Preventive treatment of congenital pseudarthrosis of tibia. If an osteotomy is carried out in a child with congenital angulation of the tibia with segmental sclerosis, a pseudarthrosis develops in many cases. This should be prevented by a bone-graft operation along the concave side of the tibia. The results described illustrate this contention.


Preserved scleral allografts in periodontal defects in man. I. Preparation, preservation and use. A method has been presented for the preparation, preservation and surgical adaptability of sclera as implant material. As a result of the knowledge gained from the use of this material in reconstructive surgery and limited reports in the dental literature, there appears to be a justification for further research on the utilization of this very available material in periodontal and other oral surgical procedures.


Localized hyperplastic lesions of the gingiva: a clinicopathological study of 302 lesions. A study was made of a series of 302 consecutive cases of localized hyperplastic lesions of the gingiva (epulides). The lesions were classified into five groups: pyogenic granuloma, calcifying fibroblastic granuloma, fibrous hyperplasia, peripheral giant cell granuloma and denture hyperplasia. The study indicates that there are some differences in age and sex distribution as well as in location between the different histological groups. Pyogenic granuloma was found to be the most common lesion on the gingiva. Pyogenic granuloma and calcifying fibroblastic granuloma occur in younger patients more often than fibrous hyperplasia, and thus may represent a stage in the development of fibrous hyperplasia. Denture hyperplasia occurs predominantly in females and it is suggested that its formation may be affected by hormonal alterations in the menopause.


Antibacterial structure-activity relationships obtained with resistant microorganisms I: Inhibition of R-factor resistant Escherichia coli by tetracyclines. Aparent partition coefficients and inhibitory activities against sensitive and resistant Escherichia coli were determined for 14 tetracyclines. The difference in the kinetics of inhibition of the two organisms is discussed in terms of their permeabilities. The partition coefficients were determined in an octanol-buffer system. Values for eight compounds were in general agreement with the literature; values for the remaining six compounds had not been reported previously. Growth of the organisms was determined by a single-point turbidimetric method in the presence and absence of tetracyclines. Inhibitory activities were obtained by a kinetic treatment. Derived rate constants for the sensitive organism were linearly related to antibiotic concentration. For the resistant organism and 12 compounds, the derived rate constants and antibiotic concentration were related in a manner typical of saturation kinetics. These inhibitory activities were related to the partition coefficients, while activities against the sensitive strain were not. These findings suggest that activity against the resistant strain is permeability controlled but that activity against the sensitive strain has a different rate-determining step.


Bioavailability and activity of topical corticosteroids from a novel drug delivery system, the aerosol quick-break foam. Experiments were conducted to: (a) compare the bioavailability of betamethasone benzoate in a quick-break aerosol foam and semisolid dosage forms, (b) compare the activity of betamethasone benzoate, betamethasone valerate, clobetasol propionate, triamcinolone acetonide, desonide, flumethasoid reservoir formation in skin, and (d) assess the effect of a natural moisturizer. Efficacy was determined by a graded response 6-hr occluded vasoconstriction test with subsequent reocclusion for reservoir demonstration. Moisturizer effect was assessed by a nonoccluded vasoconstriction test using "plain" and sodium 2-pyrrolidone-5-carboxylate-containing concentrates on arms pretreated with water or moisturizer. The activities of betamethasone benzoate concentrate, collapsed foam, ointment, and gel were similar and significantly better than the activity of the cream. Clobetasol propionate was significantly better than the other medicated concentrates, which were equivalent. Steroid-induced blanching decreased in the presence of a moisturizer.


Mutagenic activities in vitro and in vivo of five antischistosomal compounds. Five antischistosomal compounds--hycanthone, two of its chloroindazole analogs (IA-4 and IA-4 N-oxide), oxamniquine, and metrifonate--were tested for mutagenic activity, using Salmonella typhimurium strains TA 98 and TA 100 under in vitro and in vivo (host-mediated) conditions. In all assay systems hycanthone exhibited by far the highest mutagenic potency. Although oxamniquine and metrifonate had low metagenic activity in vitro and although their administration resulted in urine of low metagenic activity, their host-mediated mutagenic activities on strain TA 100 were fairly high. Confirming earlier studies with a less sensitive Salmonella strain, TA 1535, IA-4 N-oxide was found to be less metagenic than IA-4. Orally administered IA-4 and IA-4-oxide were less mutagenic under in vivo conditions than an equal dose administered intramuscularly. By contrast, the antihistosomal activity of a given dose of each compound was the same, regardless of which of these two routes was used, suggesting that mutagenic and antischistosomal effects are produced by different metabolites. The observations reported in this paper provide additional evidence that mutagenic activities can be dissociated from desired chemotherapeutic effects by suitable structural modifications.


Potentiation of the cytotoxic action of melphalan and "activated" cyclophosphamide against cultured tumor cells by centrophenoxine. Centrophenoxine, without antitumor activity itself, enhanced the cytotoxic action of melphalan and "activated" cyclophosphamide against mouse P388 lymphoma and rat W256 carcinosarcoma cells growing in static suspension culture. The concentration of alkylating agent required for 99% cell-kill was approximately halved when centrophenoxine was also present during exposure to the antitumor drug. Maximum potentiation by centrophenoxine of the cytotoxic action of melphalan occurred when cells were exposed to the two agents simultaneously; little or no potentiation was observed when cells were exposed to centrophenoxine before or after exposure to the alkylating agent.


The future of complete prosthodontics.

The future of complete prosthodontics. An improved elastomer with an optimum balance of mechanical properties, processability, environmental  stability, colorability, and esthetics, for use in fabricating extraoral maxillofacial prostheses, was sought, An arylene silicone polymer, polytetramethylsilphenylenesiloxanedimethylsiloxane, was synthesized and formulated as a pourable, viscous, room-temperature-vulcanizing liquid. Silphenylene polymers are colorless and will accept either intrinsic or extrinsic coloration. When mixed with conventional catalysts, the silphenylene vulcanizates can be easily and reliably cast in closed dental stone molds to give prostheses that are strong and tough yet soft and pliable. Typical values for tensile strength, elongation at break, modulus at 100% elongation, and hardness are, respectively, 1400 psi, 1000 psi, 50 psi, and 35 (Shore A). Since the arylene linkages in the silphenylene polymers impart unusually high values of surface energy to these silicone elastomers, they have an excellent tactual as well as visual resemblance to skin, and they adhere well to tapes and adhesives. A preclinical toxicologic evaluation has been completed, and the materials are currently undergoing clinical evaluation.


Resin registration for interocclusal records. An ideal material for registering interocclusal records should (1) have reproductive accuracy, (2) be easy to handle, (3) offer no resistance to closure during the registration, (4) be rigid when set, and (5) have a fair degree of hardness when set. The acrylic resin, Duralay, has these qualities. Techniques for utilizing Duralay to register interocclusal records for unilateral restorations, bilateral restorations, full-arch restorations, as well as fixed and removable restorations in the same arch have been demonstrated.


Kallman's syndrome: effect of repeated stimulation of pituitary-gonadal axis with LH-RH. The relative roles of the central nervous system and pituitary in the pathogenesis of olfactory gonadal dysplasia has been the subject of much speculation. Repeated stimulation of the pituitary gonadal axis with LH-RH provoked a moderate release of gonadotropins, insufficient however, to stimulate gonadal incretory function. This study supports the evidence that a hypothalamic defect is the basis for Kallman's syndrome.


Conformational studies of a family of related antimalarial phenanthrene amino alcohols. A conformational study utilizing quantum chemical methods was performed on a family of antimalarial alpha-(piperidyl)-3,6-bis(trifluoromethyl)-9-phenanthrenemethanols whose structures differ by the placement of the substituent on either the 2,3, or 4 position of the piperidyl ring. The antimalarial activity of these 3-substituted compounds has been shown experimentally to be highly stereospecific while the 2-substituted compounds are not and the 4-substituted compounds are inactive. In this study, such observed differences in behavior are correlated with conformational results and a pharmacophore is postulated. The identity of the active racemate of the 3-piperidyl compound is predicted.


Semisynthetic cephalosporins. Synthesis and structure-activity relationships of analogues with 7-acyl groups derived from 2-(cyanomethylthio)acetic acid or 2-[(2,2,2-trifluoroethyl)thio]acetic acid and their sulfoxides and sulfones. The synthesis and in vitro and in vivo activities of a series of cephalosporins having side chains derived from 2-[(2,2,2-trifluoroethyl)thio]acetic acid or 2-(cyanomethylthio)acetic acid and with acetoxymethyl or 3-heterocyclic thiomethyl substituents at the 3 position are described. In both series, increasing the oxidation state of the side-chain sulfur atom from sulfide to sulfoxide/sulfone decreased the in vitro gram-positive activity, but the effect on gram-negative activity was variable and less pronounced. The protective effectiveness in mice infected with Escherichia coli increased as the oxidation level of the side-chain sulfur was raised from sulfied to sulfoxide/sulfone. Replacement of the 3-acetoxymethyl by a 3-heterocyclic thiomethyl group resulted in overall improvement of activity both in vitro and in vivo for all oxidation states.


Quantitative structure-activity relationships of antimalarial and dihydrofolate reductase inhibition by quinazolines and 5-substituted benzyl-2,4-diaminopyrimidines. A quantitative structure-activity relationship (QSAR) for the inhibition of dihydrofolate reductase from S. faecium by quinazolines has been formulated. This is compared with a QSAR for inhibition of E. coli dihydrofolate reductase by 2,4-diamino-5-benzylpyrimidines. The QSAR for inhibition of bacterial enzyme is compared with QSAR for mammalian enzyme inhibition. A QSAR has been formulated for the antimalarial action of quinazolines against P. berghei in mice. The antimalarial QSAR is consistent with that of the in vitro bacterial study.


P-Aminobenzoic acid derivatives as inhibitors of the cell-free H2-pteroate synthesizing system of Escherichia coli. A heterogeneous series of compounds, derived from p-aminobenzoic acid (PABA), has been investigated for their PABA-antagonistic potency in a cell-free H2-pteroate synthesizing system of E. coli. A prerequisite of compounds, other than sulfones or sulfonamides, to compete with PABA for the enzyme H2-pteroate synthetase appeared to be the presence of a p-aminobenzoyl moiety. Substitution of the carboxyl group of PABA by an ester, an amide, or a ketone function, however, strongly reduces the ability to interact with the PABA binding site on the enzyme. This decrease in affinity probably has to be ascribed to the inability to create a sufficient negative charge in the carbonyl part of these p-aminobenzoyl derivatives. The relatively high affinities of L-PABG (16), PABP (22), and the alpha-phenyl derivative of 22, as compared with the other substituted p-aminobenzamides and p-aminobenzene-1-alkanones, are explained by assuming that these compounds, besides interfering with the PABA receptor site, also interact with an accessory area on the enzyme.


Synthesis and antifungal properties of certain 7-alkylaminopyrazolo[1,5-a]pyrimidines. A series of 7-alkylaminopyrazolo[1,5-alpha]pyrimidines (5-25) and one 7-alkylthiopyrazolo[1,5-alpha]pyrimidine (4) were synthesized from the corresponding 7-chloro precursors 3, which were prepared in turn from the 7-hydroxy analogues 2, obtained via condensation of 3-aminopyrazoles with acetoacetate esters, malonate esters, or acetylenedicarboxylate ester. Compounds 4-25 were found to inhibit Trichophyton mentagrophytes (in vitro). The degree of inhibition increased with increasing 7-alkylamino chain length up to C8 units and then began to decrease with longer chain lengths. Unsaturated chains were more fungitoxic than saturated chains, 5-methyl-7-oleylaminopyrazolo[1,5alpha]pyrimidine [22, R7=NH(CH2)8CH=CH(CH2)7CH3] being four times more inhibitory and 16 times more fungicidal (against T. mentagrophytes) than 5-methyl-7-n-octylaminopyrazolo[1,5-alpha] pyrimidine [11, R7=NH(CH2)7CH3]. Although 11 and 22 appeared to have some efficacy as topical antifungeal agents, when applied to T. mentagrophytes infections in vivo, both caused irritation (of abraded and unabraded guinea pig skin) as did compound 4 (R5=Me; R7=SC8H17).


Effects of mutant steel alleles on leukemogenesis and life-span in the mouse. Mutant alleles at the steel locus produce the pleiotropic effects of congenital anemia, sterility, and lack of hair pigmentation. Strain (WC/Re X C57BL/6)F1 Sl/Sld mice lived only half as long as heterozygotes and homozygous normal controls, differing only at the steel locus. Lymphocytic leukemia developed spontaneously in 37% of mice of the Sl/Sld genotype at an average age of 370 +/- 25 days and in 5% of heterozygotes and homozygous normal controls at 965 +/- 41 days. Severe ulcerative dermatitis occurred in 56% of Sl/Sld mice at an average age o4f 441 +/- 21 days and in 20% of heterozygotes and homozygous normal controls at 722 +/- 50 days. The mutant steel alleles provided an opportunity for study of the role of chronic anemia in life shortening and of a mechanism of gene action in spontaneous leukemogenesis.


Abnormalitieis of monocyte chemotaxis in patients with melanoma: effects of immunotherapy and tumor removal. The chemotactic responsiveness of peripheral blood monocytes was studied before and after immunotherapy was administered to 56 patients with melanoma. Abnormal chemotaxis was found in 36 patients (64%) prior to treatment; this abnormality correlated with severity of disease and prognosis. Immunotherapy with BCG and sensitized autologous lymphocytes and X-irradiated melanoma cells or surgical removal of the neoplasm both reduced the percentage of patients with abnormal chemotactic responses. The best prognosis was found for those patients who had normal chemotaxis prior to therapy. The data support the hypothesis that abnormalities of monocyte function might render the host less likely to destroy developing neoplasms and that malignant tumors themselves might affect monocyte function.


Effect of isonicotinic acid hydrazide on the intratumor injection of BCG. Rats with established subcutaneous tumors were treated by repeated intratumor injections of BCG over a 5-week period. Isonicotinic acid hydrazide (INH) was given to some rats to determine if this drug decreased the effect of BCG on local tumor growth. INH alone had no effect on either survival or tumor volume. Rats treated with either BCG or BCG and INH had prolonged survivals and smaller tumor volumes than did controls rats. In these experiments, INH did not decrease the effect of BCG on local tumor growth. However, the intratumor injection of BCG in rats receiving INH systematically was associated with better survival and smaller tumor volumes compared to the intratumor injection of BCG alone.


Mutagenicity of five cyclic N-nitrosamines: assay with Salmonella typhimurium. The mutagenicity of five cyclic N-nitrosamines was studied with the use of Salmonella typhimurium TA1535 in vitro with and without microsomal activation. The carcinogens nitrosopiperidine and nitrosopyrrolidine required metabolic activation before manifesting mutagenic activity. Nitrosoproline and nitrosohydroxyproline, noncarcinogens, were not mutagenic. Nitroso-3-pyrrolidinol was mutagenic in the absence of microsomes, thereby suggesting a role of hydroxylation in the metabolic activation of nitrosopyrrolidine to an ultimate carcinogenic species.


Airborne mutagens bioassayed in Salmonella typhimurium. Particulate airborne pollutants, collected in Buffalo, New York, and Berkeley, California, were asayed for mutagenic activity in the Ames Salmonella typhimurium test system. Mutagens requiring liver enzymes for activation, as well as direct acting mutagens, were readily detected in the Buffalo sample. By contrast, only direct acting mutagens were detected in the Berkeley sample.


Immediate mobilization following flexor tendon repair. A preliminary report. A method of flexor tendon repair and grafting has been described. The advantage of the technique presented is that it allows early tendon excursion, and at the same time allows healing at the tendon-repair or graft site after a 4- or 5-week period. This technique appears to offer the patient with a flexor tendon injury a satisfactory, predictable result with few complications and a relatively short period of disability.


Management of fractures and fracture complications of femoral shaft using the ASIF compression plate. Nnieteen acute fractures and fourteen fracture complications of the femoral shaft were managed with ASIF plate fixation. Two patients having femoral shortening procedures were similarly managed. Most injuries involved the distal femoral shaft, and were judged unacceptable for intramedullary nailing. Single plate fixation and immediate mobilization of the knee joint were possible in most patients. Technical failure, refracture through an end-screw hole, or nonunion occurred in 20% of the injuries. Plate fixation of the femoral shaft is not the surgical procedure of choice for management of femoral shaft injuries. It is an acceptable alternative to intramedullary nailing but carries a higher risk of complication.


Streptomycin-resistant Escherichia coli mutant temperature sensitive for the production of Qbeta-infective particles. A streptomycin-resistant Escherichia coli mutant has been isolated that is temperature sensitive for Qbeta phage, but not for the group I RNA phages f2, MS2, and R17. The growth of Qbeta in the mutant at the nonpermissive temperature (42 degrees C) results in the release of a near-normal burst of noninfectious particles that cosediment with Qbeta in a sucrose gradient. It is assumed that the mutant is defective at elevated temperatures in the suppression of nonsense codons, thereby producing Qbeta-like particles which are noninfectious because of the lack of the read-through protein A1.


Structural studies on the polyhedral inclusion bodies, virions, and DNA of the nuclear polyhedrosis virus of the cotton bollworm Heliothis zea. The polyhedral inclusion body of the cotton bollworm nuclear polyhedrosis virus contains virions occluded in an orthogonal crystalline matrix. The virions appear as rods or, more frequently, as oval structures that form upon bending of the nucleocapsid within the viral membrane. The nucleocapsid consists at least of DNA surrounded by a capsid composed of subunits, possibly helically arranged. The viral DNA is circular and supercoiled. It is heterogenous in size with contour lengths ranging from 15 to 45 mum.


Effect of spermidine on the RNA-A protein complex isolated from the RNA bacteriophage MS2. The polyamine spermidine has recently been reported to be a substantial component of the RNA phage particle. Its effect on the isolated RNA-A protein complex of the phage MS2 is investigated here. This complex infects intact Escherichia coli cells via F-pili, as does the whole phage. It is shown that the infectivity of the complex on intact E. coli cells was enhanced by incubation with spermidine. Optimal stimulation (20-fold) of the complex infectivity was achieved by incubation with 3 x 10(-4) M spermidine for 20 to 30 min at 37 degrees C. This gave a more compact structure to the complex, as could be seen by its faster sedimentation in sucrose gradients. Although spermidine and Mg2+ are known to partially replace one another in several systems, no enhancement of the infectivity of the complex, but only its considerably faster sedimentation in sucrose gradients, occurred after incubation with 3 x 10(-4) M Mg2+. Only if the Mg2+ concentration was raised by more than one order of magnitude could increased infectivity of the complex be observed. At concentrations of spermidine and Mg2+ that maximally stimulated the infectivity of the complex on intact E. coli cells, no increase in infectivity of phenol-extracted RNA to E. coli spheroplasts was detected. From these in vitro results, the role of the polyamine spermidine in the RNA phage particle for the infecting, RNA-A protein complex molecules in phage infection is discussed.


Gene D of bacteriophage phi X 174: absence of transcriptional and translational regulatory properties. The only evidence that a gene product of phi chi 174 is involved in the regulation of phage transcription was presented by Clements and Sinsheimer (1974) for gene D. I. found, in attempting to investigate this possibility further, that the D protein had no regulatory effect. When the D protein was eliminated by various nonsense mutations, all other phage proteins were synthesized at rates nearly identical to the wild-type control. There was also no significant difference in the amount of phage-specific RNA synthesis as a proportion of the total RNA synthesis when the D mutants were compared with wild type. No evidence was detected for a polar effect of gene D nonsense mutants on the expression of genes F, G, and H. The relative molar rates of synthesis of D, F, G, and H, synthesized during a normal infection were 29, 4.9, 3.3, and 1.0, respectively, with an accuracy of +/- 20%.


Homology between double-stranded RNA and nuclear DNA of yeast. The relationship between mycoviral double-stranded (ds) RNA and host cell DNA was investigated. Radiolabeled ds RNA was denatured and reannealed in the presence and absence of denatured DNA. RNA from killer strains of the yeast Saccharomyces cerevisiae and from nonkiller derivatives was utilized. The above-mentioned strains, as well as one that lacks all ds RNA, were sources for extracted DNA. Net hybridization of ds RNA to DNA occurred regardless of the strains from which the respective nucleic acids were prepared.


Increased reproductive fitness of Escherichia coli lambda lysogens. Lambda lysogens of Escherichia coli reproduce more rapidly than nonlysogens during aerobic growth in glucose-limited chemostats. If the environment is changed to anaerobic growth, the situation is reversed, and the lysogen reproduces more slowly than the nonlysogen. Based on a tetrazolium dye assay, the increased fitness of the lambda lysogen during aerobic growth seems to result from a continued high metabolic rate as glucose becomes limiting, whereas the metabolic rate of the nonlysogen declines. The lambda rex gene is required for the growth advantage of lysogens since lack of rex function causes lambda lysogens to lose their reproductive advantage over nonlysogens.


Reproductive fitness of P1, P2, and Mu lysogens of Escherichia coli. P1, P2, and Mu lysogens of Escherichia coli reproduce more rapidly than nonlysogens during aerobic growth in glucose-limited chemostats. Thus, prophage-containing stains of E. coli are reproductively more fit than the corresponding nonlysogens. If mixed populations are grown by serial dilution under conditions in which growth is not limited, both the lysogen and nonlysogen manifest identical growth rates. The increased fitness of the lysogens in glucose-limited chemostats correlates with a higher metabolic activity of the lysogen as compared with the nonlysogen during glucose exhaustion. We propose that P1, P2, Mu, and lambda prophage all confer an evolutionarily significant reproductive growth advantage to E. coli lysogenic strains.


Envelope antigens of Sindbis virus in cells infected with temperature-sensitive mutants. Indirect fluorescent-antibody studies of living and fixed chick cells infected with temperature-sensitive mutants of Sindbis virus suggest that functional envelope glycoprotein E1 must be inserted through the plasma membrane before E2. PE2 and E2 do not affect the insertion of E1. The experiments also suggest that normal PE2, a glycosylated precursor to E2, reacts with anti-E2 serum; the abnormal PE2 made by a temperature-sensitive PE2 cleavage-defective mutant did not. Abnormal E1 proteins made by E1-defective mutants also failed to react with anti-E1 serum.


Patterns of transcription in bacteriophage P22-infected Salmonella typhimurium. Two peaks of RNA synthesis (early and late) are directed by bacteriophage P22 in lytic infections of Salmonella typhimurium. Late RNA synthesis is not seen in P22 23- infections; neither early nor late RNA synthesis occurs in P22 24- infections. Genes 23 and 24 of P22 appear to be analogous to genes Q and N of lambda, respectively.


Evaluation of a vented drainage system in prevention of bacteriuria. A vented urinary drainage system was compared to an otherwise identical non-vented system in a prospective, randomized, double-blind study. Among the 316 female patients evaluated there was a significant reduction in the rate of bacteriuria after 10 days using the vented system (66 per cent in the non-vented group versus 26 per cent in the vented group, p less than 0.05), while no significant difference could be demonstrated among the 190 male patients. We used urine hemoglobin as an indicator of mucosal trauma that might predispose to bacteriuria and no significant difference could be shown between the 2 drainage systems.


Guidelines for peer review. Veterans Administration Ad Hoc Interdisciplinary Advisory Committee on Antimicrobial Drug Usage. Eigteen guideline-audits of antimicrobial usage have been prepared for use by hospital staffs for peer review. They may also be used as a national standard to assess the appropriate use of antimicrobial agents in hospitals. It is hoped that the guidelines will stimulate wide discussion and national peer review and will ultimately result in improved care of patients with infectious disease.


An optimal diuretic regimen for cirrhotic ascites. A controlled trial evaluating safety and efficacy of spironolactone and furosemide. Previous studies demonstrated the effectiveness of diuretics in mobilizing fluid, but frequent complications occur with their use in treating ascites. To develop an effective but safe regimen for treatment of cirrhotic ascites, a two-part crossover study was done. Subjects with life-threatening complications of cirrhosis were excluded. In part one it was demonstrated that a six-day diuretic regimen with dietary sodium restriction of 10 mEq/day is safe and more effective than sodium restriction alone. In part two the duration of diuretic therapy was safely extended from six to nine days with mobilization of significantly more fluid. Careful selection of subjects, use of diuretics in modest dosages for brief periods of time, and daily monitoring of subjects were important for the success of this study.


Ephedrine therapy in asthmatic children. Clinical tolerance and absence of side effects. Sixteen asthmatic children between the ages of 7 and 13 years, 13 of whom were receiving theophylline orally around-the-clock, were studied for eight weeks in double-blind manner to evaluate efficacy, toxicity, and development of tolerance to the combination of ephedrine sulfate and theophylline. Reactions to the drug combination, assessed by close observation and daily patient questioning by the nursing staff, showed no toxicity or substantial side effects. Pulmonary function was measured hourly for six hours after each morning dose, and the data were analyzed to determine the degree and duration of bronchodilator response. Comparison of data from weeks 1 and 8 showed no evidence of the development of tolerance. Ephedrine is a potent bronchodilator that, in appropriate doses, can be administered safely along with therapeutic doses of theophylline without fear of progressive tolerance or toxicity.


Clinical study of ticrynafen. A new diuretic, antihypertensive, and uricosuric agent. In a double-blind study, 20 hypertensive patients were randomly assigned to a six-week regimen of either ticrynafen or hydrochlorothiazide. Blood pressure was significantly reduced with both medications, although most patients required an increase in dosage from 250 to 500 mg ticrynafen daily. Whereas the serum uric acid level rose moderately in the hydrochlorothiazide-treated patients, it fell strikingly to less than half of the pretreatment level in patients treated with ticryafen. Body weight decreased slightly in both groups, as did serum potassium levels. Blood urea nitrogen and serum creatinine levels rose slightly in both groups. The magnitude of these changes was not significantly different between the two groups. Use of ticryafen was well tolerated. Ticryafen appears to be a useful new antihypertensive agent because of its unique combination of diuretic, antihypertensive, and hypouricemic effects.


Necrotizing fasciitis: a persistent surgical problem. Necrotizing fasciitis is a rare but specific clinical entity which, if not diagnosed early and treated aggressively, is rapidly fatal. The disease was first described during the Civil War and continues to be associated with a 50% mortality. The infectious process is diagnosed by the presence of a widespread fascial necrosis with extensive undermining of the adjacent tissues. The initial mechanism of injury as well as the location and etiologic agent of the suppurative fasciitis may vary. A review of 41 cases of necrotizing fasciitis occurring over a 22-year period disclosed an overall mortality of 39%. Most often, the mortality was related to the severity of the associated diseases and a failure to recognize the disease process promptly. The rate may be lowered by early recognition and prompt surgical intervention coupled with intensive supportive therapy.


Neonatal sepsis at The Johns Hopkins Hospital, 1969-1975: bacterial isolates and clinical correlates. The experience with neonatal sepsis at The Johns Hopkins Hospital during 1969-1975 was reviewed. Major pathogens included Escherichia coli, group B streptococcus, other streptococci, and Klebsiella. Nineteen percent of coliform isolates were kanamycin-resistant. The frequency of recovery of E. coli was increased in early-onset sepsis, and the frequency of recovery of Klebsiella was increased in late-onset sepsis. The mortality rate was 23%. The frequency of recovery of E. coli was increased in fatal cases, and mortality was highly correlated with the presence of gastrointestinal catastrophe. Ampicillin and gentamicin are the initial antibiotics of choice for neonatal sepsis at this institution; a penicillinase-resistant penicillin should be added when Staphylococcus aureus involvement is likely, and addition of chloramphenicol or clindamycin should be considered for infants at increased risk for Bacteroides fragilis sepsis.


T cell type immunoblastic sarcoma diagnosed primarily by CSF cell membrane features. The case of a 65 year-old female with an immunoblastic sarcoma of T cell type (reticulosarcoma) is reported. Post mortem tumor cell infiltrations with the typically histomorphological criteria of an immunoblastic sarcoma were found in the uterus, bone marrow and leptomeninges. With the aid of immunological markers the T cell type of this malignant lymphoma was diagnosed intra vitam on the basis of CSF cells. Until now, only one case of an immunoblastic sarcoma of the T cell type has been described in the literature.


Digitalis pharmacokinetics and therapy with respect to impaired renal function. The various cardiac glycosides differ significantly in their retention as a result of renal failure. In the case of digoxin, digitoxin, and strophanthin the retention is directly related to the normal renal clearance of these cardiac glycosides: Strophanthin has the highest clearance and the most marked prolongation of pharmacological action in renal failure, whereas digitoxin shows the lowest renal clearance and even in uremic patients a total elimination comparable to normal subjects as a result of increased hepatic clearance; digoxin takes an intermediate position. The quantity of a cardiac glycoside and its metabolites excreted by the kidneys depends, besides the renal clearance, on the plasma concentration which increases considerably during the first days after onset of treatment. From the daily dose approximately 90% of strophanthin, 70% of digoxin, 50% of digitoxin plus metabolites are excreted by normal kidneys under steady-state conditions. The efficiency of hemodialysis in the elimination of cardiac glycosides is low (3-5%) if estimated in relation to a single dose injected before dialysis and high (30-50%) if estimated in relation to the excretory capacity of normal kidneys during a period corresponding to the duration of a dialysis. During hemodialysis the plasma concentration of digoxin decreases as rapidly as in patients with normal renal function. Beside the efficiency of dialysis this finding may be explained by the decrease in the apparent volume of distribution of cardiac glycosides in patients with advanced renal failure; a reduced tissue protein binding seems likely to be the main reason for these changes in chronic renal insufficiency. A reduced volume of distribution and a reduced myocardial sensitivity are the main reasons for a very low predictability of the necessary individual maintenance dose of cardiac glycosides from the creatinine clearance. In patients with advanced renal insufficiency the tolerance to cardiac glycosides is reduced with respect to the daily dose, but it is rather increased in relation to the plasma concentration required to maintain the positive inotropic effect. The combination of hyperkalemia, hypermagnesemia, bypocalcemia and acidosis which is found almost exclusively with chronic renal failure, may explain the reduced myocardial sensitivity. Dosage regimens based on the measurement of creatinine-clearance are of little help in "effective digitalisation". Serial measurements of steady-state plasma concentration of cardiac glycosides may be the only way to reduce the risk of under- and overtreatment in patients with impaired renal function.


[Methylmalonic aciduria. Classification, diagnosis and therapy (author's transl)]. Congenital methylmalonic aciduria (MMA) is a metabolic disorder inherited by an autosomal recessive trait. The metabolic block is located in the catabolic pathway of propionyl-CoA to succinyl-CoA. Biochemically, four enzymatic defects have been recognized, i.e.: 1. Methylmalonyl-CoA racemase. 2. Methylmalonyl-CoA mutase apoenzyme. 3. Synthesis of desoxyadenosyl-cobalamine. 4. Disturbance at an earlier level of cobalamine metabolism which causes defective synthesis of both vitamin B12-coenzymes. These four enzymatic defects express themselves in three ways: non-vitamin B12-dependent MMA (defects 1 and 2); vitamin B12-dependent MMA (defect 3); MMA associated with homocystinuria (defect 4). The various forms of MMA cannot be distinguished clinically from one another. The disorder manifests itself during the first few days to weeks of life. Principal symptoms and signs are: anorexia, vomiting, muscular hypotonia and metabolic acidosis. The diagnosis is established by determination of methylmalonic acid in plasma, cerebrospinal fluid and urine, as well as by assay of enzyme activities in leukocytes, liver tissue or cultured fibroblasts (from biopsied skin). A prenatal diagnosis is feasible by the examination of cultured amnion cells, amniotic fluid and maternal urine. Therapy of non vitamin B12-dependent MMA calls for reduction of protein intake, particularly that of precursors of methylmalonic acid, such as methionine, threonine, isoleucine and valine. The treatment of vitamin B12-dependent forms is accomplished by i.m. injection of high doses of vitamin B12. No definite statement can be made as yet with regard to long-term prognosis and normalcy of mental development in treated children.


[Biochemical and pathophysiological aspects of hyperammonaemia (author's transl)]. 1. Ammonia liberated continuously in large amounts in muscle, kidney and brain is used immediately for the synthesis of mainly glutamine because of the toxic effects of elevated ammonia concentrations. After glutamine hydrolysis in the liver ammonia serves as substrate for the urea biosynthesis. In ureotelic animals urea is the quantitatively most important product for the elimination of surplus nitrogen. 2. The rate of urea biosynthesis depends on the amount of surplus nitrogen and acts as regulatory factor for the nitrogen balance of the adult organism. 3. Urea cycle abnormalities in liver diseases or inborn enzymatic defects are important factors leading to hyperammonaemia in patients. 4. The hyperammonaemia induces an increase of the rate of hepatic pyrimidine nucleotide biosynthesis as a consequence of an ineffective feedback inhibition of the glutamine-dependent carbamoyl phosphate synthetase. 5. The distribution of ammonia between intra- and extracellular space and the amount of ammonium ions excreted in the urine depend on the pH value. An alkalosis induces an intracellular ammonia load and inhibits the urinary ammonium ion excretion, which is increased in acidosis as one mechanism of protein elimination. 6. The ammonia-induced inhibition of the citric acid cycle by an alpha-ketoglutarate deficiency is one important reason for the neurotoxicity of ammonia, which is the main point in the pathogenesis of hepatic coma.


Successful retransplantation of the human heart. Cardiac retransplantation has been performed in five patients at Stanford University Medical Center. Long-term survival and rehabilitation have been achieved in two cases. In the first case retransplantation was performed 57 days after the initial procedure because of persistent acute graft rejection. The second patient underwent retransplantation 27 months postoperatively because of documented accelerated graft atherosclerosis. The major indications for cardiac retransplantation consist of intractable acute rejection and late postoperative graft atherosclerosis. These complications should prompt consideration of cardiac retransplantation in carefully selected cases.


Aortic arch anomalies in children and infants. The authors report their experience in 150 cases of aortic arch anomalies treated surgically in children and infants. The progress achieved over the past few years through improved diagnosis and resuscitative care has made it possible to obtain good results in the vast majority of cases.


The prevention and treatment of sternum separation following open-heart surgery. A method to prevent and treat sternum separation following open-heart surgery is presented. The procedure consists of passing parasternal continuous sutures placed alternatingly in front and behind the costal cartilages and then including them in the usual parasternal sutures.


Hepatic and gastrointestinal disorders in pregnancy. The presentation, nonradiologic diagnostic evaluation, and course (including complications and outcome) of gastrointestinal disorders in pregnancy are not substantially different than for the nonpregnant patient. The possible exception is the higher mortality for pancreatitis when it occurs during pregnancy. With the exception of nausea/vomiting and hyperemesis gravidarum, there does not appear to be a gastrointestinal tract disorder that is peculiar to the pregnant state. Hepatic disorders are somewhat different in that the excretory defect-pruritus gravidarum-cholestatic jaundice spectrum and perhaps part of what presents as acute hepatic failure are intimately associated with pregnancy and have an onset and course that are tied to the gestational period. Otherwise, hepatic diseases that occur during pregnancy share the characteristic of gastrointestinal diseases, that their manifestations are not clearly different from the nonpregnant state. As is true for the diagnostic approach to all medical diseases that occur during pregnancy, radiographic procedures are prohibited. Furthermore, therapy must be reconsidered with concern for its effect on the fetus. This leads to elimination of many or all measures used for purely symptomatic or nonspecific benefit. If no harm or potential harm will accrue for the fetus, therapy for hepatic and gastrointestinal disorders preceeds in pregnancy very much as it does in the nongravid individual.


Nutritional influences during pregnancy. Maternal nutrition represents one of the important influences on the course and outcome of pregnancy and attention to nutritional factors (i.e., assessment of nutritional status, dietary advice, and follow-up evaluation) properly constitute an essential component of prenatal care. Nearly all nutrients are required in increased amounts during gestation but the magnitude of the increase varies from nutrient to nutrient. Caloric needs increase by 300 kcal per day, representing an addition of 15 per cent, and should be sufficient to support a weight gain averaging 350 to 400 gm per week during the last two trimesters. Total protein intake during pregnancy should be 1.3 gm per kg for the mature woman and somewhat higher for the adolescent. Gestational needs for iron cannot be met by diet and supplementation (in the form of simple ferrous salts, 30 to 60 mg daily) should be provided. Folate requirements are doubled during pregnancy and, while these can be met by diet, supplementation may be considered as an option. Provision of the gestational calcium allowance from food sources is readily possible if (and only if) daily products are consumed. The generally increased need for other nutrients can be provided readily by the properly selected diet. Thus, with respect to supplements, iron and perhaps folate should be advised routinely while other vitamin-mineral supplements are probably neither helpful nor harmful. Prescription of vitamin-mineral supplements cannot be expected to compensate for poor dietary habits. Dietary restriction of nutrients in general, and energy and sodium in particular, has the potential for impairing the maternal capacity to make the required physiologic adjustments of pregnancy and interfering with fetal development. Restriction of any nutrient to levels below the guidelines provided by the Recommended Dietary Allowances is rarely if ever advisable.


Studies on the mechanism of action of halofenate. This paper reviews most of the clinical studies on the mode of action of halofenate, an established hypolipidemichypouricemic agent in man. In yeast cutlures and in isolated rat adipocytes, halofenate was found to inhibit the conversion of pyruvate to acetyl CoA. While pyruvate dehydrogenase was inhibited in vitro, halofenate also inhibited the activety of various other isolated enzymes. In rats maintained on halofenate in the diet (0.02-0.10%) for 2-14 days, there were 20-40% decreases in plasma cholesterol, trigly cerides, phospholipids, and free fatty acids. Inhibition of liver HMG-CoTA reductase does not appear to account for the hypocholesterolemic effect, and activation of mitochondrial alpha-glycerophosphate dehydrogenase does not explain the hypotriglyceridemic action. Kinetic measurements of the serum appearance and disappearance of triglycerides in drug-treated rats suggest that the hypotriglyceridemic activity is due to a net inhibition of hepatic triglyceride synthesis. Reduction of very low density lipoprotein (VLDL) and high density lipoprotein (HDL) levels in rats with sucrose-induced hyperlipidemia and normalization of the altered apolipoprotein profiles are in accord with the effects of halofenate on plasma triglyceride and cholesterol levels. The reduced insulin-to-glucagon ratio observed in Zucker obese hyperlipemic rats is also consistent with halofenat's hypotriglyceridemic activity. Preliminary experiments in rats on the mechanism of its hypoglycemic activity, observed in some diabetic hyperlipidemic patients, indicate that halofenate acts differently than conventional oral hypoglycemic agents. Some, but not all, of the effects of halofenate were observed with clofibrate at two to ten times higher levels.


An intervention study-the aspirin myocardial infarction study. The Aspirin Myocaridal Infarction Study is a randomized, double-blind clinical trial designed to study the potential value of aspirin in the reduction of mortality in patients who have had a prior myocardial infarction. This trial is based upon several previously published studies which suggest that aspirin may be valuable iprevention of coronary thrombosis. The requirement of 4200 patients dictates that the study must be multicenter, and good design requires that the study be collaborative with cnetral monitoring and an elaborate committee structure to insure uniformity and comparability.


The natural history of symptomatic recurrent bacteriuria in women. In 23 adult women having uncomplicated recurrent urinary tract infections treated with 10 days of appropriate antibiotic for each infection, the following findings were noted. 1. The attack rate was 0.17 infections per month. 2. 94% of infections has associated symptoms. 3. 73% of symptomatic episodes had an associated infection. 4. 21% of infections had less than 10(5) bacteria per ml. 5. 34% of all infections were followed by an infection-free interval of at least six months and averaged 12.8 months. All but one patient had at least one infection-free interval. 6. Long infection-free intervals were followed by further infections; a remission is not a cure. 7. Between infection-free intervals the infections tended to occur in clusters with an attack rate of 0.47 infections per month. 8. Prophylaxis is less costly if begun at the second infection within a six-month period.


Onset and reversibility of changes in secretory function and composition of isolated rat pancreatic islets following long-term administrationof high or low tolbutamide doses. Chronic administration of a high tolbutamide dose to rats induces islet hypertrophy associated with a decreased insulin content per islet and with a diminished insulin release in response to a glucose or leucine stimulus. These changes are reversible after discontinuation of tolbutamide. Chronic administration of a low tolbutamide dose (effective on islet size, on insulin content per islet, or on leucine-induced insulin release is normal in the presence of glucagon (5 mug/ml) or theophylline (5 mM). Since islet hypertrophy occurs following administration of high tolbutamide doses only and is associated with hypofunction rather than with hyperfunction, it seems hardly conceivable that the therapeutic principle of tolbutamide is based on a beta-cytotrophic effect. B-cell hypofunction seems to be due to at least three factors: the decrease in the insulin content per islet, an impairement in secretory signal recognition, and an interference with the process of signal transmission.


Effect of methandrostenolone on postmenopausal bone wasting as assessed by changes in total bone mineral mass. To assess the efficacy of methandrostenolone in the treatment of osteoporosis a 26-mo double-blind study was performed with 13 treated and 13 control (placebo) postmenopausal osteoporotic females. Drug effect was assessed primarily by determinations of total body calcium (TBC) by neutron activation analysis, essentially a measurement of total bone mineral mass. Results in the 16 patients completing the study (10 treated and 6 placebo), as well as in all 26 patients participating in the study, showed significant (p less than 0.01) differences in the change in TBC between treated and control groups. In patients dropping out, TBC changes through the time of dropout were similar to those in patients completing the study. In those patients completing the study, TBC increased 2% in the treated group and decreased 3% in the placebo group. An approximate sixfold difference in extraskeletal calcium balance would be required to explain the magnitude of the observed intergroup TBC difference. The drug effect appeared to persist throughout the 26-mo observation period. Thus these data strongly suggest that long-term use of methandrostenolone in postmenopausal osteoporosis prevented bone loss; the possibility that it increased bone mass above initial values is less certain.


Correlation of platelet aggregation, plasma factor activity, and megathrombocytes in diabetic subjects with an without vascular disease. Second-phase platelet aggregation induced by adenosine diphosphate (ADP) and epinephrine was measured in fasting platelet-rich plasma in normals, "prediabetics," and diabetics with or without vascular disease. "Plasma factor" potentiation of ADP-induced second-phase platelet aggregation was also estimated, as were megathrombocyte numbers in the same patient groups. There was an increased sensitivity of second-phase platelet aggregation noted with both aggregating agents in all diabetic groups except for the prediabetics. This activity was paralleled by an increase in plasma factor activity. In vivo evidence of an increased turnover of platelets in frank diabetics was suggested by increased numbers of megathrombocytes. These studies demonstrate that platelets from diabetics are sensitive to aggregating agents and that this sensitivity may be related to plasma factor(s) present in diabetics. In vivo platelet aggregation may be present in diabetics. Longitudinal studies will be necessary to establish the relationship of these findings to the genesis of diabetic vascular disease.


Improved tolerance to successive glucose loads in acromegaly. The mechanism of the Staub-Traugott effect, or facilitated glucose disposal with closely timed successive glucose loads, remains poorly understood. Progressive suppression of growth hormone has been suggested as an explanation. To test this hypothesis, three successive intravenous glucose loads were administered to seven active acromegalic patients and six healthy controls. All subjects showed a clear Staub-Traugott effect despite failure of hyperglycemia to suppress abnormally high growth hormone levels in the acromegalics. Except for higher basal and incremental insulin release in the acromegalic patients, patterns of insulin secretion and suppression of free fatty acids were not substantially different from controls. These studies clearly suggest that hyperglycemia-induced suppression of growth hormone is not the cause of the Staub-Traugott effect.


The role of vasopressin and prolactin in abnormal salt and water metabolism of obese patients before and after fasting and during refeeding. Arginine vasopressin (AVP) and prolactin (PRL) concentrations were measured in the plasma of grossly obese subjects to determine if abnormalities in salt and water homeostasis could be related to these hormones. Acute oral water loads and hypertonic saline infusions were administered during baseline obesity, after prolonged fasting, and after hypocaloric refeeding. Only 64.7%, 46.1%, and 70.1% of a water load was excreted during the respective three stages. Pre-water load plasma AVP levels were normal, but after the water load the obese failed to suppress AVP secretion in a normal fashion; this defect was corrected after fasting and with refeeding. Salt loading resulted in appropriate osmolality and AVP responses. Serum prolactin levels, normal at baseline during all phases, rose slightly after water loading during fasting. Hypertonic.saline produced no changes in prolactin levels in the obese or in the normal controls. In the disordered salt and water metabolism of the obese, persistently high AVP values during water loading appeared to be a factor in the delay of water excretion. In the observed water retentionduring dietary restriction and refeeding, secretion of AVP and PRL did not appear to have a major regulatory function.


Physical training in human hyperplastic obesity. IV. Effects on the hormonal status. Severly obese subjects and sex- and age-matched controls underwnet physical training during a 6-wk period. Evidence of training was shown in all subjects by increased aerobic power. Before training the obese subjects were characterized by the following abberations: decreased glucose tolerance, hyperinsulinemia, elevated blood glycerol and plasma free fatty acids, and a blunted plasma growth hormone response during glucose tolerance. Noradrenaline output was elevated, a finding of potential interest for the explanation of increased lipolysis, blood pressure, and heart size in obesity. With training the following changes were found:In the controls there was evidence for the beginning of a decrease of adipose tissue mass. In the obese, however, body weight, body fat, or fat cell size did not decrease during training. Plasma insulin decreased, and a corresponding increase of plasma glycerol was seen. Glucose tolerance was not changed, and this, together with decreased plasma insulin, indicated an increase insulin sensitivity of the periphery. Changes in noradrenaline or growth hormone during training could not explain this increased sensitivity. Urinary cortisol output was found to decrease after training in the obese; this might be interpreted as a decrease in cortisol secretion allowing a more effective insulin action on the periphery.


Excision-repair in mutants of Escherichia coli deficient in DNA polymerase I and/or its associated 5' leads to 3' exonuclease. The ultraviolet (UV) sensitivity of Escherichia coli mutants deficient in the 5' leads to 3' exonuclease activity of DNA polymerase I is intermediate between that of pol+ strains and mutants which are deficient in the polymerizing activity of pol I (polA1). Like polA1 mutants, the 5'-exonclease deficient mutants exhibit increased UV-induced DNA degradation and increased repair synthesis compared to a pol+ strain, although the increase is not as great as in polA1 or in the conditionally lethal mutant BT4113ts deficient in both polymerase I activities. When dimer excision was measured at UV doses low enough to avoid interference from extensive DNA degradation, all three classes of polymerase I deficient mutants were found to remove dimers efficiently from their DNA. We conclude that enzymes alternative to polymerase I can operate in both the excision and resynthesis steps of excision repair and that substitution for either of the polymerase I functions results in longer patches of repair. A model is proposed detailing the possible events in the alternative pathways.


Mapping of a gene for a major outer membrane protein of Escherichia coli K12 with the aid of a newly isolated bacteriophage. A method is described for the enrichment of phages which can adsorb to a specific determinant of bacterial cell surfaces. A phage was isolated which absorbs to E. coli cells containing the "major outer membrane= protein c but not to strains that are lacking this protein. With the aid of this phage a gene, meoA which is responsible for the lack of protein c was mapped at 48 min on the linkage map of E. coli K12.


Effect of the petite mutation on maltose and alpha-methylgucoside fermentation inSaccharomyces cerevisiae. Several hundred petite mutants were isolated from yeast strains of different genotype to examine the effect of the petite mutation on maltose and alpha-methylglucoside fermentation. In most cases petite mutants isolated retain the ability to ferment maltose and alpha-methylglucoside, although at a slower rate. In one strain (1403-7A), however, the ability to ferment alpha-methylglucoside is completely lost in all petite mutants isolated from this strain. It is suggested that mitochondrial factors may be involved in the utilization of alpha-methylglucoside in strain 1403-7A.


Development of E.coli virus T1: the pattern of gene expression. T1 infected bacteria exhibit a distinct pattern of gene expression. The control of this expression is accessible to biochemical analysis. T1 induces the synthesis of 31 proteins in E. coli. The virion contains 15 proteins. By means of T1 amber mutants, 10 gene products have been assigned to specific T1 genes. Three classes of T1 proteins are defined by the kinetics of their syntheses: early, early-late and late proteins. The regulation of protein synthesis involes at least three mechanisms: for cessation of host gene expression, for discontinuation of the early class during the late phase and for induction of the late T1 proteins. The positive control of late gene expression is not coupled to replication. The host RNA-polymerase transcribes the viral genome throughout the infectious cycle. No virus coded RNA-polymerase is induced.


Excision of a DNA sequence determining kanamycin resistance from a ColE1-Km recombinant plasmid. A 4.8 X 10(6) dalton ECoRI-generated fragment of the R-factor R6-5 carrying the gene for kanamycin resistance (Km) was joined in vitro to ECoRI-treated ColE1 plasmid DNA. Transformation of E. coli with the ColE1-Km recombinant plasmid yielded clones, which were immune to colicin E1, resistant to kanamycin and failed to produce colicin E1. During multiplication of this recombinant plasmid in the presence of chloramphenicol, cells expressed an increased resistance to kanamycin. Transformation studies with the recombinant DNA molecule showed very frequent loss of Km resistance in those cells harbouring a preexisting F'gal plasmid. Since colicin immunity is not affected and the col- phenotype is still present, one has to test for a remaining DNA sequence further existing in ColE1 DNA by cleaving the plasmid DNA with the ECoRI restriction endonuclease. The full length of ColE1 DNA (6.2 kb) was restored, which confirmed that no deletion of ColE1 DNA sequences had occured. The remaining DNA sequence was identified as a 2.0 or 2.2 kb segment. On the basis of the length of the excised fragment it is proposed that the insertion sequence ISI and a part of the inverted repeat sequence with corrdinates 21.0 to 22.0 of the R6-5 DNA are recognised by a nucleolytic function.


Joint molecules of lambda DNA as an intermediate of genetic recombination. Joint molecules of lambda DNA formed in the absence of DNA replication, which may be involved in the process of genetic recombination can be observed as branched DNA derived from different phage particles. These molecules are associated through base-pair hydrogen bonding in synaptic regions, usually with short single-stranded gaps. Furthermore, joint molecules could be accumulated up to ten fold when lambda was irradiated with ultraviolet light before infection of polI mutant of E. coli. Infection at low multiplicity did not give rise to joint molecules. These results suggest that single-strand breaks and gaps introduced in duplex lambda DNA facilitate the formation of joint molecules.


Lambdoid phages that simplify the recovery of in vitro recombinants. Derivatives of phage lambda are described for use as vectors for fragments of DNA generated with the HindIII and EcoRI restriction enzymes. With some vectors, hybrid molecules are recognised by a change from a turbid to a clear plaque morphology resulting from the insertion of a fragment of DNA into the lambda gene coding for the phage regressor. Other vectors contain a central, replaceable fragment of DNA which imparts a readily recognisable phenotype. This central fragment may include either a gene for a mutant transfer RNA (suppressor) or a part of the lacZ gene of E. coli able to complement a lacZ host. The appropriate lacZ host and indicator plates permit the ready distinction between recombinant and vector phages by the colour of the plaques.


Interaction of alleles of the relA, relC and spoT genes in Escherichia coli: analysis of the interconversion of GTP, ppGpp and pppGpp. Mutants in the spo T gene have been isolated as stringent second site revertants of the relC mutation. These show varying degrees of the characteristics associated with the spoT1 gene, viz relative amount and absolute levels of both pppGpp and ppGpp and the decay rate of the latter. The entry of 3H-guanosine into GTP and ppGpr pools in spoT+ and spoT1 cells either growing exponentially or during amino acid starvation was determined, and the rate of ppGpp synthesis and its decay constant calculated. During exponential growth the ppGpp pool is 2-fold higher, its decay constant 10-fold lower, and its synthesis rate 5-fold lower in spoT- than in spoT+ cells; during amino acid starvation the ppGpp pool is 2-fold higher, its decay constant 20-fold lower, and its synthesis rate 10-fold lower in spoT than in spoT+ cells. In one of the "intermediate" spoT mutants the rate of entry of 3H-guanosine into GTP, ppGpp and pppGpp was measured during amino acid starvation. The data form the basis of a model for the interconversion of the guanosine nucleotides in which the flow is: GDP leads to GTP leads to pppGpp leads to ppGpp leads to Y. Calculations of the rates of synthesis and conversion of pppGpp and ppGpp under various conditions in various spoT+ and spoT- strains indicate that the ppGpp concentration indirectly controls the rate of pppGpp synthesis.


[Functional disorders of distal colon in children (author's transl)]. Functional disorders of the distal part of the colon in neonates and infants should be diagnosed by X-ray investigations (defecograms), double-suction biopsies (Erlanger children suction biopsy apparatus), anorectal and sigmoidal manometry and coloscopic functional investigations. 90% of all disorders of the distal colon can be diagnosed by manometric studies, in 40% X-ray investigations will lead to an exact diagnosis, in 12% double suction biopsies and in 10% coloscopic investigations establish the right diagnosis. The double suction biopsy is important for the exclusion of aganglionosis. Either a conservative or a surgical treatment is necessary, depending on the primary lesion. Wash outs, sphinctertraining, toilet training are necessary in cases of prolonged constipation following sigmaresection with restmegacolon, in cases of rectal inertia syndrom, and in cases of overflow incontinence. A pressure reducing operation (a sphincteromyotomy) is indicated in ultrashort aganglionic segments, in special cases of elongated sigma, in cases of prolonged constipation after sigma resection and with disturbed reflex mechanism, in cases of sphincter inhibition syndrome, and in children with paradox reflex mechanism. A resection is indicated in Hirschsprung disease, mechanical obstruction of the bowel, very large and severe cases of sigma elongatum and in cases of overflow-incontinence.


Studies on mutagenicity of irradiated sugar solutions in Salmonella typhimurium. Irradiated sugar solutions are mutagenic towards Salmonella typhimurium, the effect being dose-dependent up to 2.0 Mrad. At all doses, ribose solution exhibited greater mutagenicity than did sucrose solution. The mutagenic effect was observed only in dividing cells and appears to be directly related to the growth rate. A larger proportion of revertants was observed after incubation with irradiated sugar solution for a period of 4 h than for 24 h. Irradiation of the sugar solutions in the frozen conditions was effective in completely preventing the development of mutagenic potential. Post-irradiation storage of the sugar solutions for a prolonged period (25 weeks) also minimized their mutagenic effect. The irradiated sugar solutions gave rise to both missense and frame-shift (additon as well as deletion) types of mutation; ribose was more effective in inducing the latter type. The irradiated sugar solutions failed to show a mutagenic response in the host-mediated assay with mice as the mammalian host.


Factors affecting mutagenic activity of cigarette smoke condensate in Salmonella typhimurium TA 1538. Smoke condensates from Burley tobacco, bright-type tobacco and various brands of commercial cigarettes were tested for mutagenicity by using a microsomal test system with Salmonella typhimurium TA 1538. Smoke condensate from Burley tobacco had much higher mutagenic activity than that from bright-type tobacco. Increased mutagenic activity was observed with smoke condensates from Burley tobacco grown with increasing amounts of nitrogen fertilizer, and from commercial cigarettes blended with Burley tobacco. There was a significant correlation between nitrate content of cigarette and mutagenic activity of the resulting smoke condensate. The results suggest that nitrate in cigarettes may influence the formation of potential mutagens during the burning of a cigarette.


Genetic damage induced by ethyl alcohol in Aspergillus nidulans. Heterozygous diploid conidia of Aspergillus nidulans were treated during germination with ethyl alcohol in concentrations ranging from 0.25% to 20% (v/v). The diploid strain carried three recessive conidial color mutations, in addition to genetic markers on all eight pairs of linkage groups. It was thereby possible to detect events of crossing over, non-disjunction, and mutation. An increase in the dose of ethanol was associated with a decrease in conidial viability and an increase in the relative and absolute frequencies of formation of (a) normal colonies which produced colored sectors and (b) phenotypically abnormal colonies, the majority of which (83.1%) produced normal sectors. At a concentration of 5% (v/v) ethanol, the survivors included 17.59% of the former and 44.7% of the latter colonies. Genetic analysis of the various segregants suggested that the frequencies of both mitotic crossing over and non-disjunction or the misdistribution of chromosomes were increased by ethanol. Among 133 abnormal colonies which segregated normal clones, 79 (59.4%) were associated with one of these genetic events. A total of 297 haploids and 130 diploids arose as normal segregants from the abnormal colonies. There were 31 recognizable events of non-disjunction and 14 crossing over in linkage groups I and II, where these events could be distinguished. These data suggested that the predominant effect of ethanol was a disruption of chromosome distribution. A cytological examination of ethanol-treated, germinating conidia revealed an interference with the mitotic spindle apparatus. The frequency of detectable spindles decreased more than 3-fold after 8 h exposure to 5% (v/v) ethanol. This finding supported the conclusion that ethanol disrupted chromosome distribution, and suggested the mechanism by which it does so. Human clinical data on alcohol consumption were examined in light of these findings.


The in vitro effects of imipramine on human chromosomes. The clastogenic effects of imipramine on chromosomes have been investigated in leukocyte cultures from seven healthy blood donors (2 mlae and 5 female), repeat cultures being initiated at intervals of 6 to 12 weeks. At various times prior to harvesting nine different doses of imipramine were added in vitro, the three lowest concentrations being within the range of plasma levels reported in psychiatric patients reveiving the drug therapeutically. In addition, streptonigrin was used as a positive control. No increase in chromosome breaks was found at any concentration for any duration of exposure even in those cultures where high concentration and/or long duration of exposure significantly suppressed cell growth. Only cultures to which streptonigrin had been added showed a significant increase in chromosome breaks.


Controlled comparison of amikacin and gentamicin. Amikacin or gentamicin was used to treat 174 patients with suspected severe gram-negative infections in a prospective, randomized, double-blind trial. Enteric gram-negative bacilli were pathogenic in 71 cases (39 treated with amikacin, and 32 with gentamicin). Amikacin was effective in 10 to 12 bacteremias, 21 of 24 urinary-tract infections, two of five pneumonias and four of six other serious tissue infections. The toal favorable response rate was 77 per cent for amikacin and 78 per cent for gentamicin. Nephrotoxicity and auditory toxicity could be evaluated in 124 and 67 cases respectively. Definite nephrotoxicity developed in five of 62 (8 per cent) receiving amikacin and seven of 62 (11 per cent) given gentamicin, and possible nephrotoxicity developed in four patients in both groups. Definite ototoxicity developed in four patients in both groups. Definite otoxicity developed in two of 34 (6 per cent) and three of 30 (10 per cent) respectively. These differences were not statistically significant (by chisquare analysis, P greater than 0.05). The results indicate that amikacin is effective against severe gram-negative infections and is not more and not less ototoxic or nephrotoxic than gentamicin.


A controlled trial of metoclopramide in symptomatic gastroesophageal reflux. Since metoclopramide increases lower-esophageal-sphincter pressure in patients with gastroesophageal reflux, we compared the effects of metoclopramide, 10 mg four times daily, with those of placebo on symptoms in 31 patients with chronic heartburn. Eighteen patients completed a random-order, double-blind crossover study of two consecutive eight-week periods. The final 13 patients crossed over only if their symptoms were not substantially improved after the first eight weeks. Response of low-esophageal-sphincter pressure to metoclopramide did not correlate significantly with symptomatic improvement. After the metoclopramide treatment period, mean basal pressure was unchanged from values before study. In both treatment periods, metoclopramide-treated patients had significantly more symptomatic improvement than the control group (P less than 0.05).


Children as renal donors.

Children as renal donors. With the exception of identical twins, preadolescent children have been excluded as renal donors. The justification for this policy appears to be based on a notion that renal donation is an altruistic act, primarily for the benefit of another, and that stringent standards of informed consent must be followed. This paper challenges the present policy on two grounds: consent from adults who donate kidneys is generally not informed, and therefore it is inconsistent to use the consent requirement as a justification for excluding children; and renal donation by adults can be seen as a procedure done for the benefit of the donor (as well as the recipient), and the appropriate rules for using children as donors should therefore be those pertaining to beneficial intrusions on nonconsenting subjects.


Treatment of spasmodic torticollis with amantadine: a double-blind study. Ten patients with spasmodic torticollis participated in a double-blind crossover trial of amantadine hydrochloride for a period of 2 months each. A further regimen of combined amantadine and haloperidol was tried with three patients after the conclusion of the double-blind trial. There were no therapeutic benefits of either treatment. Half of the patients reported minor side effects that resolved promptly when amantadine was discontinued.


Transfer factor therapy: clinical experience and the role of the E rosette assay. Transfer factor has been administered to 17 patients, most with infectious diseases of various kinds. In 12 patients the therapy was followed by a definite clinical improvement although in most cases conventional chemotherapy was given concomitantly. In all cases where clinical improvement followed the sheep red cell or E rosette assay showed low values initially, with an improvement following therapy. This test of T lymphocyte function may be useful both in predicting patients likely to respond to transfer factor, and in monitoring response to treatment. As no specific assay of transfer factor activity is available, an in vivo rise in E rosette formation following transfer factor administration serves as a crude indicator that the injected material has some biological activity.


Menstrual function and renal transplantation. Patients with chronic renal insufficiency usually have menstrual dysfunction. Recent methods of managing chronic renal failure include renal transplantation. In a few instances, previously infertile women have become pregnant. We have studied 23 women who have undergone renal transplantation. Our findings support previous contentions that menstrual irregularity is frequent among women with chronic renal insufficiency. Amenorrhea was the prevailing disturbance and it was not reversed by hemodialysis. Renal transplantation was associated with a return of normal menstrual patterns in 60% of our patient population, and 4 patients experienced pregnancy. These findings support our recommendation of reproductive counseling for all women between the ages of 15 and 50 years who are treated by renal transplantation.


[The psychotropic effect of beclamid (author's transl)]. 60 boys and girls between 6 and 14 years with the symptoms "psychomotoric unrest", "disturbance of behavior" and "disturbed concentration" with and without epilepsy were treated and observed in hospital during a period of 8 weeks. Group I (20 patients) was given Beclamid, 3--6 tablets a day according to weight. Group II (20 patients) was given placebos in the same dosage. Group III (20 patients) was given Beclamid during 4 weeks and placebo for the following 4 weeks. Compared with the placebo groups the influence on concentration, memory and skill was significantly better after the application of Beclamid. The extent of the improvement depended on the period of medication. The Beclamid-group could be guided more easily, showed a better sense for cooperation and turned out to be more accessable to pedagogic methods. This positive psychotropic effect again increased with the period of medication. The (positive) influence on behaviour also affected the effciency at shcool and learning. Neither a sedative nor other side effects could be seen.


Pulmonary pseudocysts in the newborn infant. Five neonates who developed a pulmonary pseudocyst are reported. All infants had clinical hyaline membrane disease and were treated with continuous distending airway pressure. The pseudocysts developed between 39 hours and 7 days of age. In all but one pulmonary interstitial emphysema preceded or occurred together with the development of the pseudocyst. All babies went on to complete clinical recovery without surgical intervention. Radiologic documentation of the spontaneous resolution of the pseudocyst was obtained in three infants and occurred over three days, five days, and three months, respectively.


Tracheal extubation of the neonate at 2 to 3 cm H2O continuous positive airway pressure. To investigate the efficacy of extubation at higher levels of continuous positive airway pressure (CPAP), 49 newborns (0.95 to 4.0 kg) were extubated at 2 to 3  cm H2O following 1 to 47 days of CPAP therapy. Pre- and postextubation measurements of Po2, PCO2, pH, FiO2, and CPAP were made in all infants. No significant differences (P less than.05) were found between pre- and post-extubation arterial blood gas values for all patients. Comparison of pre- and post-extubation blood gas data with respect to birthweight (less than 2.0 kg vs greater than 2.0 kg) and intubation time (less than 8 days vs. greater than 8 days) also indicated no statistical differences. Mean alveolar-arterial oxygen differences and FiO2 for 41 infants showed progressive decreases following extubation. Six of the 49 infants required reintubation within 72 hours following extubation. The results of this study indicate that newborns with respiratory disease requiring CPAP may be extubated at 2 to 3 cm H2O with no significant changes in arterial blood gas values, thus preventing prolonged intubation associated with weaning to 0 cm H2O CPAP.


[Intussusception following renal transplantation in dogs (author's transl)]. In a consecutive and non-selected study of 54 kidney transplanted dogs, 12 cases of intussusception of the small intestine developed in 8 dogs. The patogenesis is still unknown. It has been postulated that the time of the operation (4--7 hours) and the segmental termination of the post-operative atony in the intestine are essential factors in this fatal complication. The last 16 dogs in this material were peroperatively treated with antikolinergics (Mestinon NFN), which was continued until normal function of the intestine. In these dogs there were no evidence of intussusception. The value of this profylaxis is open to discussion and it is essential to solve the problem of intussusception through a "blind" and controlled trial.


[Treatment of parkinsonian syndromes by bromocriptin]. Nine patients suffering from Parkinson's disease and 2 cases of Parkinsonian syndrome were treated with bromocriptine, for 41 to 117 days, with a daily dose of 20 to 40 mg. The results were very good in 4 cases, satisfactory in 6 and nil in one case. Improvement concerned akinesias, rigidity and tremor, and was more marked in patients with more advanced signs. In 2 patients, amantadine was stopped. The dose of L-dopa was decreased by 2/3 without any change in clinical condition and L-dopa could be withdrawn in 5 cases out of 8. Bromocriptine appears to be an interesting development in the treatment of Parkinson's disease.


[Dynamics of hormonal modifications induced by bromocryptin during hyperprolactinemia]. In a group of 16 females and 2 males with hypogonadism and hyperprolactinemia, bromocriptine was found to suppress prolactin (PRL) high levels within one day without further significant lowering during a 3 weeks longitudinal survey. The usually effective dosage was 5 mg per day. On the contrary, sex hormones did not vary initially and increased secondarily only in those patients resuming gonadal activity. The changes were either cyclical or heterogenous when the first cycle was anovulatory. This latter situation could sometimes but not always be attributed to persistent hyperprolactinemia. Menstruation resumed in 11 patients. Persistance of hypogonadism in the remainder could be explained by incomplete PRL reduction in one case and probability of previous hypothalamo-pituitary damage in six. The latter hypothesis was based in part on impaired gonadotropins responses to LH RH which were not modified by the treatment.


[Streptococcal gangrene. Importance of surgical treatment]. The authors report five cases of streptococcal gangrene and stress the fundamental role of surgical excision. Parenteral anti-streptococcal antibiotics should not lead to this essential step being forgotten, its early application being the most important element in prognosis. It is thus essential to clearly understand the local and general criteria of rapid diagnosis in this condition, which is far from rare.


[Reduction of the effects of indomethacin by aspirin. Value of measurement of the articular index and sigma ESR]. Two groups, A and B, were selected at random amongst a total of 31 patients suffering from chronic inflammatory rheumatic disorders. The patients in group A (n = 16) received succesively: Placebo (2d), Indomethacin (5d). Indomethacin + aspirin (5d). The order of the 5 day treatment periods was reversed for the patients in group b (n = 15). The daily dose of indomethacin was 150 mg. That of aspirin was 1500 mg. Four parameters were measured at the end of each period of treatment: total serum indomethacin, articular index (Ritchie), ESR (Westergren) and the sigma ESR - a new technique for the measurement of sedimentation rate. No conclusions could be drawn from the analysis of variations in ESR. Concordant and statistically significnat variations in articular index and the sigma ESR showed a reduction in the activity of indomethacin under the influence of aspirin. The inhibitory effect of aspirin. The inhibitory effect of aspirin continues after the drug stopped. This reduction in indomethacin activity is not related to a decrease in serum concentrations of the medication which are not significantly altered when aspirin is taken.


An overview of nursing research in the United States. In a four-part article, historical perspectives (part I) are reviewed, the development of nursing research in education (part II) is outlined, the contribution of nursing research to practice (part III) is traced, and research resources (part IV) which made the growth possible are described.


Nursing research: reflection of values.

Nursing research: reflection of values. Commitment to research is a key predictor of nursing's fulfillment of its potential. This paper identifies indicators of progress toward that goal and points up commitments still to be made.


Urinary infection in a remote practice.

Urinary infection in a remote practice. The results of these studies suggest that both the 'N-Labstix' nitrite test and the 'Uriglox' test for hypoglycosuria, although highly convenient, are far too inaccurate in the diagnosis of urinary infections. As yet, methods are still not available for the speedy and accurate diagnosis of urinary-tract infections in remote areas, and, inevitably, treatment will continue to be given on an empirical basis.


Nucleotide sequence of the operator-promoter region of the galactose operon of Escherichia coli. We have derived the nucleotide sequence of a segment of the operator-promoter region of the galactose operon of E. coli, by using a variety of DNA sequencing analyses. We have previously reported the sequence of the 5' terminal portion of gal mRNA [Musso, R. E., de Crombrugghe, B., Pastan, I., Sklar, J., Yot, P. & Weissman, S. (1974) Proc. Natl. Acad. Sci. USA 71, 4940-4944] and of the 59 base pairs preceding the startpoint of gal transcription (J. Sklar, S. Weissman, R. Musso, R. Di Lauro, & B. de Crombrugghe, submitted). In conjunction with those results, the present data provide the sequence of the gal operator-promoter region. This sequence is compared with similar sequences in other promoters and operators. Tentative mechanisms for the regulation of the galactose operon are discussed.


Interaction of tetraiodofluorescein with a modified form of aspartate transcarbamylase. Low concentrations of the dye tetraiodofluorescein activate native aspartate transcarbamylase (aspartate carbomoyltransferase, carbomoylphosphate:L-aspartate carbomoyltransferase, EC 2.1.3.2), while high concentrations inhibit the enzyme's activity [Jacobsberg, L. B., Kantrowitz, E. R. & Lipscomb, W. N. (1975) J. Biol. Chem. 250, 9238-9249]. This dye is now shown to produce similar effects upon a modified form of aspartate transcarbamylase produced by Escherichia coli grown in a culture medium supplemented with thiouracil. Significantly, the ATP-induced activation is reduced in the modified form of the enzyme to the same extent as is the tetraiodofluorescein-induced activation. Thus, a relationship is demonstrated between the internal mechanisms by which ATP and tetraiodofluorescein activate aspartate transcarbamylase.


Transient accumulation of Okazaki fragments as a result of uracil incorporation into nascent DNA. Strains of Escherichia coli with a mutation in the sof (dnaS) locus show a higher than normal frequency of recombination (are hyper rec) and incorporate label into short (4-5S) DNA fragments following brief [3H]thymidine pulses [Konrad and Lehman, Proc. Natl. Acad. Sci. USA 72, 2150 (1975)]. These mutant strains have now been found to be defective in deoxyuridinetriphosphate diphosphohydrolase (dUTPase; deoxyuridinetriphosphatase, EC 3.6.1.23), the enzyme that catalyzes the hydrolysis of dUTP to dUMP and PPi. Reversion of one sof- mutation to sof+ restores dUTPase activity and abolishes the accumulation of labeled 4-5S DNA fragments. Mutants initially isolated as defective in dUTPase (dut-) are also hyper rec and show transient accumulation of short DNA fragments. Both the sof and dut mutations are located at 81 min on the E. coli map, closely linked to the pyrE locus. The sof and dut loci thus appear to be identical. A decrease in dUTPase as a consequence of a sof or dut mutation may result in the increased incorporation of uracil into DNA. Rapid removal of the uracil by an excision-repair process could then lead to the transient accumulation of short DNA fragments. It is possible that at least a portion of the Okazaki fragments seen in wild-type cells may originate in this way.


Sensory transduction in Escherichia coli: a requirement for methionine in sensory adaptation. Chemotaxis of E. coli is a behavioral response to a change in the concentration of a stimulatory compound. The response is transient; thus, E. coli undergoes sensory adaptation. In this communication, we show that L-methionine is required by E. coli for adaptation to increases in the concentration of chemical attractants, but is not required for the maintenance of the adapted state. When the concentration of the attractant is lowered to its initial level, cells regain their sensitivity to the attractant. This process of deadaptation does not require methionine. We suggest that the methylation of a membrane protein, a reaction previously shown to be involved in chemotaxis [Kort, E.N., Goy, M.F., Larsen, S.H. & Adler J. (1975) Proc. Natl. Acad. Sci. USA 72, 3939-3943] underlies these phenomena.


Proofreading of the codon-anticodon interaction on ribosomes. The fidelity of protein synthesis is substantially greater than the specificity of codon-anticodon recognition that would be expected from the known energetics of base-pairing in solution. To test the suggestion that the specificity of recognition may be increased by "kinetic proofreading" associated with GTP hydrolysis [J. J. Hopfield (1974) Proc. Natl. Acad. Sci. USA 71, 4135-4139], we have studied the interaction of ternary complexes of polypeptide elongation factor Tu, aminoacyl-tRNA, and GTP with poly(U)-programed ribosomes. With most noncognate ternary complexes, including two that pair correctly with the 5' and 3' bases of UUU, rejection occurred without GTP hydrolysis, presumably by the reverse of the initial binding reaction. However, with complexes containing Leu- or Ile-tRNAs, which may pair correctly with the 3' and middle bases, GTP hydrolysis was stimulated though the aa-tRNA was not retained on the ribosome. These results demonstrate the existence of a GTP-dependent proofreading step in aminoacyl-tRNA recognition on ribosomes. They also suggest that the 5' base of the codon is more prone than the middle base to errors that can be corrected by proofreading.


A mutant of Escherichia coli showing constitutive expression of the lysogenic induction and error-prone DNA repair pathways. A mutant of E. coli (designated the STS mutant) has been isolated in which the phage induction and error-prone DNA repair pathways appear to be expressed constitutively without the cells having received an inducing signal. Phage lambda was not able to lysogenize this mutant, whereas a noninducible mutant of lambda, lambdacIind-, known to synthesize a repressor that is insensitive to the induction mechanism, lysogenized it normally. This result suggested that normal phage repressor was synthesized in the STS mutant but was then inactivated by the induction mechanism. The STS strain also had mutator characteristics, and showed spontaneous, error-prone repair of UV-damaged phage lambda. Derived from a lexA tif sfiA parent strain, the STS mutant carried an additional mutation spr at the lexA locus that resulted in a high level of expression of the induction pathways. The properties of this and related strains provide additional evidence that induction of phage and induction of error-prone DNA repair occur by a similar mechanism, and further suggest a model for the regulation of these pathways.


Nonsense suppressors of yeast cause osmotic-sensitive growth. Many nonsense suppressors of Saccharomyces cerevisiae cause growth inhibition on hypertonic media. Eight tyrosine-inserting UAA (ochre) suppressors, eight tyrosine-inserting UAG (amber) suppressors, a leucine-inserting UAG suppressor, and a serine-inserting recessive lethal UAG suppressor cause osmotic sensitivity, whereas a serine-inserting UAA suppressor does not cause sensitivity. Although the mechanism is not understood, the growth inhibition of specific suppressors on hypertonic media is correlated with their efficiencies of suppression. This heretofore unknown property of nonsense suppressors is useful for mitotic mapping, selecting tRNA mutants, selecting antisuppressors, and scoring nonsense suppressors.


Immunological defect and its correction in the osteopetrotic mutant rat. Congenital osteopetrosis in the mutant rat "op" is accompanied by early atrophy of the thymus gland. The response of thymocytes to concanavalin A and phytohemagglutinin P was greatly diminished at age 28 days, even before pronounced thymic atrophy could be detected. The response of spleen cells to mitogens that stimulate thymus-derived (T) and bone-marrow-derived (B) cells was diminished as early as 35 days of age. A single injection of a suspension of normal bone marrow, which cures osteopetrosis, increased thymus weight and restored the normal responses of both thymus and spleen to various mitogens. These results add further support to the hypothesis that the thymus is involved in the pathogenesis of osteopetrosis.


Comparative subunit structure of HeLa, yeast, and chicken erythrocyte chromatin. We have compared the chromatin subunit structure of yeast, HeLa, and chicken erythrocyte by analyzing the DNA fragments produced by in situ digestion with staphylococcal nuclease (EC 3.1.4.7) and DNase I(EC 3.1.4.5). The repeat size of the chromatin varies among (and within two of) the three organisms but the size and the structure of the most nuclease-resistant "core" of the repeat is the same. Thus, the interspecies differences in repeat size are due to different lengths of nuclease-sensitive "spacer" DNA between the cores. There also seems to be a difference in the manner of spacing of cores; the transcriptionally active (yeast and HeLa) chromatins have spacings of variable length while the transcriptionally inactive (chicken erythrocyte) has a more regular spacing of cores.


Total breast reconstruction with either of two abdominal flaps. We describe our experience with 15 cases of total breast reconstruction, using open abdominal flaps. Of these, 13 were mid-abdominal flaps. We believe the latter, an arterial flap(axial pattern flap), is safer.


Use of muscular, musculocutaneous and omental flaps to reconstruct difficult defects. These recently popularized flaps make reconstruction of some difficult defects possible in a single operation, with surprisingly good results. They have significant advantage over free flaps (except, perhaps, in the hands ofa few experts) because the chance of failure is considerably less. We do not propose that these flaps be used instead of local tissue (when available), or instead of split-skin grafting (when an appropriate bed exists). Additionally, in some instances, the use of muscle flaps would result in a significant loss of function. However, in suitable cases their use is a rewarding addition to the peviously available methods reconstruction.


Iodinated silicone-an antibacterial alloplastic material. Iodine is readily miscible in silicones and will pass freely into and out of this material at highly predictable and constant rates. Iodinated silicone is thus an effective, controlled-rate delivery system for molecular iodine. This delivery system was shown to produce bacteriostatic and bactericidal effects in vitro, and at least bacteriostatic effects in vivo. Iodinated silicone produced a protective effect against the morbidity of infection in the mouse.


Correction of severe hemifacial atrophy with a free dermis-flat from the lower abdomen. A case of hemifacial atrophy was corrected with a free dermal-fat flap, based on the inferior epigastric vessels. Microvascular anastomosis to the facial vessels was used. Ancillary "tailoring" procedures were done later to complete the work.


Cardiac asystole secondary to carotid sinus compression in the face-lift operation. We present 3 cases of carotid sinus compression with cardiac  asystole which occurred in healthy patients undergoing routine rhytidectomies. The mechanism is discussed and suggestions are made regarding preoperative evaluation and operative management.


The psychodynamic determinants of Moses and Monotheism. Many writers have commented on the lack of Freud's usual level of logic and powers of persuasion in Moses and Monotheism. The majority attribute it to the significance of dynamic determinants in Freud himself--most notably, identification with Moses. Fromm (1972) says "one must assume that Freud's preoccupation with Moses was rooted in the deep unconscious identification with him" (p. 79). Unfortunately, the situation is much more complex. Although many pertinent observations have been made, what is needed is a detailed dissection of the text, a correlation with elements from Freud's personal life, and an overall psychoanalytic synthesis of the data. This paper makes a beginning in that direction, incorporating the ideas of other investigators with those of the author--but it is hoped that much more detailed analysis and biographical correlation will follow. There is a wealth of information about Freud in Moses and Monotheism and no one paper will exhaust it. In this examination no attempt will be made to evaluate Moses and Monotheism for its literary, psychohistorical, or scientific merit. The focus is on the psychodynamic determinants of Freud's essay.


Total-body irradiation with a high-dose-rate linear accelerator for bone-marrow transplantation in aplastic anemia and neoplastic disease. Nine children with various hematologic disorders underwent bone-marrow transplantation following total-body irradiation with 750 rads at a rate of 26 rads/min. from a 13-MeV linear accelerator in conjunction with cytotoxic drugs. This treatment was tolerated reasonably well, with acceptable side effects. Three patients were alive and well at 18, 11, and 7 months post-transplantation at the time this paper was written.


Subtraction sialography.

Subtraction sialography. Subtraction sialography is described and demonstrated to be a simple yet helpful technique in evaluating the salivary glands. The improved visualization of the ductal system is demonstrated.


Hospitalization for fractures and bone loss in adults. Why do we regard these phenomena as dull? The epidemiology of serious fractures in adults relates less to the frequency of forceful accidents and more directly to the loss of bone in middle-aged and older people. To support this statement, hospital discharge rates for fractures in recent years are examined from different geographic areas. Rates for the United States rise with age, so that serious fractures form 10 percent of all hospital discharges at 85 years and older. Saskatchewan data suggest that rates for men remain low until 60 years; for women the figures began to rise at 45 years, before many had reached the menopause. Rates are lower among women than men in Saskatchewan until around 50 years, surpassing those of men at age 55 and older. Among Medicare enrollees in 1967 in the United States, women had higher discharge rates for fractures than men of the same age and race. Whites also had higher rates than blacks, so much so that white males had higher rates than black women of the same age. Such data confirm the past impression that blacks who survive into the older ages are a biological elite, more able to maintain bone strength than whites of either sex, although by no means being exempt from bone loss with age. A fractured femur was the most frequent diagnosis, forming a higher percentage of all fractures in women than men, and rising steeply with age in both sexes. The pattern of fractures by sex differs from the epidemiology of forceful accidents, which more often involve men than women. Bone loss with age, or osteoporosis, is perhaps the most powerful host factor to dominate the picture of fractures in the elderly. The existing possibilities for preventing or slowing this change are thus assessed; women may no longer accept as natural the widespread bone loss and accompanying fractures that lower the quality of life in later years.


Pancreatitis and renal disease.

Pancreatitis and renal disease. Pancreatitis has been described previously following renal transplantation, but not in association with chronic renal failure. Analysis of 168 patients with renal transplants revealed five who developed pancreatitis, three of whom died. All five were on treatment with prednisone and azathioprine. Four patients were seen with definite attacks of pancreatitis and chronic, stable renal failure from a variety of causes. None had received immunosuppressive agents, prednisone nor thiazide diuretics, but two were on regular frusemide. One patient was on maintenance dialysis, which could not be related directly to the pancreatitis. In either group alcohol ingestion, cholethiathiasis, or hypercalcaemia was not a factor. This diagnosis of pancreatitis was established on clinical grounds and serum amylast levels of greater than 900 iu/1. Similar serum amylast elevation was not found ina random group of patients with chronic renal failure. Hyperlipidaemia was not present in any patient with pancreatitis. Although hypercalcaemia and primary hyperparathyroidism was not found in the transplant and non-transplant subjects, elevated serum parathormone levels have been described in uraemic patients with normocalcaemia. Hyperparathyroidism may be a factor in the development of pancreatitis in reanl failure. Pancreatitis carries a significant mortality risk in renal transplantation. The four non-transplanted patients have survived, despite recurrent attacks of pancreatitis.


[The isolation of enteritis causing Salmonellae from the sputum]. In the light of the author's diagnostic experience, attention is drawn to the fact that enteritis Salmonellae appear to be more frequently present in sputum than in generally supposed. The diagnostic and epidemiologic implications of this observation are discussed.