Effects of single dose supervoltage whole brain radiation in Macaca mulatta. Three groups of four Macaca mulatta were exposed respectively to a single dose of 1000, 1500, and 2000 rads of 20 MeV whole brain radiation with one animal from each group and a control scheduled for sacrifice at 6, 12, 18, and 24 months. With 1000 rads there were no abnormalities. The characteristic lesions in the animals exposed to 1500 and 2000 rads were small foci of delayed radiation necrosis that in the acute phase were relatively large due to marked local accumulation of edema fluid and at later stages were decreased in volume and showed early mineralization. Correspondingly the monkeys frequently showed papilledema, evidently from brain swelling, as the initial clinical finding, and upon histological examination at later stages, brain atrophy and ventricular dilatation. After exposure to 1500 rads the necrotic process was primarily in the white matter of the cerebral hemisphere and progressed from a small number of lesions in this location at 6 months to confluent necrosis at 12 months. At 18 and 24 months, although there was no evidence of further necrosis, there was evidence of increasing gliosis and at 24 months the occurrence of three independent glioblastomas. With exposure to 2000 rads there was a profuse wide scatter of focal necrotic lesions with a predilection for the basis pontis and a clinical deficit inconsistent with survival past 6 months. Accumulation of minute mineral deposits and atherosclerotic plaques were also noted in these monkeys and appeared to be related to both dose and survival time.


Computer assisted tomography of focal cerebral radiation necrosis in the monkey. The right occipital lobe in a series of pubescent monkeys was exposed to 3500 rads of orthovoltage radiation in a single dose. Sixteen to 38 weeks later the irradiated region broke down, rather abruptly. The visual evoked response, funduscopic photography, cerebral spinal fluid determinations for protein and lactic dehydrogenase, and computer assisted tomography (CAT) were used to anticipate and reflect the breakdown in neural tissue. CAT scanning demonstrated the two main effects of focal delayed radiation necrosis in this model (in a representative monkey): pronounced vasogenic edema from a break in the blood brain barrier, and contralateral hydrocephalus from brain distortion with obstruction of cerebral spinal fluid circulation. These findings were confirmed by postmortem examinations.


Clinical and endocrinological evaluation of 16 acromegalic patients treated by transsphenoidal surgery. Sixteen patients with acromegaly treated with transsphenoidal pituitary surgery were evaluated with the measurement of serum human growth hormone (HGH) before and after intravenous stimulation with thyrotropin-releasing hormone (TRH). Fourteen of these patients showed a significant rise of serum HGH after TRH stimulation before surgery. After surgery, 12 patients with Grade 2 noninvasive adenomas had normal fasting serum HGH levels which did not stimulate with TRH. Two of these patients showed high serum HGH levels both at fasting and after TRH stimulation and required a second operation to remove residual adenoma within the sella before adequate lowering of HGH was achieved. Evidence of recurrent adenoma has not occurred clinically or biochemically in this group of 12 patients followed for an average of 24 months (2 to 60 months). The results were unsatisfactory in four of these 16 patients. One patient who has a postoperative HGH of 9 ng/ml which still stimulates with TRH has made clinical improvement, but must have residual adenoma in the sella or invasive adenoma in the dura and tumor capsule. Additional treatment with irradiation has been given. Failure to achieve satisfactory results in the other three patients was attributed to the presence of locally invasive adenoma; one in the sphenoid sinus, and the other two possibly as a consequence of previous operative procedures.


Chronic demeclocycline therapy in the syndrome of inappropriate ADH secretion due to brain tumor. The treatment of the syndrome of chronic inappropriate antidiuretic hormone (ADH) secretion by fluid restriction is often attended by poor patient compliance. The following case report illustrates successful management of this condition by oral demeclocycline therapy in a patient who had hyponatremia in association with angioblastic meningioma of the sphenoid ridge.


Steady-state evoked potentials.

Steady-state evoked potentials. The advantages of steady-state EP recording include (1) speed in assessing sensory function in normal and sick infants (e.g., in amblyopia) and in sick adults (e.g., in multiple sclerosis); (2) monitoring certain activities of sensory pathways that do not intrude into conscious perception; (3) rapidly assessing sensory function when a large number of subjects must be tested (e.g., in refraction); (4) objective measurement at very high suprathreshold levels where psychophysical methods are difficult or ineffective; (5) rapidly assessing sensory function in normal subjects when EP variability and nonstationarity preculde lengthy experiments; and (6) proving a speedy objective equivalent to behavioral test in animals.


Use and complications of high-dose disodium etidronate therapy in fibrodysplasia ossificans progressiva. A boy with fibrodysplasia ossificans progressiva received nearly twice the usual therapeutic dose of disodium etidronate for 13 months in an attempt to prevent reossification following a second operation to correct severe torticollis. The operation was successful, but during therapy he developed weakness and distinctive bone lesions characterized by general osteopenia, widened physes, and unique radiolucent bands in the metaphyses. The osseous abnormalities were distinct from those of rickets and healed after withdrawal of the drug.


Chlorthalidone analysis using carbonic anhydrase inhibition. Chlorthalidone was analyzed in the concentration range of 0.1-3.0 microgram/ml with a precision of +/- 0.05 microgram/ml. Chlorthalidone inhibition of the enzymatic hydrolysis rate of p-nitrophenyl acetate by bovine erythrocyte carbonic anhydrase was used as a basis for the determination. The amount of p-nitrophenol formed was measured by monitoring the absorbance at 400 nm, and its formation rate was proportional to the chlorthalidone concentration. The mixing of the enzyme, substrate, and sample, the incubation of the reaction mixture, and the recording of the absorbance were automated. A survey of urine samples from 26 normal human subjects did not reveal any endogenous substances that interfered with the assay. Analyses of urine samples from six subjects after oral administration of 100 mg of chlorthalidone indicated rapid absorption and a biphasic elimination. The alpha-phase half-life was 1.5 hr, and the beta-phase half-life was 35 hr.


Absence of mutagenicity of coralyne and related antileukemic agents: structural comparison with the potent carcinogen 7,12-dimethylbenz[a]anthracene. The structural similarity between antileukemic alkaloid coralyne and the carcinogenic and antineoplastic hydrocarbon 7, 12-dimethylbenz[a]anthracene, as well as the similarity between the antileukemic alkaloid nitidine and the carcinogenic hydrocarbon 5-methylchrysene, prompted a mutagenicity evaluation of coralyne sulfoacetate, nitidine chloride, the 8-ethyl homolog of coralyne, nitidine methosulfate, and the tetramethoxy analog of nitidine by the Ames method against the histidine-auxotroph strains of Salmonella typhimurium TA-1537, TA-1538, TA-98, and TA-100; 7,12-dimethylbenz[a]anthracene was used as a reference standard. The mutagenicity of these antileukemic compounds was either completely eliminated or drastically reduced, but the mutagenic response was generally high for 7,12-dimethylbenz[a]anthracene. The results suggest that the presence of a quaternary nitrogen atom and alkoxy groups could be important in alleviating the mutagenicity of the parent mutagenic and carcinogenic hydrocarbons.


The pharmacology of SC-27166: a novel antidiarrheal agent. SC-27166 is the result of continuing efforts to discover selective and orally active antidiarrheal agents. SC-27166, which is chemically unrelated to opiates or neuroleptics, possesses potent constipating and antidiarrheal activity in several animal models. Tolerance to the constipating actions of SC-27166 did not develop in mice. On the other hand, gut tolerance rapidly developed to morphine sulfate and loperamide. The basic mechanism of the antidiarrheal action of SC-27166 is a consequence of increased intestinal circular muscle contractile activity. Supportive pharmacological studies indicated that SC-27166 has equivocal analgesia in mice which is manifested at near toxic dose levels. SC-27166 was also evaluated for potential dependence liability in morphine abstinence-induced jumping in mice. The abstinence-induced jumping was suppressed to a far lesser extent by SC-27166 than by either loperamide or diphenoxylate at equal doses. SC-27166 was also devoid of anticbholinergic activity. When compared with the reference standards morphine and diphenoxylate, these pharmacological studies indicated that SC-27166 has a high degree of separation of undesirable central nervous system actions from its antidiarrheal properties and may have important therapeutic potential.


Photic epilepsy evoked by square-wave pulses. Report of a case studied by changing stimulus intensity and duration. A spike and wave discharge of photic-evoked myoclonic epilepsy was investigated employing square-wave pulses of a stimulator having mechanical shutter, and the following conclusions were reached. The amplitude of the spike and wave complex of photogenic epilepsy depends on the intensity of photic stimulation when this is investigated in the range from 2.5 X 10(3) ergs/cm2 sec to its 4.31 log units high. A spike prior to the slow wave appears as the stimulus intensity increases. The implicit time is shortened as the intensity increases. Prolongation of the stimulus duration makes the ascending phase of the slow wave steep, and an off-response appeared when stimuli of 100 msec or longer were applied. Clinically, a biphasic myoclonic convulsion of limbs is clearly observed in on- and off-phases when stimuli of 300 msec or longer are applied. The responses become prominent when frequency increases from 0.5 to 3.0/sec.


Tetrachlorodibenzo-p-dioxin induction of renal microsomal enzyme systems: ultrastructural effects on pars recta (S3) proximal tubule cells on the rat kidney. A single oral administration of 2,3,7,8-tetrachlorodibenzo-p-dioxin to rats at a dose level of 25 microgram/kg produced marked proliferation of smooth endoplasmic reticulum in renal proximal tubule cells of the straight (S3) segments. This ultrastructural effect was associated with a pronounced induction of the microsomal enzymes glucuronyl transferase and benzopyrene hydroxylase which persisted for at least 16 days after treatment. Renal dissection studies disclosed that the activities of these enzymes in 2,3,7,8-tetrachlorodibenzo-p-dioxin-treated animals were not uniformly distributed within the kidney but followed the general known distribution of S3 cells. Enzyme activities were highest in the outer stripe of the medulla and cortex and lowest in the medulla. These studies demonstrate that the kidney does possess inducible microsomal enzyme systems, capabilities of which have not been appreciated previously due to the lack of a suitable inducing agent and their apparent concentration in a relatively small population of proximal tubule cells.


Paracellular permeability of extracellular space markers across rat jejunum in vitro. Indication of a transepithelial fluid circuit. 1. The characteristics of [51Cr]EDTA, [3H]methoxyinulin ([3H]MI), [14C]polyethylene glycol-4000 ([14C]PEG), and [3H]mannitol as markers of the extracellular space (e.c.s.) of isolated mucosa from the rat small intestine have been examined. 2. Unidirectional transmural fluxes across the rat jejunum of [3H]MI,  [14C]PEG and [3H]mannitol have been measured in the absence of glucose or in the presence of 28 mM glucose. 3. Assuming that [14C]PEG  does not enter the cells, [51Cr]EDTA and [3H]mannitol seem to have access to approximately 50 and 90% of the intracellular water respectively. 4. The commercially availabel [3H]MI had access to a space which exceeded th [14C]PEG space by 10%. Upon purification by gel filtration the high molecular weight fraction of the [3H]MI provided estimates of the e.c.s. identical with the estimates obtained with [14C]PEG. 5. For all the markers used the e.c.s. estimates remained constant between the 40th and 80th min of incubation. 6. In the absence of glucose the transepithelial net fluxes of each of the different markers were zero. In the presence of 28 mM glucose the serosato-mucosa fluxes of all markers were dramatically increased. The ratio between the serosa-to-mucosa and the mucosa-to-serosa fluxes increased in the order [3H]mannitol greater than [3H]MI greater than [14C]PEG. 7. The effect of glucose on the flux ratio of the marker substances suggests that glucose-induced net water transport to the serosa side of the gut wall represents the difference between a transcellular net water transport to the serosal side and a significant paracellular net water transport through the lateral intercellular spaces to the mucosal solution.


The natural discharges of Purkinje cells in paravermal regions of lobules V and VI of the monkey's cerebellum. 1. Conscious monkeys were trained with food rewards to perform movement tasks with the left hand and to accept manipulation of the joints and muscles and natural non-noxious stimulation of the skin of both forelimbs.2. Recordings were made from 230 Purkinje cells situated in the paravermal region of lobules V and VI or immediately adjacent folia of the left cerebellum in a region from 2 to 7 mm from the mid line. These neurones were all in a zone which was demonstrated to receive inputs from the ipsilateral hand and which is known to receive projections, via the pontine nuclei from the ;arm area' of motor cortex in the right hemisphere.3. Modulation of the natural activity of 182 of these 230 Purkinje cells (79%) occurred in a reproducible manner in temporal association, each with a particular phase of the self-paced movement tasks performed by the animal using the ipsilateral arm and hand. The patterns of modulation of Purkinje cell firing in this limited zone of cerebellar cortex could be classified into one of four groups, and each cell's discharge was associated with a particular aspect of movement such as general arm flexion, shoulder retraction, elbow extension or elbow flexion whenever it occurred.4. The cells were spontaneously active at rest. Most commonly, marked accelerations of the discharge were related to one direction of the particular aspect of movement and a reduction of activity or even total silence accompanied movement in the opposite direction.5. Variation of the amount of discharge demonstrated during a movement performance with which this discharge was characteristically associated could be related to the range of the movement or its duration, more activity being characteristic of more prolonged movement performance through larger angles of joint displacement.6. Both simple spikes and complex spikes of some cells showed characteristic modulation of their activity during the monkey's self-initiated movements. Cells whose simple spikes did not change in frequency during the movement task, also showed no modification of complex spike discharge.7. Of the 182 neurones whose discharges changed during active movement performance, 105 (roughly 60%) were demonstrated to be in receipt of an input from peripheral receptors in the hand which could be activated by brisk tapping of the skin or brushing of hairs. In contrast, none of the Purkinje cells whose discharges were unchanged during arm movements could be demonstrated to receive such an input.8. Movement of joints through their full range and prodding of muscles were completely ineffective stimuli for causing changes in Purkinje cell firing in this zone of the cerebellar cortex while the animal was passive and relaxed. Imposed perturbations of movement performance injected unexpectedly during the execution of a movement task were also ineffective in modifying the discharge of these Purkinje cells in relation to the task.


The effect of calcium ions and temperature on the binomial parameters that control acetylcholine release by a nerve impulse at amphibian neuromuscular synapses. 1. A study has been made of the effects of changing the external calcium concentration, [Ca](o), and the temperature on both the number of quanta available for release by the nerve impulse (n) as well as the increase in release probability of a quantum p(t) during the release period (from 0 to T) following a nerve impulse at synapses in amphibian striated muscle.2. When [Ca](o) was increased in the low range from 0.25 to 0.4 mM at 18 degrees C, the average quantal content of the e.p.p. (m) increased as the fourth power of [Ca](o) and this was primarily due to a third power dependence of n on [Ca](o); the dissociation constants and power dependence of n on calcium determined in the [Ca](o) range from 0.25 to 1.0 mM were successfully used to predict the changes in size of the e.p.p. in the very high [Ca](o) range from 1 to 10 mM. When the temperature was increased from 7 to 18 degrees C in a [Ca](o) of 0.6 mM or 0.35 mM, n increased with a Q(10) of 2.5.3. When [Ca](o) was increased in the range from 0.25 to 1.0 mM at 18 degrees C, the probability that a quantum initially available for release is released during the release period (p(T)) was very sensitive to [Ca](o), increasing as the third power of [Ca](o) and with a dissociation constant of 0.13 mM. When the temperature was increased from 7 to 18 degrees C in a [Ca](o) of 0.6 mM or 0.35 mM, p(T) decreased.4. The histograms of latencies of individual quanta following a nerve impulse was very temperature dependent: the time to peak of the histograms (i.e. the interval in which most quanta fell) had a Q(10) of over 4 as did the time constant of decline of the histograms in the temperature range from 7 to 18 degrees C.5. The average number of quanta released up to time t during the release period following a nerve impulse, namely np(t), was well described by a stochastic process in which p(t) was determined by two reactions; one of these reactions released available quanta from the nerve terminal whilst the other made some of the available quanta unavailable for release by the nerve impulse.


The effects of calcium ions on the binomial parameters that control acetylcholine release during trains of nerve impulses at amphibian neuromuscular synapses. 1. A study has been made of the effects of changing the external calcium concentration [Ca](o) on the binomial parameters p and n that control the average quantal content (m) of the end-plate potential (e.p.p.) during trains of nerve impulses at synapses in amphibian striated muscle.2. In high external calcium concentrations (0.4 mM </= [Ca](o) < 1.0 mM) the increase in m of a test impulse following a conditioning impulse at different intervals (< 100 msec) was due to an increase in the number of quanta available for release, n; the increase in m of successive e.p.p.s in a short high frequency train was primarily due to an increase in n.3. In high external calcium concentrations (1.0 mM </= [Ca](o) < 10 mM) there was a decrease in m of a test impulse following a short high frequency conditioning train (4-5 impulses, 20-100 Hz) at different intervals (200 msec < 5 sec) and this was due to a decrease in the number of quanta available for release, n; in a long high frequency train (20 impulses, 20-100 Hz) there was an increase in m for the first few successive e.p.p.s followed by a depression of m which eventually reached a steady state and these changes in m were due to changes in n; the higher the frequency the greater was the depression in n during the steady-state period.4. In high calcium concentrations, the steady-state m reached in the first 20 impulses during continual stimulation at high frequency gave way to a decline in m over several minutes until a new depressed steady-state value of m was reached and this was maintained during the longest periods of stimulation (30 min); this decline in m was primarily due to a decline in the number of quanta available for release.5. These changes in the number of quanta available for release during trains of impulses are predicted in terms of a hypothesis in which facilitation is due to the accumulation of a residual calcium-receptor complex in the nerve terminal that determines the fraction of a pool of quanta which contributes to n, and depression is due to a decrease in the number of quanta in this pool.


Cerebral circulatory and metabolic effects of 5-hydroxytryptamine in anesthetized baboons. 1. The cerebral circulatory effects of the intracarotid administration of 5-hydroxytryptamine were examined in anaesthetized baboons. Cerebral blood flow was measured by the intracarotid 133Xe technique, cerebral O2 consumption and glucose uptake were measured as indices of brain metabolism and electrocortical activity was continuously monitored. 2. Despite a marked reduction in the calibre of the internal carotid artery (assessed angiographically), the intracarotid infusion of 5-hydroxytryptamine 0-1 microgram/kg. min did not effect any significant changes in cerebral blood flow, O2 consumption or glucose uptake. 3. Following transient osmotic disruption of the blood-brain barrier with the intracarotid infusion of hypertonic urea, the same dose of 5-hydroxytryptamine effected a marked reduction in cerebral blood flow from 51 +/- 2 to 36 +/- 2 ml./100 g. min (mean +/- S.E.; P less than 0-01). Both indices of cerebral metabolism were reduced significantly and the e.e.g. showed a more pronounced suppression-burst pattern. 4. We postulate that the cerebral circulatory responses to 5-hydroxytryptamine are dependent upon the integrity of the blood-brain barrier and the predominant effect of the intravascular administration of 5-hydroxytryptamine is on cortical activity or metabolism, rather than on cerebrovascular smooth muscle.


Pulmonary damage associated with sodium aurothiomalate therapy. Three patients with rheumatoid arthritis developed acute respiratory distress associated with pulmonary infiltration, during treatment with sodium aurothiomalate. This manifestation of gold toxicity has only recently been recognized. The temporal relationship to the introduction of gold therapy, an exacerbation following further gold injection in one patient, the resolution which followed gold withdrawal and the associated manifestation of gold toxicity in two patients favored a diagnosis of gold-induced pulmonary disease.


Educating patients with Osteoarthritis.

Educating patients with Osteoarthritis. An education program was developed for geriatric patients with osteoarthritis utilizing adult learner methods. The format used was slide/tape with accompanying booklets. Sixty-seven patients were tested before, immediately after, and three weeks after viewing the programs. A change in knowledge was noted for all objectives and was statistically significant (P .05) in five of six objectives. Although initial production costs are substantial, duplication costs are minimal. These results suggest that geriatric patients with osteoarthritis are able to learn and the method used is a cost-effective one.


Antimalarials. 10. Synthesis of 4-substituted primaquine analogues as candidate antimalarials. Primaquine (I) has been extensively used in combination with other drugs in the radical cure of relapsing malaria as well as for prophylaxis or the interruption of transmission. This, coupled with the activity data reported for 4-methylprimaquine (II), has led to the synthesis of a series of 14 4-substituted analogues of I. In addition, three side-chain analogues of II were prepared. The compounds were tested for suppressive antimalarial activity against Plasmodium berghei in the Rane mouse screen and for radical curative activity against Plasmodium cynomolgi in the rhesus monkey. Four of the 17 compounds prepared (1a, 9c, 15, and 17) exhibited activity in at least one of the test systems.


A model for the prostaglandin synthetase cyclooxygenation site and its inhibition by antiinflammatory arylacetic acids. Conformational analysis of indomethacin and other nonsteroidal antiinflammatory drugs leads to formulation of a hypothetical complementary receptor site model. The same model can serve to describe the prostaglandin cyclooxygenase active site, and, indeed, arachidonic and other polyunsaturated fatty acids could be folded on the model in a manner which rationalizes their stereospecific transformation to cyclic endo-peroxides (PGG). The model rationalizes the structure-activity relationships of enzyme substrates and inhibitors and appears to be in agreement with biochemical studies of the enzyme.


Synthesis and biological activity of some broad-spectrum N-acylphenyglycine cephalosporins. The synthesis and the in vitro and in vivo antibacterial activities of a series of N-acylated phenylglycine cephalosporins are described. These compounds exhibit activity against a broad spectrum of gram-positive and gram-negative bacteria including some strains of Pseudomonas aeruginosa, a bacterial species normally insensitive to the cephalosporin antibiotics. The cephalosporins were prepared by acylation of cephaloglycin or its 3-tetrazolylthiomethyl analogue. In several cases, the acylations produced mixtures of diastereomeric cephalosporins, the components of which, when separated, showed different levels of antibiotic activity. Optimum activity was obtained when the acyl moiety on the phenylglycine nitrogen contained an oxygen atom centrally located between the amide carbonyl and a carboxyl substituent, preferably in a three- or five-membered ring. Replacement of acetoxymethyl by (1-methyl-1H-tetrazol-5-yl)thiomethyl at the 3 position resulted in overall improvement in activity both in vitro and in vivo. Against a group of P. aeruginosa strains, the best compounds of this series showed activity on the order of carbenicillin.


Inhibitors of Bacillus subtilis DNA polymerase III. Structure-activity relationships of 6-(phenylhydrazino)uracils. 6-(Phenylhydrazino)uracils inhibit the replication-specific enzyme DNA polymerase III of Bacillus subtilis by forming a strong, reversible complex with template-primer DNA and enzyme. The phenyl ring interacts with a hydrophobic enzyme site which, on the basis of structure-activity relationships of substituted analogues, appears to possess the following characteristics: (1) planarity or near-planarity; (2) a finite capacity to accommodate bulky substituents; and (3) location near the domain of the enzyme active site. A mutant DNA polymerase III, derived from a mutant strain of B. subtilis selected for resistance to 6-(p-hydroxyphenylazo)pyrimidines, is resistant only to inhibitors bearing p-hydroxy or amino groups and is hypersensitive to inhibitors containing nonpolar substituents; these results suggest the existence of mutable, secondary regions of the binding site which interact with para substituents and, thus, influence the strength of the primary phenyl-enzyme interaction.


Inhibitors of Bacillus subtilis DNA polymerase III. 6-(arylalkylamino)uracils and 6-anilinouracils. 6-(Benzylamino)uracils and substituted 6-anilinouracils have been found to be potent inhibitors of Bacillus subtilis DNA polymerase III by a mechanism identical with that of 6-(phenylhydrazino)uracils. Higher phenylalkylamino homologues are progressively weaker inhibitors of the enzyme. Examination of the effects of substituents on the activity of 6-(benzylamino)uracils against wild-type and mutant enzymes and preliminary results for 6-anilinouracils have permitted further dissection of the mechanism of inhibition. The experimental results indicate that (1) the polymerase inhibitor binding site is compact, accommodating only small alterations in the distance between the uracil and phenyl rings, (2) the phenyl ring, which provides the major contribution to inhibitor-enzyme binding, adopts a specific active conformation, and (3) an enzyme site which interacts with substituents in the phenyl ring forms a part of the active site of DNA polymerase III.


Pteridines. 41. Synthesis and dihydrofolate reductase inhibitory activity of some cycloalka[g]pteridines. A number of homologous 2,4-diaminocycloalka[g]pteridines varying in ring size from 5 to 15 were prepared by (a) condensation of aminomalononitrile tosylate with alpha-oximinocycloalkanones, deoxygenation of the resulting 2-amino-3-cyanocycloalka[b]pyrazine 1-oxides, and guanidine cyclization; (b) guanidine cyclization of the above pyrazine 1-oxides to give 2,4-diaminocycloalka[g]pteridine 8-oxides, followed by deoxygenation; or (c) condensation of 2,4,5,6-tetraaminopyrimidine with a cycloalka-1,2-dione (for the cyclohepta- and cycloocta[g]pteridines only). These compounds were examined for their activity as dihydrofolate reductase inhibitors against Lactobacillus casei, rat liver, L1210, and Trypanosoma cruzi. Activity was found to depend upon ring size, with the greatest activity exhibited by the cyclododeca derivatives 31.


Cebocephaly in an infant with trisomy 18. An infant who died in the perinatal period with the unusual association of trisomy 18 and cebocephaly is described. It is suggested that this association may be more common than is generally recognised because the majority of such infants are stillborn or live only briefly and often do not have chromosome studies performed.


Reticulostimulating properties of killed vaccines of anaerobic coryneforms and other organisms. Vaccines prepared from 115 strains of anaerobic coryneforms and other organisms were tested in mice for their reticulostimulating ability as judged by the degree of spleen hypertrophy produced after ip injection. Almost all vaccines caused a statistically significant increase in spleen weight, but the ability to produce spleen ratios (test mean wt:control mean wt) of 4 or more was confined to Propionibacterium acnes and P. avidum strains. P. acnes, type II, gave high spleen ratios more frequently than strains of any other type.


Inhibition of tumor growth by the peptidoglycan from Bacillus megaterium. When injected in admixture with tumor cells, the peptidoglycan extracted from Bacillus megaterium inhibited the growth of a chemically induced fibrosarcoma in syngeneic rats. In some instances, the tumor growth was totally suppressed. Animals rejecting mixed inocula exhibited a tumor-specific immunity. Peptidoglycan was not cytotoxic for tumor cells; it rendered macrophages nonspecifically cytotoxic.


Comparative metabolism of 17alpha-ethynyl steroids used in oral contraceptives. The metabolism of mestranol, ethynylestradiol, norethynodrel, norethindrone, ethynodiol diacetate, lynestrenol, and norgestrel is reviewed. The estrogenic components of the oral contraceptives, mestranol or ethynylestradiol, have nearly identical metabolic pathways since mestranol is rapidly and almost completely converted to ethynylestradiol The major fraction of the drugs plus metabolites is excreted in the urine as conjugated materials. All of the 17beta-ethynyl progestins reviewed follow similar metabolic paths. For three of these, norethynodrel, ethynodiol diacetate and lynestrenol, a principal metabolite is norethindrone. Biotransformation to more polar metabolites and conjugation proceed rapidly for these three precursor drugs and norethindrone. Norgestrel follows metabolic paths similar to those of norethindrone. However, the ethyl moiety at the C-13 position appears to slow the metabolism of this steroid so that biotransformation to more polar metabolites and the conjugation of these steroids does not proceed as rapidly as that of the other progestins. The high progestational potency of norgestrel may be attributed to this slow rate of biotransformation. Some of the pharmacokinetic parameters derived from the research reports reviewed here are summarized. The compounds appear to be readily absorbed, and they and their metabolites are excreted to a greater extent in the urine than in the feces.


Metabolism of ethynyl estrogens.

Metabolism of ethynyl estrogens. The pharmacokinetics and metabolic conversion of the ethynylated estrogens are reviewed. Special emphasis is given to the comparative pharmacokinetics of ethynyl-estradiol in different populations of women. Similarly, the variability of ethynyl-estradiol and mestranol metabolism in humans resulting from presentation of radio-labeled steroid and purification of the metabolic products is presented and discussed. The concepts of estrogen hepatotoxicity are reviewed with respect to the known phenomenon of estrogen oxidative metabolism and covalent binding. Recent evidence for the metabolic removal of the 17alpha-ethynyl group is discussed, and its relationship to estrogen hepatoxicity is considered and related to the covalent binding phenomenon.


Retention and tissue distribution of 210Pb (NO3)2 administered orally to infant and adult monkeys. The retention and tissue distribution of 210Pb were studied in 10-day-old, 150-day-old, and adult monkeys. Lead-210 nitrate was administered to the monkeys by gavage after a 12 hr fast and 210Pb excreted in urine and feces was monitored for 96 hr. All monkeys were necropsied 96 hr after dosing and the 210Pb concentrations of various tissues was determined. The data demonstrated that infant monkeys retained 64.5 and 69.8% of the orally administered 210Pb at 10 and 150 days of age, respectively, while adult monkeys retained 3.2% of the 210Pb dose. Blood 210Pb levels 96 hr after dosing did not vary significantly between age groups. Of the 210Pb contained in blood, 98-99% was found in blood cells and 1-2% in blood plasma; 5-8% of the Pb in blood cells was bound to blood cell membranes. None of these parameters varied significantly with age. The percentage of the lead dose excreted in urine did not vary significantly between age groups. Analysis of tissues for 210Pb revealed that both the tissue Pb concentrations and tissue Pb:blood Pb ratios were significantly higher in the bone structure of infants than adults. Brain Pb:blood Pb ratios were significantly greater in 10-day-old infants than 150-day-old infants or adults.


Lead intoxication among demolition workers: the effect of lead on the hepatic cytochrome P-450 system in humans. Overt clinical disease from undue lead exposure has become a relatively rare phenomenon in adult populations. However, exposure situations that may result in subclinical disease are not uncommon in various occupational settings. Five demolition workers, dismantling an old iron structure covered with lead-content paint, were studied. The use of cutting torches resulted in lead fumes, with significant exposure, albeit without gross 'lead poisoning." All five workers showed biochemical manifestations of chronic lead intoxication-that is, elevated blood lead level, inhibition of delta-aminolevulinic acid dehydratase (ALA-D), and elevated erythrocytic protoporphyrin concentration (PROTO). The effect of lead on the biosynthesis of heme was assessed by investigating the functional capacity of the cytochrome P-45O system of the liver, through drug metabolism studies. The plasma elimination rates (half-lives) of antipyrine and phenylbutazone-drugs primarily metabolized by the hemeprotein P-450 dependent hepatic microsomal enzyme system-were measured before and after chelation therapy. Prior to chelation therapy all half-lives were within the normal range. A slight decrease in the half-life of antipyrine was found after treatment. These studies show that chronic exposure to lead has only a minimal effect on hepatic cytochrome p-450 dependent enzymatic activities in adult males.


Biotransformation of diethylstilbestrol in the rhesus monkey and the chimpanzee. Diethylstilbestrol (DES) is considered a teratogen and a transplacental carcinogen in humans. In order to compare its biotransformation in nonhuman primates to that in humans, a metabolic study was carried out in rhesus monkeys and chimpanzees. After an oral dose of 1 mg/kg [14C]DES, approximately 59% of the ingested radioactivity was found in the urine and 28% in the feces of two female rhesus monkeys after 4 days, while in male rhesus monkeys urinary radioactivity accounted for 43% and fecal radioactivity for 35%. In chimpanzees, 63% of a 0.5 mg/kg dose was excreted with the urine in a female and 47% in a male animal. In both species, urinary radioactivity was predominantly (greater than 70%) associated with glucuronides. Besides DES, three metabolites were found in the urinary glucuronide fraction of rhesus monkeys and chimpanzees by radio gas chromatography and were identified as dienestrol and omega-hydroxy derivatives of DES and dienestrol. Fecal radioactivity in rhesus monkeys was shown to consist exclusively of DES. Glucuronidation of DES appears to occur in neonatal and fetal rhesus monkeys.


Pineal calcification.

Pineal calcification. The incidence of pineal calcification was studied by reviewing skull radiographs of 1400 patients admitted to a major neurosurgical centre at Karachi over an eight year period. The total frequency as well as age and sex distribution of pineal calcification were worked out and compared with frequency and age distribution of calcification reported in Western and Eastern races by different workers.


Thiothixene and trifluoperazine in acutely disturbed schizophrenic patients. In acutely disturbed newly admitted patients at Neuropsychiatric Unit, Karachi, the efficacy of thiothixene is not significantly different as compared to trifluoperazine. In trifluoperazine group also all the target symptoms improved while 'depressive mood' and 'suspiciousness' did not change significantly. In thiothixene group significant improvement was noticed on all the target symptoms except 'tension' and 'depressive mood'. The ethnic or genetic make up of the patient population was concluded to be the reason for non-effectiveness of thisthixene on effective psychopathology in acute schizophrenia. The extra-pyramidal side effects were clinically more pronounced in thiothixene group.


Amoxycillin trihydrate (Ibeamox) in the treatment of pyogenic meningitis-a preliminary report. Amoxycillin a new broad spectrum antibiotic has been found to be effective against common gram positive and negative bacteria diagnosed in clinical practice. Moreover, it achieves higher blood levels as compared to Ampicillin. Since it was available only for oral use it had not been tried in the treatment of bacterial meningitis. Recently Amoxycillin Trihydrate became available for parenteral administration. Here we report its use as a single drug in 11 cases of Pyogenic meningitis. The dose administered by intravenous route was 200-400 mg/kg/day. All the cases recovered. Only three had minor neurological sequelae. Amoxycillin Trihydrate appears to be a safe and effective drug as there were no side effects or toxic manifestation even with the high dosage schedule.


Vivalan, a new anti-depressant-report on an out-patient trial. The study on 20 patients referred from the psychiatric out-patients of the Jinnah Postgraduate Medical Centre, who were given Vivalan showed marked improvement in 14 patients (70%). Three showed mild improvement while three did not respond. The drug appears to be an advance in the range of anti-depressants presently available. It is of interest to note that Vivalan is not tricyclic compound, nor does it inhibit monoamine oxidase in vitro.


Serotyping of Pseudomonas aeruginosa from patients with cystic fibrosis of the pancreas. Serotyping of 30 mucoid strains isolated from cystic fibrosis patients was carried out by slide agglutination tests with both live and heat-killed cells and by tube agglutination test with heat-killed cells. Comparison of the results obtained by these 2 methods revealed that tube agglutination with heat-killed cells was the superior method. More than half the strains were found to be Homma's serotype 15 (group M in the new schema [2]). Slide agglutination with live cells did not give clear results: some strains showed occasionally positive or negative agglutinations against the same serotype serum. Changes in serotypes (groups in the new schema [2]) were found in some strains, although the number was very small.


Carcinogenesis in tissue culture. 28. Comparison of various effects of a chemical carcinogen, 4-nitroquinoline I-oxide, on normal human cells and on normal mouse cells in culture. A comparison of the effects on cultured cells of a chemical carcinogen, 4-nitroquinoline 1-oxide (4NQO), between normal human cells which were resistant to malignant transformation with 4NQO and normal mouse cells rather easily transformable was carried out. We studied the following effects of 4NQO on normal human and normal rodent cells; 1) cytotoxicity, 2) DNA, RNA and protein synthesis, 3) incorporation of 4NQO into cells and time course changes of the drug bound with macromolecular substances in cells, 4) DNA repair synthesis, and 5) chromosomal changes. Our results demonstrated that there were no differences in cytotoxicity and inhibition of cellular macromolecular syntheses between human and mouse cells. On the other hand, significant differences were noted in DNA repair synthesis and chromosomal aberrations between human and rodent cells. These differences suggest that mouse cells are easily transformed into neoplastic cells with chemical carcinogens as compared with human cells.


[The effect of combined therapy with buformin and dichloracetate on blood lactate concentrations in diabetics]. In animals, dichloroacetate (DCA) which activates pyruvate dehydrogenase has been shown to diminish increased blood lactate concentrations due to biguanide treatment. In 10 maturity onset diabetics, therefore, the effect of a combined therapy with buformin and DCA (200 mg b.i.d.) was studied on blood lactate concentrations and compared with an analogous pre- and postinvestigation period of 6 days with buformin treatment alone (100 mg b.i.d.). Mean blood glucose concentrations remained the same during all 3 investigation periods. Also, neither fasting nor postprandially significant differences were found in blood lactate and ketones. In association with a standardized ergometer test, however, the rise in blood lactate was significantly smaller (p less than 0.05) while the patients were on buformin plus DCA, compared to the periods when only buformin was given. Furthermore, less ketone bodies appeared to be utilized by the exercising muscle under the influence of the combined treatment (p less than 0.05). These results are in good agreement with animal studies and suggest that DCA might be as effective in decreasing enhanced blood lactate concentrations in biguanide treated man as in animals.


Serum ribonuclease activity in patients during parenteral nutrition, chronic hemodialysis and acute pancreatitis. Animal experiments have shown that malnutrition and protein deficiency states, respectively are associated with elevated tissue ribonuclease (RNase, E.C. 3.1.4.22) activities. The causal intracellular alterations are unknown. Assuming that increased tissue RNase activities are reflected by serum levels, a study was made of the serum RNase activities in 10 healthy controls eating a normal diet (group I), 7 patients on long-term parenteral nutrition (group II), 13 chronic hemodialysis patients (group III), and 9 patients with acute pancreatitis (group IV). In group I the serum RNase activity corresponded to 195.3 + or -58.8 U/ml. A significant (p less than 0.005) elevation was noted in groups II (314.6 +/- 95.3 U/ml) and III (374.1 +/- 102.1 U/ml), no difference being detected in group IV (295.1 +/- 191.9 U/ml).


Evaluation of computer-aided monitoring of patients after heart surgery. The medical and economic benefits of a computer-aided monitoring system were evaluated in a prospective, randomized study of 810 patients after open-heart surgery. The design  of the study separated benefits of systematized postoperative care from benefits unique to the computer system and established measurable criteria by which computer-aided monitoring systems could be objectively evaluated. Criteria for comparison included the rapidity, safety, and smoothness of convalescence and time spent for various nursing activities. The study showed that the computer-aided monitoring system did not provide discernible medical benefits nor favorably affect nursing activities. Downtime of the system averaged 1 day per week. Reliability and accuracy of the system were inadequate and the benefit/cost ratio was low. Future development of computer-aided monitoring systems for open cardiac surgery should stress reliability, accuracy and relevance of the monitored measurements.


Chronic oxygen therapy.

Chronic oxygen therapy. Chronic low flow oxygen is useful therapy for patients with chronic obstructive lung disease who are crippled by hypoxemia despite optimal programs of usual respiratory care. Patients should be considered for chronic oxygen therapy who have (a) a resting Pao2 less than 55 mm Hg while breathing room air; or (b) profound tissue hypoxemia measured by mixed venous Pao2 and suggested by symptoms such as cor pulmonale and congestive heart failure; or (c) pulmonary hypertension or polycythemia even though daytime Pao2 is greater than 55 mm Hg. Arterial blood must be obtained to demonstrate hypoxemia and assess the benefits of oxygen therapy. Patients on chronic oxygen must remain under close medical supervision. There are no absolute contraindications to chronic oxygen therapy, other than refusal of the patient to quit smoking. Complications of therapy appear to be negligible. The exciting suggestion of improved prognosis in patients with chronic obstructive lung disease on oxygen therapy and the possibility of delaying the long-term sequelae of chronic respiratory failure bear careful watching in the future.


Screening for breast cancer: the role of mammography. The early diagnosis of breast cancer by screening is a relatively new development in medical practice and its enthusiastic acceptance needs to be tempered by an appraisal of the costs, the risks and the potential benefits. No case can be made at present for screening well women under the age of 50 years, when such screening includes mammography. With the exception of women who have already had cancer in one breast, it is likely that those women under 50 with the associated "risk factors" are better managed by careful attention to breast self-examination and more frequent physical examinations. Provided that the radiation dose is less than one rad per examination, the benefits to women over 50 outweigh the risks of radiation-induced breast cancer. Against this must be placed the very large cost to the community of screening programmes and the relatively low additional benefits gained by incorporation of mammography into the screening process.


[Hospital infections with pseudomonas aeruginosa: I. Technical devices and wet areas as sources of infection in intensive care units (author's transl)]. In an intensive care unit system comprising three surgical intensive care wards bacteriologic investigations on the presence of Pseudomonas aeruginosa were carried out over a period of 7 months (as an example for the aetiology of hospital infections). Centers of contaminations were found to exist in wet areas and in technical devices (ultrasonic nebulizers, respirators etc.). In many cases, the bacterial strains isolated from patients were found by means of phage-typing to be identical with strains isolated from devices and wet areas. Additional experimental investigations showed the predominant role of ultrasonic nebulizers for germ dissemination. On the basis of the results obtained a patient oriented scheme of probable infection chains was tried to establish. Hereby the wet areas play a central role as reservoirs of germs and therapeutical devices as vectors. The results obtained were evaluated in order to define a catalogue of practical measures for interruption of infection chains.


[Nitroprusside-sodium and intravenous nitroglycerin in acute myocardial infarction (author's transl)]. Using Nitroglycerin (NTG) and Nitroprusside-Sodium (NPN) intravenously we tried to reduce the necrotic area following myocardial infarction by reducing the myocardial O2 consumption. In 12 patients with acute myocardial infarction the effect of NPN was compared to intravenous NTG. In all patients the blood pressure, the pulmonary artery pressure, the pulmonary capillary wedge pressure and the heart rate were continuously monitored; in few patients with cardiac output was measured using a thermodilution device. In some patients with normal blood pressure NPN lowered the blood pressure to such a degree that NPN had to be discontinued before and effect on the pulmonary capillary wedge pressure could be seen. Even in patients with normal blood pressure this effect was not seen with NTG. Intravenous NTG lowered the pulmonary capillary wedge pressure in most patients with only a moderate effect on the blood pressure. We conclude from our results that patients with acute myocardial infarction and normal blood pressure should receive NTG, if a lowering of the pulmonary capillary wedge pressure is desired. When NPN was used in this group of patients a considerable decline of the blood pressure was seen. We think that an elevated pulmonary capillary wedge pressure should be treated with NPN only in patients with an elevated blood pressure.


[Spontaneous regression of pulmonary metastases from hypernephroma: report of a case and review of literature (author's transl)]. Until now there are reported some 60 cases of spontaneous regression of pulmonary metastases from hypernephroma. An own case is shown up: There was taken nephrectomy and following local radiation of hypernephroma in a 59 years old male patient in spite of pulmonary metastases. 8 months after operation these metastases had disappeared. There was no indication for any metastases in radiologic and scintigrafic examination even 4 years following up neither in lungs nor in other organ. The causality of hormones and autoantibodies - perphaps additionally stimulated by wound infection-in the phenomenon of spontaneous regression of pulmonary hypernephroma-metastases is discussed. According to the literature and to experience in an own case nephrectomy and following local radiation - possibly additional progesterone-therapy for one year - is recommended in hypernephroma even in case of pulmonary metastases.


Connubial lymphoproliferative malignancies: a report of nine couples. Nine marital partners with lymphoproliferative malignancies are detailed and their cases summarized in Table I. This 30-year observation represents the largest series of such associations from a single institution. A brief review of similar reported cases is presented.


Physical characterization of neutron beams produced by protons and deuterons of various energies bombarding beryllium and lithium targets of several thicknesses. Protons of 35 and 65 MeV and deuterons of 35 MeV were used to bombard beryllium and lithium targets of various thicknesses. Four types of experiments were conducted in order to characterize the neutron fields. They were (1) central axis depth-dose measurements in a water phantom, (2) dose buildup at small depths in tissue-equivalent plastic, (3) microdosimetric measurements and LET distributions, and (4) neutron yields and energy spectra at an angle of 0 deg. The results generally show that (a) the central axis depth doses for the 35 and 65 MeV particles roughly approximate those of 60Co and 4-MeV bremsstrahlung photons, respectively, (B) the neutron dose buildups are more rapid than those of the above-mentioned photon sources, (C) the microdosimetric spectra show differences which are consistent with the measured neutron energy spectra, and (D) P-Li compared to p-Be neutron spectra have larger high-energy particle flux for similar target and beam configurations.


Neutron spectral measurements in an intense photon field associated with a high-energy x-ray radiotherapy machine. High-energy x-ray radiotherapy machines in the supermegavoltage region generate complex neutron energy spectra which make an exact evaluation of neutron shielding difficult. Fast neutrons resulting from photonuclear reactions in the x-ray target and collimators undergo successive collisions in the surrounding materials and are moderated by varying amounts. In order to examine the neutron radiation exposures quantitatively, the neutron energy spectra have been measured inside and outside the treatment room of a Sagittaire medical linear accelerator (25-MV x rays) located at Yale-New Haven Hospital. The measurements were made using a Bonner spectrometer consisting of 2-, 3-, 5-, 8-, 10- and 12-in.-diameter polyethylene spheres with 6Li and 7Li thermoluminescent dosimeter (TLD) chips at the centers, in addition to bare and cadmium-covered chips. The individual TLD chips were calibrated for neutron and photon response. The spectrometer was calibrated using a known PuBe spectrum Spectrometer measurements were made at Yale Electron Accelerator Laboratory and results compared with a neutron time-of-flight spectrometer and an activation technique. The agreement between the results from these independent methods is found to be good, except for the measurements in the direct photon beam. Quality factors have been inferred for the neutron fields inside and outside the treatment room. Values of the inferred quality factors fall primarily between 4 and 8, depending on location.


Arc technique for total-body irradiation by a 42-MV betatron. An arc technique for total-body irradiation (TBI) has been developed using a Siemens 42-MV betatron. Dose is administered with the isocenter approximately one-third the distance from source to patient. A modified inverse-square function for a beam arcing isocentrically was derived and confirmed experimentally. Relationships between stationary and arcing beam equilibrium and depth doses have been established theoretically and experimentally. Depth doses for TBI by 42-MV beams are compared with those for 60Co and 4-MV beams. The simplicity of setup and short treatment times are comparable to setup and treatment times of 60Co and linear accelerator TBI techniques.


Evidence for an excess of rDNA in the testis of Drosophila melanogaster during rDNA magnification. Hybridization of rRNA and DNA extracted from different tissues of different genotypes have been performed. The results show that: 1) in DNA extracted from the testis of premagnified males there exists an excess of rDNA, which is consistent with the model proposed by Ritossa (1972) and by us (1973) to explain the phenomenon of magnification. 2) in DNA extracted from diploid tissues of different genotypes the percent of rDNA is directly proportional to the number of ribosomal genes. 3) in polytene cells the percent of rDNA for all genotypes so far studied is less than that in diploid cells and is not significantly dependent on the genotype. This last result is consistent with those of Spear and Gall (1973).


Computational analysis and dosimetric evaluation of a commercial irregular-fields computer program. The proper evaluation of the accuracy of a new computer program for radiation-therapy dosimetry requires consideration of both the mathematical algorithm used in the program and the performance required in clinical applications. As an example, our evaluation of the irregular-fields dosimetry program currently marketed by SHM for their Rad-8 system is described. The evaluation begins with an explanation of the mathematical computation described. The evaluation begins with an explanation of the mathematical computation method, with emphasis on the points where the calculation differs from previous methods. Next, the procedure for setting up the beam data file is discussed. Finally, a step-by-step procedure is described in which calculated doses are compared with measured doses, using a Varian Clinac-4 with lead flattening filter, and the limits within which a +/- 5% accuracy is attainable are estimated. Some sources of error and areas for possible improvements are mentioned.


Extended expression for tissue-maximum ratio fitted to the Varian Clinac-4 and Clinac-6 accelerators. An expression which generates tissue maximum ratio (TMR) data for the Varian Clinac-4 and Clinac-6 accelerators is presented. This semiempirical expression can be programmed easily for radiotherapy computer systems or the new generation of scientific calculators. Our technique leads to good agreement with the published data, as demonstrated by a total average percent deviation of the measured TMR values of -0.115% for the Clinac-4 and -0.002% for the Clinac-6.


Somatic segregation and rate of greening after ultraviolet irradiation of Euglena gracilis. 1. During multiplication of irradiated cells, a segregation may take place between bleached cells, whose progeny is unable to green, and green ones. Some of the green cells give progenies exclusively made of green cells; the progeny of others is partly composed of bleached cells. 2. If one assumes that greening results from the activity of functional units endowed with genetic continuity (Plastidial Segregating Units = PSU), segregation of these units seems to occur according to a model involving random sorting out during the three first divisions. During the following divisions, functional units seem to multiply faster than those impaired by irradiation. 3. The greening rate of colonies issued from irradiated cells seems to be conditioned mostly by the number of functional PSU remaining in the mother cell of the colony.


Selective enrichment for genetic markers in DNA released by competent cultures of Bacillus subtilis. Deoxyribonucleic acid is released into the growth medium by Bacillus subtilis at the time of competence. This DNA is enriched for the genetic markers which have previously been demonstrated to be elevated in membrane-DNA preparations and more recently in cell wall-DNA complexes. Furthermore, the purA16/leu-8 relative marker enrichment varies with time, reaching its highest point at the time of maximal competence. Enrichment remains elevated for at least 60 min further in the competence regimen. Thr results suggest that certain genetic markers of the B. subtilis chromosome are preferentially more available to the external medium as the development of competence proceeds.


[Diagnosis of alcoholism. The Munich Alcoholism test (MALT) (author's transl)]. From the extensive literature on alcoholism 250 relevant diagnostic items were selected and tested for their selectivity in 3 independent inquiries among 1335 patients (661 of them alcoholic), both outpatients and inpatients. The outcome is a two-part test: a section of 7 questions answered by the doctor and a self-assessment section comprising 24 questions answered by the patient. Its validity (validity of the whole test r=0.85) and reliability (reliability of the self-assessment section r=0.94) are high. A diagnosis of alcoholism made according to the usual clinical aspects was confirmed in 90% of 675 unselected medical, surgical and psychiatric patients and alcoholism was suspected in a further 8%.


[Important prognostic factors for the results of physiotherapeutic exercises in intermittent claudication (author's transl)]. In 240 patients with peripheral circulatory disorders (Fontaine Stage II) who had participated in intensive physiotherapeutic interval training daily for 6 weeks between October 1974 and July 1976, it was established that the therapeutic results were not related to age or sex. The "risk" factors of smoking, diabetes mellitus, hypertriglyceridemia, hypercholesterolemia and hyperuricemia individually show no connection with the results. Only overweight, hypertension and coronary heart disease appear to have an unfavorable influence. It is distinctly recognizable that the more risk factors there are combined in a patient with intermittent claudication, the less chance he has of success in physiotherapeutic vessel training.


[Electrodynamic discrepancy of the heart]. Electrodynamic discrepancy was observed in the hearts of 15 out of 144 patients with myocardial infarction who died on account of various complications. Autopsy revealed cardiac rupture with pericardial tamponade in each of the 15 cases. If the ECG shows no typical signs of a myocardial infarction, then with great probability an aortic rupture is present. The pathomechanism of electrodynamic discrepancy of the heart may be explained with the help of Laplace's law and "neuropraxia", "Afterload" and "preload" are reduced to practically nil, the tension of the myocardial walls falls, the effective work of the heart muscle stops and with the considerably lower oxygen requirement of the myocardium the bioelectric activity of the heart is still maintained for 12-30 minutes.


[Blood volume displacement under oral dihydroergotamine during orthostatic strain (author's transl)]. During the course of a double-blind study in 30 orthostatically unstable adolescent subjects, the effect of oral dihydroergotamine (DHE) on the orthostatic circulatory regulation was examined. During standardized orthostatic strain the volume of blood sinking into the two legs is statistically significantly reduced to 125 +/- 61 ml (29%) under the influence of DHE after standing for only 11 sec. Furthermore, there is a significant reduction of the maximal arterial influx into the lower extremities as well as the resting heart rate and the maximal heart rate during orthostatic strain. No significant changes could be detected in the placebo group. Consequently, DHE is suitalbe for the treatment of the these disturbances of orthostatic circulatory regulation due to increased elasticity of the capacitive vessels in the lower extremities.


[Resection procedure or splanchnecotomy in chronic pancreatitis. Indications and comparative results (author's transl)]. The late results of 18 splanchnectomies-principally in chronic pancreatitis-are reported. One patient died during the clinical follow-up treatment. Four patients died later. In the 13 survivors, the observations extended over 5 to 10 years with an average of 7 years after the operation. 11 of them are free from pain.


[First clinical experiences with cholestyramine for the prophylaxis of stress ulcer (author's transl)]. In a general and accident surgical intensive care ward, the possibility of prophylaxis with the exchange resin cholestyramine (which combines with bile acids) was investigated in 68 patients threatened by stress ulcers. Whereas two patients in the control group treated with an antacid (N = 24) developed deep stress ulcers, only one patient among those treated with cholestyramine alone (N=8) developed superficial erosions; no bleeding occurred at all when it was combined with an antacid (N=36). Entefal tolerance of cholestyramine was good during parenteral feeding. No side-effects were observed. The elimination of the ulcerogenic function of duodenogastric reflux in stress ulcer is discussed as a mode of action.


[Atraumatic complete esophageal rupture (Boerhave's syndrome) (author's transl)]. Two of our own patients with Boerhave's syndrome are reported. A disturbance of the vomiting process with abrupt increase of pressure in the esophageal lumen combined with a circumscribed constitutional weakness of the esophageal wall appears to be the decisive factor in the etiology of atraumatic complete esophageal rupture. The clinical picture is characterized by vomiting and painful sensations in the abdomen and thorax in addition to subsequent acute epigastric symptomatology. A water-soluble contrast medium is very useful in the radiological diagnosis. Thoracotomy with suture and drainage is recommended as the treatment of choice. Operative treatment treatment has a mortality of 38% compared with more than 60% with drainage alone.


[Studies on the risk of complications in transfemoral arteriography in infancy (author's transl)]. Four cases of restricted circulation were found during follow-up examination of 42 infants after arteriography. In 3 of the 4 patients with restricted circulation, arteriotomy with vascular suture had preceded or had been performed in direct association with the arteriography. This strengthened the suspicion that such additional manipulations increase the risk of restricted circulation as a sequel to arteriography. Restricted circulation following Seldinger's method of transfemoral arteriography in children occurs more frequently than would be assumed from the collected statistics. The indication for angiography in infancy must be strictly given, for this reason.


[First experience with the practical year in internal medicine (author's transl)]. The first experience with the training program carried out in the University of Ulm presents a number of problems which could be important for its realization in teaching hospitals. The seminar and course program should be related to practice and be organized with the active cooperation of the students. The quality of the training to a great extent depends on the didactic skill, willingness to teach and a not inconsiderable expense of time for the chief physician, the assistant chief physician and the physician in charge of the wards during visits and when working in the ward. The omission of the "Junior Intern" status seems to be a disadvantage to the teaching organization. Condensing the seminar sessions into one month in a three-month period is possibly a logical compromise to guarantee the necessary continuity of the ward work and additional theoretical preparation for the final examination which the student requires.


[Psychological medical aspects of the management of the tumor patient (author's transl)]. Psychodynamic processes in the sense of secondary psychic reactions which can be regularly demonstrated in tumor patients are described: object loss with subsequent narcissistic insult and aggression defense and the inherent defense mechanisms; especially is denial which appears as adaptive misadaptive. Dealing with tumor patients includes emotional receptivity on the one hand and supportive psychotherapy on the other. Furthermore, of additional importance is management of the relatives and pre-operative and post-operative care by means of selfhelp groups. From this broadly based psychological medical program arise possibilities for specific psychosomatic interventions to supplement the somatotherapeutic measures.


[Psychosocial factors and cancer. A study of 80 women by means of a psychosocial questionnaire (author's transl)]. The psychosocial questionnaire compiled by C. B. Bahnson and M. B. Bahnson and adapted for the German-speaking area was used to question 40 female cancer patients (30 mammary, 6 gastric and 4 pulmonary carcinomata) aged between 36 and 64 years and 40 control subjects selected by the matched pairs method. The cross section examination showed significant differences (p less than or equal to 0.05) between cancer patients and control subjects on single variate examination in 10 individual variables. Discriminant analysis (multivariate examination) revealed a discriminant function of 12 variables which enabled the classification of the entire collective of subjects with 95 percent accuracy in the carcinoma and control groups. Our results confirm largely the hypotheses developed in the USA.


[The influence of humoral immune mechanisms on metastasizing tumors in humans (author's transl)]. Long-continued stimulation of the immune system by chronic infections or tumors leads to dysfunction of the immunoregulation. Different types of antibody, anti-antibody and immunocomplex point to the fact that it is not a matter of the weakening of the patient's immune defense but that these antibodies are important regulating mechanisms for the immune system. While antibodies directed against a tumor have a useful function for the patient with dissemination of metastasizing tumors, the anti-antibodies and antigenotypic antibodies represent a counterregulation which, in the advanced stage of the disease, eliminates the initial control.


[Multiple carcinomas (author's transl)]. Of the patients at the Chirurgische Universitätsklinik Würzburg, 29 were treated for multiple carcinomas in the period from 1970 to 1976. Reports in the literature confirm this relatively high figure. The generally greater life expectancy and increasing survival rate in treated first carcinomas suggest a further increase in this figure for the future. This possibility should therefore be borne in mind for every carcinoma patient, particularly since a second carcinoma has the same prognosis as the first and not the unfavorable prognosis of a metastasis or a recurrence.


[Treatment of cerebrovascular insufficiency. A double blind trial of Cetal retard against cinnarizine (author's transl)]. The results of a double blind trial in a total of 54 outpatients with cerebrovascular insufficiency are reported. With reference to objective test criteria (flicker frequency analysis and reaction test) and the change in the existing symptoms of this clinical picture the behavior of a new preparation, Cetal retard, was compared with the well-known drug (cinnarizine) with regard to the therapeutic efficacy on these symptoms. Although a therapeutic success was demonstrable in both groups after 21 days, Cetal retard was found to be significantly better in a number of the criteria tested.


[Early arteriosclerosis with increased thrombocyte aggregation (author's transl)]. The importance of thrombocyte function in atherogenesis is discussed in the light of experimental and clinical results. Adhesion and aggregation of thrombocytes on an intact or injured artery wall may be the first step to atherosclerotic plaque. In vitro measurements of aggregation, in vivo measurements of thrombocytic survival time and microscopic and histological examinations are all consistent in showing a rise in aggregation of thrombocytes in the early stages of arteriosclerosis. The measurement of thrombocyte function is therefore recommended in addition to the known risk factors in patients with a greater risk of arteriosclerosis.


[Embolization of the lung in echinococcosis (author's transl)]. Four months before her death of right heart failure, a 38-year-old woman with a known inoperable echinococcosis of the liver developed fever, increasing eosinophilia and pleuropneumonia. After improvement of the clinical, radiological and laboratory parameters under steroid medication, two months before her death hemoptysis and multifocal perfusion defects in the lung scintigram as a sign of pulmonary embolism occurred, for which heparin therapy was introduced. At autopsy a recurrent embolization due to echinococcus cysts with extensive displacement of the arterial pulmonary blood circulation were found.


[Monocytic leukemia. Analysis of clinical and hematological data in 21 patients (author's transl)]. A clinical hematological survey is given of 21 patients with monocytic leukemia. About 1/3 of all immature cell leukoses are monocytic leukemias; a classification of the acute leucoses by enzyme histochemical methods should be attempted. Since more than half of the patients exhibited subleukemic to aleukemic peripheral leukocyte levels, the histological findings of a sternal puncture are diagnostic pointers. The bone marrow picture of monocytic leukemia is characterized by a great preponderance of atypical cell elements of the monocyte series which give a distinctly positive reaction in the non-specific esterase test. The combined use of cytostatics producing remission brought marked improvement in half the patients. Remission lasted from 2 to 8 weeks.


[Ascending tetraplegia after embolic occlusion of medullary arteries by nucleus pulposus tissue (author's transl)]. A 19 year old woman developed an acute ascending tetraplegia, for which no reason could be found. 9 months later the patient died from a septicemia starting from a decubitus. Postmortem examination showed an occlusion of a medullary artery by emboli of nucleus pulposus tissue. A survey is given of similar cases reported in the literature and the cause of the embolism discussed. It seems most probable that invasion of the misshapen vessel by tissue from a pathological nucleus pulposus was responsible.


[Complication with contrast medium in endoscopic retrograde cholangiopancreaticography (author's transl)]. After more than 2000 endoscopic retrograde cholangiopancreaticographies (ERCP) without contrast medium allergy, a case of severe allergic shock induced by contrast medium injected into the pancreatic duct is reported. The indication for ERCP in patients with known allergy to contrast media must therefore be restricted to those cases in which other examination procedures have given no useful results and yet diagnostic evaluation is vital to the interests of the patient.


[New sulfonamide-trimethoprim combination, Supristol. Results of a joint therapeutic trial (author's transl)]. The efficacy of a new low dosage trimethoprim-sulfamoxole combination (Supristol) was tested in a joint therapeutic study in 6 medical clinics or departments and in a general practice. A good therapeutic result (healing) was achieved in about 80% of the 143 patients included in the trial. The preparation was well tolerated. Symptoms of intolerance appeared in only 2% of the cases. It is assumed that the low dosage of the preparation influences the tolerance favorably without affecting the efficacy.


[Echographic diagnosis of the pancreas. Catamnesis of 481 cases (author's transl)]. In order to assess the efficiency of ultrasonic diagnosis of the pancreas, echographic findings in 481 patients were compared with the final diagnosis in the case sheets. Agreement between the echographic results and the final diagnosis was found in 94.6% with normal findings, in 77% of patients with pancreatic carcinoma and in 85% of patients with chronic pancreatitis. Altogether we have found agreement between the echographic results and the final diagnosis in 86.6% of all cases referred for diagnosis of the pancreas. The results correspond to the fiqures given by Rettenmaier. With adequate experience ultrasonic diagnosis should therefore be used as early as possible with a broad indication for all diseases of the pancreas.


[Diagnostic value of thoracic and abdominal x-ray in acute pancreatitis (author's transl)]. Chest and abdominal films were retrospectively examined in 100 patients with acute pancreatitis excluding cases with pancreatitis concomitant to other diseases. Most frequently we found gastric and duodenal distension, diffuse distension of small bowel loops, localized meteorism of transverse colon as well as left flexure and diffuse colonic distension. The chest-films showed: elevated diaphragm and pleural effusion on the left, pneumonitis, pleuritis and and basal platelike atelectases. Pathologic radiological signs were absent in only 1% of the cases.


[Growth hormone determination in a combined adenohypophyseal stimulation test (author's transl)]. The authors sought the simplest but still reliable method for evaluation of the functional reserve of the anterior lobe of the pituitary gland. The proposed test is stimulation of those various functions by injection of insulin, gonadotropin releasing hormone (LH-RH = GnRH) and thyrotropin releasing hormone (TRH). The test fulfils the clinical requirements. Furthermore it forms a valuable first step for the classification of more scientific problems.


["No-touch" measurement of skin temperature in cerebral ischemia and lesions of the sympathetic trunk. Clinical and technical testing of a new infrared apparatus for measuring skin temperature (Ultrakust Thermophil M 202) (author's transl)]. The clinical test was carried out in extracranial carotid occlusions and acute peripheral paralysis with sympathetic lesions. The measurements obtained were compared with those of the infrared thermovision. Both in the technical and in the clinical tests, the device proved to be very suitable. The practical procedure of temperature measurement (cerebral ischemia and lesions of the sympathetic trunk) is described.


[The clinical value of an oral test of pancreatic function with fluorescein dilaurate (author's transl)]. Exocrine insufficiency of the pancreas was identified by decreased splitting of the ester substrate and thus diminished excretion of fluorescein in the urine of persons with normal pancreatic function (test excretion). Unesterified fluorescein served to ascertain the standard excretion of fluorescein (= 100%). The relation of test excretion to standard excretion was expressed in %. Values of less than 20% in collected urine are pathologic. The range of 20-30% is questionable. Normal persons showed 30% or more. The method described is simple and without problems for the patient. The test was accurate in 93% of patients with a false negative in 1%. Practicability and results recommend the test as a screening method.


[Human larva migrans visceralis infections with toxocara in the German Federal Republic. Serological investigations (author's transl)]. The microprecipitation test on second generation larvae of Toxocara canis has proved to be highly specific for the diagnosis of human larva migrans visceralis infection caused by Toxocara species. Out of a total of 2864 samples examined from 1969 to 1976, 248 were found to be positive. Besides a very frequently occurring eosinophilia eye affections, lung changes and involvement of the CNS are prominent clinical symptoms. The investigations show that larva migrans visceralis infections also occur in West Germany, even if more rarely than in other countries. The diagnosis is only seldom made because of the lack of uniformity of the clinical symptomatology.


Successful chemoprophylaxis for Pneumocystis carinii pneumonitis. In a randomized, double-blind, placebocontrolled study to evaluate the efficacy of trimethoprim-sulfamethoxazole for the prevention of Pneumocystis carinii pneumonia, we studied 160 patients with cancer who were at high risk for this pneumonia over a two-year period. Seventeen of the 80 patients receiving a placebo acquired P. carinii pneumonitis, whereas none of the 80 given 150 mg of trimethoprim and 750 mg of sulfamethoxazole per square meter per day had the infection P less than 0.01). Bacterial sepsis, pneumonia other than that caused by P. carinii, acute otitis media, upper-respiratory-tract infections, sinusitis and cellulitis occurred less frequently in recipients of the drug than in the placebo group (P less than 0.01 in each case). Oral candidiasis was the only adverse effect ecountered from trimethoprim-sulfamethoxazole administration. The study shows the combination to be highly effective in the prevention of P. carinii pneumonitis.


[Evidence of the haptenic nature of peptidomannans from two yeasts: Saccharomyces oviformis and Candida mycoderma]. Following the observation that it is not possible to immunize rabbits against peptidomannans, extracted from Saccharomyces oviformis and Candida mycoderma, these glycopeptides have been coupled to bovine serum albumine in order to make them immunogenic. Two methods have been used for the coupling: the cyanogen bromide method and the carbodiimide method. Rabbits have been injected intravenously with these conjugates. Using different serologic technics: agglutination, immunodiffusion, counterimmunoelectrophoresis, immunoelectrophoresis we have shown that only peptidomannan-SAB conjugates prepared by the cyanogen bromide method are immunogenic.


Evidence for the parasexual cycle in a strain of Aspergillus flavus containing virus-like particles. Eight isolates of A. flavus and A. parasiticus were screened for the presence of virus-like-particles (VLP). Only A. flavus strain NRRL 5565 contained detectable VLP. Spore color and auxotrophic mutants were induced in this strain and evidence for the parasexual cycle was obtained. Attempts to form heterokaryons between 3 auxotrophs of the VLP-containing strain and 9 auxotrophs from two different aflatoxigenic strains were unsuccessful.


Purification of a positive regulatory subunit from phage SP01-modified RNA polymerase. A phage-induced subunit has been purified from phage SP01-modified Bacillus subtilis RNA polymerase. This subunit binds in vitro to RNA polymerase core from uninfected B. subtilis thereby template-selective transcription and asymmetric synthesis of SP01 middle RNA.


Endogenous inhibitor of prostaglandin synthetase. Mammalian serum and plasma contain an endogenous inhibitor of prostaglandin synthetase (EIPS). Human plasma fractions rich in EIPS show anti-inflammatory activity in vivo. In rats, glucocorticoids raise EIPS activity of plasma and serum. These findings suggest the existence of a natural mechanism of controlling prostaglandin synthesis, possibly related to corticosteroid action.


[Participation of hypothalamic formations in regulation of the neuronal activity of rabbit visual cortex]. Electric stimulation of different hypothalamic nuclei was used during the effect of extracellular polarizing current on neurons of the rabbit optic cortex. It was found that stimulation of the hypothalamus caused a decrease in the medium rate of impulsation of a great number of studied optic cortex neurons under conditions of anodic polarization when the background level of activity was considerably enhanced. The same stimulation increased the activity under conditions of cathodic polarization when the initial level of the activity was considerably lowered. The same tendency to restore the initial (background) level of the neuronal activity after hypothalamic stimulation was observed under conditions when this level was shifted by application of rhythmic light. The greatest effect was observed during stimulation of the preoptic region. Stimulation of the posterior hypothalamic nucleus was less effective in this respect.


Complex of IgA1-lambda paraprotein and albumin. The complex of IgA1-lambda paraprotein and albumin was analysed and its pattern was demonstrated in electrophoresis, immunoelectrophoresis, gel filtration and sedimentation analysis.


Effects of antiepileptic drugs on thalamocortical excitability. Comparative effects of anticonvulsant drugs on the thalamocortical system were analyzed quantitatively. Paired stimuli were delivered to the ventrolateral thalamus with evoked responses recorded from the ipsilateral sensorimotor cortex in the cat. Threshold and excitability profiles were developed with an on-line computer. Effects of phenytoin and diazepam were generally similar, with depression of excitability and slight elevation of thresholds. Ethosuximide produced a pronounced pair-interval dependent effect of unchanged or increased excitability and lowered threshold at shorter intervals, with depressed excitability and raised threshold at longer intervals. These data demonstrate a marked difference in effect of the petit mal and grand mal agents tested and suggest a basis for the effectiveness of ethosuximide in controlling 3-per-second repetitive activity.


Anterograde transneuronal degeneration in the limbic system: clinical-anatomic correlation. A 64-year-old man with diffuse atherosclerosis developed an organic mental syndrome, followed by hypothalamic symptoms. Autopsy showed an old large cystic infarct involving the left temporal lobe including the hippocampus, and atrophy of the ipsilateral fornix, mammillary body, hypothalamus, mammillothalamic tract, and the anterior thalamic nucleus. The clinical deterioration and pathologic findings may be explained by anterograde transneuronal degeneration within the limbic system following the infarction.


Adenocarcinoma of the fallopian tube. Experience with 41 patients. Forty-one cases of primary fallopian tube carcinoma treated at our institution over the years 1946 to 1976 are described. The overall 5-year survival rate was 34.4%, although patients with early tumors had a 72.7% survival rate. The single most important factor affecting survival appeared to be the extent of disease at the time of diagnosis. Past and present treatment modalities are discussed, and proposals for management of this disease are outlined.


Subclinical infection with mycobacteria in southern Iran. In 50 non-tuberculous adult patients hospitalized in the Pahlavi University Medical Center skin testing with 5 tuberculin units of purified protein derivative of mammalian Mycobacterium tuberculosis (PPD-M) and equivalent amounts of antigen from Mycobacterium kansasii (PPD-Y) and Mycobacterium Gause (PPD-G), as well as 0.1 ml mumps antigen was carried out. Thirty four per cent, 26 per cent and 12 per cent of the patients had induration greater than 10 mm in diameter to PPD-M, PPD-Y and PPD-G respectively. However, only 28 per cent, 8 per cent and 2 per cent had induration to the above antigens which was greater than 10 mm in diameter and in which the induration was greater than that produced by the other mycobacterial antigens tested. Thirty per cent of the patients had positive reactions to mumps antigen. The results indicate that subclinical infection with Mycobacterium tuberculosis is relatively common, that infection with atypical mycobacteria may occur and that the incidence of mumps skin reactivity is low in this part of the world.


A two-dimensional thin layer chromatographic procedure for the sequential analysis of oligonucleotides employing tritium post-labeling. Two dimensional PEI-cellulose thin layer chromatography can resolve sequentially degraded oligonucleotide fragments of tRNA. This technique entails the sequential degradation of the oligonucleotide with snake venom phosphodiesterase in the presence of bacterial alkaline phosphatase, and periodate oxidation followed by tritiated sodium borohydride reduction of the 3' terminal nucleoside. Subsequently the tritiated oligonucleotide fragments were resolved by two dimensional PEI-cellulose TLC. The results of these experiments indicate that, in some cases, the complete nucleotide sequence of a large oligonucleotide fragment may be determined by interpretation of the observed mobility shifts, thereby eliminiating the need for additional analysis of the oligonucleotide. In addition, the use of two-dimensional rather than one-dimensional resolution of the tritium labeled fragments allows for a complete separation of any interfering background spots from the sequentially degraded oligonucleotides. This procedure was applied to the complete nucleotide sequence analysis of several ribonuclease T1Val and ribonuclease A digestion products from human placenta tRNA.


Sequence of the 3'-terminal 21 nucleotides of yeast 17S ribosomal RNA. The sequence of the 3'-terminal 21 nucleotides of 17S ribosomal RNA from the yeast Saccharomyces carlsbergensis has been determined to be (Y)G-m62A-m62A-C-U-C-G-C-G-G-A-A-G-G-A-U-C-A-U-U-AOH. This sequence shows extensive homology with the 3'-terminal sequence of 16S rRNA from Escherichia coli including the presence of the two adjacent N6-,N6-dimethyladenosines observed in the small subunit rRNA of eukaryotes as well as of many prokaryotes.


Diagnosis of Chagas' cardiomyopathy. Non-invasive techniques. The natural history of Chagas' disease and its manifestations when the heart is involved are detailed clinically and pathologically. Three phases are recognized: the acute phase, lasting from 1-3 months, the latent phase, which may last from 10-20 years, and the chronic phase, which has the most serious manifestations. This phase is subdivided into three clinical stages. An analysis of the varied cardiac manifestations on 235 patients is included.


Echocardiographic diagnosis and evaluation of cardiomyopathies: idiopathic hypertrophic subaortic stenosis, Chagas' heart disease and endomyocardial fibrosis. Echocardiographic investigations on patients with hypertrophic cardiomyopathy with obstruction have been detailed and compared with the changes found in sixty patients with chronic Chagas' 'cardiomyopathy'. These changes are similar to those encountered in congestive cardiomyopathy. Endomyocardial fibrosis is rare in Venezuela, but six patients have been found in that country and the echocardiographic changes in one of these patients has been included in this study.


[Testosterone secretion and the gonadotropic function of the pituitary gland under condition of limited food intake]. Experimental data on testosterone secretion and gonadotropic function of the hypophysis and their changes under conditions of a limited nutritional ration are presented. Experimental rabbits proved to display a sharp fall of testosterone in the blood flowing from the testes and a rise of gonadotropic hormones in the hypophysis. The mentioned fact should be taken into consideration when the nutritional ration is diminished for experimental purpose or under clinical conditions on certain indications connected with the necessity of decreasing the caloric value and the quantity of food consumption.


Nonspecific DNA binding of genome-regulating proteins as a biological control mechanism: measurement of DNA-bound Escherichia coli lac repressor in vivo. Binding of genome regulatory proteins to nonspecific DNA sites may play an important role in controlling the thermodynamics and kinetics of the interactions of these proteins with their specific target DNA sequences. An estimate of the fraction of Escherichia coli lac repressor molecules bound in vivo to the operator region and to nonoperator sites on the E. coli chromosome is derived by measurement of the distribution of repressor between a minicell-producing E. coli strain (P678-54) and the DNA-free minicells derived therefrom. Assuming the minicell cytoplasm to be representative of that of the parent E. coli cells, we find that less than 10% of the repressor tetramers of the average cell are free in solution; the remainder are presumed to be bound to the bacterial chromosome. The minimum in vivo value of the association constant for repressor to bulk nonoperator DNA (K(RD)) calculated from these results is about 10(3) M(-1), and analysis of the sources of error in the minicell experiment suggests that the actual in vivo value of K(RD) could be substantially greater. The value of K(RD), coupled with in vitro data on the ionic strength dependence of this parameter, can be used to estimate that the effective intracellular cation activity of E. coli is no greater than about 0.24 M (and probably no less than 0.17 M) in terms of sodium ion equivalents. The minicell distribution experiments also confirm that the association constant for the binding of inducer-repressor complex to bulk nonoperator DNA (K(RID)) is [unk] K(RD)in vivo. These results are used to calculate minimum in vivo values of K(RO) and K(RIO) (association constants for repressor and for inducer-repressor complex binding to operator) of about 10(12) M(-1) and about 10(9) M(-1), respectively. The results fit a quantitative model for operon regulation in which nonspecific DNA-repressor complexes play a key role in determining basal and constitutive levels of gene expression [von Hippel, P. H., Revzin, A., Gross, C. A. & Wang, A. C. (1974) Proc. Natl. Acad. Sci. USA 71, 4808-4812].


[Paths of corticosteroid biosynthesis in the adrenal glands of rhesus monkeys]. In experiments in vitro corticosteroid formation from radioactive cholesterol in tha adrenal glands of monkeys (Macaca rhesus) was studied. A conclusion was drawn that pregnenolone and its hydroxy-derivatives were of the leading significance in the cortizol and corticosterone synthesis in the adrenal glands of monkeys. Progesteron was produced in insignificant amounts and was almost unutilized for steroidogenesis. The formation of 17.21-dioxypregnenolone was revealed; its role in the capacity of cortizol precursor was proved; 17-oryprogesteron was found to be of no great significance in cortizol synthesis; 21-oxypregnenolone, but not progesteron proved to serve as the principal intermediate product in corticosterone formation.


Sequences homologous to ribosomal insertions occur in the Drosophila genome outside the nucleolus organizer. Many repeating units of Drosophila melanogaster rDNA contain a DNA sequence within the gene for 28S rRNA that does not code for rRNA. This sequence has been called the ribosomal insertion [Wellauer, P. K. & Dawid, I. B. (1977) Cell 10, 193-212]. We report here that members of the same sequence family occur outside the ribosomal locus. "Non-rDNA insertion DNA" was separated from rDNA by density gradient centrifugation, and sequences homologous to the ribosomal insertion were detected by hybridization with restriction endonuclease fragments derived from a cloned rDNA repeating unit. Pure insertion sequences from cloned rDNA separated from main band DNA and behaved like a component with high G + C content. Non-rDNA components hybridizing to the insertion also separated from main band DNA but less so than pure insertion sequences, suggesting that non-rDNA insertion sequences are linked to DNA of different nucleotide composition. Restriction endonuclease analysis of non-rDNA insertion DNA showed many fragments of different sizes. The patterns obtained were similar in embryonic, larval, pupal, and adult DNA and DNA from cultured cells (Schneider cell line 3). Non-rDNA insertion sequences account for about 0.2% of the genome or about 400 kbases of DNA per haploid complement.


Gene-sized DNA molecules of the Oxytricha macronucleus have the same terminal sequence. The DNA in the macronucleus of the ciliated protozoan Oxytricha exists as small linear molecules with a number average size of about 3000 base pairs. Most, and possibly all, of these DNA molecules contain the same inverted terminal repeat sequence of approximately 26 base pairs. In addition to its terminal location, two inverted copies of this same sequence surround single-strand interruptions within these DNA molecules. This sequence arrangement may function in the processing of these molecules from large chromosomal precursors or in the subsequent replication of these small linear DNAs during cell reproduction.


Genetics of the connective tissue proteins: assignment of the gene for human type I procollagen to chromosome 17 by analysis of cell hybrids and microcell hybrids. Somatic cell hybrids between mouse and human cell lines have been used to identify the specific chromosome that governs the synthesis of type I procollagen. Fourteen hybrid clones and subclones were derived independently from crosses between mouse parents [LM (thymidine kinase-negative) or A9 (hypoxanthine phosphoribosyltransferase-negative)] and human cells (human diploid lung fibroblasts WI-38 or diploid skin fibroblasts GM5, GM17, and GM9). The cultures were labeled with [(3)H]proline in modified Eagle's medium without serum. Radioactive procollagens were purified from the medium by the method of Church et al. [(1974) J. Mol. Biol. 86, 785-799]. DEAE-cellulose chromatography was used to separate collagen and type I and type III procollagen. Human type I procollagen was assayed by double immunodiffusion analysis with type I procollagen antibodies prepared by immunizing rabbits with purified human type I procollagen. These analyses combined with karyology and isozyme analyses of each hybrid line have produced evidence for the assignment of the gene for human type I procollagen to chromosome 17. A human microcell-mouse hybrid cell line containing only human chromosome 17 was positive for human type I procollagen, lending further support to the assignment of the human type I procollagen gene to chromosome 17. Finally, by using a hybrid line containing only the long arm of human chromosome 17 translocated onto a mouse chromosome, the type I procollagen gene can be assigned more specifically to the long arm of chromosome 17.


Myosin types during the development of embryonic chicken fast and slow muscles. We have studied the myosin types present in developing fast and slow muscles of the chicken embryo. Myosin light chains were characterized by their mobility on sodium dodecyl sulfate/polyacrylamide gels; myosin heavy chains were identified by their reaction with antibodies specific for adult fast or adult slow myosin heavy chains. During development, the pectoralis muscle, a fast muscle in the adult, contains heavy chains and two of the three light chains characteristic of adult fast muscle myosin. However, the anterior latissimus dorsi muscle, a slow muscle in the adult, also contains fast myosin light and heavy chains during early development. Only after the time of innervation does this muscle begin synthesizing predominantly the slow myosin heavy and light chains. We hypothesize that the synthesis of fast myosin in both early fast and slow muscles is the result of the endogenous program for muscle development; initiation of the synthesis of slow myosin, however, is dependent upon exogenous factors.


Adaptive response due to changes in gene regulation: a study with Drosophila. In spite of the critical role of the process of adaptation in evolution, there are few detailed studies of the genotypic and molecular basis of the process. Drosophila melanogaster flies selected for increased tolerance to ethanol exhibited higher levels of alcohol dehydrogenase (alcohol:NAD+ oxidoreductase; EC 1.1.1.1) activity than unselected controls. A series of tests (electrophoresis, product inhibition, temperature stability, pH optima, substrate specificity, and Michaelis constants) gave no evidence of structural differences in the enzyme of the selected and the control flies. However, quantitative immunological assays showed that the selected flies contained significantly higher amounts of alcohol dehydrogenase. Adaptation of the selected flies to higher alcohol tolerance has most likely taken place by changes not in the structural gene locus coding for the enzyme, but by regulatory changes affecting the amount of gene product.