A heterologous system for detecting eukaryotic enzymes which synthesize pseudouridine in transfer ribonucleic acids. tRNA pseudouridylation activities have been detected in embryonic mouse cell fractions and in extracts from HeLa, mouse L-cell and baby hamster kidney (BHK) cell lines. These activities were identified by the use of heterologous reaction systems, with tRNA from hisT strains of Salmonella typhimurium as substrate. hisT mutants are defective for an enzyme that forms psi residues in the anticodon region of many tRNAs and accumulate undermodified species of tRNA. The pseudouridylation activity from BHK cells has been examined in detail and quantitated by a modified tritium release assay (Cortese, R., Kammen, H.O., Spengler, S.J., and Ames, B.N. (1974) J. Biol. Chem. 249, 1103-1108). Maximal rates of tritium release required a suitable cationic environment (optimally, a combination of Mg2+ and NH4+) and a thiol reductant. The activity was totally inhibited in the presence of thiol-reactive reagents, such as 5,5'-dithiobis(2-nitrobenzoic acid) and p-chloromercuribenzoate. A major portion of this 3H release activity was associated with psi modification reactions. This conclusion stems from the following observations: (a) BHK extracts preferentially catalyzed a release of 3H from hisT [5-3H]tRNA, rather than from similarly labeled wild type tRNA; (b) this activity was specific for protons attached to C5 of the pyrimidine rings; no release of 3H was obtained with hisT or wild type [6-3H]tRNA as substrate; (c) the reaction products of hisT tRNA with BHK enzyme were examined by reverse phase column chromatography of tRNAPhe isoacceptors on RPC-5 columns. The enzyme modified both of the principal isoacceptors of hisT tRNAPhe to an equal extent, yielding products indistinguishable from wild type tRNAPhe. Significant levels of 3H release were obtained by the action of enzyme on wild type [5-3H]tRNA, even after gel filtration of the enzyme. This suggests that the enzyme may be able to hypermodify certain species of wild type S. typhimurium tRNA. The activities for wild type tRNA and hisT tRNA appeared to be associated with the same enzyme.


Acyl carrier protein metabolism and regulation of fatty acid biosynthesis by Lactobacillus plantarum. Endogenous fatty acid biosynthesis in the bacterium Lactobacillus plantarum is greatly decreased upon addition of exogenous fatty acids (Henderson, T.A., and McNeil, J.J. (1966) Biochem. Biophys. Res. Commun. 25, 662-669). We have demonstrated the presence of five pantothenate-containing compounds in L. plantarum which have been identified by co-chromatography with authentic samples: pantothenate, 4'-phosphopantetheine, 3'-dephosphocoenzyme A, coenzyme A, and acyl carrier protein (ACP). The concentrations of the above pantothenate-containing compounds were found to be: 0.009, 0.13, 0.067, 0.69, and 0.22 nmol/mg of protein, respectively. L. plantarum ACP was shown to have a molecular weight near that of Escherichia coli ACP but to have a lower isoelectric point (pI = 3.75). Oleate in the presence of Triton X-100 was found to reduce the concentration of ACP by 80% with little effect on the concentrations of the other pantothenate-containing compounds. The synthesis of ACP apparently ceased soon after the addition of oleate and the rate of decrease in concentration of ACP was quanitatively consistent with the previously observed rate of decrease in the initial rate of fatty acid biosynthesis in this organism (Weeks, G., and Wakil, S.J. (1970) J. Biol. Chem. 245, 1913-1921). Thus, the change in rate of fatty acid biosynthesis in L. plantarum upon addition of oleate to the medium can be quantitatively related to the concentration of ACP (and probably to the concentration of co-repressible enzymes of fatty acid biosynthesis).


A comparative study of the early vascularization of porous carbon and bone as a graft. Utilizing rats as a model, it was demonstrated that both iliac crest bone and porous carbon disks, when used as only grafts, become vascularized as early as 3 days. There is no significant difference between the two. The soft tissues, periosteum, and recipient bone are all capable of supplying vascularization to the graft or implant.


Secretion rates of LH and FSH during infusion of LH-FSH/RH in normal women and in patients with secondary amenorrhea: suggestive evidence for two pools of LH and FSH. Normal women in the early follicular phase and in the luteal phase of the cycle, and patients with secondary amenorrhea received on consecutive days a rapid intravenous injection (50 mug) and a two or four-hour infusion (25 mug/h) of synthetic LH-FSH/RH. The responses of LH and FSH were evaluated by the measured plasma concentrations, as well as by the calculated pituitary secretion rates and by the amounts of hormone released. To estimate these pituitary secretion rates of LH and FSH, a simplified mathematical model is proposed. During an infusion of LH-FSH/RH the secretion rates of both LH and FSH increased in the three groups of women in a biphasic way with a dip after 1 to 2h of infusion, suggesting that besides the pool mobilized by a rapid intravenous injection of LH-FSH/RH there is a second pool of (stored) gonadotropins. For LH the increase above baseline concentrations was higher in group II (luteal phase) than in group I (follicular phase) or in group III (amenorrhea) and this both after a bolus injection and during infusion of LH-FSH/RH. For FSH a similar pattern of response prevailed during an infusion of LH-FSH/RH. After a bolus administration, however, the FSH release was relatively higher in group III (amenorrhea) than in both groups of normal women in which the increases were about the same. The latter finding suggests that the first pool of FSH is released by a different mechanism than the second pool.


Assessments of the functional capacity of the gonadotrophs in men: effects of estrogen and clomiphene. Serum LH and FSH responses to serial injections of LRF with small (10 mug x 5), large (150 mug x 5), decremental (300 to 10 mug), and incremental (10 to 300 mug) doses at 2-hour intervals were assessed in eugonadal men. At constant doses, pulses of LRF induced pulsatile LH release which was qualitatively similar but quantitatively greater for the large than for the small dose of LRF. There were no periods of refractoriness or augmentation of subsequent responses from prior exposure to LRF when administered at 2-hour intervals. LH responses to incremental and decremental doses of LRF resulted in corresponding measurable changes in the magnitude of pituitary LH release. The FSH responses to pulses of LRF at all doses tested were uniformly small. These data suggest that analyses of the initial and integrated release (10 h experiment) to pulses of LRF may disclose the functional capacity of the gonadotrophs and that small variations in the endogenous LRF delivered may represent a significant factor in the control of LH release. The small dose (10 mug x 5) of pulses of LRF was utilized in the assessment of estrogen and clomiphene treatments on the functional capacity of the gonadotrophs in normal men. Compared with the pretreatment results, both constant doses of ethinyl estradiol (50 mug/day x 7 days) and incremental doses of estradiol benzoate (100 to 400 mug, twice daily injections x 4 d) induced an attenuation of the initial release as well as of the integrated response 10 h) to pulses of LRF. Clomiphene treatment (100 mg/day x 5 d), likewise, resulted in a reduction of gonadotropin release to all pulses of LRF. These data suggest that circulating estrogen in intact men may have both a negative and a positive feedback effect on the gonadotrophs and that the testicular estrogen secretion as well as the extraglandular sources of estrogen, may play a critical role in the regulations of gonadotropin secretion in man.


Gonadotropin and sex steroid response to luteinizing hormone-releasing hormone in patients with premature adrenarche. Luteinizing hormone-releasing hormone (100 mug iv) produced a response of LH, FSH, testosterone, and estradiol in children with premature pubarche that was not different from that among normal prepubertal children. Hence, this study provides no evidence that hypothalamic-pituitary-gonadal maturation occurs with the onset of premature sexual hair.


Plasma gonadotropin and gonadotropin-releasing hormone levels after intranasal administration of gonadotropin releasing hormone. Intranasal administration of gonadotropin hormone (GnRH) in doses ranging from 2-4 mg produced a consistently prolonged LH response in patients with secondary amenorrhea. In 4 cases, a delayed secondary rise occurred. A similarly prolonged FSH response was observed in the majority of patients. Six hours after intranasal GnRH, FSH and LH values were well above basal levels and were higher than those observed at a similar interval after intravenous GnRH. Plasma GnRH levels after intranasal administration failed to achieve the high peaks found after the intravenous route but maintained elevated levels for at least an hour and often longer. Despite the much lower plasma GnRH levels, intranasal GnRH produced a sustained effect on LH and FSH secretion, greater than GnRH given by the intravenous route.


Gonadotropin determinations in times 3-hour urine collections during the menstrual cycle and LHRH testing. The usefulness of timed 3-hour urine collections as a substitute for serum gonadotropin (LH and FSH) determinations during the menstrual cycle and during LHRH testing was examined. The timing of the 3-hour urine collection is not important in mature individuals, since no significant temporal trend was found when aliquots were collected every 3 hours throughout two 24-hour periods in one mature woman. Good correlation was found between serum LH and FSH concentrations and the quantity of LH and FSH in timed 3-hour urine specimens throughout normal, ovulatory menstrual cycles in two women. Studies before and during 51 LHRH stimulation tests in normal men, children, and women during different phases of the menstrual cycle and in patients with a variety of hypothalamic-pituitary-gonadal axis disorders were performed. There was good correlation between the quantity of the gonadotropins in time 3-hour urine collections and the mean serum LH and FSH concentrations before and during the LHRH test. The "response area" for serum LH and FSH also correlated well with the amounts of LH and FSH in the urine collected during this period. Therefore, the timed 3-hour urine collection for gonadotropin estimation provides a simple, accurate method for the integration of fluctuating serum concentrations of LH and FSH during such instances of physiologic variability as the menstrual cycle and LHRH stimulation tests.


The response of pituitary gonadotropes to a constant infusion of luteinizing hormone-releasing hormone (LHRH) in normal prepubertal and pubertal children and in children with abnormalities of sexual development. The pattern of LHRH-evoked release of LH and FSH by pituitary gonadotrophs and the concomitant gonadal steroid secretion were studied in 28 pubertal and 16 prepubertal children. LHRH was administered at doses of 100 mug and 10 mug by a constant-infusion pump over 3 hours following a 2-hour control period. Gonadotropin concentrations were measured at 15-minutes intervals. Mean LH concentrations rose from 2.0 +/- 0.4 (SE) mIU/ml (IRP-2-hMG) to 6.2 +/- 0.9 (P less than .001) in normal prepubertal and from 5.8 +/- 0.9 to 28.0 +/- 3.6 (P less than .001) in normal pubertal children. The peak rise of LH, the mean level attained during the LHRH infusion, and the area under the time-response curve were greater (P less than .001) in pubertal than prepubertal children. The serum LH rise had two components in pubertal children in contrast to a single-phased increase in prepubertal children. Pulsatile release of LH was demonstrated during the basal period in pubertal children and during the LHRH infusion in both groups. FSH release was greater in girls than boys at both stages of pubertal development. A 10 mug LHRH infusion released less LH than did 100 mug in the pubertal children, but more than in prepubertal children. In pubertal boys, plasma testosterone rose (P less than .001) from 222 +/- 45 ng/dl in the control period to 301 +/- 59 following 100 mug LHRH. There was no change in plasma testosterone in the prepubertal boys after 100 mug LHRH or in the pubertal boys following 10 mug LHRH. Plasma estradiol did not rise in girls of either maturity group. In children with hypogonadotropic hypogonadism and structural abnormalities of the hypothalamic-pituitary region, there was no LHRH-evoked gonadotropin release. In 2 agonadal girls, the secretion of LH and FSH was greatly exaggerated. The 3-hour LHRH infusion evoked a maturity-related pituitary LH release and a sex-specific FSH  release; a 2-phased pattern of LH secretion was present in pubertal but not in prepubertal children; pulsatile LH release was evoked by the LHRH infusion in prepubertal children.


Endocrinologic characteristics of partial ovarian failure. Three young women with primary ovarian failure, secondary amenorrhea or oligo-ovulation, and normal gonadotropin levels are reported on here. Vaginal cytology and serum estradiol levels indicated the two women to be persistently hypoestrogenic. The third case, who had the Turner phenotype, was hypoestrogenic during anovulatory cycles but occasionally ovulated. Basal serum LH and FSH were normal. All were tested with synthetic LH-releasing hormone and had a brisk response, LH levels rising 51-198 ng/ml above baseline and FSH rising 278-536 ng/ml. Plasma levels of testosterone, dehydroepiandrosterone sulfate, and progesterone were normal. Gonadal dysgenesis was suggested in two on the basis of an abnormal karyotype, and isochromosome of the short arm of X in Case 2, and an isochromosome of the long arm of X in Case 3. The diagnosis of primary hypogonadism was established by laparoscopy and ovarian biopsy. The latter studies revealed small ovaries with a scarcity of primordial and primary follicles, yet with evidence of current or previous follicular activity. The observation that hypoestrogenism was so marked in two of our patients that elevated serum FSH would have been expected, suggests that the presence of a limited number of ovarian follicles suffices to prevent hypergonagotropism in hypoestrogenic women by a mechanism which does not involve elaboration of sex steroids.


Pituitary hormone levels in plasma of the human fetus after administration of LRH. The concentrations of hFSH, hLH/hCG, hGH, and hTSH1 were measured in maternal and fetal blood during the second trimester of pregnancy before and after the administration of 10 mug LRH to 9 fetuses. A comparison was performed with 9 control fetuses not receiving LRH. The initial value of hFSH was significantly higher in female than in male fetuses (P less than 0.01) and in both sexes exceeded the low maternal hFSH level. A similar fetomaternal difference existed also for plasma hGH, in contrast to plasma hLH/hCG, which concentration was higher in maternal than in fetal blood LRH did not cause any change of circulating hFSH, hLH/hCG, and hTSH levels in the fetus 10 min after its administration. A rise of fetal hGH levels occurred during the observation time irrespective of LRH administration. In amniotic fluid, the hFSH concentration accorded with that in fetal blood, and the hLH/hCG concentration with that in maternal blood. The fetal plasma levels of these pituitary hormones suggest selective release mechanisms for the various peptides. The causes of the absent response of blood gonadotropin levels to LRH in the fetus are discussed.


Rapid method for identification of gram-negative, nonfermentative bacilli. A rapid system (OA), based on oxidative attack of substrates, was developed for identification of gram-negative, nonfermentative bacillia (NFB). One hundred and twelve strains of NFB from 25 species (representing the genera Pseudomonas, Alcaligenes, Acinetobacter, Bordetella, Flavobacterium, Moraxella, and Xanthomonas) were assayed by OA, buffered single substrate, and oxidative/fermentative methods. The 38 substrates consisted of salts of organic acids, nitrogen-containing compounds, alcohols, and carbohydrates. Ninety-four percent of the test strains were identified by the OA method in 24 h, and 99% were identifiable in 48 h. Reproducibility was 99%. Correlation with buffered single substrate was 98% (all substrates) and 90% with the oxidative/fermentative method (carbohydrates only). Biochemical profiles of all strains are presented, as well as tables showing the most useful tests for identification.


Combined serotyping and biotyping of Serratia marcescens. The API (Analytab Products, Inc., New York, N.Y.) biotypes of 117 clinical isolates of Serratia marcescens were determined and fell into 13 different patterns. The O and H antigens were determined by tube agglutination, and 27 serotypes were identified. The biotype and serotype appeared to vary indepently. Serotyping and biotyping combined divided these isolates into 56 different types. There was a problem interpreting the end points for inositol fermentation and urease production, which could affect reproducibility of API biotypes. Biotyping is a simple way of screening for possible nosocomial outbreaks of S. marcescens.


Preparation of rabies fluorescein isothiocyanate-labeled immune globulin from mouse hyperimmune ascitic fluids. Immunization conditions for the production of mouse immune ascitic fluids to be used for the preparation of rabies fluorescent antibody (FA) conjugate are presented. The use of optimal concentrations of ammonium sulfate for precipitation of gamma globulin resulted in a fraction consisting of 75% gamma globulin and 25% alpha-beta globulins with no detectable albumin. Dialysis labeling of the globulin fration with fluorescein isothiocyanate produced a specific rabies FA conjugate with negligible nonspecific background staining. This procedure represents a simple means of producing rabies FA conjugate.


Comparative isolation of vaginal yeasts on selective and nonselective media. The isolation of vaginal yeasts was compared on a selective medium, phosphomolybdic acid agar, and on starch agar, a nonselective differential medium used primarily to isolate Corynebacterium vaginale. The majority of the Candida albicans strains were isolated on starch agar, but the selective medium was required for isolating all yeasts from the greatest number specimens.


Ripazepam (CI-683): double-blind comparison with placebo in anxious patients. Thirty anxious, neurotic patients were treated in a general practice setting with single-blind placebo for one week followed by two weeks of double-blind treatment with either placebo or 40 or 80 mg/day ripazepam (CI-683), a new potential antianxiety agent of the pyrazolodiazepinone series. As rated by both physician and patient, ripazepam was found significantly superior to placebo at both dosage levels. Some evidence of greater improvement at 80 mg/day than at 40 mg/day was also obtained. The drug appeared to be well tolerated, with side effects reported by only four patients.


Curing and caring -- a proposed method for self-assessment in primary care organizations. Key research in the area of quality assessment is reviewed and a method for periodic assessment in primary care organizations is proposed. The suggested approach is designed for administrative, rather than research, purposes. Therefore, it focuses on indicators that are both practical and realistic for use in periodic monitoring. The proposed method is two-staged and includes both technical performance (curing) and satisfaction (caring). At the first level of evaluation, general areas of performance are examined; these are key performance indicators in prevention, diagnosis, and management of illness, and questionnaires dealing with the accessibility and acceptability of care, coupled with objective measures of satisfaction. Those areas of performance that are not up to management standards are then examined in greater detail at the second level of evaluation. Using this approach, organizations can build a longitudinal picture of performance and chart their progress annually.


Reproductive physiological responses of cattle to exogenous prostaglandin F2alpha. Prostaglandin F2alpha caused rapid regression of the corpus luteum and initiated normal transitory hormonal patterns that culiminated in ovulation. PGF2alpha was effective in heat stressed heifers and a thermal stress of 32 C caused no major hormonal alterations from the time of CL regression to ovulation. A luteolytic dose of PGF2alpha tham salt (33.5 mg) given intramuscularly caused no major alterations in blood pressure, heart rate, and uterine or aortic blood temperatures. However, the same dose given as an intravenous jugular infusion over a 2 min period caused major alterations in circulatory homeostasis and body temperature. Treatment of all cattle twice with PGF2alpha tham salt (33.5 mg), 12 days apart, increased the number of responsive heifers at the second PGF2alpha injection. Synchronization of ovulation after the second injection is apparently precise enough to allow for a single timed insemination. Blood injection of estradiol benzoate and GnRH after PGF2alpha treatment will synchronize occurrence of estrus and the preovulatory surge of LH, respectively. However, GnRH treatment at 48 h lowers the frequency of PGF2alpha induced heats and this may be due to alterations in plasma progestins and estradiol.


The choice of suture material for skin closure. Sutures must be chosen on the basis of known biologic properties of the wounds in which they are to be placed, the known interactions of the chosen suture material with tissues of wounds in particular sites, and the intended purpose of the suture material. The following paper concentrates on suture material used to approximate cutaneous wounds, and briefly, the wounds themselves.


Teaching social skills to isolated children. The effects of a social skill training program on socially isolated children are reported. The training program was derived from the results of a previous study of the specific social skills that discriminated popular from unpopular children. Training effects in the present investigation were assessed on sociometric position, and on the quality, frequency, and distribution of social interaction to peers. Time-series analyses were performed on the frequency and distribution of peer interaction. Two isolated children received social skill training with an adult coach, and two isolated children spent an equivalent amount of time with an adult. Results indicated that socially isolated children in the treatment group changed significantly in sociometric position on a follow-up assessment 9 weeks after the end of the intervention, did not change in the total frequency of peer social interaction, but did redistribute their interaction to peers. The two isolated children who did not receive the treatment program did not change significantly on the total frequency of peer interaction, and tended to withdraw from peers rather than redistribute their interaction. The insensitivity of total peer interaction frequency as a measure of outcome was discussed.


Chronically ill children. A psychologically and emotionally deviant population? The study evaluated the psychosocial functioning levels of a group of chronically ill (diabetic, asthmatic, cystic fibrotic, and hearing-impaired) children across a battery of standardized personality instruments. The assessments were performed to provide a rigorous test of the popular hypothesis that chronically ill children are especially vulnerable to psychopatholgy. In contrast to this sterotype, results across measures demonstrated the normalcy rather than the deviance of these children. Although exceptions were noted, the children's functional strengths and coping abilities noticeably outweighed their weaknesses.


Double-blind study of prednisolone and papase as inhibitors of complications after oral surgery. Both prednisolone and papase are effective in reducing the oral surgical sequelae of trismus and pain, although prednisolone apparently is the more potent drug. The countervailing case for the routine use of prednisolone includes the relatively serious complications produced in some patients.


Immunotherapy for mountain cedar pollinosis. A double-blind controlled study. In this study, the effect of a single preseasonal course of injection therapy on the symptoms of patients with allergic rhinitis or asthma due to pollen from the conifer, mountain cedar, was evaluated in a double-blind controlled manner. Patients treated with specific injection therapy were found to have significantly fewer symptoms than those who received placebo injections. Specific serum IgE antimountain cedar antibody decreased during the pollen season in the treated group and increased in the placebo group.


Beclomethasone dipropionate aerosol in the treatment of chronic bronchial asthma. In a double-blind, randomized study, 93 corticosteroid-independent patients with chronic bronchial asthma were treated with either beclomethasone dipropionate aerosol at 400 mug per day of its vehicle for 4 wk to determine and compare the effectiveness and safety of the preparations. Evaluations made before, at weekly intervals during, and 1 wk after treatment indicated that beclomethasone dipropionate aerosol was superior to its vehicle is improving FVC, FEV1, FEF25%--75%, and clinical signs and symptoms, and in the overall evaluations by both the investigators and the patients. Plasma cortisol levels measured at the end of the second and fourth weeks were not substantially different from those before treatment in either group. No significant side effects or abnormalities in laboratory results were noted.


Food safety--then and now. A Bicentennial study. Although this is our Bicentennial year, effective measures to insure food safety date back less than a century. The first efforts toward reform were begun by Accum in England early in the nineteenth century, but they did not bear fruit there--in even a beginning form--until 1875, when Parliament passed the Sales of Food and Drug Act. Legislation came even later in the U.S.--not until the first Pure Food and Drugs Act became law in 1906, largely due to the unswerving efforts for almost twenty years of Harvey W. Wiley. Today, the scientific approach is applied in developing criteria for judging the safety of food and for regulations to insure that healthful, safe food reaches the consumer. Amendments to this law in 1938 and 1958 have further strengthened the protection the public is provided in its food supply. Today, the substances on the "GRAS" list are being examined individually to determine their safety when used in foods. However, the legalistic invoking of absolutes, as in the Delaney Clause of the 1958 amendments, goes beyond the limits of common sense. The challenge is to insure the benefits of science and technology without the loss of basic individual freedom.


Beneficial physiologic action of beans.

Beneficial physiologic action of beans. The author reviews the literature indicating the beneficial effects of a diet high in fiber and the detrimental effects of highly refined carbohydrate intake, which characterizes the present   Western diet. Reduction in serum cholesterol and stimulation of peristalsis can be demonstrated by incorporating beans in the diet. In studies with male volunteers, serum cholesterol has been lowered, despite a high-fat or sucrose diet, and an investigation with rats is cited in which substitution of beans for wheat starch decreased intestinal transit time. The author points out the difference between "crude fiber," figures for which are available in food composition tables, and "indigestible food residue"; he urges that the latter phrase replace the terms "fiber" and "rough-age."


B-vitamin retention in meat during storage and preparation. A review. In this review, the authors bring together present information on B-vitamin retention in frozen meat as it is affected by: Aging before freezing, the freezing process and length of frozen storage, cooking from the frozen or thawed state, method of thawing, cooking methods, and holding and reheating conditions. Literature reports on various cuts of pork, chicken, beef, lamb, turkey and veal are cited. Thiamin, riboflavin, niacin, vitamin B6, pantothenic acid, vitamin B12, biotin, choline, and folic acid are considered.


Three recessive genes for congenital osteopetrosis in Norway rat. In the rat, the autosomal recessive toothless (t1) mutation exhibits an acute form of osteopetrosis. This gene is not an allele of either ia or op that causes respectively, a transitory and acute form of the disease. Comparative radiographic study of t1/t1 and op/op mutants reveals some differences in respect to the size and shape of long bones. In contrast to op/op mutants, homozygous t1/t1 animals failed to respond to either parabiosis or bone marrow transplants.


Approach to three-dimensional mapping of quantitative histochemical measurements applied to studies of the cochlear nucleus. After reviewing the historical development of some procedures for localizing quantitative histochemical measurements, an approach is presented which combines some aspects of these procedures to make possible a permanent, objective record of the location of each sample. The method further allows direct comparisons to be made with drawings of other nearby sections during the process of sampling. Illustrations are given of various applications to a study of the cochlear nucleus. A particular benefit of the approach is to facilitate comparison of chemical with anatomical and physiologic data.


Measurement of H-2 and non-H-2 antigens in the mouse with the footpad swelling test. The footpad swelling (FPS) test for delayed-type hypersensitivity in the mouse was evaluated for its ability to measure histocompatibility (H) antigens present on intact spleen cells or solubilized from a methylcholanthrene-(MCA) induced fibrosarcoma. Mice were immunized to H-antigens (H-2 or non-H-2) with skin allografts and challenged 14 days later with test antigens. Spleen cell-bound and solubilized H-antigens elicited strong and specific FPS reactions in allograft-immunized but not in unimmunized mice. The test could distinguish H-2 from non-H-2 antigens as well as D from KI region specificities of the H-2 gene complex. These experiments suggest that the FPS test is a reliable in vivo method for measuring both cell-bound and solubilized H-antigens in the mouse.


The inhibitory effect of chemotactic factors on erythrophagocytosis by human neutrophils. The effect of various chemotactic factors on phagocytosis of sheep erythrocytes sensitized with IgG and complement (EAC1423) by human neutrophils (PMN) was studied. The bacterial chemotactic factor, a butanol extract of an Escherichia coli culture filtrate, the pronase sensitive and insensitive chemotactic substances isolated from this extract, C5a, a chemotactic fragment of the fifth component of complement, and a chemotactic synthetic peptide, formlymethionyl-leucine all significantly reduced the initial rate of ingestion at concentrations that are chemotactic for PMN. The bacterial chemotactic factor produced a 45 to 75% decrease in the initial rate of ingestion, but did not affect adherence of the EAC1423 and PMN. This same substance had no consistent effect on the total number of EAC1423 ingested at 90 min or longer or on the time interval from the addition of the EAC1423 to the start of ingestion. The inhibitory effect of the bacterial factor increased as the amount of bacterial factor was increased and the inhibitory effect was reversible. Inhibition by bacterial factor could be decreased by increasing the concentration of EAC1423; and if the concentration was increased 3-fold, the inhibition was abolished. These results suggest that inhibition by bacterial factor is competitive in nature.


Lack of association of human "B cell" antigens and Fc receptor activity of antibody-dependent cytotoxic lymphocytes. Heterologous antisera directed against human B cell antigens were tested for their ability to inhibit the function of Fc receptors on human lymphocytes. These antisera coated on the attacking cells in a lymphocyte-dependent antibody-mediated cytotoxic assay inhibited lysis of sensitized target cells. However, the F(ab)2 fragments of the IgG fraction of an anti-human Ia antiserum failed to inhibit the killing of sensitized targets by attacking cells. Antisera against other lymphocyte membrane antigens also inhibited target cell lysis when coated on attacking cells. These results suggest that there is not identity between human B cell antigens and Fc receptors of antibody-dependent cytotoxic lymphocytes.


Mechanisms involved in elimination of organisms from experimental cutaneous Candida albicans infections in guinea pigs. Experimental cutaneous Candida albicans infections were produced in guinea pigs either by using occlusive dressings over the organisms or by applying them to the shaved skin directly without occlusive dressings. In either model there was clearance of the infecting organisms from the skin by a process involving profuse scaling of the keratinized layer in which they were confined. However, for each type of infection the mechanisms producing this scaling seemed to involve different parts of the host defense system. Infections produced under occlusive dressings were characterized by a rapid accumulation of polymorphonuclear leukocytes (PMN) in the epidermis and formation of thick crusts in which organisms were trapped. Sloughing of the crust removed the organisms. In this model, evolution of the lesions and the rate of clearance of the organisms did not depend on prior immunity to Candida. Two possible mechanisms for attraction of PMN into the lesions were direct activation of the alternative complement pathway by the organisms in the lesions and direct chemotactic activity in components of Candida albicans. In contrast, infections produced without occlusive dressings showed only minimal epidermal PMN infiltration, but also underwent profuse scaling of the keratinized layer. This response appeared to depend on cell-mediated immunity. Only animals with previously-acquired delayed hypersensitivity to Candida antigens could undergo this type of scaling, and indeed, this response was transferable to nonimmue animals with peritoneal exudate cells from Candida-immune animals. Clearance of the infecting organisms from this type of infection was significantly faster in immune than in nonimmune animals. It is postulated that a lymphokine released from lymphocytes in the upper epidermis acts on epidermal cells to increase the rate of keratin turnover either by the mitotic rate of the germinal cells or by increasing their rate of keratinization.


Lymphokine-like factors produced by human lymphoid cell lines with B or T cell surface markers. In the present series of experiments we examined the ability of eight continuous cell lines derived from human lymphocytes to release lymphokines into their culture media. We have demonstrated that all could produce a macrophage migration inhibitory factor and a neutrophil chemotactic factor. This ability was independent of the B or T cell origin of the cell lines. As a further extension of previous reports, we report that the migration inhibitory effect does not seem to be due to cytotoxic effects as judged by trypan blue exclusion studies, and more important by the demonstration that the inhibition is reversible. The demonstration that neutrophil chemotactic activity is removable by treatment with a previously described and characterized anti-lymphokine antiserum suggests that this factor may be chemically similar to some of the lymphokines (migration inhibitory factor or chemotactic factor for macrophages) produced by antigen-activated guinea pig lymphocyte cultures. The failure to effect similar removal or inactivation of the macrophage migration inhibitory factor may simply reflect greater interspecies heterogeneity in this factor, or more interestingly, that this does not correspond to "classic" MIF. These results extend previous observations by defining further the capacity of lymphoid cell lines in continuous culture to produce mediators and by characterizing their relationship to conventional lymphokines produced by antigen or mitogen-activated lymphocytes.


Demonstration of binding sites for IgG Fc and the third complement component (C3) on isolated hepatocytes. Isolated hepatocytes from rabbits with experimental acute serum sickness showed immune complexes bound to the hepatocellular membrane with a coarse granular fluorescent pattern. Also in vitro preformed immune complexes (BSA-anti-BSA) or aggregated gamma-globulin from human and rabbit could be bound to the surface of isolated hepatocytes. In contrast, immune complexes with F(ab')2 anti-BSA were not fixed on the membranes. Hepatocytes incubated in fresh serum showed membrane-fixed C3 in a coarse granular pattern. This deposition could be abolished by heating (56 degrees C, 30 min) the serum or by adding EDTA (0.02 M). Also, purified human or guinea pig C3 could be bound to the hepatocellular membrane but in a linear fluorescent pattern. Thus, fixation of immune complexes on hepatocytes appears to operate through binding sites for IgG Fc and, possibly, also through binding sites for C3. It is suggested that these hepatocellular-binding sites may have a physiologic clearance function. In vivo fixed IgA could be detected on the membranes of isolated hepatocytes from healthy persons. It is assumed that the membrane-fixed IgA has a carrier function for antigens from the gut.


Biologic properties of nontoxic derivatives of a lipopolysaccharide from Escherichia coli K235. Lipopolysaccharide (LPS)2 from Escherichia coli K235 was treated with o-phthalic anhydride to obtain a high degree of esterification of available hydroxyl groups, leaving a free carboxyl for each hydroxyl esterified (SPLPS). Although there was no demonstrable loss of fatty acids, this conversion of LPS to a polyanionic molecule altered dramatically the spectrum of biologic properties, most of which are normally attributed to the lipid A (LA) moiety. Mitogenicity for mouse B cells was decreased several hundred-fold; reaction with antibodies to LPS was abolished; pyrogenicity and toxicity were decreased by factors of 10(5) and 10(4); the ability to induce the Shwartzman reaction in rabbits was decreased 500-fold, and the ability to stimulate production of interferon in mice was decreased by more than 2 x 10(3). However, despite the loss of these properties, SPLPS retained the ability to act as an immunologic adjuvant. The nature of the anionic group is important, e.g., sodium succinyl-LPS (SuLPS) is 10-fold more pyrogenic and toxic than sodium phthalyl-LPS (SPLPS). Data on another LPS derivative, from which ester-linked fatty acid residues were removed before phthalylation, suggest that the ester-linked fatty acid groups in the lipid A moeity of SPLPS may not be necessary for its immunologic adjuvant effect.


Suppression of allogeneic lymphomas in spleens of irradiated mice: importance of the D end of the H-2 complex. Dispersed lymphoma cells were transplanted into heavily irradiated mice of a series of congenic resistant strains. Newly synthesized deoxyribonucleic acid was subsequently measured to estimate tumor cell proliferation in spleen and liver. Despite host irradiation, growth of lymphoma cells was suppressed 4 to 7 days after transplantation in the spleen of mice of certain allogeneic strains, but it was barely affected in the liver. The genetic differences resulting in "localized" resistance were mapped in the D region of the H-2 complex. Differences at other regions, including those most important for transplantation resistance in nonirradiated mice (K, I), were inconsequential for lymphoma growth in irradiated hosts. There was a striking resemblance with hemopoietic histoincompatibility, i.e., the rejection of foreign bone marrow grafts by irradiated mice, suggesting that the products of strong Hh gene(s) were expressed in the lymphoma cells.


Percutaneous absorption of betamethasone 17-benzoate measured by radioimmunoassay. Percutaneous absorption was studied in patients following topical application of betametahsone 17-benzoate cream and gel with occlusion by means of a sensitive and specific radioimmunoassay method. Concentrations of betamethasone 17-benzoate in plasma were between 0.3 and 5 ng/ml, indicating approximately 0.05 to 0.3% of the steroid applied to the skin was detected in plasma. Plasma betamethasone 17-benzoate levels increased in proportion to the amount of the steroid applied to the skin. High correlation between plasma betamethasone 17-benzoate levels and percent inhibition of plasma cortisol was also observed. Approximately 3 ng/ml levels of betamethasone 17-benzoate in plasma induced 90% inhibition of plasma cortisol. The data suggest that betamethasone 17-benzoate in gel base was more readily absorbed than in cream base.


Challenge of dogs with live enterotoxigenic Escherichia coli and effects of repeated challenges on fluid secretion in jejunal Thiry-Vella loops. Dogs were evaluated as experimental models for the study of diarrheal disease produced by enterotoxigenic Escherichia coli. Although a suitable whole model for orogastric bacterial challenge could not be developed, chronic jejunal Thiry-Vella loops were used to study the secretory effects of multiple jejunal challenges with enterotoxin of either Vibrio cholerae or E. coli. The heat-stable and heat-labile E. coli enterotoxins could be differentiated clearly in this model. Sequential weekly challenges over a four-week period showed a significant decrease in loop secretory response to homologous enterotoxin, although levels of antitoxin in serum remained unchanged, a finding suggesting a local immune response. Dogs challenged with E. coli enterotoxin were markedly protected against subsequent challenge with V. cholerae enterotoxin; the converse was not true. Histologic studies of the loops showed only minimal atrophy, and results of absorption studies in the loops were normal. These studies suggest that mongrel dogs are resistant to colonization by enterotoxigenic E. coli and partially resistant to challenge with enterotoxin, perhaps on an immune basis due to prior antigenic exposure. Multiple challenges with enterotoxin effect a decreased secretory response; this finding also suggests a local immune mechanism.


Relative efficacy of clindamycin, erythromycin, and penicillin in treatment of Treponema pallidum in skin syphilomas of rabbits. The currently recommended antibiotic for treatment of fetal syphilis in pregnant women who are allergic to penicillin is erythromycin. However, clindamycin crosses the placenta more effectively than erythromycin. Therefore, an in vivo rabbit model of intradermal syphilomas was used to determine the effect of clindamycin compared with the effects of erythromycin and penicillin on the growth of virulent Treponema pallidum. The average number of motile treponemes in two, paired, mature lesions was determined before and after therapy in groups of four rabbits per dosage. Single intramuscular doses of clindamycin (15 and 40 mg/kg) and erythromycin (12 and 40 mg/kg) did not decrease treponeme counts significantly. Single injections of penicillin (10,000 units/kg) reduced treponemal counts by more than 250-fold. Multiple intramuscular injections of clindamycin reduced counts by five- to sevenfold, whereas multiple doses of erythromycin and penicillin decreased treponeme counts by greater than 300-fold. These studies indicate that clindamycin is far less active than erythromycin or penicillin in treatment of established syphilitic lesions in rabbits.


Suggested minimum performance characteristics of data acquisition instrumentation in computer-assisted ECG processing systems. The increasing importance of electrocardiogram (ECG) interpretation by computers warrants consideration of the specific technical requirements for ECG recorders used in computer-assisted ECG interpretation systems. An almost uniform characteristic of these devices is their capability to transmit the ECG signal over common carrier lines. This paper suggests minimum performance characteristics for the different components of a teletransmitting ECG recorder to facilitate the use and evaluation of computer-assisted interpretation systems. Considered are the need for signal fidelity, features for automatic quality control, and features for patient and technician safety. The performance characteristics for the ECG amplifier are only stated where they exceed the most recent recommendations of the Committee on Electrocardiography, American Heart Association. The features of the teletransmission section are based on a widely used mode and format of transmission.


The concepts of sensitivity, specificity and accuracy in evaluation of electrocardiographic, vectorcardiographic and polarcardiographic criteria. The concepts sensitivity and specificity are critically evaluated in the light of case studies drawn from electrocardiographic literature. These terms are often misused, and the meaning of these elementary statistical concepts is often misunderstood in studies on ECG, VCG and PCG criteria. Specificity figures reported in literature commonly refer to the fraction of true negatives with a negative test in normals. Limiting the test to two-group analysis and eliminating other disease categories tend to give overoptimistic values for specificity and diagnostic accuracy in general. It is pointed out that various performance indices for diagnostic accuracy depend heavily on the composition of the test groups and the fraction of test cases in each group. Sensitivity and specificity appear inadequate performance indices for evaluation of event detection schemes such as classification of ectopic beats. Alternative performance indices are considered, including the error ratio, association index, accuracy of positive test, accuracy of negative test, and overall diagnostic accuracy. Increased utilization of simple statistical tests for significance estimation in ECG criteria evaluation is suggested. The development and application of better diagnostic performance evaluation schemes based on concepts of cost of misclassification, entropy and information is encouraged.


Normal and abnormal function of the pacemaker magnetic reed switch. Application of the special test magnet over a demand pacemaker actuates a magnetic reed switch which converts the pacemaker to fixed-rate pacing. The magnetic reed switch is a simple and generally very reliable component. This review discusses the normal and abnormal functions of the pacemaker magnetic reed switch. An understanding of the theoretical and practical aspects of this subject is important in the overall management of patients with implanted pacemakers.


Priming effect of luteinizing hormone releasing factor elicited by preoptic stimulation and by intravenous infusion and multiple injections of the synthetic decapeptide. We have investigated whether the priming effect of LH-RF can be elicited by electrical stimulation of the medial preoptic area, or by i.v. infusion or multiple i.v. injections of the synthetic decapeptide. All experiments were carried out on animals anaesthetized with sodium pentobarbitone at 13.30 h. In pro-oestrous rats, the LH response to the second of two electrical stimuli, 15 min in duration and separated by 60 min, was significantly greater than the response to the first stimulus. When synthetic LH-RF was infused at a constant rate for 90 min, plasma LH increased gradually for the first 45-60 min after which it increased markedly. This enhanced secretion of LH did not occur in rats which were infused with the same total dose of LH-RF, either 15 or 75 ng/100 g body wt, over periods of 45 min or less. When a dose of 15 ng LH-RF/100 g body wt was administered in six divided doses by i.v. injections, each separated by 15 min, there was a marked increase in plasma LH after 75 min. The profile of the mean plasma LH concentration in rats subjected to preoptic stimulation for 90 min was similar to that in rats infused for 90 min with LH-RF, but the variation in response was much greater in the stimulated rats. These results indicate that the priming effect can be elicited by endogenous as well as synthetic LH-RF, and that whether LH-RF reaches the pituitary at a constant rate or in a pulsatile manner the factor is capable of significantly increasing the responsiveness of the gonadotrophs. The relevance of these findings with respect to the development of the spontaneous preovulatory LH surge is discussed. A priming effect could not be elicited by constant LH-RF infusion in dioestrous rats; this supports the view that steroid hormones, especially oestradiol-17phi, determine the magnitude of the effect. The LH response in male rats subjected to i.v. infusion of LH-RF was much lower than in females. Pre-treatment with oestradiol benzoate did not increase the response significantly, suggesting that this sex difference cannot be ascribed simply to low levels of plasma oestrogen in the male.


Priming effect of luteinizing hormone releasing factor: in-vitro and in-vivo evidence consistent with its dependence upon protein and RNA synthesis. The aim of this study was to determine whether the priming effect of LH-RF depends upon RNA and protein synthesis. In in-vivo studies saline, actinomycin D, or cycloheximide was administered i.p. 3-5-4h before the first i.v. injection of synthetic LH-RF into pro-oestrous rats anaesthetized with sodium pentobarbitone at 13.30 h. The LH-response to the second injection of LH-RF (given 60 min after the first) was markedly reduced by the inhibitors, but the response to the first injection was not significantly affected. Studies with cycloheximide given i.v. showed that the inhibition of protein synthesis up to the second injection of LH-RF reduced the magnitude of the priming effect, the reduction being greatest when the inhibitor was administered up to 30 min after the first LH-RF injection. Pituitary incubation studies showed that the priming effect could also be elicited in vitro and that it could be significantly reduced by actinomycin D, cycloheximide and puromycin. As in vivo, the inhibitors had relatively little effect on the LH-response to the first exposure to LH-RF. The protein synthesized after an injection of LH-RF may be new LH, and/or a protein(s) concerned with 'activation' of the receptor or release components of the LH-secretory apparatus.


Pattern formation in early developmental stages of amphibian embryos. An internal factor (or factors), which determine the endoderm and the mesoderm anlage, seem to exist already in certain regions of the oocyte and very early developmental stages. The factor(s), which is (are) protein in nature, has (have) similar properties to the one isolated from chicken embryos. The induction of the neural plate seems to be mediated by a membrane mechanism. The segregation of the primarily formed anlagen occurs by secondary tissue interactions.


Implantation and early postimplantation development of the bank vole Clethrionomys glareolus, Schreber. The development of the bank vole Clethrionomys glareolus is described from implantation to the formation of the foetal membranes. The embryonic development of this species combines features of primitive rodent species, for example Geomys bursarius and highly specialized ones, for examples Mus musculus. The egg-cylinder is formed by invagination into the blastocoelic cavity of the inner cell mass and polar trophoblast overlying it; this resembles in many respects the early stages of development of primitive species. The fully formed egg-cylinder, however, resembles that of the mouse and the formation of foetal membranes is also similar to that in Muridae. It is concluded that in the bank vole and also in other rodents, the extra-embryonic ectoderm of the egg-cylinder is derived from the polar trophoblast rather than from the inner cell mass.


An experimental investigation into the possible neural crest origin of pancreatic APUD (islet) cells. It has recently been contended that pancreatic APUD cells are neural crest derivatives. In an experimental investigation, isotopic grafts of neural tube containing neural crest cells were transplanted from chick and quail embryos labelled with tritiated thymidine, and from unlabelled quail embryos, to host chick embryos at the same stage of development. Transplantations were performed at various levels between somites 5 and 24 in embryos at 6- to 24-somite stages. In operated embryos at 3 3/4 days of incubation, the pancreatic APUD cells were not labelled; nor did their nuclei show quail features. Migration of cells from the graft was evidenced by the presence of quail nuclei and/or radioactive label in autoradiographs, in spinal and sympathetic ganglia in the operated region. It is concluded that the pancreatic APUD cells of the 3 3/4-day-old chick embryo are not derived from the trunk neural crest up the level of somite 24. It is unlikely that more caudal levels contribute, because APUD cells are already concentrated in the dorsal pancreatic bud region at the 24-somite stage, by which time no migration of crest cells has occurred caudal to somite 24. This conclusion probably concerns A, B and D pancreatic endocrine cells.


Allergy skin testing of children.

Allergy skin testing of children. Skin tests are important aids in the management of patients with inhalant allergy. Their usefulness will be increased if these basic principles are kept in mind: (1) Scratch test should be sufficiently deep, (2) Antigen extracts used for intradermal tests should be fresh enough to insure their activity, (3) Two control tests should be used each time tests are done, (4) Hydroxyzine and promethazine may diminish skin reactivity; therefore, negative skin tests should not be relied upon until repeated in the absence of such medication,  and (5) Skin tests for food allergy are quite unreliable, whether positive or negative. Food allergy is best studied by means of elimination trial diets.


Duration of the cycle of the seminiferous epithelium in the prairie vole (Microtus ochrogaster ochrogaster). The cycle of the seminiferous epithelium in M. o. ochrogaster was divided into eight readily recognizable stages based on the morphology of the developing spermatid. The mean relative frequencies of Stages I through VIII were 11.6, 19.25, 20.00, 19.00, 8.42, 6.17, 9.25 and 6.58%, respectively. The duration of one cycle of the seminiferous epithelium in this species, as determined from autoradiographs of thymidine-H3 injected testes was 7.17 days (S.E. +/- 0.03). This is the shortest spermatogenic cycle reported for any mammal to date. The approximate durations of the meiotic prophase, meiotic divisions, and spermiogenesis were 8.8, 0.4 and 12.2 days, respectively. The entire process of spermatogenesis was estimated to span approximately 28.68 days. The number of cycles that spermiogenesis spanned in this species was compared to values calculated for other species. Values within groups of related species appear relatively constant, but between groups the values are variable.


The development of regional pigmentation patterns in black and tan (at) mice. Mice which express the black and tan (at)allele at the agouti locus have black dorsal and yellow ventral hairs. To determine the site of action of this allele, the kind of hair pigment produced by various dermal-epidermal recombinations of dorsal and ventral black and tan (at/at), ventral nonagouti (a/a) and ventral yellow (Ay/a) embryonic skin has been investigated. The results indicate that it is the dermis which is responsible for the development of regional pigmentation patterns in black and tan mice.


Properties of a DNA ligase mutant of Escherichia coli: introduction of strand breaks in DNA. Strand breaks accumulated in the DNA of a temperature-sensitive DNA ligase mutant of Escherichia coli growing at the restrictive temperature, as detected by zone sedimentation through alkaline sucrose density gradients. The rate of strand breakage was increased by concomitant thymine starvation. Rifampicin and chloramphenicol inhibited the accumulation of strand breaks in the DNA. There was a correlation between the accumulation of strand breaks in the DNA and lethality, suggesting that such breaks are the basis for lethality at the restrictive temperature.


Porphobilinogen-accumulating mutants of Salmonella typhimurium LT2. Four independent porphobilinogen-accumulating mutants of Salmonella typhimurium LT2 were isolated by selecting for dwarf colony formation on neomycin agar media. Cell-free extracts of the parent strain, but not of the mutants, were able to convert 5-aminolaevulinic acid or porphobilinogen to porphyrins. The results indicated that the mutants were deficient in uroporphyrinogen I synthase (EC. 4.3.I. 8) activity: these are the first mutants of this type reported in S. typhimurium LT2. Mapping of the hemC locus (for uroporphyrinogen I synthase) by F-mediated conjugation and by P22-mediated transduction showed the gene sequence ilvEDAC-hemC-cya-metE.


Isolation and characterization of mutants of Escherichia coli K12 resistant to the new aminoglycoside antibiotic, amikacin. Spontaneous mutants of Escherichia coli K12 that are resistant to the new aminoglycoside antibiotic, amikacin, were isolated. These mutants have simultaneously acquired cross-resistance to kanamycin, gentamicin and neomycin but not to streptomycin or spectinomycin. Sensitivity of the mutant strains to the non-aminoglycoside antibiotics, ampicillin, tetracycline and polymyxin, was unaffected. The mutation responsible for amikacin resistance was mapped by PI transduction and found to be tightly linked to strA, distal with respect to spcA and aroE.


The effects of proteins on bacterial attachment to polystyrene. Bovine serum albumin, gelatin, fibrinogen and pepsin impaired the attachment of a marine pseudomonad to polystyrene Petri dishes, apparently through adsorption on the dish surface. Serum albumin also appeared to affect the bacterial surface. The basic proteins protamine and histone did not markedly inhibit attachment. These findings are discussed in relation to comparative experiments using tissue cells.


Effect of propranolol on acute withdrawal tremor in alcoholic patients. The effect of the beta-adrenergic blocking agent propranolol was tested on positional tremor occurring during acute alcohol withdrawal using a double-blind crossover method and electrical recording of tremor amplitude and frequency. The difference between the effects of propranolol and placebo was not significant.


Trans-unco-discal approach. A combined anterior and lateral approach to cervical discs. A series of 40 patients with degnerative discopathy was effectively treated to means of trans-unco-discal approach, which is a combined anterior and lateral approach to cervical discs. Interbody fusion is not performed except for special cases such as significant kyphosis and unstable cervical spine. Twenty patients who had this approach without interbody bone graft have been followed clinically and radiographically for 9 to 36 months. The author describes the surgical techniques, complications, and results.


Histologic evaluation of intraoral skin grafts and pedicle flaps in humans. Histologic evaluation of biopsy specimens from six split-thickness skin grafts and seven pedicle flaps was made two months to 15 years after intraoral cancer reconstruction. In the transplanted skin, there was persistence of all epidermal layers with production of orthokeratin and melanin, and persistence of papillary and reticular dermis with viable hair follicles and sweat glands. The junction of epidermis and mucosa was distinguished by a strongly positive PAS staining of the mucosal epithelium. There were no differences in the observations on split-thickness grafts and pedicle flaps. After 15 years of exposure to an intraoral environment, "mucosalization" of the skin was not evident.


Recurrence of group B streptococcal infection. It is clear that the group B streptococcus has become a major pathogen of young infants within the comparatively recent past. Further it is clear that, as with other endemic and epidemic pathogens, increasing clinical and laboratory experience brings to light variations not initially evident. In addition, therapy presumably effective in initial cases may not continue to be so. The following papers by coincidence were received over a relatively brief period of time. Hence, for emphasis of some of the problems related to this organism, they are presented as a group.


Failure of penicillin to eradicate the carrier state of group B Streptococcus in infants. Serial cultures were obtained from 12 patients being treated with a form of penicillin for group B streptococcal disease or asymptomatic colonization. These cultures were collected prior to initiation of therapy, during therapy, and at the end of the treatment period. Pencillin eradicated GBS from the involved system (blood, CSF, bone, and joint). Cultures remained positive from at least one of three carrier sites (throat, umbilicus, and rectum) in 70% of patients cultured between days one and eight of treatment and 66% between days 10 and 21. These data demonstrate the failure of penicillin to eradicate GBS from mucous surfaces of young infants.


Antibiotic-killing kinetics of group B streptococci. Group B streptococci are uniformly susceptible to penicillin or ampicillin. Nevertheless, morbidity and mortality in newborn infants infected with group B streptococci is a major clinical problem. Bacteriologic determinants in the outcome of this infection were studied. Streptococcal killing kinetics were studied for ampicillin alone and in combination with gentamicin. In all cases killing was accelerated by the combination. The practice of discontinuing administration of the aminoglycoside antibiotic when group B streptococcal infection is confirmed should be re-evaluated.


Early onset group B streptococcal disease: clinical, roentgenographic, and pathologic features. Thirty-one neonates with early onset of serious group B streptococcal infections were observed in a four-year period. The mortality was 52%. Premature infants with clinical signs of respiratory distress syndrome were at highest risk of death; clinical signs of RDS were typical until apnea, shock, respiratory failure, and worsening of the radiographic pattern unexpectedly intervened. Pathologic material from infants with radiographic evidence either of RDS or of pneumonia showed both typical hyaline membrane disease and pneumonia in most instances. Factors which may be helpful in recognizing premature infants at risk for GBS disease in the much larger group of premature infants with uncomplicated RDS include: history of artificial, premature, or prolonged rupture of membranes; localized pulmonary infiltrates on chest roentgenogram; low absolute neutrophil count; and an unusually rapid progression of RDS.


The role of exchange transfusions in the management of low-birth-weight infants with and without severe respiratory distress syndrome. II. Further observations and studies of mechanisms of action. Exchange transfusion, as a form of therapy, was contrasted with the use of fresh frozen plasma or conventional supportive care alone in the management of 19 infants with birth weights of less than 1,000 gm, without severe respiratory distress, and in the management of 82 infants, birth weights less than 2,000 gm, with severe respiratory distress whose disease manifested itself within the first 24 hours of life. Survival for more than five days was similar, regardless of therapy, in infants weighing less than 1,000 gm without severe RDS. In contrast, the use of exchange transfusion significantly decreased the case fatality rate of infants with severe RDS. In the groups receiving exchange transfusion, the mortality rate was 41%, whereas the groups receiving either plasma or supportive care alone the mortality was 80%. Study of coagulation factors and red cell concentrations of fetal hemoglobin and of 2,3-DPG failed to demonstrate any relationship between either improvement in coagulation or oxygen unloading and the improved survival of infants receiving exchange transfusion. Following exchange transfusion there was a significant decrease in the ratio of FIO2 to PaO2, suggesting that pulmonary perfusion and/or ventilation was improved by the procedure.


Rationale for stabilization.

Rationale for stabilization. 1. The subjective separation of the normal and the diseased periodontium for splinting purposes is artificial. With the exception of cases of secondary trauma from occlusion, the diseased periodontium should be treated in the same manner as the normal periodontium with regards to splinting. 2. Retionales for stabilization found to be valid are: I. Prevention of mobility A. Post acute trauma. B. In occlusal therapy. II. Prevention of drifting A. Replacement of missing teeth. B. Postorthodontics. III. In treatment of secondary trauma for occlusion. A. For functional stability. B. With unknown effects on the progression of periodontitis. 3. The relationship of trauma from occlusion and periodontitis is unclear at this time. 4. A need exists for a clinical test correlating histologic signs of trauma from occlusion and clinical findings. 5. Temporary splinting generally is not indicated during the initial or surgical phase of treatment of the periodontal patient, because mobility short of secondary trauma from occlusion does not impair healing.


Pharmacokinetics of methyldopa in man.

Pharmacokinetics of methyldopa in man. Single doses of methyldopa were administered orally and intravenously as aqueous solutions to 12 healthy volunteers in a crossover study. Serial plasma and urine samples were analyzed specifically for methyldopa and its O-sulfate conjugate. Kinetic analyses of the results indicated that methyldopa disposition could be adequately represented by a two-compartment open model. Renal excretion accounted for about two-thirds of the plasma clearance of methylodopa. Absorption profiles were constructed with the aid of the pharmacokinetic model and contrasted with estimates of absorption which were model-independent. The mean fraction reaching the systemic circulation as methyldopa was estimated to be 0.25 (range 0.08-0.62 for n = 11). Although most of the absorption occurred within the first 5 hours oral administration, a minor component, suggestive of limited enterohepatic circulation, persisted from 9 to 36 hours. O-sulfate conjugation was route-dependent and appeared to be derived predominantly, if not exclusively, as a first-pass effect of absorption and/or enterophepatic circulation.


The effect of A23187 ionophore on calcium movements and contraction processes in single barnacle muscle fibres. 1. Ca movements were studied in single giant muscle fibres of the barnacle before and after exposure to the Ca ionophore A23187. 2. In fibres micro-injected with the photoprotein aequorin, the resting rate of light emission (resting glow) reversibly increased when the external Ca was augmented in the presence of A23187. This resulted from an increased Ca influx through the outer membrane. In zero external Ca, A23187 induced a delayed increase of the resting glow which was related to Ca leakage from intracellular storage sites. 3. When the experiment was carried out at 5 degrees C instead of 22 degrees C, the resting glow about doubled (temperature-sensitive mechanisms for maintaining a low myoplasmic Ca2+ were thus depressed) but A23187 was much less effective in increasing Ca influx in high external Ca. 4. In 45Ca efflux experiments, A23187 increased both the Ca-Ca exchange diffusion and the net Ca outflux at the outer membrane of the fibre. The Na-Ca exchange process was not affected to a significant extent. 5. The Ca2+ transient and the force of the contraction elicited by imposed membrane depolarizations (below the threshold of the propagated action potential) were markedly increased by A23187, but the electromechanical threshold was not significantly modified. The linear relation between membrane depolarizations and the area of the Ca transient became much steeper in the presence of A23187. However the relation between the area of the Ca transient and the force output was not affected which suggests that A23187 specifically involved the Ca2+ intracellular release, but not the subsequent Ca-troponin reaction. 6. A23187 potentiates by ionophoretic action the Ca movements at the outer membrane, and it also acts inside the intact muscle fibre to intensify the intracellular release of Ca.


On the metabolism of the rod outer segments. 1. The high energy phosphate esters available for the luminescent reaction of the firefly lantern extract correspond, in the dark adapted rods of the frog, to 7 X 10(-16) mole of ATP per rod, corresponding to ca. 1-4 mM. 2. Rods isolated from light adapted eyes contain a smaller amount. 3. The high energy phosphate esters are reduced spontaneously at a rate of 50% in 24 min, in the isolated rods in darkness. 4. Bleaching a few per cent of the rhodopsin molecules of a rod suspension induces a 60% decrease achieved in less than 12 sec. 5. The ionophore A23187 decreases the high energy phosphate esters when the extracellular free Ca concentration is greater than 10(-7) M, suggesting that ATP is consumed in pumping Ca ions out of the rods, or into the disks contained in the rods, or both.


A comparison of the pepsin stimulating effects of secretin preparations. 1. The peptic responses to Boots, GIH and synthetic secretins have been compared in fasting anaesthetized cats in which the pylorus and bile duct were occluded to prevent the release of duodenal hormones by acid and bile salts. A quantity of dilute acid introduced into the stomach at regular intervals ensured the total recovery of viscid secretions and preserved peptic activity. 2. The mean peak outputs of pepsin obtained in response to Boots secretin were significantly greater than the mean peak outputs of pepsin stimulated by equipotent doses of GIH secretin (4 Crick-Harper-Raper units of Boots secretin have been shown to stimulate a flow of juice and bicarbonate from the pancreas equal to that produced by 1 clinical unit of GIH secretin). The maximum output of pepsin stimulated by Boots secretin, 16 C.H.R. u./kg hr was 3 times the observed maximum output in response to the 4 times more potent dose of GIH secretin, 16 c.u./kg hr. The slopes of the log dose-response lines were significantly different for these two products indicating that their modes of action in stimulating pepsin may not be identical. 3. The outputs of pepsin following GIH and synthetic secretin were similar. Both these secretins stimulated the secretion of pepsin when infused in doses which stimulated the pancreas supramaximally. The less pure product Boots secretin evoked significantly higher peptic responses at doses submaximal for pancreatic stimulation, suggesting that a substance other than secretin exists in Boots preparations which contributes significantly to the overall output of pepsin in response to this product. The peptic response which was accompanied by a slight increase in acid output, but without any increase in pancreatic lipolytic activity, was not inhibited by atropine. This substance which is not present in highly purified GIH secretin does not appear to be cholic acid, gastrin, pancreozymin, glucagon or insulin. 4. The possibility that a vasodilator substance is present in Boots secretin which by expanding the splanchnic bed increases the concentration of secretin at target sites in the stomach and pancreas seems unlikely, as the flow of pancreatic juice does not increase proportionately with the vast increase in pepsin. A vasodilator substance which specifically affects the gastric vasculature remains a theoretical but unlikely explanation for our observation.


The interaction of secretin and stimulants of gastric acid secretion in anaesthetized cats. 1. In fasting anaesthetized cats in which the pylorus and common bile duct were occluded, acid secretion in response to caerulein, desulphated caerulein, histamine and N methyl histamine given singly and combined with Boots secretin 4 C.H.R. u./kg hr has been studied. 2. Eight separate estimates of the calculated maximal response of acid (four acid stimulants given with and without secretin) did not differ significantly from one another. In the presence of secretin the E.D.50 of each acid stimulant was lowered. 3. Outputs of acid in response to the smallest doses of desulphated caerulein, histamine and N methyl histamine increased significantly when secretin was infused (P less than 0-05). 4. On a weight basis caerulein was 23, 474 and 95 times more potent than desulphated caerulein, histamine and N methyl histamine respectively. 5. When secretin was infused simultaneously caerulein was 8, 171 and 165 times more potent than desulphated caerulein, histamine and N methyl histamine respectively. 6. N methyl histamine was 5-6 times more potent than histamine on a weight basis when infused on its own; and 1-16 times more potent than histamine when given in the presence of secretin.


Fenoprofen calcium therapy in rheumatoid arthritis. Fenoprofen calcium (FC) was compared to aspirin (ASA) in 20 patients with rheumatoid arthritis in a double-blind parallel study. The average daily dose was 2.0 gm of FC, or 3.6 gm of ASA. Most patients on FC therapy responded similarly to those receiving ASA, but FC was slightly better in reducing morning stiffness, walking time, fatigue severity, and activity index. More FC treated than ASA treated patients became worse when placebo was substituted after one year of therapy, with a greater increase in the number and severity of painful and swollen joints, in addition to the above mentioned parameters. This suggests a greater suppression of the inflammatory process during FC therapy. FC was well tolerated and had a greater antirheumatic effect than aspirin. Both drugs were superior to placebo.


Fenoprofen in rheumatoid arthritis: a controlled crossover multi-centre study. The pooled data of a multi-clinic, double-blind, crossover study (16 weeks' duration), comparing fenoprofen and aspirin in 116 patients with active rheumatoid arthritis are reported. Each patient received fenoprofen (400 mg Q6H) and aspirin (1,000 mg Q6H) for six-week periods, in random fashion. Usual objective and subjective parameters were used to evaluate rheumatic activity. Side effects were obtained by daily telephone interviews, and appropriate laboratory tests were performed during weekly out-patient evaluations. Both fenoprofen and aspirin were significantly more effective than placebo in controlling rheumatoid activity. At the dosage level employed, no significant differences were noted between the two anti-inflammatory agents in regard to efficacy. However, fewer side effects were observed with fenoprofen than with aspirin. The data indicate that fenoprofen is an additional valuable agent for rheumatoid arthritis.


Fenoprofen in patients with rheumatoid arthritis receiving maintenance gold therapy. Thirty patients with active definite or classic rheumatoid arthritis (RA), participated in a double-blind crossover study comparing fenoprofen calcium with placebo. All patients were receiving maintenance gold therapy. Fenoprofen was administered in doses ranging from 200 to 800 mg every six hours. The median daily dose was 1.8 gm. During this 16-week trial, most parameters of efficacy showed fenoprofen to be significantly more effective than placebo. Adverse reactions, which were minimal, suggest that fenoprofen will be useful in the management of patients with RA, particularly in those with gastrointestinal intolerance to the usually employed drugs. The longterm effectiveness in RA, and the side effects associated with chronic administration remain to be assessed.


Fenoprofen calcium in steroid treated rheumatoid arthritis: efficacy, safety, and steroid-sparing effect. Twenty-one patients with active rheumatoid arthritis on maintenance corticosteroids were studied during a double-blind, crossover trial with fenoprofen. Fenoprofen showed significantly greater effect than did placebo on several subjective and objective measurements. In addition, patients were able to reduce their dose of corticosteroid to a level significantly lower than that during placebo periods. Though three patients dropped out of the study with gastrointestinal complaints while on fenoprofen, only one of these was believed to be drug-related. No serious adverse effects were encountered.


Longterm fenoprofen therapy in patients with rheumatoid arthritis. Fenoprofen, a new antirheumatic agent, was evaluated in 45 patients with rheumatoid arthritis in an open study design to simulate the conditions under which the drug will be used. No control agents were used. The effectiveness of fenoprofen was demonstrated by the per cent of patients who improved during fenoprofen therapy. Duration of therapy varied from one to 629 days. Pain was the first parameter to respond, followed by an anti-inflammatory effect, which was observed after four to six weeks of therapy. Side effects consisted mainly of minor gastro-intestinal symptoms.


Comparison of benefit-to-risk ratios of aspirin and fenoprofen: controlled multicentre study in rheumatoid arthritis. The benefit-to-risk ratios of fenoprofen (2.4 gm/day) and aspirin (3.9 gm/day) were compared in a randomized, double-blind, 26-week parallel study involving 216 patients. Criteria for inclusion, exclusion, subjective, and objective evaluations were based on the PMA-FDA Nonsteroidal Anti-Inflammatory Drug Clinical Testing Guidelines. Thirty-four of 109 aspirin-treated patients and 23 of 107 patients on fenoprofen dropped out of the study. Both fenoprofen and aspirin brought about improvement in most efficacy parameters measured, but fenoprofen was superior to aspirin (p less than 0.05) in reduction of swollen joints, grip strength, activity index, and patients' preference of medication. The number and frequency of complaints and the incidence of abnormal SGOT levels, were greater with aspirin than with fenoprofen. The study suggests that fenoprofen has a better benefit-to-risk ratio than aspirin, when given in equally effective doses.


Some problems in the interpretation of clinical trials: longterm parallel study of fenoprofen in rheumatoid arthritis. Fenoprofen calcium was compared with acetylsalicylic acid in the treatment of 27 patients with definite or classic rheumatoid arthritis, over a period of one year. Both drugs appeared efficacious, with a slight edge to fenoprofen in the doses employed. Fewer side effects were noted with fenoprofen. Effectiveness continued undiminished throughout the year, and mean values of most parameters continued to improve in both groups over the entire period. Three problems which influence extrapolation of results from this and similar studies to the general setting are discussed. (1) Individual patients show great variation from the mean and from one observation point to another. Thus, expectations developed from mean values will seldom be accurate in a particular patient. (2) The relative doses chosen for two drugs in the clinical trial can profoundly influence both efficacy and toxicity. The qualification "at the doses employed" is seldom emphasized in clinical reports. (3) Patient compliance in the general clinical setting is importantly different from that in a clinical trial, and this potential problem must be assessed by the physician choosing an appropriate medication for a particular patient.


Double-blind crossover study of fenoprofen and aspirin in osteoarthritis. In a randomized, double-blind, six-week, crossover comparison, fenoprofen (200 mg to 600 mg every six hours) had similar efficacy to aspirin (325 mg to 975 mg every six hours) in the treatment of patients with osteoarthritis affecting the spine, hip, knee, or shoulder. Both fenoprofen and aspirin had greater efficacy than placebo. The overall incidence of side effects was similar during aspirin and fenoprofen therapy.


Fenoprofen therapy in large-joint osteoarthritis: double-blind comparison with aspirin and longterm experience. This study, designed to evaluate fenoprofen in patients with osteoarthritis, consisted of two phases: I. A double-blind crossover comparison of fenoprofen, 200 to 600 mg every six hours, to aspirin, 325 to 975 mg every six hours; II. Longterm use of fenoprofen in an open study design. During the first part of the study, both fenoprofen and aspirin were significantly better than placebo in relieving the severity and duration of pain, and in reducing stiffness. In most of the variables fenoprofen was also slightly better than aspirin. The most frequently observed side effects were abdominal discomfort, headache, pruritus, nervousness, and tinnitus. Longterm administration demonstrated the safety of fenoprofen or periods exceeding two years. Fenoprofen did not precipitate or aggravate chronic disorders, nor did it mask the symptoms of any developing disease. No interaction with concomitant drug therapy was observed.


Controlled evaluation of fenoprofen in geriatric patients with osteoarthritis. A double-blind, crossover study compared the use of fenoprofen to aspirin in patients with osteoarthritis of large joints, most of them with knee involvement. A total of 24 patients participated in the study. Their ages ranged from 48 to 75 years, with an average age of 63 years. The mean daily dose was 1.8 gm of fenoprofen and 3.1 gm of aspirin in divided doses. Efficacy parameters showed that fenoprofen and aspirin provided significantly greater relief of osteoarthritis symptoms than placebo, and that the two active drugs were essentially equal in effectiveness. Fenoprofen was well tolerated in this group of patients. Only one patient discontinued the study during fenoprofen therapy because of side effects. The overall incidence of adverse reactions with fenoprofen compared favorably to that with placebo; the highest incidence was associated with aspirin therapy.


Clinical pharmacology of fenoprofen: a review. This review summarizes available data concerning fenoprofen. The pharmacodynamics, in vivo interactions, gastrointestinal microbleeding, screening for anti-inflammatory action, and tests for antipyretic and analgesic efficacy are discussed.


Veterinary public health implications of U H T processing of milk. The introduction of U H T treatment of milk into South Africa raises problems for local public health authorities controlling milk hygiene in their respective areas because of the legislation concerning milk produced and sold for various purposes. It is essential that the raw milk supply be derived from healthy cows with healthy udders, and be produced under sanitary conditions. Uniform control standards are necessary for U.H.T. milk and other forms of milk supplying throughout the Republic. Uniformity is also desirable for efficient local authority veterinary health services. The progress of veterinary control and supervision of Johannesburg's milk supply is discussed to indicate what has been achieved. There is need for a national scheme for controlling mastitis. Tests for the purchase of milk on quality must include tests for udder health by regular electronic cell counting of raw milk sources. Appropriate mastitis control incentive or penalty schemes for milk producers should be instituted.


Some diseases of domestic rabbits encountered in the western Cape. The most common disease conditions encountered in domestic rabbits under intensive conditions in the Western Cape are discussed. Chlamydiosis is of paramount importance; it might be the limiting factor in the developing Rabbit Industry.


A review of mineral imbalances of grazing animals in southern Africa. A historical review of mineral imbalances recognised in Southern Africa is given. The survey procedures which were followed are described in terms of sample sources, as well as the analytical procedures with emphasis on the problems encountered at each stage of the developments. A concise summary is given of the mineral patterns known to date according to the ten regions currently recognised where specific patterns of mineral imbalances are known to occur.


Immunity to Salmonella infections.

Immunity to Salmonella infections. The results of current investigations regarding the mechanisms of immunity to Salmonella infections and the use of vaccines are presented. Since chemical suppression of the humoral immune response in chickens does not jeopardise immunization with a live vaccine and immunized guinea-pigs exhibit distinct inhibition of macrophage migration, it is concluded that cellular immunity is a prominent factor in protection. Data is presented to show that the mice and calves can be equally well immunized with either live or inactivated S. typhimurium and S. dublin vaccines and the practical advantages of inactivated vaccines are discussed.


Semisynthetic cephalosporins. Synthesis and structure-activity relationships of 7-sulfonylacetamido-3-cephem-4-carboxylic acids. The synthesis and in vitro and in vivo activities of a series of 7-sulfonylacetamido-3-cephem-4-carboxylic acids with acetoxymethyl or heterocyclic thiomethyl substituents at the 3 position are described. Lengthening the alkyl chain attached to the sulfonyl group increased gram-positive activity but the effect on gram-negative activity was variable. Other structural changes on the 7-acyl side chain resulted in only minor changes in vitro activity.  the protective effectiveness in infected mice generally paralleled the in vitro activity, except that the butylsulfonyl derivatives were less protective than predicted by in vitro activity. replacement of the 3-acetoxymethyl by a 3-heterocyclic thiomethyl group resulted in an overall improvement of activity both in vitro and in vivo.


Imidazo(1,2-c)pyrimidine nucleosides. Synthesis and biological evaluation of certain 1-(beta-D-arabinofuranosyl)imidazo(1,2-c)pyrimidines. The first chemical syntheses of the arabinosylhypoxanthine and arabinosylguanine analogues of the imidazo-[1,2-c]pyrimsdine series are described. Condensation of trimethylsilyl-7-chloroimidazo[1,2-c]pyrimidin-5-one (1) with 2,3,5-tri-O-benzyl-alpha-D-arabinofuranosyl chloride (2) gave 7-chloro-1-(2,3,5-tri-O-benzyl-beta-arabinofuranosyl)imidazo[1,2-c]pyrimidin-5-one (3) which on catalytic dehalogenation furnished 1-(2,3,5-tri-O-benzyl-beta-D-arabinofuranosyl)imidazo[1,2-c]pyrimidin-5-one (4). Amination of 3 gave 7-amino-1-(2,3,5-tri-O-benzyl-beta-D-arabinofuranosyl)imidazo[1,2-c]pyrimidin-5-one (5). Reductive hydrogenolysis of 4 and 5 gave 1-(betaD-arabinofuranosyl)imidazo[1,2-c]pyrimidin-5-one (6), the arabinosylhypoxantine analogue, and the corresponding 7-amino isomer 7, the arabinoosylguanine analogue, respectively. The unequivocal assignment of the site of glycosylation and the anomeric configuration have been established. None of the compounds exhibited significant antiviral or antimicrobial activity in vitro.


Antimalarials. 3. 1,2,4-Triazines.

Antimalarials. 3. 1,2,4-Triazines. The syntheses of a number of substituted 1,2,4-triazines as potential antimalarials are described. The structural requirements for antimalarial activity are discussed with reference to the substituents of a phenyl group in the 6 position and amino groups at the 3 and 5 positions. Of the compounds tested, 2,5, and 7 produced cures in mice infected with plasmodium berghei. Compounds 2(3,5-diamino-6-(4-trifluoromethylphenyl)-1,2,4-triazine),3,5,8,12,and 37 produced cures in chicks infected with Plasmodium gallinaceum.


Synthesis, antimalarial activity, and phototoxicity of some benzo(h)quinoline-4-methanols. Nine alpha-dibutylaminomethylbenzo[h]quinoline-4-methanols were synthesized from the corresponding 1-amino-naphthalenes by the following sequence: 1-aminonaphthalene leads to 1H-benz[g]indole-2,3-dione leads to benzo[h]quinoline-4-carboxylic acid leads to acid chloride leads to bromomethyl ketone leads to epoxide leads to benzo[h]quinoline-4-methanol. Several acid chlorides substituted in the 3 position reacted incompletely with ethereal diazomethane but were efficiently converted, without isolation of the intermediates, to the bromomethyl ketones by reaction with ethoxymagnesium diethylmalonate, bromination, hydrolysis, and decarboxylation. Several compounds prepared, especially alpha-dibutylaminomethyl-2-(2',4'-dimethylphenyl)-3-methyl-6-chlorobenzo[h]quinoline-4-methanol, showed significant antimalarial activity against Plasmodium berghei in infected mice but were moderately phototoxic.


Synthetic inhibitors of Escherichia coli, calf thymus, and Ehrlich ascites tumor thymidylate synthetase. In a study of active site binding the inhibition of thymidylate synthetase derived from Escherichia coli, calf thymus, and Ehrlich ascites tumor was examined using eight inhibitors. 5-Substituted 2'-deoxyuridine 5'-phosphate analogues used in this study are the hydroxymethyl, methoxymethyl, benzyloxymethyl, formyl, acetyl, allyl, and two potential active site alkylating substituents: 2,3-oxypropyl and the azidomethyl analogues. All compounds were competitive with the substrate, 2'-deoxyuridine 5'-phosphate; the most potent inhibitor was 5-formyl-dUMP (Ki = 0.1, 0.09, and 0.08 muM for the respective enzyme). The 5-hydroxymethyl, 5-benzyloxymethyl, and 5-azidomethyl derivatives of dUMP showed some differential inhibition; these compounds were two to three times more active against the ascites tumor enzyme than against the thymus enzyme.


Analogues of luteinizing hormone releasing factor modified at positions 2, 6, and 10. Eighteen analogues of luteinizing hormone releasing factor (LRF, pGlu-His-Trp-Ser-Tyr-Gly-Leu-Arg-Pro-Gly-NH2) were synthesized. The ten agonistic analogues were [D-Lys6], [D-Orn6], [D-Lys6,des-Gly10,Pro9-NHEt], [D-Orn6,-des-Gly10,Pro9-NHEt]-LRF plus their respective lauric acid conjugates as well as [(Nepsilon-Ac)-D-Lys6] and [(Ndelta-Ac)-D-Orn6]-LRF. The eight antagonistic analogues were [des-His2,D-Lys6], [des-His2,D-Orn6], [des-His2,D-Lys6,des-Gly10,Pro9-NHEt], [des-His2,D-Orn6,des-Gly10,Pro9-NHEt]-LRF as well as their respective lauric acid conjugates. Biological activities of these analogues were determined in vitro, using LRF as the standard for the agonists and [des-His2,D-Ala6]-LRF for the antagonists. The potency of the agonists ranged from 1 to 17 times the activity of LRF while the antagonists had between 1 and 3 times the potency of [des-His2,D-Ala6]-LRF.


Preliminary biological studies of certain amino acid analogues. Among four amino acid analogues and their corresponding hydantoins prepared synthetically, two of the amino acids, 2-amino-2-methyl-5-hexenoic acid and 2-ethylphenylalanine, were found at moderately high concentrations to inhibit growth of Escherichia coli 9723 and the growth inhibition is prevented by methionine and phenylalanine, respectively. Mammalian studies showed no toxic effects in albino male mice, and the analogues were excreted unchanged primarily in the urine.


Antimalarials. 9. Methylthio- and methylsulfonyl-substituted 9-phenanthrenemethanols. Nine di- and trisubstituted 9-phenanthrenemethanols bearing methylthio and methylfulfonyl substituents in the 2 and/or 6 positions of the phenanthrene nucleus were prepared and screened for antimalarial activity against Plasmodium berghei in mice. Six of the nine compounds were curative at or below 160 mg/kg. The most active structures contained a methylthio substituent in combination with two chlorine atoms.


The implications of medical ethics.

The implications of medical ethics. In this paper, Mr Thompson, one of the research fellows appointed to the Edinburgh Medical Group research project, seeks to define medical ethics in relation to traditional ethics in the philosophical sense of enquiring into right and wrong modes of thought and conduct, and to carry that study further into the field of moral decisions made by doctors and other professional people who care for the sick. Until very recently the Victorian definition of medical ethics - medical etiquette - served the doctor well but the complexity of modern medicine and the involvement of other professional workers in medical care appears to have swept away the old framework and left a vacuum. A new medical ethic must be evolved to fill that vacuum, taking account not only of technological advances but also of relationships between doctors and other professionals associated with them and of the role in caring for the sick.


A copper block method for freezing non-cryoprotected tissue to produce ice-crystal-free regions for electron microscopy. I. Evaluation using freeze-substitution. A wide variety of plant and animal tissues were prepared for electron microscopy by freeze-substitution, after rapid freezing on a liquid nitrogen cooled copper block by the van Harreveld method. Measurements were made of ice crystal size versus depth in tissues that had not been treated with any cryoprotectants. Ice crystal size increased exponentially with depth. It was confirmed that a narrow surface band increased exponentially with depth. It was confirmed that a narrow surface band (approximately 12 mum) was frozen sufficiently rapidly to prevent the formation of electron microscopically-visible ice crystals.


A copper block method for freezing non-cryoprotected tissue to produce ice-crystal-free regions for electron microscopy. II. Evaluation using freeze fracturing with a cryo-ultramicrotome. Two methods are described for fracturing unfixed, uncryoprotected mouse liver that had been frozen by contact with a copper block at liquid nitrogen temperature. The best method involved precise fracturing of a few microns of surface tissue with a cooled glass knife,  using the Cryokit attachment of the LKB III ultramicrotome. The resulting replicas were free from electron microscopically-visible ice crystals. A noticeable feature of replicas from unfixed, uncryoprotected tissue was the extent of plastic deformation of certain cellular structures. Cytoplasmic macromolecules, and to a lesser extent intramembranous particles, often appeared to be 'stretched' to form fibrils.


Quantifying "pattern": a stereological approach. At present, a number of stereological techniques are available for the estimation of size parameters of aggregates (such as Vv, Sv, size distributions, and so forth) from data measured on plane sections. In this paper, an attempt is made to find a suitable quantification of spatial relationships which can be satisfactorily used for discrimination purposes whenever the traditional size parameters fail to do so. The proposed techniques of pattern analysis are very simple and strongly connected with the classical theory and practice of stereology; this should render them very accessible to scientists working in different fields, such as biology, geology, ecology, geography, etc.


Cell surgery by laser micro-dissection: a preparative method. A new UV-laser device is introduced as a micro-manipulator and micro-dissection apparatus for experimental cell research. High energy irradiation is produced by a quasi-continuous N2-laser. The laser micro-beam can be focused to a minimal diameter of 0-75 mum. The micro-laser can be used for cutting and, hence, as a micro-surgical instrument at the level of cellular organelles. Cytoplasmic actomyosin fibrils (AM fibrils) from tissue culture cells (RMCD-cells) are isolated from the surrounding ground cytoplasm. It is shown that the contractile proteins are not damaged by the laser dissection method to an extent that would prevent their normal function, e.g. contraction.


Penetrating trauma of the neck.

Penetrating trauma of the neck. Two hundred forty-six patients admitted to the Trauma Unit of Cook County Hospital with penetrating neck wounds have been reviewed. A policy of mandatory neck exploration combined with a systematic approach to resuscitation and a diagnostic evaluation including neck and chest X-rays, endoscopy, and arteriography has been employed. The study has revealed a high incidence of negative neck explorations (63%) but minimal morbidity (less than 1%), no mortality, and a brief duration of hospitalization in the negative exploration group. Patients with positive explorations had an 8% morbidity and a 9% mortality rate. In addition, 13 of the patients with positive explorations had clinically negative wounds which might have been overlooked if selective management had been utilized in this series. We conclude that a policy of mandatory neck exploration is justified and advisable for patients sustaining penetrating neck injuries.


Genetic studies of coliphage P1. II. Relatedness to P7. Using semiquantitative spot tests, 107 independently isolated amber mutants of P1 were shown to be rescued by a nonpermissive strain of Escherichia coli lysogenic for P7 (previously called phiamp), indicating extensive genetic relatedness between P1 and P7. The amount of rescue observed varied with mutants from different genetic linkage clusters of P1. Although these rescue tests cannot distinguish between recombination, complementation, transactivation, or combinations thereof, a major role is indicated for recombination.


SAMase gene of bacteriophage T3 is responsible for overcoming host restriction. Deletion and point mutants of T3 have been isolated and used to show that the early region of T3 DNA is organized in the same way as that of T7 DNA. Homologous early RNAs and proteins of the two phages have been identified by electrophoresis on polyacrylamide gels in the presence of sodium dodecyl sulfate. Both phages have five early mRNA's, numbered 0.3, 0.7, 1,1.1 and 1.3 from left to right, although no T3 protein that corresponds to the 1.1 protein of T7 has yet been identified. In general, corresponding early RNAs and proteins of the two phages migrate differently on gels, indicating that they differ in molecular weight and/or conformation. In both T7 and T3, gene 0.3 is responsible for overcoming the DNA restriction system of the host, gene 0.7 specifies a protein kinase, gene 1 specifies a phage-specific RNA polymerase, and gene 1.3 specifies a polynucleotide ligase. The 0.3 protein of T3 is responsible for the S-adenosylmethionine cleaving activity (SAMase) induced after T3 (but not T7) infection. However, cleaving of S-adenosylmethionine does not appear to be the primary mechanism by which T3 overcomes host restriction, since at least one mutant of T3 has lost the SAMase activity without losing the ability to overcome host restriction.