The permeability of the skin of a neotenous urodele amphibian, the mudpuppy Necturus maculosus. 1. The permeability of the isolated skin of a neotenous urodele amphibian, the mudpuppy Necturus maculosus, to Na, Cl, urea and water was measured. 2. Unidirectional transcutaneous flux measurements and the action of ouabain and amiloride, showed that there was normally no active Cl or Na transport, nor a Cl/Cl exchange diffusion process. 3. Amphotericin B initiated a transcutaneous potential difference and short-circuit current, which could be inhibited by ouabain. 4. The short-circuit current was nearly equivalent to the net Na Transport and this was also inhibited by ouabain. 5. A transcutaneous active Na transport mechanism thus appears to be incipient in the mudpuppy but is limited by a low permeability of the outer barrier of the cells. 6. Vasotocin increased the skin's diffusion permeability for water but had no effect on the influx of Na or urea. 7. The function of Necturus skin is in several respects unique compared to that of other amphibians.


Inhibition of the intracellular release of calcium by Dantrolene in barnacle giant muscle fibres. 1. Ca movements in resting and in activated single giant muscle fibres of the barnacle were analysed before and after exposure to Dantrolene Na, a synthetic hydantoin derivative. 2. In fibres micro-injected with the photoprotein aequorin, the resting rate of light emission (resting glow) reversibly decreased upon exposure to Dantrolene. Similar results were obtained if the fibre had first been equilibrated in a O Ca-1 mM-EGTA medium. 3. The influx of 45Ca into resting muscle fibres was not modified by 35 micronM Dantrolene which also failed to significantly reduce the influx of 45Ca into muscle fibres which had been depolarized by exposure to external solutions in which K+ had been increased to 60 or 200 mM. 4. In fibres micro-injected with 45Ca, the calcium efflux was reversibly decreased by Dantrolene. This effect was still observed in O Ca medium and in O Ca-ONa medium. A possible effect of Dantrolene on the Na-Ca exchange process at the outer membrane was excluded by showing that when the direction of the Ca2+ movement was inverted in aequorin-loaded fibres by the sudden removal of Na+ from the external medium, a marked increase in the resting glow was recorded which was not affected by exposure to Dantrolene. 5. It is argued that the reduction of Ca2+ efflux by Dantrolene does not result from any direct inhibitory effect on the metabolically driven Ca pump at the outer membrane, but that it is rather related to the reduction of the concentration of myoplasmic Ca2+ which is indeed demonstrated by the reduced resting glow. This in turn is thought to result from a shift in the balance between Ca2+ movements into and out of the intracellular storage sites, and namely the sarcoplasmic reticulum (SR). 6. The Ca2+ transient in aequorin-loaded fibres and the force of the isometric contraction elicited by imposed membrane depolarizations were markedly reduced by Dantrolene. The electrochemical threshold for eliciting intracellular Ca2+ release was not significantly modified. The linear relation between membrane depolarization and Ca2+ transient became less steep. The process of sequestration of myoplasmic Ca2+ back into SR was not significantly affected by Dantrolene which appeared to inhibit rather selectively the Ca2+ release from SR into the cytosol.


Plasma concentrations of ethynyl oestradiol and norethindrone after oral administration to women. Plasma concentrations of ethynyl oestradiol and norethindrone in women were measured by radioimmunoassays after oral administration of 50 microng and 1000 microng respectively. The maximum values were obtained 1 h after administration. The calculated half-life was 6 1/2 h for ethynyl oestradiol and 7 h for norethindrone. At most 2-3% of the administered dose was present in the plasma at 1 h and had decreased to about 0-5% by 24 h.


Adrenergic activity of the oviduct of the domestic fowl. The adrenergic activity of the domestic hen was investigated. Administration of noradrenaline to laying hens at dose levels of 3-5, 7-0, and 14-0 microng/kg produced an increase in the magnal pressure, and a simultaneous decrease in the uterine pressure. Similar doses given to ovariectomized hens caused an inhibition of activity in both segments. Strips of tissues from the vagina and the uterovaginal junction of laying hens were exposed in vitro to noradrenaline at concentrations of 1-5 x 10(-6) and 2.9 x 10(-6) M. The vaginal strips reacted with a sharp increase in tension, while the uterovaginal preparations showed a more gradual and prolonged response. It is suggested that the beta inhibitory activity of the uterus and the alpha excitatory activity of the rest of the oviduct are involved in the regulation of ovum transport.


Serum corticosterone concentrations in reproductively mature and inhibited deermice (Peromyscus maniculatus bairdii). Serum corticosterone concentrations were measured to see if there was any correlation between adrenal activity and reproductive inhibition. Males and females from two growing and one stable (asymptotic) population had significantly smaller reproductive organs (seminal vesicles, testes, uteri, ovaries) than controls. The weights of the adrenal glands of population mice were smaller, often significantly so, than those of controls, but the mean serum corticosterone concentrations were higher than those of control mice for the two growing populations and significantly higher for the asymptotic population. These data suggest that adrenal function may be associated with the reproductively inhibited condition, but not in a direct or dose-response fashion and that adrenal hyperfunction in this species may not be reflected by adrenal hypertrophy.


Accumulation of steroids in rabbit preimplantation blastocysts. The concentrations of progesterone, androstenedione, testosterone, oestrone and oestradiol were measured by radioimmunoassay in blastocysts and uterine fluid flushings collected from rabbits 110 to 159 h post coitum (p.c.). None of the blastocysts or uterine flushings contained detectable levels of androstenedione, testosterone or oestrone. All uterine flushings contained large amounts of progesterone and some of the flushings also contained oestradiol. A small amount of progesterone (approximately 7-5 pg/blastocyst) was first detectable in some blastocysts at 135 h p.c.; progesterone levels/blastocyst then increased progressively, reaching levels of about 122-158 pg/blastocyst at 159 h p.c. Micropuncture of blastocysts at 159 h p.c. indicated that greater than or equal to 90% of the progesterone in the embryo was in the blastocoelic fluid. Blastocysts from rabbit uterine horns containing oestradiol also contained oestradiol but those in which oestradiol was detected were never observed in uteri lacking the hormone. It is inferred that rabbit blastocysts accumulate both progesterone and oestradiol from uterine fluid.


The effect of RMI 12, 936 synthetic antiprogestional steroid, on ovarian steroidogenesis in the rat. A series of physiochemical investigations confirmed that the product of chemical and enzymatic isomerization of RMI 12,936 was 7alpha-methyltestosterone. The total activity per pair of ovaries of delta5 3-ketosteroid isomerase in vitro was unchanges by RMI 12,936 pretreatment or by advancing pregnancy, significant changes in ovarian weight being accompanied by reciprocal changes in enzyme activity/mg tissue. The initial rate of isomerization of RMI 12,936 was approximately five times greater than the corresponding rate of delta5-progesterone isomerization at equal substrate concentrations. It is concluded that RMI 12,936 does not inhibit progesterone biosynthesis by alteration of delta5 3-ketosteroid isomerase activity, but that it may do so by acting as an alternative substrate for this enzyme.


Some effects of cyproterone and cyproterone acetate on the reproductive physiology of the male rat. Male rats were treated with 5 or 20 mg cyproterone acetate/kg/day or 20 mg cyproterone/rat/day for 1, 2, 3, 4, or 5 weeks. There was some reduction in fertility with both compounds, the maximum effect occurring after 5 weeks with the higher dose of cyproterone acetate and after 2 weeks with cyproterone. A significant increase in testosterone levels was found after treatment with the high dose of cyproterone acetate by 1 week and with cyproterone by 2 weeks. Dose-dependent atrophy of the seminal vesicles occurred after treatment with cyproterone acetate; with cyproterone atrophy occurred at 1 and 2 weeks but approximated to control values at 3, 4 and 5 weeks. Epididymal weights were reduced with the high dose of cyproterone acetate but the low dose had little effect. Reduction in the weight of the testes was only observed after 5 weeks of treatment with the high dose of cyproterone acetate. Since plasma testosterone levels were not depressed below normal values, accessory sex organ regression evidently resulted from the local antiandrogenic action of the drugs. There was some indication of interference with the secretory and absorptive activity of the lining cells of the epididymis but in general treatment with either steroid caused only relatively small and variable changes in the composition of epididymal plasma.


Characteristics of semen collected from the cauda epididymis of conscious rams. A technique which permits collection of the total output of spermatozoa and fluid from the cauda epididymidis of conscious rams is described. The volume of epididymal semen collected varied in an approximately inverse proportions with the frequency of collection, but there was little variation in the concentration of spermatozoa. Chemical analyses showed that cell-free cauda epididymidis fluid contained lactic acid at various concentrations, only traces of glucose but relatively high amounts of phospholipid, pregenenolone, androgen-binding protein and 5alpha-dihydrotestosterone (5alpha-DHT). Testicular spermatozoa maintained their metabolic activity and cellular integrity when stored in cauda epididymidis fluid in vitro at low temperature. After exposure to cauda epididymidis fluid for 14 days, testicular spermatozoa were predominantly glycolytic in their mode of glucose dissimilation and in this respect they resembled ejaculated spermatozoa.


Activity of 3beta-hydroxyteroid dehydrogenase in the postovulatory follicle of the domestic fowl (Gallus domesticus). The activity of delta5-3beta-hydroxysteroid dehydrogenase (3beta-HSD) in the postovulatory follicle (POF) of the domestic hen was studied; it declined rapidly during the first 15 h after ovulation and then fell gradually until 52 h when there was no detectable activity. Comparison of 3beta-HSD and glucose 6-phosphate dehydrogenase activities in the theca and granulosa cells indicated that the changes in enzymatic activity can be attributed to the thecal component; the enzyme activity in granulosa cells was stable up to 35 h after ovulation. The results appear consistent with the hypothesis that the POF is a source of steroid hormones.


The production of chorionic somatomammotrophin in sheep. The production of ovine chorionic somatomammotrophin (OCS) was demonstrated in the trophoblast from Days 16-17 of pregnancy. Concentrations in the placenta rose slowly until about Day 100 when there was a rapid increase to reach 70 +/- 5 microng prolactin equivalent/g fresh placental tissue and 15 +/- 2 mg/placenta on Day 120. After Day 140, the concentrations decreased. It is suggested that OCS may be luteotrophic and have an effect on fetal growth.


The influence of season of lambing and lactation on reproductive activity and plasma LH concentrations in Merino ewes. Groups of Merino ewes which were lactating for 40 days (Group I) or had had their lambs removed at birth (Group II) after lambing in the winter (June) or spring (November) were fed on a high plane of nutrition. Ovarian inspections were carried out at 15 and 30 days after lambing and plasma LH levels were measured at 6-h intervals for 20-30 days. First ovulation was earlier in ewes lambing in the winter (16-6 days, range 11-26) than in the spring (24-7 days, range 15-30) but there was no difference in the number of ewes ovulating. LH levels were higher in winter-lambing ewes (2-79 +/- 3-4 ng/ml) than in those lambing in the spring (1-78 +/- 0-23 ng/ml). LH peaks were usually associated with an ovulation in spring lambing ewes but were not consistently so in the others. More ewes ovulated in Group II (72%) than in Group I (40%) but the mean time of first ovulation was similar. In the winter-lambing ewes the mean daily LH concentration was 2-40 +/- 0-32 ng/ml in Group I and 3-18 +/- 0-31 ng/ml in Group II but there were no differences between the spring-lambing ewes, (I, 1-75 +/- 0-20 ng/ml; II, 1-80 +/- 0-26 ng/ml). There were more elevations in LH levels in Group II ewes (64%) than in Group I ewes (43-8%). After lambing the LH levels increased slowly, indicating a gradual recovery of pituitary function.


Functional maturation of the epididymis in the rat. Weight, histological and biochemical changes in the rat epididymis were investigated during prepubertal, pubertal and postpubertal periods. The phase of most rapid growth of the epididymis commenced at 21 days and extended to 60 days of age; this period corresponded closely to the onset of androgen production at 3 weeks and stabilization of the leydig cell number at 60 days. Histological differentiation in the caput epididymis started before sperm entry and was complete in the cauda only several days after the spermatozoa had appeared. The presence of appreciable quantities of glycerophosphorylcholine (GPC) and sialic acid in the epididymis of 21-day-old rats suggested inherent secretory ability of the epididymal epithelium. The concentrations of GPC, sialic acid, phospholipids and glycogen in the epididymis gradually increased with age, but each came under the influence of androgen at a different age. There was no evidence to suggest that the presence of spermatozoa has a stimulatory effect on the epididymis. Maximal secretory activity of the epididymis became established only by 90 days of age.


Histological changes in the cervix of the rabbit after coitus. The histology of the rabbit ectocervix was investigated by light, transmission and scanning electron microscopy before and after insemination. The cervix became oedematous and heterophil polymorphs invaded the portio vaginalis within 30 min of mating or artificial insemination of whole semen, but not after insemination with sperm-free seminal plasma or mating with a vasectomized buck.


Plasma concentration of LH and testosterone in castrated rams treated with testosterone or testosterone propionate. After injection of castrated rams with 600 mg testosterone or testosterone propionate, plasma LH levels were biphasic, with significant decreases at 6-10 and 96 h after treatment. These results support the suggestion that testosterone acts at the hypothalamo-pituitary level by two different mechanisms.


Response of the Mongolian gerbil uterus to oestradiol-17beta at various times after ovariectomy. Treatment of ovariectomized gerbils with 2 microng oestradiol-17beta/day for 3 days resulted in decreasing alkaline phosphatase activity in the uterus at 15 days, 30 days 3 months and 18 months. Relative uterine weight decreased at 3 months but increased at 18 months.


The constant ratio of the zinc content of boar spermatozoa of 4 degrees C and room temperature. The ratio of the zinc content of boar spermatozoa obtained from semen cooled to 4 degrees C for 30 min to that of the original room temperature control (20-26 degrees C) was constant at 2-28 +/- 0-16 in 22 samples of fresh whole semen from 12 animals. The same ratio occurred when zinc (0 to 0.6 mM in citrate buffer) was added to semen or washed spermatozoa. The increase is dependent only on the initial sperm zinc content at room temperature.


Degradation of phagocytosed spermatozoa by mouse peritoneal macrophages in vitro. Mouse peritoneal macrophages were cultured in vitro in the presence of autologous spermatozoa. The spermatozoa were found to be phagocytosed and degraded, with accumulation of pigment in the cytoplasm, during the first 5 days.


A statistical-heuristic methods for automated selection of drugs for screening. A statistical-heuristic method for selecting drugs for animal screening is developed with molecular structure features as predictors of biological activity. The method is intended to work on large amounts of data over varied structures. A trial of this method on a small data set allows some comparison with more sophisticated pattern recognition methods. Problems connected with interdependence among structure predictors are critical in this method and schemes to eliminate redundancy are reviewed. Alternate sets of structure predictors are considered. The discussion here outlines directions to be taken in the near future.


Combined high oxytocic with negligible antidiuretic and pressor activities in multisubstituted oxytocins. Oxytocin analogues which combine high oxytocic activities with negligible antidiuretic and pressor activities have been studied. [4-Threonine,7-glycine]oxytocin, [1-(L-2-hydroxy-3-mercaptopropionic acid),4-threonine,7-glycine]oxytocin, and [1-(L-2-hydroxy-3-mercaptopropionic acid)]oxytocin were found to possess the following specific biological activities respectively: rat uterotonic, 270 +/- 10, 337 +/- 23, 1542 +/- 0.4; rat antidiuretic, 0.002 +/- 0.0008, 0.048 +/- 0.005, 40.3 +/- 2.4. The results are analyzed from a conformation-activity viewpoint in a continued attempt to evaluate the scope and limitations of this approach in comparison to structure-activity studies.


Pharmacological effects of introducing a double bond into a binding site of oxytocin. Analogues with L-3,4-dehydroproline in position 7. The side chain of the proline residue in position 7 of oxytocin has been proposed as a binding site of the hormone for the uterotonic receptor. This is the first in a series of studies in which the possibility is explored that amino acid residues located at such sites and bearing unsaturated side chains may contribute more strongly to binding than neutral, aliphatic side chains. To test this hypothesis [7-(L-3,4-dehydroproline)]oxytocin, [1-beta-mecaptopropionic acid,7-(L-3,4-dehydroproline)]oxytocin, and [1-L-alpha-hydroxy-beta-mercaptopropionic acid,7-(L-3,4-dehydroproline)]oxytocin were prepared by the solid-phase technique of peptide synthesis. Some of the pharmacological properties of the analogues were determined, and the following specific activities, respectively, were found: rat uterotinic, 1071 +/- 59, 1066 +/- 95, 880 +/- 180; avian vasodepressor, 548 +/- 10, 1008 +/- 42, 1295 +/- 62; rat antidiuretic 5.9 +/- 0.2, 23.3 +/- 1.1, 76.7 +/- 2.3. All analogues possess a lower rat pressor activity than ocytocin. Compared to oxytocin, [7-(L-3,4,-dehydroproline)]oxytocin exhibits a parallel displacement of the cumulative uterotonic log dose vs. response curve toward lower concentration (pD2 = 9.26 vs. 8.63) but elicits the same maximum response. These data would seem to support the hypothesis that the introduction of unsatuation into binding element of a peptide hormone can enhance the affinity of the hormone for some of its receptors and thereby its selectivity.


Polyamine biosynthesis in rat prostate. Substrate and inhibitor properties of 7-deaza analogues of decarboxylated S-adenosylmethionine and 5'-methylthioadenosine. The 7-deaza analogue of 5'-methylthioadenosine, a nucleoside end product in polyamine biosynthesis, has been synthesized. This analogue has been shown to competitively inhibit the hydrolytic cleavage of the purine-ribose bond in methylthioadenosine with Ki congruent to Km. In addition, the 7-deaza analogue of decarboxylated S-adenosylmethionine, a cofactor in the biosynthesis of both spermidine and spermine, has been synthesized. This analogue has been shown to act as a substrate in the reaction catalyzed by spermidine synthase, in which severe substrate inhibition by both the normal nucleoside substrate and the 7-deaza analogue is observed. These results are discussed in terms of possible end product regulation of polyamine biosynthesis and the possible substitution of the nucleoside antibiotic, tubercidin, for adenosine in reactions involving S-adenosylmethionine and its metabolites.


Inhibition of histidine decarboxylase. Derivatives of histidine. Twenty-eight derivatives of histidine were tested as inhibitors of histidine decarboxylase from rat stomach. Potent inhibition was observed with the methyl ester of L-histidine (1) which had a Ki = 1.8 X 10(-6) M. Substitution on 1 at various positions resulted in a decrease or complete loss of inhibition. Substituent requirements for inhibition of histidine decarboxylase are discussed. A simple disposable apparatus for the radiometric assay of histidine decarboxylase is described.


Synthesis and structure-activity relationships of bestatin analogues, inhibitors of aminopeptidase B. Stereoisomers and analogues of bestatin, [(2S,3R)-3-amino-2-hydroxy-4-phenylbutanoyl]-L-leucine, were synthesized and tested for aminopeptidase B and leucine aminopeptidase inhibiting activity. Among the eight stereoisomers, the 2S stereoisomers exhibited strong activity. In a series of compounds in which the L-leucine residue of bestatin was substituted with other amino acids, only the one containing isoleucine showed more activity than bestatin. Norleucine, norvaline, methionine, valine, serine, glutamine, phenylalanine, glutamic acid, proline, and lysine analogues gave, in that order, decreasing activity. Alkyl and phenyl sub stitution for the benzyl group of bestatin decreased the activity markedly. p-Methyl-, p-chloro-, and p-nitrobestatins showed greater activity than bestatin.


Potential antitumor agents. 22. Latentiated congeners of the 4'-(9-acridinylamino)methanesulfonanilides. N1-Acyl derivatives of the tumor inhibitory 4'-(9-acridinylamino)methanesulfonanilide agents act as prodrugs undergoing deacylation to liberate the core agents on incubation with pH 7.5 buffer or mouse blood. Against L1210 tumor implanted remotely from the drug administration site, lower acyl derivatives often provide enhanced effects over that obtained with nonacylated precursor alone. In certain homologous series of acyl derivatives, toxicity first increased with increasing lipophilic character, until greater than that of the core agent alone, and then at higher lipophilic levels decreased. Tumor inhibitory properties of the acyl derivatives in such series appeared inversely related to their toxicity. Several 3-(3,3-dialkyl-1-triazeno)acridine-substituted congeners provided excellent L1210 activity. Contrasting with most other tumor-active triazenes, one alkyl group need not be a methyl group of antileukemic activity to be observed. 3-Methyl-3-propyl-1-triazene and 3,3-diethyl-1-trazene analogues had comparable lipophilic-hydrophilic balance, toxicity, and antileukemic effectiveness; usual metabolic activation of the triazene N-methyl group may make little contribution to antitumor properties in the examples presented. Prepared as a nonalkylated triazene analogue, a 3-azidoacridine congener had high L1210 activity.


Experimental antiulcer drugs. 1. Indole-1-alkanamides and pyrrole-1-alkanamides. The synthesis and gastric antisecretory activity of a series of indole-1-alkanamides and pyrrole-1-alkanamides are presented. A marked elevation of the pH of the gastric secretions of the rat was observed after oral administration of 100 mg/kg of 2,3-dimethylindole-1-acetamide (2), -1-propionamide (8), and -1-butyramide (13). Replacement of either methyl group by a hydrogen atom or an ethyl radical resulted in greatly diminished activity. In the acetamide and propionamide series the 3-hydroxymethyl-2-methyl (14 and 15) derivatives exhibited activity but only when administered by the subcutaneous route. 2,3-Dimethylindole (18) was active and 2,3,4,5-tetramethylpyrrole-1-acetamide was moderately active. A number of the activ compounds were tested in the mouse mydriasis test for anticholinergic activity and found to be inactive. They were also found to be inactive in blocking histamine-induced acid secretion in the dog.


Synthesis, antifertility activity, and protein binding affinity of 7(8 leads to 11 alpha)abeo steroids. A series of 7(8 leads to 11 alpha)abeo steroids was synthesized by a modification of the previously described total synthesis of this class of compounds and evaluated for biological activity. In general, there was a marked reduction in the relative binding affinities of these compounds for the rabbit uterus estrogen and progestin receptor proteins. None of the compounds which were subjected to uterotropic, antiuterotropic, postcoital, progestational, antiprogestational, or antiandrogenic assays showed any significant activity.


Total syntheses of (+/-)-1-carbacefoxitin and -cefamandole and (+/-)-1-oxacefamandole. The total syntheses of the (+/-)-1-carba analogues of cefoxitin (11), 7 alpha-methoxydeacetylcephalothin (5) and cefamandole (31) and the (+/-)-1-oxa analogue of cefamandole (43) are described. Their bioactivity spectra against 14 typical organisms are similar to those of their natural 1-thia counterparts, with the 1-carba compounds somewhat less active and the 1-oxa compound more active than the natural ones.


Mercapto heterocyclic carboxylic acids, analogues of 3-mercaptopicolinic acid. 3-Mercaptopicolinic acid (3-MPA), a potent hypoglycemic agent in fasted rats, provided the impetus for substituting this compound with a 5-mercapto group (1), a 6-carboxyl group (2), and a 5-mercapto and 6-carboxyl group (3) and for replacing the pyridine ring with other heterocycles: quinoline (4), thiazole (5), pyrazine (6), isoquinoline (7), and indole (8). The methyl sulfoxide (9) and sulfone (10) of 3-MPA were also prepared. The new compounds 1-10, with the exception of 8, did not lower blood glucose levels in 48-h fasted rats. 8 was toxic at doses which were hypoglycemic.


Isolation and identificaton of an in vivo reaction product of 6-hydroxydopamine. The product of oxidized 6-OHDA and GSH reacted in vitro has been identified by a variety of chemical and physical methods to be 2,4,5-trihydroxy-6-S-(glutathionyl)phenethylamine. Its chemical properties show it easily undergoes a variety of oxidative condensations and polymerization. Its oxidized form, the p-quinone, can be identified in small quantities in rat brain and mouse brain 1-3 h after 6-OHDA injection. This is believed to be the first report of a chemically identified species resulting from the in vivo interaction of 6-OHDA with CNS tissue.


Quinazolines as inhibitors of dihydrofolate reductase. 4. Classical analogues of folic and isofolic acids. A series of classical quinazoline analogues of folic and isofolic acids was evaluated for inhibitory activity against the dihydrofolate reductases from rat liver and from Streptococcus faecium. Included in this group were the known active antitumor agents methasquin and chlorasquin as well as methotrexate. Two new compounds, N10-formyl-5,8-deazaaminopterin and N10-formyl-5,8-deazafolic acid, were synthesized specifically for this study. The latter displayed modest activity against L1210 leukemia in mice.


Hydantoins as antitumor agents.

Hydantoins as antitumor agents. A series of 27 hydantoins was prepared and tested as antitumor agents. These were variously substituted in the 5 position but with special emphasis on the substituents (chloro, acetyl, chloroacetyl, and methyl) in the 1 and/or 3 positions. The most active compound was 5,5-bis(4-chlorophenyl)-1,3-dichlorohydantoin with a T/C value of 190% against P-388 lymphocytic leukemia in mice.


Antiinflammatory activity of isomeric phenylnaphthaleneacetic acids. The isomeric phenylnaphthaleneacetic acids were prepared and tested for antiinflammatory activity by the anti-UV-erythema method. High potency was exhibited by 4- and 5-phenyl-1-naphthaleneacetic acid and 5- and 6-phenyl-2-naphthaleneacetic acid. The results are discussed in terms of a hypothetical receptor site.


In vitro metabolism of a new 4-hydroxycoumarin anticoagulant. Structure of an unusual metabolite. The metabolism of clocoumarol, 3-[1-[P-(2-chlorethyl)phenyl]butyl]-4-hydroxycoumarin, by rat liver microsomes was investigated. The chemical structure of the main metabolite is 6-[1-hydroxy-2-oxo-3-[p-(2-chloro


Synthesis of spiro[isobenzofuran-1(3H),4'-piperidines] as potential central nervous system agents. 2. Compounds containing a heteroatom attached to nitrogen. The synthesis and antitetrabenazine activity of a series of N-heteroatom derivatives of 3-phenylspiro[isobenzofuran-1,4'-piperidines] are reported. Optimal antitetrabenazine activity is associated with compounds containing a sterically unhindered, basic nitrogen. Hydroxylamines 6, 11, 12, and 13 possess the most significant activity with ED50's of 1.4, 3.5, 4.7, and 4.0, respectively.


Programs and positions available to U.S. medical students through NIRMP, 1976. An analysis of programs and positions in the first year of graduate medical education regarded as acceptable by U.S. medical students suggests that the ratio for all positions is about one per graduate and even less in primary care programs. Since approximately 95 percent of positions are now in institutions affiliated with academic health centers, these medical-school-hospital complexes should be supported to increase positions in primary care programs in order to accommodate the two-thirds of U.S. graduates who want to begin their graduate medical education in these disciplines.


A computer-assisted admissions process.

A computer-assisted admissions process. A computer-assisted admissions process has been implemented at the Ohio State University College of Medicine to systematize the procedures for managing a greatly increased volume of applications. The historical development, continuing research efforts, and computer support system for the process are discussed. This system has served well over a five-year period of development, implementation, and regular use. The system has increased security against loss of records and has enhanced the orderly consideration of individual cases. It continues to provide ongoing support to the College of Medicine admissions process.


A preparatory course for medical students who lack a conventional academic background. McMaster University School of Medicine admits students who may not have had an extensive education in physics, chemistry, and biology. For several years a short preliminary course was offered to those students. The course has since been discontinued, and its objectives have been incorporated into the M.D. program. This approach has been taken in an attempt to conform to the educational policy of the program. However, since the course was seen to be highly successful and, therefore, may be of use to others, its objectives and teaching methods are described.


A special tutorial for minority medical students: an account of a year's experience. A small number of minority medical students were referred for a year-long tutorial to improve their problem-solving skills and to assist them in retaking failed basic science courses. Both the operation of the tutorial and attemtps to reconstruct what had gone wrong the previous year brought attention to the crucial importance of affective factors in the students' learning efforts. It proved to be possible to elucidate some of the dynamics whereby affective reactions apparently enter into instructor-student interactions and are significantly involved in the process of adjusting to medical school. Following the tutorial, which dealt with issues of trust and self-esteem as well as with cognitive problems, the students all had a successful year and were able to rejoin the main stream of students entering clinical training. It was concluded that cognitive problems of medical students experiencing academic difficulty may not be resolvable without dealing with affective considerations. Recommendations are given for dealing with affective issues.


The independent study program at the University of Wisconsin Medical School. A program for 30 additional medical students for the first two years of the University of Wisconsin Medical School curriculum has been developed, and two groups of students have advanced to the clinical years. Design included providing modules of course materials to students and utilizing faculty predominantly in the developmental and managerial role. Preliminary results are based on student and faculty opinion of the program in categories of faculty acceptance, faculty-student interaction, certifying examinations, student attitudes, material developed, and course objectives. The course has been accepted as a continuing part of the medical school curriculum and provides a more flexible track for some students. There has been no significant difference in performance on Part I of the examination of the National Board of Medical Examiners for the first two groups. The concepts of individualized medical education have strengthened the basic science and core curriculum of the medical school.


Transport and demand of oxygen in severe burns. The balance equation or oxygen-conservation equation in which oxygen consumption is equal to cardiac output times the maximal oxygen binding capacity times the oxygen saturation difference between arterial and mixed venous blood shows the three factors by which the oxygen supply to the tissues can be regulated according to the need. The release of oxygen to the tissues is regulated directly through the venous oxygen tension and indirectly through cardiac output, the 2,3-DPG system, and erythropoietin. Of these indirect regulation mechanisms, cardiac output has the most rapid response and erythropoietin the slowest. As the pool of oxygen in the tissues is comparatively small, the transport and the demand of oxygen under normal conditions are approximately equal over a longer period of time. The tissue oxygen tension (Fig. 21) is thus directly a result of the flows (Fig. 21), solid lines) and indirectly a result of the regulation mechanisms (Fig. 21, broken lines). Hypermetabolism, weight loss, and severe protein wasting characterize the metabolic response to thermal injury. The increased adrenergic activity following severe burns signifies a shift of flow of body substrate from storage to utilization and an increase in energy requirements. The greater the stress, the greater the response. All systems operate at maximal or near maximal levels. The critically injured patients have an accelerated glucose turnover and increased nitrogen loss; the main source of catabolized protein seems to be from skeletal muscle. The metabolic wheel has a tremendous speed. It is thus essential to feed the patient. Energy support with heat supply and nutrition must equal energy demand to avoid weight loss. Most important is to avoid loss of "lean body tissue." No hypermetabolism was found in burned patients when the patients themselves controlled the heat supply from infrared heaters. The metabolic rate corrected for rectal temperature was independent of the total body surface burned. The energy expenditure of patients with burns was studied during the daily treatment routine and showed that it is important to avoid hypovolemia, underhydration, pain, fear, and anxiety, all of which increase the metabolic demands. To prevent hypermetabolism, infrared radiation is a practical way of distributing energy from the environment to the patient. Weight loss can be essentially prevented as energy support equals energy demand (Fig. 20). Furthermore, the method has the advantages that many patients can be treated individually, the method is inexpensive, and the ambient air temperature can be kept normal. From the results of the present investigation, it may be concluded that in patients with burns treated with infrared heaters the energy intake can be predicted in an appropriate way from the calculated basal metabolism, the rectal temperature, and the activity of the patient. The effect of storage of blood on oxygen, proton, and carbon dioxide transport is mainly mediated over the concentration of 2,3-DPG...


Ruptured thoracic aorta due to blunt trauma. Thirty-six ruptured thoracic aortas have been diagnosed in a total of 3,500 patients seen at the Maryland Institute for Emergency Medicine in the past 5 years. To our knowledge, no ruptured thoracic aortas have gone undetected. A new method of performing portable chest radiography has been developed which we feel clarifies the diagnosis of mediastinal hematomas and which allows us to determine which patients will undergo aortography. The reported survival rate of 75% is felt to be due to the rapidity with which these patients are brought to the hospital and use of a carefully planned protocol which permits early diagnosis and treatment. These results are due to the combined efforts of the Maryland State Police Helicopter System, the traumatologists, anesthesiologists, nurses, paramedics, radiologists, and thoracic surgeons working together as a completely integrated team.


Systemic corticosteroid therapy for high-pressure injection injuries of the hand. Two cases of high-pressure injection injuries of the hand have benefited from early administration of high doses of systemic corticosteroids. The pathophysiology of these injuries relates to: 1) Local mechanical tissue destruction from the injection; 2) Deleterious tissue responses to the injectant; and 3) Sequelae of secondary bacterial infection. Steroids have been shown experimentally to play a beneficial role in the second group of factors without increasing the incidence of secondary infection. The rapid favorable response to steroids demonstrated in the two reported cases suggests further use and investigation of this treatment modality is warranted.


Biophysics of rotary mower and snowblower injuries of the hand: high vs. low velocity "missile" injury. We have shown a basic biophysical difference between clinically similar hand injuries and suggest that some rotary lawn mower injuries more closely resemble high-velocity missile injuries. A treatment protocol is suggested.


Fractures of long bones in Duchenne muscular dystrophy. The dangers of bed-confininf procedures in children with Duchenne Muscular Dystrophy should be recognized, and their fractures treated so as to encourage continued independent ambulation as long as feasible.


Tibial shaft fractures treated with intramedullary nailing. A series of 132 patients with 139 tibial shaft fractures treated with intramedullary nailing is presented. Nailing was performed either primarily or secondarily and reaming was performed in most cases. A rigid fixation was secured in most patients. At followup of 124 patients the results were good or fair in 96% (107 had good results, 12 had fair results). Only one patient had a lasting poor result, while 4 patients had uneventful healing and ultimately good result after renailing.


Stainless steel mesh-acrylic cranioplasty. Twenty-four steel mesh-acrylic plates have been used for repair of skull defects in 1970-73. Three plates had to be removed due to complications, two due to infection and one due to an allergic reaction. The plate is easy to mould, strong, and light. The cosmetic results are excellent.


Post-traumatic venticular septal defect, mitral insufficiency, and multiple coronary cameral fistulas. A patient who developed severe congestive heart failure subsequent to a stab wound of the heart is described. He was demonstrated to have a ventricular septal defect, mitral regurgitation, and two coronary-cameral fistulas. He underwent successful operative correction.


Pneumoperitoneum associated with pneumothorax: a surgical dilemma in the post-traumatic patient. Two patients with pneumoperitoneum associated with post-traumatic pneumothorax are described. The role of artificial respiration in the production of pneumoperitoneum is descussed. This association presents a curious diagnostic dilemma. If the diagnosis of perforated hollow viscus can be eliminated with considerable certainty, then conservative management with careful observation and monitoring may avoid unnecessary surgery, so long as other causes of pneumoperitoneum have been ruled out.


Traumatic amputation of the finger with complete avulsion of flexor profundus tendon. A case of traumatic amputation of the left third finger at the proximal interphalangeal joint is presented. The injury was associated with complete avulsion of the flexor profundus tendon from the forearm. The possible mechanism of injury is discussed.


An uncommon fracture dislocation of the radius. Two cases of fracture of the proximal third of the radius, one with anterolateral, and one with posterior dislocation of the radial head are described. In both the ulna remained intact. To the best of our knowledge, only one other similar case had been reported.


Dissecting hematoma of the internal carotid artery following chiropractic cervical manipulation. A patient with a dissecting hematoma of the internal carotid artery following chiropractic neck manipulation is described. This injury, apparently previously unreported in the literature, is thought to be caused by trauma to the artery by rotatory movement of the neck and pressure against the artery by the transverse process of C-2.


Clinical use of tissue pressure measurements: a case report. This report presents a patient in whom measurement of intracompartmental pressures objectively supported the need for fasciotomy. Method of measurement, technique of using the opposite extremity as a control, and normal tissue pressure of 14--19cm H2O are also discussed.


Symptomatic giardiasis in Sudanese adults and its treatment with tinidazole. The main symptoms of infection with Giardia intestinalis in 33 Sudanese adults were abdominal pain, flatulence and diarrhoea. Other symptoms were offensive stools, loss of weight, milk intolerance, mucoid stools, nausea and vomiting. Tinidazole given orally as 150 mg. twice daily dose for seven days or as a single 1,000 mg. dose, eradicated the infection in 32 out of the 33 patients. This parasitological cure was obtained in all 21 patients who received the seven day course and in 11 out of 12 patients who were given the single dose. All symptoms disappeared in 16 out of the 32 patients and in the remaining half improvement was marked particularly as regards the three main symptoms of the disease. The single dose gave no side effects but nausea, headache, skin rash and worsening of abdominal pain and diarrhoea occurred in some patients who received the seven day treatment course.


Salmonellosis complicating schistosomiasis in the Sudan. Salmonella typhi or Paratyphi A was isolated from the blood in 16 out of 21 Suanese patients who had prolonged fever of one of 10 months' duration and hepatesplenic schistosomiasis. Most patients had severe anaemia. The serum alkaline phosphatase was raised in 16 patients. Bilharzial lesions were demonstrated in the liver biopsies of 10 patients. Three patients had in addition the nephrotic syndrome and moderate proteinuria was present in nine other patients. Changes of proliferative glomerulonephritis were noted in the renal biopsies of two patients with the nephrotic syndrome. Treatment with chloramphenicol cured the salmonella infection in all patients, reversed the raised alkaline phosphatase and the proteinuria, and led to a marked reduction in the size of the hepatosplenomegaly.


Electron microscopy of late adenovirus type 2 mRNA hybridized to double-stranded viral DNA. R loops were generated with late adenovirus type 2 (Ad2) mRNA in double-stranded viral DNA, and visualized by electron microscopy. Unpaired DNA sequences in Ad2:Ad2+ND4 heteroduplex DNA served as a visual marker for the orientation of R loops with respect to the conventional DNA map. The most abundant classes of late Ad2 mRNA observed by this technique hybridized, in order of R-loop frequency, with midpoints near posit1ons 0.57, 0.88, 0.77, and 0.40 to 0.50 of the DNA map. The R loop at position 0.57, 0.88, 0.77, and 0.40 containing the hexon gene; the one at position 0.88 corresponded to a region containing the fiber gene. The relative frequencies of these two R loops paralleled those of the encoded gene products. The mRNA sizes, calculated from those of the respective R loops, were slightly larger than needed to code for these polypeptides. Using the R-loop technique, two locations at which adjacent mRNA's hybridized to different strands were accurately mapped at positions 0.61 and 0.91 of the DNA. The map positions of late Ad2 mRNA correlated well to published RNA and protein maps.


Early gene expression of adenovirus type 2: R-loop mapping of mRNA and time course of viral DNA, mRNA, and protein synthesis. Adenovirus type 2 DNA was hybridized to early mRNA isolated from the cytoplasm of infected cells prior to the initiation of viral DNA synthesis. Resulting R loops were visualized in the electron microscope, and their positions were oriented with the help of DNA fragments generated by digestion with the restriction endonuclease BamHI. Early RNA was found to map (in order of relative R-loop frequency) with midpoints near positions 0.95, 0.80, 0.03, 0.65, and 0.09 on the conventional adenovirus map. The time of appearance of individual viral mRNA's was compared to the time course of viral protein and DNA synthesis. We present a refined map of adenovirus gene functions which is based on results documented in this and the accompanying study by Meyer et al. (1977), as well as on data published by other laboratories.


Circular forms of Uukuniemi virion RNA: an electron microscopic study. Because the ribonucleoprotein forms of the segments of the Uukuniemi virus genome have previously been characterized as circular, we examined the isolated RNAs by electron microscopy under conditions of increasing denaturation. After spreading under moderately denaturing conditions (50 or 60% formamide), 50 to 70% of the molecules were circular. Increasing the formamide concentration to 70 and 85% decreased the number of circular forms, and only linear forms were observed after incubation of the RNA at 60 degrees C for 15 min in 99% formamide. When spread from 4 M urea-80% formamide--another condition known to denature RNA--only 5 to 30% circular molecules were observed. Pretreatment of the RNA with 0.5 M glyoxal at 37 degrees C for 15 min prior to spreading from 50% formamide gave less than 5% cirucular forms. Length measurement of the molecules showed that they were not significantly degraded by any of the methods employed. The circular molecules were destroyed by treatment with pancreatic RNase, but were unaffected by DNase or proteinase K treatment. After complete denaturation of the RNA, the circles could be reformed under reannealing conditions. We conclude that the three size classes of RNA that comprise the Uukuniemi virus genome are circular molecules probably maintained in that form by base pairing between inverted complementary sequences at the 3' and 5' ends of linear molecules.


Characterization of a temperature-sensitive mutant of human adenovirus type 7. The properties of a naturally occurring temperature-sensitive (ts) mutant of human adenovirus type 7 (Ad7) were studied. Mutant Ad7 (19), or E46-, was the nonhybrid adenovirus component derived from the defective simian virus 40 (SV40)-Ad7 hybrid (PARA). Growth of the mutant was restricted at 40.5 degrees C, and the ratios of virus yields in KB cells at 40.5 and 33 degrees C were 10(-2) to 10(-3). Viral DNA synthesis and the synthesis of adenovirus-specific antigens (tumor, capsid, hexon, and penton antigens) appeared normal at the restrictive temperature. The assembly of virus particles was aberrant, as determined by thin-section of infected cells. The infectivity of mutant virions was heat labile at 50 degrees C, suggesting a ts defect in a structural component of the viron. Analysis by polyacrylamide gel electrophoresis of [35S]methionine-labeled polypeptides synthesized in mutant-infected cells suggested that at least the major virion polypeptides were synthesized at the restrictive temperature. A lack of inhibition of host protein synthesis late in mutant infections, as compared with wild-type (WT) infections at both the permissive and nonpermissive temperatures, made quantitation of infected-cell polypeptides difficult. Analysis of the assembly of capsomeres from cytoplasmic extracts of infected cells on sucrose gradients and by non-dissociating polyacrylamide gel electrophoresis suggested that hexon capsomeres were made at 40.5 degrees C. The hexon capsomeres made by the mutant at either 33 or 40.5 degrees C displayed a decreased migration in the non-dissociating gels compared with the WT hexon capsomeres. The molecular weights of the mutant and WT hexon polypeptides were identical. These results suggest that the ts lesion of this group B human Ad7 mutant may be reflected in altered hexons. The mutant Ad7 interfered with the replication of adenovirus types 2 and 21 at the elevated temperature.


P1 and P3 proteins of influenza virus are required for complementary RNA synthesis. Members of two temperature-sensitive (ts) mutant groups of influenza A/WSN virus defective in complementary RNA synthesis were analyzed with respect to the identity of their defective genes. RNA analysis of recombinants having a ts+ phenotype derived from the mutants and HK virus permitted the identification of RNA 1 and RNA 2 as the single defective gene in mutant groups I and III, respectively. Based on knowledge obtained by mapping the WSN virus genome, it then was possible to determine that biologically functional P3 protein (coded for by RNA 1) and P1 protein (RNA 2) are required for complementary RNA synthesis of influenza virus.


Identification of the defective genes in three mutant groups of influenza virus. Seven complementation-recombination groups of temperature-sensitive (ts) influenza WSN virus mutants have been previously isolated. Recently two of these groups (IV and VI) were shown to possess defects in the neuraminidase and the hemagglutinin gene, respectively, and two groups (I and III) were reported to have defects in the P3 and P1 proteins which are required for complementary RNA synthesis. In this communication we report on the defects in the remaining three mutant groups. Wild-type (ts+) recombinants derived from ts mutants and different non-ts influenza viruses were analyzed on RNA polyacrylamide gels. This technique permitted the identification of the P2 protein, the nucleoprotein, and the M protein as the defective gene products in mutant groups II, V, and VII, respectively. Based on the physiological behavior of mutants in groups II and V, it appears that P2 protein and nucleoprotein are required for virion RNA synthesis during influenza virus replication.


Biochemical studies on a reovirus-like agent (rotovirus) from lambs. Ten polypeptides were detected in double-capsid lamb rotavirus; four of these appeared to be associated with the outer capsid. Lamb rotavirus RNA, which consisted of 11 or 12 segments, differed from pig rotavirus RNA in the electrophoretic mibility of one of the genome segments.


Proteins of hepatitis B surface antigen: amino acid compositions of the major polypeptides. The major polypeptides isolated from two different preparations of hepatitis B surface antigen/adw were analyzed for their amino acid compositions. The results indicated a high degree of compositional relatedness between the P-1 (23,000, molecular weight) and P-2 (29,500, molecular weight) polypeptides for each of the two preparations. A considerable proportion of the major P-1 and P-2 polypeptides may be composed of a common structure. No amino sugars were detected in the preparations of isolated polypeptides.


RNase activity in human interferon preparations. The level of RNase activity in human interferon preparations was examined. Although sequential purification of interferon resulted in nearly a 300-fold increase in specific activity, RNase-specific activity remained more or less constant. The implications of this finding for the analyses of the mode of action of interferon are discussed.


99mtechnetium penicillamine: a renal cortical scanning agent. 99mTechnetium penicillamine, a renal cortical imaging agent, can be used to provide a rapid, safe and non-invasive assessment of renal morphology and the renal vascular supply. Since this agent is not excreted significantly during the imaging procedure cortical scans of high quality can be obtained without image deterioration owing to a superimposed collecting system. These scans, which are clearly superior in anatomical detail to earlier scans using 131I hippuran, can be obtained along with the 131I hippuran renogram when the patient comes to the nuclear medicine department. Herein we demonstrate the anatomical detail it is now possible to achieve by presenting the cortical renal scans and accompanying radiograms from 5 patients with different renal pathology.


Renal malacoplakia.

Renal malacoplakia. Malacoplakia often is considered a benign disease. Our recent experience with renal parenchymal malacoplakia and a review of the literature have revealed the clinical and pathologic features as well as the prognosis of this renal disease. Upper urinary tract malacoplakia is neither benign nor self-limited, and bilateral renal parenchymal involvement has been uniformly fatal.


Hormones in renal cancer.

Hormones in renal cancer. Plasma renin, erythropoietin and chorionic gonadotropin levels were evaluated in 57 patients with renal adenocarcinoma. Renin elevation, found in 37 per cent, was unrelated to blood pressure levels but was associated with high grade, high stage lesions of mixed histologic cell type and predicted a poor prognosis. Erythropoietin was raised in 63 per cent of patients and was more sensitive than renin in indicating the presence of renal adenocarcinoma. However, it was less specific and did not correlate directly with tumor grade, stage, histologic type, prognosis or hematocrit and hemoglobin levels. None of the patients had elevated chorionic gonadotropin levels. Therefore, we believe that renin and erythropoietin determinations may be of value as biochemical tumor markers in renal adenocarcinoma.


Extrarenal manifestations of renal cell carcinoma. Renal cell adenocarcinoma can be one of the great masqueraders in medicine. More common extrarenal manifestations of renal cell carcinoma include fever, anemia and gastrointestinal symptoms. Other rarer systemic symptoms are caused by amyloidosis, neuromyopathy and tumor thrombus. Humoral manifestations include polycythemia, hypercalcemia, galactorrhea and Cushing's syndrome. Metastatic disease commonly presents as the initial symptom.


Reflux as a cause of end stage kidney disease: report of 32 cases. Of 32 patients with end stage renal failure secondary to bilateral, primary, low pressure reflux 10 had sterile reflux and 22 had reflux associated with recurrent urinary tract infection. These cases clearly document a potential terminal phase in the natural history of reflux. In addition, the study indicates the absolute necessity of early diagnosis and surgical correction of severe reflux, regardless of whether the reflux is sterile or associated with infection, and before chemical evidence of renal functional impairment.


Duplication of the male urethra.

Duplication of the male urethra. Our experience with 4 male subjects with accessory urethras is reported. The anatomic types, clinical presentations and treatment modalities of urethral duplication are discussed. Our scrutiny of all cases reviewed in the literature led us to classify patients into 3 types, depending upon the anatomic and embryologic features. Type 1 is a complete accessory urethra arising from a separate or confluent opening within the bladder and extending to an external orifice. Type 2 includes accessory urethras that arise from the primary urethra and may or may not extend to a distal orifice. Type 3 is the most unusual anomaly, in which 1 of the duplicated urethras arises from the bladder or proximal urethra and opens onto the perineum.


Estramustine phosphate: a specific chemotherapeutic agent?. Estramustine phosphate is a nitrogen mustard derivative of estradiol that has been advocated for the treatment of prostatic cancer. The compound was designed with the hope that the estrogen moiety would direct the alkylating moiety to estrogen-dependent malignancies, where the alkylating moiety would be released specifically. Preclinical and clinical data are reviewed to determine to what extent that challenging concept is fulfilled. In addition, we have examined critically the efficacy of this drug for the treatment of prostatic cancer. From available data it appears that there is no evidence that the alkylating moiety of estramustine phosphate is specifically freed in estrogen-dependent tissues. Estramustine phosphate appears to be an active compound with acceptable toxicity in prostatic cancer. However, further clinical trials must be undertaken to clarify the future role of estramustine phosphate in the treatment of prostatic cancer.


Multiple drug chemotherapy regimen for patients with hormonally-unresponsive carcinoma of the prostate: a preliminary report. Of 25 patients with estrogen-unresponsive prostatic adenocarcinoma submitted to multi-drug chemotherapy 6 had partial objective regression, 12 had objectively stable disease and 7 had progressive disease. The survival rates in the 3 groups were 63, 52 and 40 weeks, respectively.


Pathological semen and anatomical abnormalities of the genital tract in human male subjects exposed to diethylstilbestrol in utero. The in utero effects of diethylstilbestrol on the human male genital tract are reported in our followup study of male offspring of mothers treated with diethylstilbestrol. Anatomical and functional abnormalities were significantly greater in male patients exposed to diethylstilbestrol compared to male controls whose mothers were all participants in a prospective, randomized double-blind study on the effects of diethylstilbestrol on pregnancy at our hospital during the early 1950s. Epididymal cysts, hypotrophic testes and capsular induration of the testes were among the more common genital lesions found in more than 25 per cent of 159 male patients exposed to diethylstilbestrol compared to a 6.8 per cent incidence in 161 male controls. Spermatozoal analysis revealed severe pathological changes (Eliasson score more than 10) in 32 per cent of 31 patients exposed to diethylstilbestrol and 0 per cent of 20 male controls. Abnormal findings on physical examination combined with severe sperm abnormalities (Eliasson score more than 10) were found in 23 per cent of the male patients exposed to diethylstilbestrol versus none of the male controls. Cytologic examinations revealed no malignant cells from urine samples before and after prostatic massage or ejaculation, prostatic fluids and aspirates from epididymal cysts.


The phentolamine test in neurogenic bladder dysfunction. In an attempt to improve the selection of patients with neurogenic bladder dysfunction likely to benefit from phenoxybenzamine therapy, the effect of intravenous phentolamine (Regitine) on the urinary flow rate was determined in normal and abnormal subjects. A nomogram relating mean flow rate to volume voided was constructed to aid in the interpretation of results. In 16 patients with neurogenic bladder dysfunction it was found that a response of more than 0.8 nomogram units indicates a likelihood of clinical improvement with phenoxybenzamine therapy. The clinical applications of this test are discussed.


A 25-year prospective mortality study in the spinal cord injured patient: comparison with the long-term living paraplegic. Herein we combine 2 studies: a 25-year prospective followup on 270 spinal cord injury patients and a more than 20-year (average 24.2 years) evaluation of 175 paraplegics. The mortality rate was 49 per cent after 25 years, with renal disease as the major cause of death (43 per cent). Vascular deaths were just as prevalent during the last 5 years of spinal cord life. There are probably several reasons why some patients have long-term survival (more than 20 years), including patient motivation (better followup), less vascular problems, less chronic decubitus and a higher percentage of lower motor neuron lesions. Patients with lower motor neuron lesions had the best bladder status associated with less upper tract deterioration.


Anteromedian external urethral sphincterotomy: technique, rationale and complications. Experiences are presented with bilateral (3 and 9 o'clock incisions) and anteromedian (12 o'clock incision) external urethral sphincterotomy in 84 patients with neuropathic vesicourethral dysfunctions. Hemorrhage and loss of reflexogenic erections have been notably absent in 31 patients who underwent anteromedian sphincterotomy. The rationale is discussed for the preference of anteromedian over bilateral sphincterotomy based on postoperative complications. The postoperative, radiologically aided cystosphincterometric and electromyographic studies during micturition indicated the adequacy of the surgical procedures, satisfying the urodynamic criteria, although dyssynergic myolectric activity of the periurethral striated muscle continued to exist.


Functional contribution of autonomic innervation to urethral striated sphincter: studies with parasympathomimetic, parasympatholytic and alpha-adrenergic blocking agents in spinal cord injury and control male subjects. Mechanisms underlying urethral pressure changes at the external sphincter region after administration of neuropharmacologic agents were investigated with cystosphincterometric studies and electromyography of the external urethral sphincter in adult patients with spinal cord injury and control male subjects. Bethanechol chloride, propantheline or phentolamine were administered to 37 spinal cord injury men and 3 normal controls. After cystectomy 3 additional spinal cord injury patients were subjected to bethanechol studies. The results of these studies suggested that the pressure changes in the external sphincter zone were caused predominantly by the concurrent changes produced in the detrusor and/or the smooth muscle components of the proximal urethra and of the external sphincter zone.


Deep hypothermia.

Deep hypothermia. Early correction of congenital cardiac defects has been facilitated by the use of deep hypothermia and cardiocirculatory arrest. The technique currently used by us consists of surface cooling to 24 degrees C, total hemodilution, cardiopulmonary bypass to 20 degrees C and complete cardiocirculatory arrest. Rewarming is achieved with a pump oxygenator. In over 266 small children, 67% of whom were in the first year of life, lesions corrected included transposition of the great arteries (TGA)(43%), ventricular septal defect (16%), tetralogy of Fallot (16%), and total anomalous pulmonary venous drainage (5%). Early primary correction with deep hypothermia has a risk that is comparable to or better than staged repair.


Surgical treatment of patients with transposition of the great arteries. The prognosis of infants born with transposition of the great arteries has greatly improved in the last ten years. Some principles of diagnosis and treatment are generally accepted. However, considerable uncertainty still exists about the optimal age for elective Mustard operation, and about the details of surgical technique that would minimize the incidence of obstructive complications and post-operative dysrhythmias. These problems are discussed in the light of the surgical technique used in our unit since 1973 (143 Mustard operations) and our recent electrophysiological studies performed during the various phases of the Mustard operation.


[Clinical report of a conservative management in treating acute vitreous haemorrhage (author's transl)]. In the first hours after a vitreous haemorrhage dense enough to obscure the retina, the blood is usually confined to the posthyaloid space in an aqueous phase. Binocular occlusion and elevation provides sufficient immobilization of the eyes in 9 out of 10 patients for the blood cells to settle to the bottom of the space and make the retina available for examination and repair. Is this not done, blood will eventually enter the vitreous gel through holes that develop in the posterior hyaloid membrane. Blood in the gel does not settle and requires months to clear.


[The effect of filtering operations (author's transl)]. The effect of filtering operations on 133 eyes was investigated by fluorescence photography after intracameral injection of fluorescein. The following drainage mechanisms could be found: 1. the transconjunctival route, 2. the diffuse resorption through degenerated veins, 3. bulkflow through lymphatic vessels, 4. bulkflow through atypic aqueous veins, 5. outflow through normal aqueous veins. A filtering bleb develops, if the transconjunctival route and the diffuse resorption is predominent. Newly incorporated veins and lymphatic vessels enable the drainage of the aqueous humour without a visible bleb. Most important for the formation of these vessels is the surgical technique. Therefore it is not only necessary to cover the fistula with a scleral flap but also to gain a physiological intraocular pressure immediately after the operation. If the tension is too low in most cases a filtering bleb will form. If it is at a physiological level (i.c. above the episcleral vein pressure) new vessels can develop and drain the aqueous humour by bulkflow from the scleral fistula and that means a good pressure regulating effect without a filtering bleb.


[On the therapy of tractional retinal detachment without hole formation (author's transl)]. The authors describe 6 cases of tractional retinal detachment without hole formation--five as a result of intraocular metal splinter injuries and the sixth after scleral perforation following windshield injury which was overlooked. Splinter extraction was performed twice through the perforation and three times though the pars plana from the ouside. The time between the injury and appearance of the retinal detachment varied between four months and nine years. In every case there was a diffuse falt detachment without obvious tent formation. Reattachment was successful in five cases by release of the traction from the outside by cerclage with folding of the point of traction in the vitreous body and diathermy with drainage of the subretinal effusion. This method described gives relief only when vitreous strands traverse the whole bulbus crosswise. The follow-up period is up to the present three months to a year.


[Results of operative treatment in chronic glaucoma with marked visual-field defects (author's transl)]. The authors analysed the cases of 13 patients, operated upon for chronic glaucoma with marked visual-field defects. The visual field was examined with a Zeiss spherical perimeter. The field area was calculated in cm2 by planimetric method before the operation and then some months after it, and the obtained results were compared. Special attention was paid to vascular disturbances. In most patients with regular vascular system, post-operative examination had revealed an increase of the visual field. The best results were obtained in patients with medium-size defects: in these cases the increase in the visual field amounted to ca. 33%. The authors recommended proceeding to operative treatment in glaucoma patients without delay whenever there are defects in the visual field, even when they are very pronounced.


[Star-like cataract in a diabetic child (author's transl)]. In a 14-year-old diabetic boy a star-like cataract was observed after the first insulin treatment. This cataract later disappeared again.


[Treatment of spastic entropion by cautery (author's transl)]. Ziegler's cautery is our operation of choice for the treatment of most cases of spastic entropion. The advantage of this technic is the fact that the procedure is very efficient with regard to function and cosmetic effect and takes very little time.


[Assessment of eye damage for private accident. Part III. Assessment of bilateral eye damage (author's transl)]. In continuation of part I and II (Klin. Mbl. Augenheik. 169 [1976] 647, 774) of this essay deals with eye damage afflicting both eyes (caused by an accident or pre-existing lesion) regarding the approbiate disablement benefit. In these cases the degree of disablement should be set between 30 and 70%.


[Experience with a new slit lamp concept (author's transl)]. Since the development of the first slit lamp by A. Gullstrand in 1911 this instrument is an indispensible part of our diagnostic repertoire. Nevertheless it was not until almost 40 years later that the slit lamp could be able to be used for the examination of the fundus as a result of the development of the Goldmann 3-mirror contact glass. Because of the increasing importance of antiretinal detachment prophylaxis the slit lamp examination also of the rear end of the eye its becoming more and more important because of its good stereoscopy, the excellent illumination and the high magnification. A newly developed slit-lamp apparatus fulfils these special requisites which have firstly been demanded recently. This apparatus is easy and comfortable to use, which makes easier above all the contact glass examination. Technical factors, possibilities of application and experience with this slit-lamp are discussed.


[Fluorescein photography with polaroid film (author's transl)]. There are no difficulties in performing documentation of fluorescein pictures by slit lamp polaroid photography. This suitable method is recommended for control of corneal lesions in fitting contact lenses, and in special cases of fluorescein angiography.


[Clinical experience with the O'Malley LOG2 photocoagulator (author's transl)]. Clinical experience with a combination of the Clinitex photocoagulator and the Sadamel auxiliary apparatus (Fankhauser and Lotmar) is reported. This equipment proved to be very suitable for the photocoagulation therapy of degenerative and vascular processes and appeared to be only slightly inferior to the Zeiss apparatus. The coagulation at the posterior pole of the eyeball, within the distribution area of the temporal vessels, was somewhat more difficult than with the Zeiss apparatus: the longer coagulation times which are involved when smaller coagulation fields are used require more skill and experience. With coagulation outside the distribution area of the temporal vessels, on the other hand, no differences were observed in comparison with the Zeiss equipment. The Clinitex-Sadamel combination provides a practical apparatus for the photocoagulation therapy of retinal and choroidal disorders. In this combination the use of the O'Malley coagulator was extended to include photocoagulation, also through the three-reflector contact glass.


[A new apparatus for testing binocular vision (author's transl)]. The Optometer can be used in a binocular manner if the loupe-lens is replaced by a concave mirror of appropriate size and form. The concave mirror or the plane mirror connected to it can be partially transparent. With an appropriate arrangement of these elements the test field can be seen in free space. The image can be adjusted from infinity to 35 cm by displacement of the test object. Choice of the test object makes possible testing the stereoscopic vision under natural conditions. Other test objects can be used to test further functions of the eyes-monocular, binocular or separately.


[Treatment results with isoglaucon eye drops in sympatheticotone patients with early appearing primary glaucoma (author's transl)]. The sympatholytic substance Clonidin (Isoglaucon) that lowers the intraocular pressure as well as the general blood pressure was tested on a small but homogenous group of patients. This group consisted of 11 middle aged male patients with wide angle glaucoma, elevated blood pressure and sympathicotonia. The intraocular pressure was well controlled in 9 of these, and sufficiently lowered in the remaining two. At the same time the general blood pressure was consistently lowered to some extent and the sympathicotonia improved.


[Combined A- and B-scan echography of the eye (author's transl)]. The combined use of A- and B-scan echography gives far better diagnostic results than either one used alone. Both methods have their advantages and disadvantages and each complements the other. A-scan echography provides more information about the structure of a lesion. B-scan is better in demonstrating the topography of a lesion. For A-scan echography the standardized unit 7200 MA Kretz-Technik is used; for B-scan the practical Bronson-Turner contact B-scan be used. Opaque media are the main indications for echography of the globe. However, echography is also indicated in the presence of clear media for the differential diagnosis of solid lesions.


[Necrotizing hypersensitivity-angiitis Zeek with ocular involvement (author's transl)]. A clinical and pathological report is given of a case of necrotizing angiitis Zeek. This rare condition is related to polyarteriitis nodosa, but has an acute course and involves the small vessels. The histology of ocular complications has not been observed up to now. Clinically it appeared as a severe panuveitis and hemorrhagic retinitis. Histologically the vessels of the retina, the choroid, the sclera and the optic nerve show inflammatory signs similar to those of the viscera and the brain. The literature concerning the ocular involvement due to necrotizing angiitis is reviewed and compared with the present case.


[Acute intraocular Toxocara canis infection, similar clinical picture of juxtapapillar chorioretinitis (author's transl)]. A case report is given on acute intraocular Toxocara canis infection. A complete clinical development from the beginning of infection until healing without defect is described. Therapy was Vibramycin (Doxycyclin), Durenat, Prednisolon.


[Hypernephroma and choroidal metastasis: case report and angiographic findings (author's transl)]. The rare occurrence of metastasis to the posterior segments of the eye by a hypernephroma is described. Based on fluorescein-angiographic findings the possibilities of differential diagnosis of choroidal tumors are discussed. The distinction on the one hand between different metastatic choroidal tumors and on the other hand between primary and secondary choroidal tumors does not seem possible.


[Recent aspects in the pathomechanism of glaucoma (author's transl)]. The NEFA-content of the blood serum increases in cases of acute glaucoma. The Cortisol content of the plasma of glaucomatous persons is above 20 microng% and the free cortisol-content of the plasma shows an increase in glaucoma cases. Macrofibrils can be observed by electron microscopic observation of acute glaucoma cases. The combination of diabetes and glaucoma appears more and more frequently. The pseudoglaucomatous excavation has a vasogenic origin. The use of contraceptives may provoke glaucoma.


[A schematic fundus completing Gullstrand's schematic eye (author's transl)]. Based on the anatomical section of an emmetropic eye a spherical or circular fundus is developed by application of a mathematical-statistical method resulting in an optimal approach to the anatomy. The same method is applied to a fundus which is derived by mere computation exclusively from the data of the schematic eye. The results of both methods coincide remarkably well. In this way a schematic fundus is defined as circle with 11.6 mm radius. Its center has a distance of 12.8 mm from the anterior corneal vertex. The applicability of this fundus is discussed.


[A comparative study of the difference in the evolution of refraction in the two eyes in patients with convergent strabismus (author's transl)]. In 329 cases of concomitant convergent strabismus, the alterations of refraction in the two eyes were compared over periods ranging from 10 to 30 years. In the group with unilateral strabismus (245 cases), a significant difference between the two eyes was observed. The change of refraction, if any, in the non-fixing eye (emmetropization or myopization) clearly lagged behind that in the fixing eye. This difference was particularly pronounced in the cases showing myopization. In the group with equivalent function of both eyes--alternating strabismus and cases with complete normalization, including functional normalization--a total of 84 cases, any emmetropization or myopization was found to run practically parallel in the two eyes. This shows that it is true of refraction, also that the genetically determined evolutive pattern may be modified by a functional abnormality.


[Development of refraction and visual acuity of squinting children (author's transl)]. The refraction and visual acuity rates of 170 children from the age of 2 to the age of 7 suffering from squint were recorded and analysed. On the basis of our investigation we could not prove the process of emmetropisation during the growth of the eyes of squinting children in this age group. That means that the process of emmetropisation of squinting children takes place slower and later than with non-squinting children and is apparently stabilized at an age between 8 and 12 years. On the other hand--the increase of visual acuity of the normal eyes of squinting children is--as a rule-completed at the age of 5, like that of non squinting children.


[Exogenous keratitis due to chromomycosis (author's transl)]. The author presents a case of exogenous, retrocorneal, limbal infiltration due to chromomycosis, following cataractextraction. Since the etiology of this keratitis was not recognized at the beginning, steroids were applied causing an exacerbation of the keratitis with hypopyoniritis. A perforating, excentric keratoplasty was performed, yielding material for the histological diagnosis, and for the identification of the responsible agent. The cultural and morphological properties were typical of those of a dematiaceous fungus, a chromomycosis. In vitro studies demonstrated this fungus to be less sensitive to 5-fluorcytosin and clotrimazole, and to be less resistant to natamycin, mystatin and amphotericin-B, paving the road for an effective conservative therapy following surgery.


[Prematurity and retinal detachment (author's transl)]. Cases of retinal detachment due to retinopathy of prematurity are presented. 1. There are cases of total retinal detachment without a complete retrolental fibroplasia. 2. Very typical are cases with a dragged disc and mascular ectopy due to preretinal strands in the temporal periphery, the symptoms of an earlier retinopathy of prematurity. By traction these temporal alterations can cause a retinal detachment, the distortion of the retinal vessels can heavily increase after surgical reattachment of the retina. 3. There are cases of juvenile myopes without further signs of a retinopathy of prematurity. A retinal detachment may occur, due to round holes.


[Results of the clinical examination of the cosmonauts after a 63-day flight]. The cosmonauts P. I. Klimuk and V.I. Sevastyanov during their 63-day flight showed functional changes that were identical to those they demonstrated during their shorterterm flights. During the long-term mission they adapted to the weightless state better than previously. Post-flight medical examinations revealed no pathologies. The following functional changes were found: general asthenization and signs of vegetative-vascular intolerance, sensory-motor and stato-kinetic disorders, moderate muscular dystrophy of lower extremities, slight inhibition of erythropoiesis. P.I. Klimuk displayed vestibular disturbances postflight. Both cosmonauts recovered without any complications.


[Change in the hemodynamics and phase structure of the cardiac cycle in the crew of the 2d "Saliut-4" expedition]. Medical examinations of the Salyut-4 crewmembers included bicycle ergometry tests. During the tests the heart rate and the time intervals of the left ventricle were measured. On the 46th flight day the arterial pressure, cardiac output and peripheral resistance were also determined. In the course of the 63-day flight responses to the 5 min workload of 2100-2200 kgm did not differ essentially from the preflight level, and did not increase with the flight time. Circulation changes noted in zero-g and upon return to I g were similar and can be accounted for by a reduction of the circulating blood volume. Inflight during the first minutes after the workload more marked changes in the cardiac output and cycle were detected. This can be attributed to a relatively stronger effect of blood pooling in working muscles on the venous return of the blood. On the 3rd postflight day the arterial pressure and the velocity of the aortal propagation of the pulse wave were higher.


[Electrocardiographic examination of the crew of the 2d "Saliut-4" expedition]. The inflight electrocardiograms in 12 leads of the cosmonauts P.I. Klimuk and V.I. Sevastyanov showed a trend towards a decrease of the atrio-ventricular and an increase of the intraventricular conduction as well as a decrease of the T voltage. These changes seemed to be adaptive and developed as a result of the positional changes of the heart. Metabolic changes in the myocardium should not be, however, ruled out.


[Prediction and analysis of pulse frequency in cosmonauts by the method of extrapolation modelling in the class of differential equations]. The paper discusses the use of the methods of the theory of automatic control and identification for predicting and analyzing the cardiovascular function of crewmembers in long-duration space missions. On the basis of the inflight heart rate data models characterizing the cardiovascular function can be built. The models have the form of linear differential equations of the second order and are used to calculate values of the heart rate. With respect to the parameters of the equations, the characteristics of the quality and specificity of the cardiovascular regulation inflight are determined. The paper describes the practical application of the above methods to predict and analyze the cardiovascular function of the crewmembers of the Soviet Salyut-1 and Salyut-4 and US Skylab-3 space stations.


[Results of a study of metabolic processes in members of the crew of the 2d expedition of the "Sliut-4" orbital station]. A detailed biochemical analysis of the venous blood and daily urine samples of the crewmembers of the Salyut-4 second expedition after their 63-day space flight showed metabolic changes as compared with the preflight level. The changes were more marked immediately postflight. On the 7th postflight day most parameters studied tended to return to the preflight values. This study did not demonstrate any adverse biochemical changes that may prevent long-duration manned space flights.


[Effect of a 22-day space flight on the lymphoid organs of rats]. The effect of a 22-day space flight on lymph organs of rats was studied. The exposure produced hypoplasia of lymph organs and reduced the weight of the spleen and the thymus to the greatest extent. It was shown histologically, morphometrically and cytologically that hypoplasia of the spleen was associated with the decreased number of lymphocytes and erythrocytes whereas hypoplasia of the thymus and lymph nodes was related to the diminished number of lymphocytes. Changes in the lymph organs of flight rats were reversible. The structure of lymph organs restored by the 27th postflight day. The paper discussed pathogenetic mechanisms of the changes in the lymph organs of rats due to space flight effects and compares the data with the postflight medical examination of cosmonauts.


[Dynamics of the venous circulation in the cosmonauts of the 2d "Saliut-4" expedition]. During the first month of the orbital flight the cosmonauts showed an increase in the blood pressure and filling in the jugular veins whereas during the second month they exhibited a decrease in these parameters below the preflight level. Throughout the mission the pressure in the pulmonary artery remained slightly increased. The time of contractions of the right heart changed. The changes in the blood pressure and filling in the jugular veins can be explained by blood pooling there and subsequent extravasation of blood into the abdominal cavity.


Pancreatectomy in a teleost fish, Anguilla rostrata (American eel). A technique for pancreatectomy was described for the American eel. In this fish, the operation was not followed by the typical signs of diabetes mellitus. Histodensitometric determination of liver glycogen showed no major differences between operated controls and pancreatectomized eels. The absence of a specific hyperglycemia, previously reported with the hexokinase method, was confirmed with the glucose oxidase technique; however, the more specific hexokinase method gave consistently lower values. Breakdown of adipose tissue and hyperlipemia were absent.


[Rheographic study of the human cardiovascular system during a many-day exposure to high pressure]. A rheographic study of the cardiovascular system in a N2-O2 atmosphere at 5 ata showed significant changes in the regulation of the leg vascular tone of most test subjects at rest. The study did not reveal marked changes in the pulsed blood inflow to the brain and lungs at rest. After moderate and especially after heavy work changes in the blood inflow were more pronounced in the hyperbaric atmosphere than at 1 ata. During the exposure an increase in the vascular tone of the systemic and pulmonary circulation was noted.


[Evaluation of the effectiveness of electrostimulation of the muscles in preventing disorders related to prolonged limited motor activity in man]. The purpose of the experiments was to evaluate electrostimulation and physical exercises as countermeasures against the adverse effects of diminished motor activity of man in space flight. Electrostimulation of muscles increased their strength and tolerance to static loads, prevented their atrophy; it did not, however, prevent the cardiovascular system deconditioning. Physical exercises used in combination with muscle electrostimulation maintained the cardiovascular system conditioning.


[Experimental evaluation of the relationship between lesser circulation engorgement, the state of water-salt metabolism and the orthostatic reactions in man]. In 12 series of short-term (4.5 hour) experiments the exposures that influenced the blood distribution relative to the long axis of the body (postural changes, lower body excessive pressure, lower body negative pressure, axial loads) were studied. A close correlation between the blood flow in lung capillaries, water losses and orthostatic responses was established. The correlation was dysproportional when LBEP or LBNP was applied in certain postures. This may be attributed to the effect of these exposures on vessel compliance.


[Study of the mechanical activity of the skeletal muscles of dogs in vivo]. Mechanical activity of gastrocnemius and plantaris muscles of dogs at different locomotion patterns was analyzed qualitatively and quantitatively by the method of dynamomyography. Quantitative correlations between the strength parameters and electric activity of the muscles were studied. In walking and running the above muscles showed different types of contractions. This may be related to their morphological, anatomical and topographic features. The data obtained can be used to evaluate the state of skeletal muscles in different experimental models of a diminished motor activity.


The parasitic ecology of the rodent mite, Myobia musculi. IV. Life cycle. The life cycle of Myobia musculi was determined by daily examination (under anesthesia) of experimentally infested mice. It was found that the larval period lasted 10 days followed by a 5-day nymphal period. Adult forms were seen on the 16th day. Adults produced fertile eggs within 24 hours of their appearance and eggs hatched in 7 days. Thus, the life cycle was completed in 23 days. Application of this information for a successful treatment regimen was discussed. Any treatment which does not kill embryonated eggs must be repeated subsequent to hatching of the eggs but prior to oviposition of fertile eggs by newly hatched females.


Hematopoiesis in hereditarily athymic mice. Hematopoiesis was studied in hereditarily athymic (nude) mice and athymic mice given congeneic thymus cells. Athymic and reconstituted mice had mild anemia which resulted from both hypoplasia of the bone marrow erythrocytic series and decreased iron incorporation in erythroid precursors. Untreated nude mice had hypoplastic marrows due to decrease of both erythrocytic and lymphocytic precursors. The latter was associated with a marked peripheral lymphopenia. Transplantation of thymocytes caused the number of bone marrow and peripheral lymphocytes to return to normal whereas the granulocytic series decreased. Mice reconstituted with thymocytes had marked neutrophilia, eosinophila, and monocytosis compared with either normal or athymic siblings. The number of granulocytic colonies produced by bone marrow cells in agar was very similar in normal and athymic mice with neutrophilia, thus reflecting a normal functioning granulocytic series in a marrow with decreased lymphocytic and erythrocytic cells. The transplantation of thymocytes into athymic mice had no effect on the number of colonies produced by bone marrow cells and the number of spleen colony forming units. It was postulated that maturation of the additional thymocytes permits them to interact with the few endogenous thymocyte precursors present in the nude mice for promotion of bone marrow erythrocytic and lymphocytic proliferations. Alternatively, mature thymocytes may produce factors that were responsible for the effect on lymphoid and erythroid cells.


Uptake of colostral immunoglobulins by the suckling rat. The sequential appearance of immunoglobulins was studied in serum samples from rats during the suckling period. At birth both IgG1 and IgG2 were present, but IgM was not detected until the 7th day and IgA until the 17th day. No intestinal transmission of intact homologous IgA was demonstrable after oral administration of radiolabelled preparations (125I) of either serum or colostral IgA to suckling rats. When 125I labelled IgG 2a+b rat immunoglobulins were given orally there was a selective transport of the slower moving subclass from the gut into the serum. The rat appeared to differ from several other species in which some intestinal absorption of passively transferred IgA by the newborn has been demonstrated. It was suggested that retention of colostral and milk IgA in the intestine may serve to enhance local defense mechanisms in the newborn rat.


Effect of cage size on patterns of activity and health of beagle dogs. Thirty-two male beagle dogs were assigned at random, 16 to standard size cages (30 X 30 X 30 inches) and 16 to large cages (90 X 30 X 30 inches) for a period of 13 weeks, and then were "crossed-over" for an additional period of 13 weeks. The dogs were observed daily and weighed weekly. Electrocardiographic and ophthalmologic examinations were made once and hematologic and biochemical measurements were made twice during the control period and at monthly intervals during the study. Photographs were taken of each dog every 60 seconds, 7 days a week, for about 8.5 hours each day. The film was processed and analyzed for the acf standing sitting, lying, or sleeping. In addition, dogs in the large cages were scored for the region (front, middle, or back) occupied. No statistically significant differences were found between dogs in the standard or large cages with respect to weight gain, percent of time standing, and percent of time sleeping. Statistically significant (p less than 0.05) differences were found for percent of time sitting (standard cages 12.7%; large cages 9.4%) and percent of time lying (standard cages 6.6%; large cages 8.3%); however, the differences were not large enough to be of any practical concern. Transient patterns of response over 13-week periods of the study were essentially the same (statistically verified) for dogs in either size cage. Also statistical results showed that there was no significant carryover (residual) effect associated with any of the parameters measured. No beneficial or adverse effects were noted that could be related to the size of the two cages. The size of the standard cage appeared adequate for laboratory beagle dogs and no advantage was found when the dogs were in larger cages with respect to behavior, patterns of activity, or health.


Cardiovascular and respiratory responses to ketamine hydrochloride in the rhesus monkey (Macaca mulatta). Catheters were placed in the left ventricle and pulmonary artery of 12 rhesus monkeys (Macaca mulatta). Heart rate, left ventricular systolic pressure, pulmonary arterial systolic and diastolic pressure, and respiratory rate were measured before and 5, 15, and 30 minutes after intramuscular injection of the monkeys with ketamine HCl (10 mg/kg). Heart rate, systolic pressure in the left ventricle, and respiratory rate decreased significantly. No significant changes occurred in the pulmonary arterial pressure.


Restrainer and cell for dermal dosing of small laboratory animals. A versatile small animal restrainer and glass dermal dosing cell were designed for use in metabolism studies of dermally applied chemicals. Through use of the restrainer it was possible to apply a chemical to the skin of an unanesthetized rat and leave it there for hours or days without contact between the application site and the restrainer. The dermal dosing cell, when affixed to the skin of a restrained rat, formed a non-occlusive covering for the dermally applied dose and prevented contamination of excretion products by flaking of the applied dose or by desquamation of dosing site skin.


Effects of prolonged high temperature on testicular development and fertility in the male rat. High temperatures for more than 2 days in a large rat production colony resulted in the death of one-third of the animals. The temperature in the room was as high as 89 degrees F (31.6 degrees C) and it is estimated that temperatures in individual cages reached 100 degrees F (37.7 degrees C). In addition to the deaths, 25% of the surviving males, 4-66 days of age at the time of exposure to the high temperature, were found after 18 days, to have irreversible bilateral testicular atrophy. These animals were sterile whereas survivors with normal testes bred successfully.


Some guidelines for collection and reporting of nonhuman primate growth data. Some basic guidelines were offered to aid researches in planning and implementing the collection and reporting of data on growth and development of nonhuman primates. Weight and linear dimensions are the most frequently used measures of growth, and asseous and dental development are the most useful indicators of general bodily maturity. Estimates of sexual development can be made from general bodily maturity but more accurate assessments are based on the appearance of certain secondary sex characters. The most useful growth data are obtained from repeated, regularly scheduled examinations of the same individual. Standard procedures for measuring the external body utilize certain specific measuring points and measurements. Serial radiographs are also extremely valuable. When reporting data, age of subjects should be given in years and decimals. Means and other measures of central tendency and variability should be reported separately for each species, subspecies, and sex.


Pregnancy diagnosis in the orangutan (Pongo pygmaeus) using the subhuman primate pregnancy test kit. A determination was made of the gestational interval over which the Subhuman Primate Pregnancy Test, a hemagglutination inhibition test for urinary chorionic gonadotropin, accurately indicated conception and the continuation of pregnancy in an orangutan (Pongo pygmaseus). The initial positive diagnostic test response occurred about 8 months before parturition and positive responses continued throughout gestation. A test made one day after parturition was positive indicative of some residual urinary chorionic gonadotropin. Tests made 3 days after parturition and later were negative.


Multiorgan scans for staging lung cancer. Correlation with clinical evaluation. One hundred consecutive patients with findings suggestive of resectable bronchogenic carcinoma were studied prospectively to determine if routine liver, brain, and bone scans (multiorgan scans) detected metastases which were not suggested by a history, physical examination, and serum chemistries. Multiorgan scans were compared with clinical evaluations in 52 patients found to have operable bronchogenic carcinoma. There was a discordance between scans and clinical evaluations in 25/153 scans (16 per cent). Two of the 22 negative scans in patients with abnormal clinical findings were false negative. Sixteen of the 17 positive scans in patients with normal clinical findings were false positive. One of the 131 scans done in patients with no evidence of metastases on clinical evaluation was true positive. These data indicate that the routine use of multiorgan scans in the initial staging of potentially resectable bronchogenic carcinoma is not justified.


Effects of open-heart surgery on carbohydrate and lipid metabolism. The concentrations of blood glucose, serum insulin, free fatty acids, and triglycerides were examined preoperatively, during anesthesia, during extracorporeal circulation, and during the following 3 postoperative days in 29 patients. The patients were divided into three groups according to the duration of extracorporeal circulation and the use of hypothermia: short perfusion group (SPG, bypass time shorter than 60 minutes, 15 patients), long perfusion group in normothermia (LPGN, bypass time longer than 60 minutes, 8 patients), and long perfusion group in hypothermia (LPGH, temperature during bypass below 33 degrees C., 6 patients). In all three groups, the concentrations of free fatty acids and blood glucose rose significantly because of anesthesia (p less than 0.001). After cardiopulmonary bypass, the concentrations of free fatty acids diminished significantly. The blood glucose remained at high level until the second postoperative day and was significantly higher in the LPG than in the SPG (p less than 0.05). The serum insulin level remained low during anesthesia and extracorporeal circulation in the SPG and LPGH but rose during the postoperative period; the maximal values were recorded on the first postoperative day. There were no significant differences between the groups with regard to serum insulin during the study. These changes and their metabolic background are discussed.