives with ethynyl, 2- or 3-furyl, or 2-thienyl substituents in the 17alpha position was prepared. The products were highly active orally in the Allen-Doisy test in rats, but most of them were only weakly active in the uterotrophic assay in the mouse. A 7alpha,8alpha-methylene analog and a 7alpha,8alpha-difluormethylene analog were less active than the corresponding epoxides.


A radioprotective stereostructure-activity study of cis- and trans-2-mercaptocyclobutylamine analogs and homologs of 2-mercaptoethylamine. For purposes of studying stereostructure-activity relationships at the molecular, cellular, and animal levels and probing the mechanism of 2-mercaptoethylamine (MEA) radioprotection we synthesized several conformationally constrained cyclobutyl analogs. The comparative radioprotective properties for MEA, cis- and trans-2-mercaptocyclobutylamine (2), cis- and trans-2-mercaptocyclobutylmethylamine (3), and trans-2-mercaptomethylcyclobutylamine (4) are discussed in terms of their ability to chemically reduce transient free radicals, the formation of single strand breaks in DNA, and protect Chinese hamster cells (in vitro) and mice against the lethal effects of ionizing radiation. The results are interpreted in light of current proposed mechanisms of action for MEA. No correlation exists between ability of these analogs to enhance mice survival times and their ability to protect against the induction of DNA single strand breaks and the inactivation of proliferative capacity of hamster cells growing in vitro. Analysis of two isomers (cis- and trans-3) on the repair of single strand breaks showed both isomers only marginally influenced the rate and did not influence of extent of single strand break rejoining. The results are consistent with a mode of action involving chemical repair of transient radicals and protection against DNA and critical enzymatic sites.


ara-Cytidine acylates. Use of drug design predictors in structure-activity relationship correlation. This manuscript if one of a series of investigations into modifying the pharmacologic properties of the antitumor, antiviral, and immunosuppressive nucleoside ara-cytidine (cytarabine, Cytosar). The present paper summarizes our studies on depot ester derivatives of the nucleoside. We are able to predict with reasonable accuracy the biological activity as measured by increased life span in the L1210 leukemic mouse from a combination of two predictor variables: (1) the solubility of the ester in water and (2) its rate of hydrolysis by the mixed esterase system of animal plasma. We have tried unsuccessfully to correlate enzymatic hydrolysis rates with an alkaline hydrolysis model. Calculated Hansch partition (p) values had a correlation of r equal to 0.86 with water solubility. These p values had no additional predictive value. Based on our results, two esters were selected for clinical trial in cancer and rheumatoid arthritis.


Linear regression analysis of inhibitory potency of organic disulfides against Histoplasma capsulatum. The Free-Wilson equations are derived for the case of symmetrical substitution and are applied, in four modifications, to in vitro inhibitory activity of 77 organic disulfides against Histoplasma capsulatum. Substituent constants are listed to aid in the design of new inhibitory agents against this human pathogen (and perhaps other fungal organisms).


Prostaglandins and congeners. Synthesis of simplified prostaglandins. Inhibition of gastric acid secretion by 2-(omega-carboxyalkyl)-3-alkylcycloalkanones. Simplified prostaglandin analogs were prepared and tested for inhibition of gastric acid secretion. An alkyl moiety of 1-8 carbon atoms was substituted for the C-13 to C-20 chain of the PG's. Analog variations included shortened and lengthened acid side chains, beta-oxidation blockage, beta-ketol, Falpha-hydroxyl, and cyclohexanone substitution. Maximal inhibitory activity was obtained with the shorter alkyl moieties.


Potential antitumor agents. 12. 2-Formyl-4-aminophenylpyridine thiosemicarbazones. The antitumor agent 2-formyl-4-(m-amino)phenylpyridine thiosemicarbazone (4-APPT) has been synthesized by a new route to give significantly better overall yields than previously reported. 4-Phenyl-2-picoline was formed by methylation o4-phenylpyridine with CH3Li which upon nitration produced a mixture of o-, m-, and p-nitro-substituted derivatives. These isomers were separated by the solubility differences of their hydrochloride or nitrate salts in 10, 27, and 40% yields, respectively. Identification and confirmation of the structure of these isomers were carried out by mmr. Each isomer was individually subjected to a series of reactions to oxidize the 2-CH3 group to the corresponding carboxaldehyde and to reduce the NO2 function to an amino group. These agents were tested for antineoplastic activity in mice bearing Sarcoma 180 ascites cells; while the o- and p-amino-substituted derivatives were inactive, the m-amino-substituted agent (4-APPT) approved to be an extremely potent antineoplastic agent.


Synthesis and tumor-uptake study of phosphate esters of polyhedral hydroxyboranes. The phosphorylations of B12H11OH2-,B12H10(OH)2-2-, and B20H17OH4-with POCl3 and (C6H5O)2POCl were investigated and the following derivatives were isolated: B12H11OPO3H3-,B12H11OPO3H2-2-,B12H11OPO(OC6H5)-2-2 minus, B12H11OPO(OC6H5)OH2 minus, b12h10(op2o6h2)2-4 minus, B12H10(OPO3H2)2-2 minus, B12Br10(OPO3H)2-4 minus, B12H10[O-PO(OC6H5)2]2-2 minus, B20H18OP2O6H2-4 minus, B20H18OPO3H2-3 minus. The B-O-P bonds proved very resistant to hydrolysis and the phosphates were administered in the for of Na+ salts at pH 7.2 to rats bearing subcutaneous glioma. The boron concentrations in tumors and the tumor/blood concentration ratios were compared with those of parent hydroxy derivatives. Except when the POH function was blocked by phenyl groups the phosphorylation invariably resulted in a greatly enhanced uptake of the borane into tumors and improved the tumor/blood boron ratio. The phopshate function appears to be one of the most effective handles for the incorporation of boron into brain tumors and the compounds show considerable promise for use in the neutron capture therapy of brain tumors.


Studies on cyclophosphamide metabolites and their related compounds. 2. Preparation of an active species of cyclophosphamide and related compounds. A synthetic study was made on the active metabolite of cyclophosphamide. Ozonolysis of O-(3 butenyl)-N,N-bis(2-chloroethyl)phosphorodiamidate, prepared by reaction of POC13 with 3-buten-1-ol followed by treatment with N,N-bis(2-chloroethyl)amine (nor mustard) and NH3, afforded 2-[bis(2-chloroethyl)amino]-4-hydroperoxytetrahydro-2H-1, 3,2-oxazaphosphorine 2-oxide (4-hydroperoxycyclophosphamide). Deoxygenation of 4-hydroperoxycyclophosphamide by triphenylphosphine yielded 4-hydroxycyclophosphamide in a pure crystalline state. These products exhibited high cytostatic activity in both in vitro and in vivo experiments. The results give confirmatory evidence for the hypothesis that C4-hydroxylation on the 1,3,2-oxazaphosphorinane ring of cyclophosphamide is necessary for its activation.


Anticonvulsants. 5. Derivatives of 5-ethyl-5-phenylhydantoin and 5,5-diphenylhydantoin. Alkoxymethyl, acyloxymethyl, and mixed alkylalkoxymethyl or alkylacyloxymethyl derivatives of 5-ethyl-5-phenylhydantoin exhibit anticonvulsant activity. Also effective are bis(alkoxymethyl) and mixed alkylalkoxymethyl derivatives of 5,5-diphenylhydantoin. Of particular interest are 1,3-bis(methoxymethyl)-5,5-diphenylhydantoin and 3-acetoxymethyl-5-ethyl-5-phenylhydantoin, which show good activity against maximal electroshock seizures, and 3-methoxymethyl-5-ethyl-5-phenylhydantoin, which is effective against both maximal electroshock and pentylenetetrazole. None of the above compounds show greater activity against maximal electroshock seizures than the parent compounds, however.


Antiinflammatory fluoroalkanesulfonanilides. 3. Other fluoroalkanesulfonamido diaryl systems. A series of isosteres of 3-benzoyltrifluoromethanesulfonanilide involving alternatives to the carbonyl linking group was synthesized and screened for antiinflammatory activity in the carrageenan rat paw edema test. The systems examined were of the type m-CF3SO2NH-C6H4-X-C6H5, where X was -CROH-, -CHR-, -CH(OH)CH2-, -COCH2-, -CH2CO-, greater than C equal to CR2, -CR equal to CH, -C identical to C-, -CH2CH2-, CONH-, -NR-, -O-, -S(O)n- (n equal to 0,1,2), and carbon-carbon single bond. Many ortho and para derivatives were also tested. Several of these new trifluoromethanesulfonanilides proved equipotent with phenylbutazone. The effects on the anticarrageenan activity of both the nature and ring position of X are discussed.


Antiallergic activity of 4-hydroxy-3-nitrocoumarins. Twenty-four substituted 4-hydroxy-3-nitrocoumarins have been prepared for nitration of the corresponding 4-hydroxycoumarins. All were found to possess antiallergic activity as measured by the homocytotropic antibody-antigen induced passive cutaneous anaphylaxis reaction in the rat.


Cyclopenta[f]isoquinoline derivatives designed to bind specifically to native deoxyribonucleic acid. 1. Synthesis of 3-ethoxy-8-methyl-7(5)H-cyclopenta[f]isoquinoline. By the use of space-filling models, a novel compound, 6-carbamylmethyl-8-methyl-7(5)H-cyclopenta[f]isoquinolin-3-(2H)-one was devised which would be expected to hydrogen bond specifically to GC pairs in the major groove of the double helix such that (i) the amino group of the cytosine molecule donates a hydrogen bond to the C-3 carbonyl of the isoquinoline moiety and (ii) the amide proton of the side chain donates a hydrogen bond to the N-7 of guanine. 3-Ethoxy-8-methyl-7(5)H-cyclopenta[f]isoquinoline (4) which constitutes the basic ring system of 1 was synthesized in a multistep procedure starting from m-methyl-N-acetylbenzylamine (5). Friedel-Crafts reaction of 5 led to 2,4-bis(chloromethyl)-5-methyl-N-acetylbenzylamine (6) which on treatment with KCN, hydrolysis of the resultant nitrile, and subsequent esterification afforded 6-carbethoxymethyl-7-methyl-1,2,3,4-tetrahydroisoquinolin-3-one (9). Treatment of 9 with triethyloxonium fluoborate followed by dehydrogenation of the product gave 6-carbethoxy-methyl-3-ethoxy-7-methylisoquinoline (14). Chain extension of 14 followed by cyclization led to 3-ethoxy-8-methyl-5,6-dihydro-7H-cyclopenta[f]isoquinolin-5-one (19) which on reduction and subsequent dehydration yielded 3-ethoxy-8-methyl-7(5)H-cyclopenta[f]isoquinoline (4).


Electronic structures of cephalosporins and penicillins. 4. Modeling acylation by the beta-lactam ring. Molecular orbital calculations by the CNDO/2 method are used to study the molecular and electronic details involved in the initial phases of the opening of the beta-lactam ring of a model cephalosporin structure, 7-amino-3-acetoxymethyl-3-cephem. The effect of a simple nucleophile, OH-, approaching the carbonyl carbon center of the beta-lactam ring is monitored by following the charge redistributions that occur in the bicyclic system and in the 3 side chain. A migration of electron density to the ester oxygen of the CH2OAc group is observed with concomitant weakening of the CH2-OAc bond. The results are discussed in relation to the mechanism of acylation of bacterial cell wall enzymes by beta-lactam antibiotics and in relation to the hydrolysis of these molecules. The results indicate that the ability of the 3' substituent of cephalosporins to stabilize electron density transferred to it, i.e., the leavability of the 3' moiety, can be an important factor in activating the beta-lactam toward nucleophilic attack.


Isotope effects in enzymatic N-demethylation of tertiary amines. The N-demethylation of 1-(N-methyl-N-trideuteriomethylamino)-3-phenylpropane (1) by rodent liver homogenates was studied. The ratio of 1-trideuteriomethylamino-3-phenylpropane (2)/1-methylamino-3-phenylpropane (3) was determined by gc-ms. The ratio of 2/3 in the product of N-demethylation of 1 by liver homogenate from phenobarbital-treated rats was 1.31 and from untreated rats was 1.32, and the differences between the two groups were not statistically significant. The ratio of 2/3 in the product obtained from N-demethylation of 1 by liver homogenates from mice was 1.45. The ratio of 2/3 of greater than unity indicates the presence of a kinetic primary isotopes effect in the enzymatic N-demethylation reaction. This effect is exclusive of the secondary isotope effects on the amino nitrogen. The presence of this primary isotope effect indicates that the cleavage of the C-H bond of the N-methyl group is a rate-limiting step in the N-demethylation of tertiary amines by rodent microsomal enzymes.


Cycloalkanones. 6. Separation of hypocholesterolemic and antifertility activities in derivatives of 2,8-dibenzylcyclooctanone. Fluoro and hydroxy derivatives of 2,8-dibenzylcyclooctanone were prepared. Separation of antifertility activity from hypolipidemic and uterotropic effects was achieved with 2,8-bis(4-acetoxybenzyl)cyclooctanone. Some enhancement of the hypolipidemic effect in relation to the uterotropic and antifertility activities was seen in 2,8-bis(4-fluorobenzyl)cyclooctanone. Synthetic methods for the hydroxy compounds are presented.


Synthesis of 8-(3'-deoxy-alpha-D-threo-pentofuranosyl) adenine and 9-(3'-deoxy-alpha-D-threo-pentofuranosyl) adenine. 3-Deoxy-2,5-di-O-p-nitrobenzoyl-alpha-D-threo-entofuranosyl bromide (1) reacted with mercuric cyanide to give 2,5-anhydro-4-deoxy-D-lyxo-hexononitrile (2) which upon acid hydrolysis of the CN group gave acid 3. Saponification of the protecting groups gave 2,5-anhydro-4-deoxy-D-lyxo-hexonic acid (4) which reacted with 4,5,6-triaminopyrimidine forming an amide (5) that was pyrolized to give 8-(3'-deoxy-alpha-D-threo-pentofuranosyl) adenine (6). Reaction of bromide 1 with 6-(benzamido) chloromercuriopurine followed by saponification yielded 9-(3'-deoxy-alpha-D-threo-pentofuranosyl)adenine(8). 8-(beta-D-Ribofuranosyl)adenine, 8-(beta-D-arabinofuranosyl)adenine, and 8-(3'-deoxy-beta-D-erythro-pentofuranosyl)adenine, as well as compound 6, showed no antimalarial activity.


Beta-aminocinnamonitriles as potential antiinflammatory agents. A number of beta-aminocinnamonitriles have been prepared by the reaction of salts of acetonitrile and propionitrile with benzonitrile. These materials were evaluated in the carrageenan antiinflammatory screen in Royal Hart, Wistar strain rats. Despite good weight gains in the parent molecule, beta-aminocinnamonitrile (1), only marginal activity was found in related compounds and some possible "metabolites."


Oesophageal atresia in the South West of England. A retrospective anatomical and family study was made of 345 patients with oesophageal atresia who were born in the South West of England between 1942 and 1973. There were 186 males and 159 females. Twenty-one cases were stillborn. Eighty-five percent of the patients had a combination of oesophageal atresia with a tracheo-oesophageal fistula to the distal oesophageal segment, and 9 percent had atresia without a fistula. Fifty-five per cent of the patients had other congenital malformations and these tended to be multiple rather than single. Thirty-six per cent of singletons had unequivocal fetal growth retardation, and there is some evidence that nearly all cases have poor fetal growth. There appeared to be a maternal age effect, with an excess of mothers under 20 and over 35, and there was an unexplained excess of fathers employed in the Armed Forces. Ten per cent of the cases were illegitimate. There were 21 twins which is nearly three times the expected number; there were two pairs of twins concordant for oesophageal atresia, one being monozygotic and the other dizygotic. In one case there were two sibs with oesophageal atresia. Five out of 365 sibs had anencephaly. The blood group distributions of the patients and their mothers did not significantly differ from the expected distribution. Oesophageal atresia is aetiologically heterogenous. In this series there were at least five, and probably 10 cases of trisomy 18 and four cases of trisomy 21. Five mothers had overt diabetes, and there is some suggestion from other work that maternal diabetes or its treatment may be aetiologically important. Oesophageal atresia was part of a possibly recessively inherited malformation syndrome in two cases. A sibship with a case of rectal atresia, a case of Hirschprung's disease and a case of oesophageal atresia may represent the action of another recessive gene. It seems likely that oesophageal atresia is a rather non-specific consequence of several teratological processes.


Trisomy 13 and Rubinstein-Taybi syndrome. Initial diagnosis of Rubinstein-Taybi syndrome was made in an infant with a prominent nose and broad thumbs and first toes. However, due to the presence of other anomalies such as low-set, malformed ears, anti-mongoloid slant of the eyes, colobomata of the iris, and cleft palate, cytogenetic studies were carried out and the diagnosis of trisomy 13 was confirmed. Since, occasionally, trisomy 13 syndrome may mimic the Rubinstein-Taybi syndrome, cytogenetic studies should be considered in all patients with clinical diagnosis of Rubinstein-Taybi syndrome.


Partial 12p deletion: a cause for a mental retardation, multiple congenital abnormality syndrome. A severely mentally retarded man displayed the following main symptoms: short stature, microcephaly, antimongoloid slant of palpebral fissures, big ears with hyperplastic helices, imperfect dental enamel, short and webbed neck, short arms, short hands, brachymetaphalangy, short second fingers, broad thumbs, short metatarsal bones, and unusually big first toes. It seems almost certain that the syndrome was caused by a chromosome deletion involving about half of 12p which was present in all of the lymphocytes examined.


Neonatal testicular torsion in two brothers. Two brothers presenting neonatal testicular torsion are reported. The findings suggest an autosomal or X-linked recessive pattern of inheritance for the anatomical underlying anomaly.


A genetic study of torsion dystonia.

A genetic study of torsion dystonia. A family study of 32 patients with torsion dystonia has shown at least two forms of generalized dystonia with onset in childhood. These two forms, an autosomal dominant and an autosomal recessive, are clinically indistinguishable. There were at least three families and probably about six to eight patients with the autosomal recessive variety. The remaining nine to 11 patients with generalized childhood dystonia are thought, because of a probable paternal age effect, to be examples of new dominant mutations. Since fitness with childhood onset is 1/20 of normal, most childhood dominant cases appear sporadically. Most of the other 15 patients (12 with onset in adult life) appear to have a non-genetic torsion dystonia, although an example of a benign adult-onset dominant form associated with a tremor has been observed. It is concluded that there are at least two forms of genetic torsion dystonia, an autosomal recessive form with onset in childhood, which, on evidence from America, is particularly common in Ashkenazi Jews, and one or more dominant forms, with onset in childhood or adult life. The majority of adult-onset isolated cases of idiopathic torsion dystonia seem to be due to exogenous but unidentified causes.


Thalassaemia in northern Liberia. A survey in the Mount Nimba area. A population survey in northern Liberia showed an average incidence of 9 percent of beta-thalassaemia trait. There was considerable tribal variation, the highest rates being mainly found in tribes having a low incidence of Hb S. A single example of deltabeta-thalassaemia trait was also found; the incidence of delta-chain variants was 1.8 percent. The effect of malaria on Hb A2 levels was investigated but appeared to be negligible. The problems of beta-thalassaemia and Hb S occurring in the same population are discussed. It is considered that, although made on a local sample, the results of this survey indicate a high incidence of beta-thalassaemia trait elsewhere in Liberia and that this is a suitable are for investigations of linkage at beta- and delta-chain loci. No conclusion is at present possible from the data on the presence of alpha-thalassaemia although 10 percent of neonates were found to have increased levels of Hb Barts.


The occurrence of gonadal dysgenesis in association with monozygotic twinning. A case is presented of a monozygotic twin pair, discordant for phenotypic sex, in which the female member showed gonadal dysgenesis and chromosomal mosaicism. Review of the pertinent literature reveals that in monozygotic twin pairs, phenotypic and karyotypic concordance is the usual occurrence for Down's and Klinefelter's syndromes, whereas discordance often accompanies gonadal dysgenesis. Mosaicism is a frequent concomitant of gonadal dysgenesis in monozygotic twins. Our case strengthens the probability of a real association between mosaicism and monozygotic twinning in gonadal dysgenesis.


A family study of coeliac disease.

A family study of coeliac disease. Thirteen of 141 cases (9 percent) of overt, biopsy proven coeliac disease had a definitely affected relative. The pattern of inheritance in these families is compatible with an incompletely penetrant autosomal dominant gene. There was a female preponderance in the adults and the sporadic cases, but not in the children or the familial cases. The series included a pair of concordant and probably monozygotic twins. The authors believe that coeliac disease, as defined at present, is a heterogeneous condition.


Haemoglobin Lepore Boston and elliptocytosis in a family of Indonesian-German ancestry. A family is presented in which Hb Lepore Boston was found in six individuals over three generations. The gene must have had its origin either in Java (Indonesia) or in what is now the Federal Republic of Germany. The haemoglobin was characterized by amino-acid analysis of the six tryptic peptides that have a different composition in the beta- and the delta-chain. The ratio of glycine to alanine in position 136 of the fetal haemoglobin, which was somewhat raised in the Hb Lepore carriers, averaged 31:39. In addition an elliptocytosis gene was found, which was inherited independently from Hb Lepore; the simultaneous presence of elliptocytosis in three family members did not seem to aggravate the mild anaemia caused by Hb Lepore.


Aglossia-adactylia syndrome.

Aglossia-adactylia syndrome. Aglossia-adactylia is described in two male patients, aged 31 and 21 years old. Including a previous reported case (Nevin, Dodge, and Kernohan, 1970) there are three patients with this syndrome in Northern Ireland. The aetiology is unknown but in spite of the extreme variability of the clinical manifestation, a dominant mutant gene cannot be ruled out.


Ultraviolet photoalteration of ion channels in voltage-clamped lobster giant axons. An analysis of the ultraviolet light-induced changes in ionic conductances of lobster giant axon membranes has been carried out using the double sucrose gap voltage-clamp technique. The predominant effect of monochromatic light from a xenon arc source in the 255 to 305 nm region is an irreversible reduction in the magnitude of sodium conductance, without change in sodium channel activation or inactivation kinetics. A considerably smaller reduction in the magnitude of potassium conductance occurs, with some slowing of potassium channel activation kinetics. Leakage conductance is essentially not altered. The fall in sodium conductance follows an exponential time course toward a zero asymptote. The rate constant for conductance decrease was used as an assay for the wavelength dependence. The sodium conductance was maximally sensitive at 290 nm. It is suggested that individual sodium channels are closed upon absorption of single photons by aromatic amino acid residues in membrane proteins.


The density of cholinergic receptors at the endplate postsynaptic membrane: ultrastructural studies in two mammalian species. Electron-microscope autoradiography of diaphragm endplates of the American brown bat, labeled to saturation with tritiated alpha-bungarotoxin, has been used as a means to localize and quantitate the acetylcholine receptor there. Analysis of the grain distribution in these autoradiographs reveals that the receptor sites in this endplate are located on the postsynaptic membrane at an average density of 8,800/mu2. The sites are distributed asymmetrically along that membrane, being concentrated at the crests of the postjunctional folds--that portion nearest to the presynaptic membrane. The receptor site density at these regions of the postsynaptic membrane is estimated to be 20,000--25,000/mu2 of membrane surface. A comparison of these membrane site densities with those of endplates of red and white fibers of the mouse reveals a close similarity. On this basis, it is suggested that the receptor site density at the crests of the folds may be a characteristic feature of endplates of vertebrates. In contrast to the acetylcholine receptor sites, cholinesterase sites (determined autoradiographically in 3H-diisopropylfluorophosphate-labeled endplates) are largely distributed in a uniform manner over the postjunctional folds. The function of the secondary folds is, therefore, reassessed. Ultrastructural evidence available from other laboratories on the spatial characteristics of transmitter release and of postsynaptic dense particles is in accord with a model drawn for this molecular architecture at the vertebrate endplate.


Cation permeability and ouabain-insensitive cation flux in the Ehrlich ascites tumor cell. The components of Na and K flux across the plasma membrane have been investigated in the Ehrlich ascites tumor cell. At intracellular K levels of approximately 100 mM, unidirectional K influx is composed of a ouabain-sensitive component, a ouabain-insensitive, nondiffusional component and a diffusional component. Unidirectional K efflux is composed of an external K-dependent component and a diffusional component. Upon reduction of intracellular K to approximately 50 mM, the external K-dependent component becomes maximal and diminishes upon further reduction of intracellular K. Unidirectional Na efflux is composed of a ouabain-sensitive component, a diffusional component and a saturable, external Na-dependent, ouabain-insensitive component. Unidirectional Na influx may be accounted for by a diffusional component, based on estimates of membrane permeability to Na, membrane potential and Na distribution. This would suggest that the ouabain-insensitive, external Na-dependent Na efflux is not Na--Na exchange. The origin of the cell membrane potential has not been previously established in the Ehrlich ascites cell. From the diffusional components of Na and K flux determined in these experiments, the membrane permeabilities to Na and K have been estimated. These permeabilities, in conjunction with the Na and K distributions across the plasma membrane, predict a cell membrane potential of - 18mV (inside negative). Passive Cl distributions in these cells predict a cell membrane potential of - 21 mV, which is in agreement with previous microelectrode measurements and dibenzyldimethylammonium distributions. The results are therefore consistent with the conclusion that the magnitude and polarity of the cell membrane potential in the Ehrlich ascites cell is dictated primarily by Na and K.


Some blood indices in three groups of Nigerians and in very severe but ambulatory cases of anaemia. This study determined the haemoglobin concentrations, packed cell volumes and mean corpuscular haemoglobin concentrations of healthy students and soldiers as well as "non-anaemic" outpatients. The same indices were also determined in small groups of moderately and severely anaemic but fully ambulatory outpatients. On the basis of the haemoglobin values most commonly observed in healthy male subjects it is suggested that the usual or "normal" haemoglobin concentration of a healthy male adult averages 14-7 gm. per cent; the packed cell volume averages 44 per cent and the mean corpuscular haemoglobin concentration averages 32-6 per cent. It is further suggested that subjects with haemoglobin values less than 11-0 gm. per cent (75 per cent of normal average) should probably be sent for further haematological investigations because such persons are probably anaemic. This study also reports some startlingly low haemoglobin values in fully ambulatory outpatients. There tended to be a compensatory rise in pulse rates as the degree of severity of anaemia increased.


Endemic tropical sprue in Africa.

Endemic tropical sprue in Africa. Twenty-four patients have been found who appear to have endemic tropical sprue, with malabsorption on biochemical, radiological and histological grounds. Patients with the tropical sprue syndrome responded equally well clinically and biochemically to folate and tetracycline. Jejunal histology responded least well to treatment. It is suggested that as more Gastrointestinal Units are opened, especially in humid sea level areas in Africa, more cases of endemic tropical sprue will be found.


A field survey on child health in a rural community in Egypt. A field survey in a village was carried out to study child health in a rural area. The vaccination scheme was found to be inadequate and the value of health education is stressed. Parasitic infestation was found to be higher than urban areas but significantly lower than 1959 and the latter is attributed to a safer water supply. Growth and development lagged behing the whole national standards particularly during the 1 - 6 years age period. Health care for the pre-school age, taking advantage of co-operation from medical faculties and local health authorities, is recommended.


Attendance at a child health clinic in Malaysia. One hundred and ninety-nine children brought by 181 adults to a child health clinic based in a rural health sub-centre in Peninsular Malaysia are studied. It is noted that the families from which they come are relatively poor, with a large number of children, and that they are fairly highly motivated. Forty-four per cent of children attending the clinic at the time of the study are symptomatic indicating the need to organise the child health clinic on a "preventive-curative" basis. It is also noted that the young child is initially seen in early infancy but is lost to the clinic when he is older making it judicious to formulate immunization schedules that take this into account.


The mean circulatory pressure, reproducibility of its measurements and the effect of phenylephrine with a note on the effect of pentobarbital. With 7 repeated measurements of the mean circulatory pressure (MCP) over a course of 35 minutes in one and the same dog, and also with paired measurements of MCP 10 minutes apart in 6 other dogs, the MCP was shown to be stable and reproducible in anesthetized, open-chest and vagus-intact dogs. Administered to 7 dogs with initial mean arterial blood pressure as low as 64 mmHg in dose of 20 mug/kg intravenously, phenylephrine nearly doubled the mean arterial blood pressure, total peripheral resistance and the MCP, indicating a marked vasoconstrictor effect on the resistance and capacitance blood vessels of the systemic circulation. The effect was transient and there were signs of tachyphylaxis. Influence of a cardiotoxic dose of pentobarbital on the peripheal circulation was discussed.


The stroke volume in juvenile borderline hypertension. Hemodynamic changes in supine and upright position and during exercise were studied in 144 men including 37 normal subjects and 107 patients with borderline hypertension. Borderline hypertensives were classified in 4 groups, according to the basal level of heart rate and stroke index. In the first two groups, stroke index was normal, but heart rate was either decreased (Group I) or elevated (Group II): supine total peripheral resistance was superior (Group I; p less than 0.02) or equal (Group II) to normal values; plasma volume was normal or slightly decreased; hemodynamic response to tilt test closely approximated the normal; impaired adaptation of cardiac index and stroke index to exercise was observed in Group II (p less than 0.001). In the other two groups, stroke index was significantly elevated (p less than 0.0001) but heart rate was either decreased (Group III) or increased (Group IV); supine total peripheral resistance values were decreased (p less than 0.001); plasma volume was equally reduced (p less than 0.001); abnormal percentile increase in diastolic arterial pressure (p less than 0.02; p less than 0.001) and total peripheral resistance during tilt test were observed; during exercise, only the patients of Group IV had an impaired adaptation of cardiac index (p less than 0.001) and total peripheral resistance (p less than 0.02). The study provide evidence that in boderline hypertension i) a high basal level of stroke volume is associated with a reduced plasma volume and an imparied adaptation of total peripheral resistance during tilt, ii) a high basal level of heart rate is associated with an impaired adapatation of cardiac output during exercise, and iii) only patients having an increase in both heart rate and stroke volume exhibited a specific hemodynamic pattern including: reduction of plasma volume, impaired adaptation of cardiac output during exercise, impaired adaptation of total peripheral resistance during tilt and exercise.


Regulatory factors on immunocytolysis of cardiac cells and mesenchymal cells. The mode and degree of tissue specific immunocytolysis closely depend on the nature of cell-surface antigens and on the competition or balance of humoral and cell-mediated immunity. The modification of cell surface membrane by neuraminidase-treatment induced the higher susceptibility to complement-dependent cytolysis, probably on account of exposure of cryptic sites or aggregation (clustering) of sites which may be tissue specific and/or histocompatibility antigen determinants. Under the existence of large amount of antisera, complement-dependent cytolysis was dominant. On the contrary, under the situation of low dose anti-sera, normal adherent-cell-mediated cytolysis was more effective. This kind of cytolysis was inhibited easily by serum factor(s), which could be IgG, and block Fc receptor of adherent cells in competition with anti-Ig14. Although the role of serum-factor(s) is still unknown, it may act an important role in the process of establishment of autoimmune diseases.


Immunological aspects of aortitis syndrome. 1. Anti-aortic antibodies were frequently detected from the sera of patients with aortitis syndrome. 2. Aortic antigens were demonstrated to exist mainly in the media. The antigenicity was inactivated by collagenase, trypsin and pepsin, but not by DNase-I. Analyses of aortic antigens were also made by ultracentrifugation and column chromatography. 3. Experimental arteritis could be produced in animals by isologous active immunization and heterologous passive immunization. 4. From these results, participation of antigen-antibody reaction in the development of the disease has been speculated. Possible role of streptococcal infection as one of the trigger mechanisms in antibody production has been suggested in combination with evidence indicating hypersensitivity of the patients to infections.


Anti-heart antibodies in patients with chronic cor pulmonale. In patients with chronic cor pulmonale caused by pulmonary emphysema, circulating autoantibodies against the heart tissue were investigated by the HA and HI techniques using the myocardium as antigen. Quantitative analysis of serum IgG, IgA and IgM were carried out by use of the radial immunodiffusion method. These results were compared with clinical findings, especially cardiopulmonary hemodynamics and pulmonary function tests and with the prognosis. Circulating anti-heart antibodies were found in 15 of 29 (51.7 per cent) patients with chronic cor pulmonale. The titers of circulating anti-heart antibodies indicated a good correlation with pulmonary hypertension, hypoxia and respiratory impairment. Furthermore, a good correlation was noted between anti-heart antibody titers and the serum IgG level. Five of 15 (33.3 per cent) patients with positive results for anti-heart antibodies died, while one of 13 (7.7 per cent) with negative results died. In this investigation, circulating anti-lung antibodies were also searched in sera from patients with chronic cor pulmonale, but they showed no cross reaction with anti-heart antibodies, of which the specificity was found in the patients. These data could be utilized in evaluation and discussion of the pathophysiological findings of the patients with chronic cor pulmonale.


Sympathetic nervous activity in renal and DOC hypertensive rats. The sympathetic tone of the splanchnic nerve was quantified in renal and deoxycorticosterone (DOC) hypertensive rats under pentobarbital anesthesia by measuring equivalent stimulation frequency (ESF). ESF is the frequency of stimulus to the peripheral cut end of the nerve required to restore the preseverance level of arterial pressure. It is assumed to represent the average discharge rate of the nerve before severance. ESF was markedly increased in DOC hypertension 2 weeks after initiation of the DOC-salt treatment. It was relatively decreased after 10 weeks, but was still higher than in the controls. In renal hypertension (clipping of the left renal artery), ESF was decreased considerably 2 weeks and slightly 10 weeks after clipping. When the contralateral kidney had been removed simultaneously with clipping (clip plus uninephrectomy, ESF was not significantly changed. It is suggested that the sympathetic nervous system participates greatly in the pathogenesis of DOC hypertension but not of renal hypertension.


A case of a traumatic systemic-pulmonary arteriovenous fistula. A case of systemic-pulmonary arteriovenous fistula is described. Chest trauma with multiple bone fractures 9 years prior to this admission was the suspected cause. Three years after the trauma, chest X-rays revealed abnormal vessels in the right lung. Eight years after the trauma, the patient developed congestive heart failure. This has been well controlled with digitalis and occasional diuretics.


Motorized exercise wheel for exposure of small animals to environmental pollutants. For environmental inhalation studies a motorized exercise wheel was designed for small laboratory animals. Mice or hamsters were separated in individual enclosures, and each animal was required to perform the same exercise. The wheel was driven by a common barbecue spit motor, the speed of which may be varied by a standard variable transformer, from 1-6 revolutions per min. This unit can be adapted for a variety of laboratory applications.


Pericutaneous phlebotomy and intravenous injection in the guinea pig. Rapid and repetitious blood collections or intravenous injection were accomplished in the guinea pig via the lateral metatarsal vein. One person could perform the procedure by using an abdominal hold on the animal. There was no morbidity or mortality.


Lymphocyte cultures of Macaca mulatta and Macaca fascicularis. Lymphocytes of Macaca mulatta and Macaca fascicularis were cultured using a microculture technic. The use of RPMI-1640 with fetal calf serum as a culture medium and an extra dose of phytohemagglutinin produced excellent results. Staining of the chromosomes by the Gemsa banding technic did not reveal any differences between the karyotypes of the Macaca species.


A normobaric hypoxia facility for preparing polycythemic mice for assay of erythropoietin. A normobaric hypoxia chamber was designed in which large numbers of mice (up to 250) were made polycythemic, after which they were used in an erythropoietin assay. The hypoxic atmosphere was composed of air diluted with N2 gas generated from liquid N2. Continuous exposure of mice to 8% O2 for 11 da resulted in a polycythemia of sufficient magnitude and duration to provide appropriate erythropoietic conditions for the erythropoietin assay. The chamber, which has been in almost continuous operation for 3 yr, requires little attention and maintenance and has proved to be reliable, safe, and economical.


The collared lemming (Dicrostonyx stevensoni Nelson) in biomedical research. The collared lemming, Dicrostonyx stevensoni Nelson, possesses special characteristics which make it a useful animal model for the study of hypercholesteremia, atherosclerosis, breast cancer, kidney disease, and other biomedical research problems. Hematologic values for the lemming were similar to those for the laboratory white mouse except for smaller erythrocytes and fewer leukocytes. Organ weights, when compared as a percent of total body parts, differed only slightly from those of white mice. The basal metabolic rate, measured between 25-30 degrees C, was 40% higher than the standard metabolic rate for a mammal of similar size. Litter size at birth averaged 2.8 in captivity. The mean life span of 254 colony-reared lemmings dying from natural causes was 189 da. Growth rate was rapid during the first 2 mo of life, with moderate increases thereafter to an adult weight of approximately 70 g. Husbandry requirements included the use of shavings as litter and facial tissue as nesting material, all of which was changed weekly. Oats, wheat germ, rabbit pellets, carrots, and lettuse were offered as food.


Impairment of metabolic capability in feral house mice by Klossiella muris invection. Kidney infection by Klossiella muris in highland house mice from Peru was associated with lowered metabolic capability (57%) and endurance time (25%) at maximum metabolic rate. Administration of coccidiostatic preparations improved the metabolic capability from 7.8 to 10.5 cc 0-2 g hr and the endurance from 2.8 to longer than 10 min. Their colony-reared offspring, which were free from parasites, sustained maximum metabolic rates of 13.8 cc 0-2/g hr also for longer than 10 min. This rate was slightly higher than the values found in both healthy lowland controls: feral house mice from Arkansas and laboratory white mice [lab: HA(ICR)]. Although clinically inapparent under oridinary conditions, the effects of K muris infection were easily demonstrated at high metabolic loads stimulated by cold. Thus emphasizing the importance of such performance tests in assessing the status of experimental subjects.


An epizootic of cerebral nematodiasis in rabbits due to Ascaris columnarus. An epizootic of cerebral nematodiasis due to ascaris columnaris occurred in a commercial rabbitry, and 80 diseased rabbits died or were killed. The morbidity was high in groups of recently purchased rabbits and in the offspring of 12 breeder rabbits. The breeder rabbits which had been on the farm for more than a yr survived the outbreaks. Wild animals and birds had access to the facilities, but raccoons and skunks were never observed. A columnaris larvae were found on histopathologic examination. and live larvae were recovered from brains of 2 diseased rabbits.


Fatal intussusception associated with intestinal coccidiosis (Eimeria perforans) in a rabbit. Fatal intussusception was observed to be the proximate cause of death in a young (14 wk old) pet male New Zealand white rabbit. The intussusception was ileo-ileal, and this region was shown to be extensively parasitized by Eimeria perforans. It was concluded that the intussusception was consequent to hyperperistalsis induced by the coccidial infection of the intestines.


An improved technic for thyroidectomy in guinea pigs. A technic for thyroidectomy in the guinea pig was presented. After anesthetizing the guinea pig with methoxyflurane, the thyroid was removed by electric cautery. The step-by-step procedure was described. Possible complications such as recurrent laryngeal nerve damage and the stimulation of aberrant thyroid tissue were discussed.


Localized nocardiosis due to Nocardia caviae in a baboon (Papio cynocephalus). Nocardia caviae was identified as the causative agent of draining, multinodular swelling of the hand of a 16-yr-old female baboon (Papio cynocephalus). The baboon's general physical condition was poor and menstrual cycles had ceased. The baboon improved after systemic and topical antibiotic therapy, but the lesion recurred after antibiotic treatment was discontinued. Since excision of the mass, the baboon's physical condition has improved to the extent that regular menstrual cycles have resumed and she has been returned to the assigned investigative program. Radiographs of the lungs, hand, and arm failed to disclose evidence of dissemination of the infection.


Task analysis in National Health Service Corps field stations: a methodological evaluation. An occupational survey using a task inventory as survey instrument was conducted at four National Health Service Corps clinics providing primary ambulatory care. The prime objective of the study was to determine whether the methodology of task analysis could validly be applied to obtain data of potential value in improving personnel management in clinics. It is concluded that the taskinventory could generate such data. A first level analysis provides some interpretations of task interrelationships and role definition among clinic staff. In the clinics studied, no staff member's role was sufficiently well defined for efficient utilization of his capabilities. In particular, many tasks performed by the physicians and nurses could also be performed by less well-trained personnel. A number of steps are suggested for examining the task profiles of clinic staff and identifying areas of potential task redistribution. Also discussed are ways of improving the presentation of data obtained through task analysis to enhance the data's usefulness to local clinic management.


Evaluating an information system for medical care evaluation studies. The purpose of this study was to evaluate a computerized information system, the Professional Activity Study-Medical Audit Program (PAS-MAP), when used by the medical staff of a hospital to conduct medical care evaluation studies. PAS-MAP was compared to a manual system for collecting data not contained on the face sheets of medical records. The results indicated that, compared to the manual system, PAS-MAP: was less costly if more than 41 per cent of hospitalized patients were included in medical care evaluation studies; was as timely as the manual system for data it could provide but provided fewer clinical data elements than physicians requested; and was less protective against human error. Three decision makers assigned weights indicating the relative importance of these results. The weights were combined in an additive model to arrive at a score for each system. Based on these scores, the manual system was recommended for implementation.


Antibiotic use and abuse among physicians in private practice in Shiraz, Iran. From 120 practicing physicians in Shiraz, Iran, 40 were selected to identify their attitude toward the use of antibiotics. A young, healthy man  who complained of mild fever and cold symptoms was referred to them and 37 of them prescribed inappropriate doses of antibiotics. It is assumed that the behavior of the physicians is based on pressure by the patient to receive more medicine, particularly antibiotics.


A patient and family number assignment and chart filing system for family physicians. The Department of Family Medicine and Practice at the University of Wisconsin-Madison has devised and implemented an alpha-numeric system of identifying patient records together with a system of chart filing based on a variation of terminal digit filing. The system provides each patient with a unique identification number. This permanently assigned number is used as part of the medical record (chart) information, as the basis for assigning an account number, as the basis for determining the storage location of the chart in the record room, and as the basis for a family identification number. The number defines the patient's sex and position within the family, and its permanency ensures a capability for conducting both short- and long-term ambulatory care research in the family context.


Early diagnostic signs and symptoms of laryngeal disease. A compilation of late and early symptoms of patients who ultimately were found to have laryngeal disease was carried out. Notation of even minor changes in the indirect laryngoscopic appearance of the same patients was made routinely. Correlation of symptoms with signs has made possible a better understanding of the natural history of certain laryngeal lesions such as contact ulcer, polyps, nodes, dysphonia plica ventricularis as well as some of the pareses, paralyses and fixations. Identical early symptoms and numerous signs have apparently been ignored in subsequently proven cases of cancer of the larynx. The expanded list of symptoms (33 in number) and the detailed list of signs (54 in number) may now assist the Otolaryngologist in earlier diagnosis. Although the reported findings are not specifically diagnostic of cancer of the larynx, they should draw earlier attention to the larynx as the etiological site of such symptoms. Earlier recognition of minor laryngeal changes, as detailed in the text, should lead to earlier biopsy and tissue diagnosis, earlier and more enlightened public awareness, and earlier and, therefore, more effective utilization of present day day modalities in the management of carcinoma of the larynx.


The enigma of post-radiation edema and recurrent or residual carcinoma of the larynx. Persistence of significant edema of the larynx beyond six months after completion of radiotherapy presents the laryngologist with a diagnostic dilemma. Review of the results of 43 cases demonstrated a high incidence of residual or recurrent carcinoma. Based upon this experience earlier and frequent laryngeal biopsies are recommended for these cases.


The conservative management of the Negro nose. The difficulties in obtaining an adequate result in the Negroid nose have been elucidated by other authors. Paucity of lobular cartilage; the flat dorsum; short columella; wide flaring nares; and skin that tends to keloid formation have led many surgeons to attempt radical surgical techniques to obtain rather limited results. To circumvent the complications in the more radical procedures, a more conservative concept of an entirely intranasal operation without external skin incisions is outlined. This technique consists of tip rotation andlobular cartilage trimming; the use of a non-absorbable basal bunching suture, and the placement of a dorsal implant without performing osteotomies. A comparison with other techniques is made, as well as surgical aims, limitations and a discussion of results. Pertinent illustrations and photographs are presented.


Description of a team approach to the rehabilitation of the laryngectomized speaker. This article describes the multi-disciplinary approach to rehabilitation of the laryngectomee followed by the Michigan Cancer Foundation-Wayne State University Laryngectomee Clinic. The program serves a patient population in excess of 100 each year in a total rehabilitation paradigm. The rehabilitation effort centers around an intensive speech rehabilitation program encompassing as much as 10 hours of speech therapy per week. This effort is supplemented by a professional staff including a psychologist, social work staff, audiologist, public health nurse, vocational rehabilitation specialist, and atrained laryngectomized esophageal speech teacher. The contribution of each member of the team and the benefits of a unified approach are described.


The Pickwickian syndrome with hypertrophy of tonsils: a re-appraisal. Pronounced tonsilar hypertrophy was found in two obese patients suffering from hypersomnolence, periodic attacks of apnea and disturbing snoring at night. Both patients underwent tonsillectomy. Immediately after the operation the hypersomnolence disappeared, the breathing became normal, and the disturbing snoring at night ceased. Follow-up over a period of three years did not reveal any recurrence of these symptoms, even though the patients had not lost any weight during this period.


Truamatic ophthalmoplegia: a complication of fractures of the zygomaticomaxillary complex. Review of etiology with report of an unusual case. Ocular muscle imbalance is a common complication in fractures of the zygomaticomaxillary complex. Involvement can be direct; caused by entrapment of either the muscle or tendon in the fracture; or indirect, produced by central or peripheral damage to the cranial nerves supplying the muscles, massive orbital edema or hemorrhage. A case of complete paralysis of the extraocular muscles caused by a critical reduction of the size of the orbit as a result of fracture of the zygomaticomaxillary complex is described.


Voice following radiotherapy.

Voice following radiotherapy. This study was undertaken to provide information on the voice of patients following radiotherapy for glottic cancer. Part I presents findings from questionnaires returned by 227 of 235 patients successfully irradiated for glottic cancer from 1960 through 1971. Part II presents preliminary findings on the speaking fundamental frequencies of 22 irradiated patients. Normal to near-normal voice was reported by 83 percent of the 227 patients; however, 80 percent did indicate persisting vocal difficulties such as fatiguing of voice with much usage, inability to sing, reduced loudness, hoarse voice quality and inability to shout. Amount of talking during treatments appeared to affect length of time for voice to recover following treatments in those cases where it took from nine to 26 weeks; also, with increasing years since treatment, patients rated their voices more favorably. Smoking habits following treatments improved significantly with only 27 percent smoking heavily as compared with 65 percent prior to radiation therapy. No correlation was found between smoking (during or after treatments) and vocal ratings or between smoking and length of time for voice to recover. There was no relationship found between reported vocal ratings and stage of the disease. Data on mean speaking fundamental frequency seem to indicate a trend toward lower frequencies in irradiated patients as compared with normals. A trend was also noted in both irradidated and control groups for lower speaking fundamental frequencies in heavy smokers compared with non-smokers or previous smokers. These trends would indicate some vocal cord thickening or edema in irradiated patients and in heavy smokers. It is suggested that the study of irradiated patients' voices before, during and following treatments by means of audio, aerodynamic and acoustic instrumentation would yield additional information of diagnostic value on recovery of laryngeal function. It is also suggested that the voice pathologist could assist in evaluating and guiding patients in vocal usages during and following treatments.


Voice problems following limited surgical excision. The published literature contains relatively few references to vocal rehabilitation for persons with partial laryngectomy. Articles on various types of surgery indicate that many individuals develop satisfactory voice following limited surgery, particularly supraglottic procedures. An informal questionnaire completed by 10 larngologists who had had substantial experience with sub-total laryngectomy revealed that an average of 25 percent of their patients with laryngeal cancer receive partial laryngectomy. Lesions limited to the epiglottis, supraglottic areas or one vocal cord are regularly treated by limited excision. Half of the questionnaires indicated that partial laryngectomy can be used for bilateral vocal cord lesions under certain circumstances. The questionnaire confirmed the published reports that most of the subsequent voices were satisfactory or good and many recover without special vocal retraining. Non reported employment of partial laryngectomy for sub-glottal cancer. Hemilaryngectomy and cordectomy frequently resulted in some impairment of voice. Speech therapy is often recommended when possible. Therapy applicable to voice following partial laryngectomy combines five emphases: 1. strengthening glottic closure and loudness of the voice; 2. improving the efficiency of breath expenditure; 3. increasing the articulatory skill and intelligibility of speech; 4. recognizing and compensating for hearing loss; and 5. aiding the patient to reduce detrimental environmental influences and to adjust to his environmental requirements.


Functional evaluation after partial resection in patients with carcinoma of the larynx. This paper presents the results of conservative operations on patients with laryngeal carcinoma in the ENT Department of the University Hospital "Dr. Mladen Stoianović," Zagreb, Yugoslavia, during the last 20 years. The authors have evaluated the functional results after partial vertical and horizontal surgical interventions on the larynx and after the reconstruction of the larynx following these operations. Functional analysis of the voice was performed by stroboscopic, indirect microlaryngostroboscopic and sonagraphic examinations of the laryngeal function, as well as by the spirometric analysis of the respiratory potential of these patients, especially the degree of obstruction of the upper respiratory tract and changes on the cardiovascular system. Attention has been given likewise to the examination of the act of swallowing, especially after horizontal partial resections of the larynx. Radiography and radiocinematography was used for these examinations. Based on this research the authors have formulated new conceptions and opinions about the voice generator.


Some scientific foundations for voice restoration. Laryngeal cancer, though not high in incidence, may have a devastating effect on the affected individuals' total adjustment. Esophageal speech, while a desirable form of substitute speech, cannot be learned by all, thus requiring a re-evaluation of the artificial larynx and consideration of such special operations as that of Dr. Ryoso Asai. The acoustical characteristics and deficiencies of all pseudo voices are stated and discussed. The female voice is generally identified as such. Methods for the prognosis of learning speech include a systemic questionnaire for pre-evaluation which was based on behavior patterns of the laryngectomee.


Restoration of voice after laryngeal surgeries. Some aspects of speech deficiency in Japanese-speaking patients who had undergone surgeries for laryngeal malignancy were studied. Surgical procedures included reconstructive surgeries after total laryngectomy and conservation surgeries. A series of listener-judgments and some acoustic analyses of speech were made. The recorded voices of the patients were more or less hoarse. The median speaking pitch varied greatly from patient to patient, and often assumed an unusual value. The average articulation score for five Japanese vowels was computed for each subject. The score varied from patient to patient, and was thought to be useful in quantitatively evaluating speech quality. It was shown that certain glottal consonants such as /h/ can be affected by laryngeal surgeries. It was emphasized that the larynx should be regarded not only as a generator or a vibrator, but also as an articulator which produces consonants. The listening tests also revealed that the intonation pattern of Japanese two-syllable nouns can be influenced by laryngeal surgeries, and that distinction among certain words may become impossible as a result. This type of speech problem may require serious consideration in some language environments.


Fiber-optic video study of the post-laryngectomized voice. Simultaneous video-fluoroscopy and fiber-optic video laryngoscopy was carried out on a series of eight laryngectomees. Previous concepts supported by an earlier report1 indicated that the folds of the rebuilt cricopharyngeal sphincter were seen to represent the primary source of sound vibration for voice production. Fold vibration was envisioned as an essential for sound production. Present findings present a challenge to the older concept. The fluoroscopic studies showed a considerable variation in the vertical thickness of the sphincteric area--from several millimeters to as many as 10 centimeters. Mucus bubbles in rapid motion were easily visible immediately above the narrowest portion of the reconstructed cervical esophagus. Ingestion of barium only enhanced the visualization of this bubbling. Vibration of a long vertical area of the thin anterior and thicker posterior esophageal walls well above and well below this point was regularly noted. Fiber-optic visualization failed to show actual fold vibration at any time. Momentary opening of the food tract during air injection or intake, immediately prior to the onset of phonation, was seen on many occasions. During phonation, routinely, the anticipated pseudoglottic opening was obscured by bubbles of mucus or barium. These findings suggest that the air, when accumulated below the narrowest spot in the hypopharyngeal-esophageal tract and when forced upward through a narrow opening, sets the accumulated mucus, not the mucous membrane, into vibration; further, that this vibration is of sufficient amplitude to transmit itself to both the anterior wall and the posterior wall of an extensive vertical portion of the neck.


Laryngeal microcirculation and pathways of cancer spread. The microcirculation of the human larynx was studied in cleared anatomic specimens.  The distribution of the endolaryngeal blood supply was constant enough to permit naming of the subdivisions of the superior and inferior laryngeal arteries. There was a remarkable correlation between arteriolar and capillary distribution and the laryngeal routes of cancer spread within the larynx. Compartmentalization of the larynx was not apparent. The paraglottic space was filled with blood vessels.


The vascular supply of the cervical skin with reference to incision planning. Wound breakdown, especially following preoperative radiotherapy, is a complication following neck surgery. The anatomy of the blood supply of the neck skin, which is an important factor in neck incision planning, was determined by silicone rubber injection studies. Some of the more common incisions interrupt the cervical blood supply, which descends from the facial and occipital arteries and ascends from the transverse cervical and suprascapular arteries, and this is discussed in relation to wound breakdown.


Use of thermography to evaluate the optimum time for surgery after preoperative radiation. At the University of Virginia Hospital, patients undergoing preoperative irradiation for carcinoma in the head and neck region are usually scheduled for surgery four to six weeks after completion of therapy. Since preoperative irradiation produces no significant difference in the operative difficulty or postoperative morbidity, it is assumed that the vascularity of the area has returned to the pre-treatemtn level. Thermography is being used to quantitatively gauge the amount of vascularity and thus, help predict the optimum time for surgery. Thermography is obtained at two-week intervals after a pre-treatment baseline and is carried out for eight weeks after completion of therapy. During therapy the vascularity as determined by thermography is noted to increase to a maximum at approximately three to four weeks or 3 to 4,000 rads. Following completion of treatment, the vascularity subsides gradually and returns to the pre-treatment level at four to six weeks after completion of therapy.


The bifid uvula in ear, nose and throat practice. Out of 2,000 consecutive ear, nose and throat patients, 44 were found with bifid uvulas. Five of the cleft uvulas were associated with submucous cleft palate, and eight were associated with short palates; however, dyslalia was evident in only one case. Compensation for the wide palato-pharyngeal space can occur by hyperplasia of the nasopharyngeal tonsil and hypertrophy and increased mobility of the pharyngeal constrictors and Passavant's ridge. On the other hand, otologic manifestations were complained of in 13 cases. The asymptomatic cases were examined under magnification and audiometrically and a further three cases were, then, diagnosed as secretory otitis media. Hypoplasia of the tensor palati is the probable explanation of otologic manifestations in bifid uvula.


Allergic secretory otitis media: an approach to management. An allergic etiology should always be suspected in those children having recurrent secretory otitis media. These children often have a seasonal recurrence of middle ear effusion, a history of allergic disease in infancy or early childhood, and a family history of allergy. An approach to allergic management is presented. Inhalants are tested by the serial dilution titration technique and treated at optimum dose levels. Several food tests are used to detect offending foods. They are used in progressive fashion which utilized each technique to best advantage. Fifty allergic children with recurrent secretory otitis media, despite conventional surgical therapy, were treated for inhalant and food allergy for one year. There was a significant reduction in the recurrence of secretory otitis media and need for myringotomy.


[Drug use leading to death (author's transl)]. 23 cases are demonstrated, in which the connection between drug use and sudden death is to be accepted. The victims are only males and juveniles. It is demonstrated by the cases reported, that upon the sudden death of a juvenile increased consideration must also be given to a possible connection between death and drug use. First and foremost the drug used is susceptible of leading to death by way of an intoxication due to too large a dosage or owing to oversensitiveness. Far advanced putrefaction, the combined effects of several drugs including alcohol, the difficulty in furnishing chemical proof of the presence of hashish and LSD in body-fluids and organs can make it nearly impossible to clarify the cause of death. Only what has been related in respect of the manner of living and drug use by members of the family, mates and friends makes the connection between death and drug use appear quite likely. The indirect connection between drug use and the juvenile's death is to be accepted if it comes to the accident under the influence of drugs - be it under the impression of invulnerability or omnipotence or in a state of hallucinations. Depressions under the influence of drugs are also susceptible of resulting in real suicidal actions. In case of inexplicable accidents or entirely unexpected suicide drug effects must, therefore, nowadays be thought of.


[Syndrome of Touraine, Solente and Golé: report of two cases (author's transl)]. Report of two patients with pachydermia, clubbing of the fingers and hyperostosis. This clinical syndrome corresponds to the pachydermal periostosis. Etiologic factors, clinical and radiologic symptoms, differential diagnosis, histological alterations, prognosis and therapy are discussed.


[The pycnodysostosis (author's transl)]. Two own observations of pycnodysostosis initiated our description of this disease. Inherited as an autosomal recessive trait the syndrome is characterized by a medium degree generalized osteosclerosis, open craniial sutures and fontanels until adult lige, hypoplastic mandibles with deficiency of the angle, prominence of the forehead and occiput, hypoplasia of the paranasal sinuses, commonly observed dysproportionate dwarfism, acro-osteolysis and increased bone fragility. Contrary to osteopetrosis the prognosis is good.


[Trichotillomania as a phenomenon of unexplained loss of hair in childhood (author's transl)]. As a contribution to the differential diagnosis of ambiguoug "loss of hair" we forward a report on 24 children and 2 adolescents with trichotillomania. Patients with this pathological habit tear out hair from their own head -- sometimes eyelashes or eyebrows as well -- mostly in unobserved moments. Therefore the diagnosis is frequently delayed for months or even years. Most of these patients have normal intelligence are motorically overactive, and sensitive. They suffer from a lack of selfne assurance, and an inhibition to establish initial social contacts or to give expression to their aggressive tendencies. The manipulation of their own body serves as an outlet for the inner and outer strain resulting form the pressures of a permanent conflict-situation. The calming effect, combined with the apparently highly satisfying physical experience, induced repetition and the development of a fixed habit. In early childhood the factors contributing to the emotional strain are almost always found in a conflicting mother-child relationship, very often against the background of a general deficiency in family interaction. Moreover at school level the symptom occurs most frequently as a result of pressure on the child to achieve more. Trichotillomania has to be considered in children with focal or diffuse alopecia in areas of normal scalp, where almost no hair is lost by combing or gentle pulling. The trichogram gives specific results. Diagnosis must be based on a behaviour analysis and psychodiagnosis of the child. In addition, personal interactions within the family must be investigated. The first goal of therapy is the elimination of the emediate causes through counselling the parents. The improvement of the child's ability to communicate is essential. Depending on the age of the child the approach to the treatment of the social disturbances through psychotherapy or medical pedagogy should be combined with a symptom--centered treatment through behaviour therapeutical techniques with the aim of eliminating this fixed habit.


[A further example of chromosome 18q-associated with IgA deficiency in serum and saliva (author's transl)]. In a 3 1/2 years old boy with congenital malformations, statomotoric and mental retardation and immunological defects the chromosomal aberation 46,XY, 18q- was found. The result of the G-band analysis was 46,XY, del (18) (pter yields q11::q21 leads q ter) or 46,XY, del (18) (pter leads q21). The structural genes for the systems Gm, PGM-1 and HL-A presumably are not localized on the deleted chromosomal segment.


[Minimal brain dysfunction and social class (author's transl)]. The dependence of early occuring minimal brain dysfunction on the standard of living was tested. 1355 6-15 year old patients with psychosomatic and psychiatric disorders were examined and divided into the 3 groups: "no brain dysfunction", "suspected brain dysfunction" and "brain dysfunction" (diagnosed medically). A highly significant correlation between brain dysfunction and a low socio-economic status--evaluated in terms of living conditions and the fathers occupation--was found. A similar dependence of both, early mortality and morbidity on the living standard of different groups of the population is described in the literature.


[Subacute necrotizing encephalomyelopathy (Leigh's disease) (author's transl)]. The characteristic neuropathological features of subacute necrotizing encephalomyelopathy (Leigh), their histology and distribution are described. Clinical findings are unspecific. Impairment of feeding. vomitus, respiratory abnormality, retardation of psychomotor development, familial incidence and onset in early childhood are prominent symptoms. Atactic and athetoid movements, optic atrophy, oculomotor abnormalities are observed in most cases. An enzyme inhibitor excreted in the urine seems to be related to an inborn error of thiamine dependent metabolism in brain tissue. Treatment with thiamine derivatives may have a beneficial effect on the clinical course.


[Ollier's disease in a dizygotic twin (author's transl)]. Bone alterations in Ollier's disease are mainly unilateral. The etiology and pathogenesis are still unknown. Hereditary factors probably do not play any rolle in this disease. The authors discribe Ollier's disease in a maly dizygotic twin. Investigations of the family members do not discover any hereditary factors.


The effect of higher structures of macromolecules on the genetic consequences of the action of mutagens. An explanation of some discrepancies between the known chemical data and the genetic consequences of chemical mutagenesis is proposed, based on the functional role of the higher structure of macromolecules. In a single-stranded DNA- or RNA- containing genome, some primary (induced) point mutations, even if not manifested phenotypically, can result in local disturbances of the double-helical regions. Secondary (spontaneous) mutations at the complementary site of a polynucleotide can restore the higher structure. If a certain higher structure is more significant as a selection factor than the base substitution, the secondary, phenotypically detectable, mutants can accumulate during reproduction of a mutangenized phage. The higher structure of some nucleoprotein complexes and proteins could also serve as a selection factor causing accumulation of secondary mutants.


Chromosome aberrations in human lymphocytes after irradiation with 15.0-MeV neutrons in vitro. I. Dose-response relation and RBE. Human peripheral lymphocytes were irradiated with different doses of 15.0-MeV neutrons. The frequency of different aberration types was determined and the dose-response relation was calculated. The data were fitted by least-squares regression analysis to different models. The dicentric, dicentric plus centric ring, and different acentric data gave the best fit to the linear quadratic model. The RBE of 15.0-MeV neutrons versus 220 kV X-rays decreased significantly with increasing dose.


Chromosome aberrations in human lymphocytes after irradiation with 15.0-MeV neutrons in vitro. II. Analysis of the number of absorption events and the interaction distance in the formation of dicentric chromosomes. The rejoining distance for the formation of dicentric chromosomes in human lymphocytes after irradiation with 15.0-MeV neutrons has been derived on the basis of microdosimetric concepts. For the formation of a dicentric chromosome, primary lesions produced by absorption events can interact within the nucleus over a distance of at least I.8 mum. The mean number of absorption events within this range is lower than for sparsely ionizing radiation. The intercellular distribution of dicentric chromosomes is consistent with a negative binomial distribution.


Effects of p-fluorophenylalanine on the induction of mutations in bacteriophage T4. II. Nitrous acid mutagenesis. The effects of rho-fluorophenyalanine (PFPA), an analogue of phenylalanine (PHE), on the potency and the specificity of nitrous acid (NA) mutagenesis in the gamma system of bacteriophage T4 were measured. (a) Forward mutation. THE frequencies of NA-induced gamma mutants were approximately doubled when mutagenized phage infected E. coli B in the presence of the analogue compared to controls where PHE was substituted for PFPA, or where no amino acid was added. The spontaneous forward mutation frequency was not affected by the analogue, nor was the specificity of the NA mutagenesis. (b) Reverse mutation. The frequency of spontaneous and NA-induced reversion of an gammaII transition mutant was unaffected by PFPA if the phage were plated direct on the restrictive growth in the presence of PFPA the induced reversion frequency was increased about 3-fold compared to the control.


Development of an attenuated strain for Japanese encephalitis live virus vaccine for porcine use. To develop Japanese encephalitis live virus vaccine for the prevention of stillbirth in swine, an attempt was made to produce an attenuated virus. Primary bovine kidney cell culture was used to carry out serial passages of a field strain at 30 degrees C for a long time. During these passages cloning was repeated with the character of reproductive capacity at given temperature (rct) and plaque sizes as markers. As a result, an attenuated S- strain was produced successfully. It was rct/37- and rct/40- and formed small-sized plaques. In this strain a marked attenuation was seen in peripheral infectivity to suckling mice and in intracerebral infectivity to adult mice. When inoculated with this strain, newborn piglets manifested no abnormal clinical signs or pathological changes of the brain tissue at all. A minute amount of virus was rarely recovered from some lymph nodes and blood. Little virus was recovered from various organs. No viremia was detected from any piglet more than one month of age inoculated with recovered virus. No infection of the placenta or fetus was recognized in any pregnant sow inoculated with recovered virus. Inoculated sows gave birth to normal young. Furthermore, when mosquitoes of Culex tritaeniorhynchus summorosus were allowed to suck infected blood by the membrane feeding technique, the virus recovered from them showed an infectivity more reduced than the field strain. From these results, it was presumed that the S- strain might be safe enough to be used as live virus vaccine for swine.


Histopathological changes of the brain in swine fetuses naturally infected with procine parvovirus. During a period from 1971 to 1972, some cases of stillbirth and abortion associated with porcine parvovirus infection were recognized in swine herds in Japan. The brain was examined histopathologically in five stillborn piglets and four dead fetuses from which the parvoviruses had been isolated. Similar histological changes were observed in all the piglets and fetuses, except one piglet which was free from recognizable lesions. The brain lesions were considered to belong to the category of meningoencephalitis consisting of perivascular cuffing of proliferating adventitial cells and a few plasma cells. They were localized in the cerebral gray and white matter and leptomeninges, but not in the cerebellum. These histological lesions were thought to be pathognomonic to porcine parvovirus infection. The difference in brain lesions between porcine parvovirus infection and Japanese encephalitis virus infection was discussed.


Effects of diethylstilbestrol and testosterone propionate implanted in the hypothalamus on spermatogenesis in rats. Small quantities of diethylstilbestrol and testosterone proprionate were implanted into the hypothalamic arcuate nucleus of male rats of the Wistar-Imamichi strain at 43 days of age. The animals were sacrificed at 64 or 76 days of age. Diethylstilbestrol suppressed the development of all genital organs and disturbed spermatogenesis. The damage was found to have recovered slightly in rats sacrificed at 76 days of age. Testosterone propionate was also effective for the atrophy of some genital organs. Its influence was not so severe as that of diethylstilbestrol. It extinguished almost completely 33 days after implantation. On the contrary, the numbers of spermatogonia and spermatocytes per cross section of the seminiferous tubule were smaller at 76 days than at 64 days of age. The diameter of the seminiferous tubule in the rat implanted with testosterone propionate was longer at 76 days than at 64 days of age. Therefore, the tubular diameter did not always represent the quantity or quality of spermatogenesis. The results also suggested that spermatogenesis might have been disturbed in some of the rats in which androgen was considered to be secreted almost normally.


Changes of adrenal hormones in goats with experimentally induced arthritis. An experiment was carried out to clarify the mechanism of occurrence of arthritis in goats. In it changes of the adrenal hormones in blood and urine were examined in goats with experimentally induced arthritis. Four groups of goats were used. A goat of group B was inoculated with anaerobic Corynebacterium organisms isolated from a joint of a field case. Group H was treated with hormones (deoxycorticosterone acetate and adrenalin). Group BH was inoculated with those organisms and treated with these hormones. The other group served as an untreated control. Arthirits was induced to three of the four goats of group BH. The blood level of 11-hydroxycorticosteroids and the urine level of 17-hydroxycorticosteroids were higher in group BH than in any other group at the time of appearance of clinical signs. The hypofunction of the adrenal cortex was seen in two of three goats with induced arthritis. Serotonin increased transitorily in group BH around the time of appearance of clinical signs, but there was finally no difference in its level among goats with or without induced arthritis. There was no definite tendency in the fluctuation of level of adrenalin or noadrenalin.


[Angiographic patterns erroneously suggesting aneurysm of the anterior part of circulus arteriosus]. In the light of a material including 600 cerebral angiographies the authors analyse the incidence of diagnostic difficulties in cases of pseudoaneurysms of the brain resulting from superposition of vascular loops and kinks in the anterior portion of the circulus arteriosus. Methods of prevention of diagnostic errors by additional head positions during angiography are discussed.