Plasma levels and clinical effects of thioridazine and thiothixene. The effects of thioridazine and thiothixene were studied by a double-blind technique on 40 schizophrenic patients. The doses were adjusted for optimal clinical and therapeutic effects and side effects were rated after three and eight weeks of treatment. No statistically significant differences were observed between the two drugs or between either of the two drugs and the previous medication. Plasma levels were estimated by a fluorometric technique after three and eight weeks of treatment. No correlation was found between plasma levels and clinical effects for either thioridazine or thiothixene. Plasma levels of both drugs were clearly correlated to dosage after three weeks of treatment. After eight weeks this correlation persisted for thioridazine but not for thiothixene. By that time plasma levels of thiothixene had decreased to about 30 per cent of the initial value, indicating strong enzyme induction.


Histologic studies of human skin test responses to ragweed and compound 48/80. II. Effects of corticosteroid therapy. In a controlled study, a 1-week course of a moderate dosage of corticosteroids given to ragweed-sensitive subjects was associated with a statistically significant decrease in blood eosinophi, levels and tissue esosinophil, but not mast cell, responses to ragweed antibody levels or gross whealing responses to antigen or compound 48/80. While these findings suggest indirectly that a major component of the corticosteroid effect is likely an alteration of the mobilization of eosinophils to the inflammatory site, additional studies will be required to more directly characterize the mechanisms involved.


Effects of diphenylhydantoin on mental abilities in the elderly. An assessment was made of the effects of diphenylhydantoin (DPH) on the mental functions of clinically normal elderly persons. Their basic intelligence levels ranged between normal and bright-normal and they represented middle and lower-upper socio-economic group. The 10 subjects, 4 male and 6 female volunteers (average age, 69.3 years), were given pretrial intelligence tests, repeated twice during a double-blind, cross-over study of drug and placebo effects. Each cross-over period lasted three weeks. The dosage of DPH (Dilantin) was 100 mg twice daily, and placebo capsuales of identical appearance were given on the same schedule. The Wechsler Intelligence Scale series in three alternate forms was used to measure specific mental functions. The weighted scores of the altervate forms were directly compared to measure the difference between drug and placebo conditions. Significant increases in favor of DPH were observed in the Information, Comprehension, and Digit Symbol subtests, and in the Verbal Scale and Full Scale Intelligence Quotients. The first two measures indicated significant improvement in long-term memory and social comprehension. The third reflected an increase in the ability to learn new material and increased speed in visual-motor coordination. The fourth and fifth showed the effectiveness of DPH in improving general mental functioning. Apparently the underlying factor synthesizing these general DPH-associated improvements is mental concentration.


Specificity of brain-reactive antibodies in serum of old mice. Previous studies in our laboratory demonstrated that brain-reactive antibodies are present in the serum of old mice and these are separated from the brain antigen by the blood-brain barrier. In this paper the specificity of these antibodies to neuronal antigen has been studied using sera from old mice with or without absorption by the homogenates of different organs and also by direct treatment with sections of those organs. The results indicate that these brain-reactive antibodies found in sera of old mice are specific to neuronal antigen in the central nervous system.


Normal function of transplanted marrow cell lines from aged mice. Transplantation experiments indicated that losses with age in erythrocyte production were not intrinsically timed within marrow cell lines. In most cases marrow cell lines from old donors functioned as well as those from young donors after transplantation into either W/W-v anemic or lethally irradiated normal recipients. After normal marrow cells had been serially transplanted into successive W/W-v mice 5 times, both old and young cell lines began to fail; the old cell lines had produced erythrocytes normally for 77 to 84 mo. Transplanted old and young control marrow cell lines, identified by T6 chromosomes, saved the lives of lethally irradiated recipients; the oldest cell lines functioned normally for 54 mo. The hypothesis is suggested that senescence of an organism is caused by intrinsically timed functional declines in only a few vital cell types. In transplantation experiments to identify these cell types, four criteria--function, identification, control, and health--should be met. The marrow transplantation experiments led to and illustrate the hypothesis and the four criteria.


Defective erythropoietic responses of aged mice not improved by young marrow. Defective responses to severe bleeding in 25-mo.-old C57BL/6J mice were not improved by injections of 8-mo.-old marrow cells. Such injections greatly improved responses of genetically anemic W/W-v mice that have defective erythropoietic stem cells. Apparently the defective responses of old mice were not intrinsic to their erythropoietic stem cells.


Diarrhoea in general practice: a sixteen-year report of investigations in a microbiology laboratory, with epidemiological assessment. Results are presented of the laboratory examination of faeces specimens from  20,273 patients with acute diarrhoea. These were household index cases seen in general practice in a London borough during the years 1953-68. An annual average of about 2 per cent of households in the area were affected, but there was considerable fluctuation with year and season. Half the patients were children although only one-fifth of the population at risk was under 15 years of age. The greatest incidence of diarrhoea was among children under 5 years old. Male children, but female adults predominated. Specimens were sent for laboratory diagnosis at the discretion of the general practitioner. The laboratory found some abnormality in nearly a third and there were indications that transmissible infection was involved in about one-fifth of patients. The most common diagnosis was Sonne dysentery (9 per cent) which came in epidemic waves and made its greatest impact among young school children. Microscopy was useful, and giardiasis was diagnosed in 1-4 per cent of index patients. Other parasites were less commonly found. Fatty globules characteristic of an infectious condition we have called 'fatty diarrhoea' were frequently observed by microscopy in stools from young children and occasionally from older persons. Blood or pus cells were seen in less than half the shigella and salmonella infections and in a much smaller proportion of the remainder. A test for occult blood performed on specimens from all patients of 40 years or older was positive, in the absence of visible red cells, in a tenth of these cases. Other studies on the bacteriology of diarrhoea in general practice are referred to and some epidemiological comparisons made. The possible place of unidentified infective agents in the aetiology of undiagnosed diarrhoeas and of 'fatty diarrhoea' is discussed.


Incubation at raised temperature or enrichment media, combined with secondary enrichment in Rappaport's medium, for the isolation of salmonellas from sewage. Two FMDV strains which had been previously differentiated by complement-fixation were compared by guinea-pig protection test, kinetic neutralization and micro-neutralization tests. It was found that these tests, which have not been previously applied by the methods described, were all capable of FMDV STRAIN DIFFERENTIATION. Similar differences were found by all methods, which suggests that comparisons made by cross-CF, cross-neutr-alization or cross-protection involve measurement of the same antigen/antibody interactions.


The problem and implications of chloramphenicol resistance in the typhoid bacillus. Transferable chloramphenicol resistance has become common in the typhoid bacillus in countries such as Mexico, India, Vietnam and Thailand. Situations such as this, and others analogous to it in many parts of the world, are the result of the long-term indiscriminate use of chloramphenicol and other antibiotics in the affected areas. They can be rectified only by more rational antibiotic usage.


Canine marrow transplantation: are serum blocking factors necessary to maintain the stable chimeric state? Nine long-term canine radiation chimeras and their canine histocompatibility locus (DL-A) compatible, mixed leukocyte culture negative littermate marrow donors were studied between 545 and 1282 days after 1,200 R total body irradiation and marrow grafting. Before the time of testing, marrow donors were immunized against their chimeras by repeated skin grafts which they rejected. Skin fibroblasts from chimeras and their donors were tested for cell inhibition (CI) in the microcytotoxicity assay be exposure to lymphocytes from chimeras, donors and normal dogs and the effects of various sera on CI were evaluated. Lymphocytes from sensitized marrow donors consistently inhibited fibroblasts from the chimeras (eight of nine dogs); CI was abrogated by chimeric serum in only three of eight cases. Only two chimeras showed consistent CI of their "own" fibroblasts; CI was blocked by chimeric serum in one of the two. The remaining seven chimeras did not show consistent CI. Sequential studies in 16 additional recipients of DL-A compatible littermate marrow were carried out from 45 to 439 days after marrow grafting. Seven of the 16 did not show CI of chimeric fibroblasts by chimeric lymphocytes at any time. Nine showed CI on one or several occasions. Serum blocking factors were seen on one occasion in each of two chimeras. In conclusion, the CI assay is able to detect immunity against "minor" histocompatibility systems in dogs. Both long- and short-term chimeras occasionally demonstrated CI of chimeric fibroblasts but serum blocking factors did not appear to be necessary for maintaining stable graft-host "tolerance."


Canine radiation chimeras: an attempt to demonstrate serum blocking factors by an in vivo approach. An attempt was made to demonstrate in vivo the presence of blocking factors in the serum of canine chimeras with grafts of chimeric skin onto the marrow donor as an indicator system. Even very large amounts of chimeric serum (one-fourth of the plasma volume infused daily from day 2 before skin grafting until rejection) failed to modify first and third set skin graft rejection patterns. Thus, serum blocking factors could not be demonstrated by this in vivo approach.


The production of anti-guinea pig lymphokine antibody. Rabbit antiserum to lymphokine-containing supernatant fluids has been prepared by means of a two-stage immunization procedure. Migration inhibiting factor (MIF)-containing and control supernatants were obtained from guinea pig lymphocyte cultures. Both were fractionated on Sephadex G-100. Fractions of control supernatants corresponding to active fractions from the MIF-rich material were used to immunize rabbits. The anti-"control" antibody so obtained was conjugated to agarose beads to prepare an immunoadsorbent column. The MIF-rich Sephadex fractions were passed through this column to remove materials corresponding to those found in control supernatants and which could react with the anti-control antibody. The eluted MIF-rich fraction was concentrated and used to immunize a second group of rabbits. The anti-"lymphokine" antiserum so obtained was studied for its effect in vitro and in vivo. It was found capable of suppressing the activity of MIF, macrophage chemotactic factor, and skin reactive factor. It could also suppress delayed hypersensitivity skin reactions in actively immunized guinea pigs.


Differential regulatory effects of accessory cells on the generation of cell-mediated immune reactions. Conditions for the in vitro generation of cell-mediated immunity to H-2 and non-H-2 alloantigens by mouse spleen cells were compared to conditions for generation of in vitro humoral immunity to sheep red cells. Normal spleen cells grown in standard or allogeneic cell-conditioned media developed strong cellular responses to H-2 antigens but little or no response to non-H-2 antigens. Subpopulations of spleen cells from which the adherent cells had been removed generated strong cellular responses to both H-2 and non-H-2 antigens, provided the cells were cultured in conditioned media. Both cellular responses were shown to be mediated by T cells. Accessory cells from the peritoneum and/or spleen differentially inhibited the non H-2 cellular responses at doses which did not inhibit humoral responses.


Immune mechanisms in leukemia: evaluation of immunocompetent cell populations. Dose-response curves of the cellular immune response of C58/wm mice to syngeneic line Ib malignant lymphoid cells (Ib cells) were computer analyzed by the PROBT subroutine in the IBM Scientific Subroutine Package. An analysis of the relative immunogenicity of various admixtures of x-irradiated (XIb) and viable Ib cells (VIb) after i.p. injection showed that the ratio had to be approximately 100:1 to be immunogenic. Viable Ib cells contained in immunogenic mixtures multiplied in vivo at a logarithmic rate up to 5 or 6 days but were eliminated immunologically by 8 or 9 days. Adoptive cell transfer techniques were used to quantify the protective effect of immune spleen cells (ISC). Essentially a constant dose of ISC (10-6.4) protected mice against a challenge dose of 10-2 to 10-5 VIb cells; more than 10-5 VIb cells were lethal. Two techniques were used to quantify immunity even though mice ultimately died of transplanted leukemia, viz., mean survival time (MST) with a fixed challenge dose of VI b cells, or MST with a fixed time for death. The sensitivity and statistical limitations of these assays are presented.  To amplify the sensitivity of assays for adoptive cellular immunity a technique of antigenic stimulation was used, viz., 1 day after x-irradiated mice (600 R) received an i.p. injection of normal or immune spleen, bone marrow or thymic cells they received an i.p. injection of XIb cells containing an admixture of VIb cells. The technique amplified the sensitivity of ISC transfer tests approximately 100-fold and made it possible to detect protective effects of bone marrow and thymic cell populations.


Chemotaxis of basophils by lymphocyte-dependent and lymphocyte-independent mechanisms. Guine pigs basophils obtained from blood or bone marrow have been studied for their chemotactic responsiveness. Chemotactic factors for basophils include a substance (lymphokine) present in culture fluids from antigen-stimulated lymphocytes, a material generated in zymosan-activated guinea pig serum, a C5 cleavage factor, and a bacterial factor. When compared with homologous neutrophils and monocytes, basophils respond most rapidly to a chemotactic stimulus. The lymphokine basophil chemotactic factor is physicochemically similar to the previously described monocyte chemotactic factor but appears to be distinct from it as well as MIF and neutrophil chemotactic factor present in the same fluids, Part of the evidence for this is the ability to detect basophil chemotactic factor in the absence of other lymphokine activities under appropriate experimental conditions. More evidence, specifically relating to the monocyte factor, is that monocytes can adsorb basophil chemotactic activity but not vice versa. This latter observation may have implications for the mechanism whereby the accumulation of basophils is controlled and limited in vivo. In addition, it was noted that specific antigen could also suppress basophil chemotaxis. Although the mechanism of this phenomenon is unclear, it could serve as a second means by which basophil accumulation may be controlled in the intact animal. Taken together, these observations provide further definition of the chemotactic behavior of basophils in general, and underscore some of the ways in which lymphocytes can influence basophils through lymphokine-dependent mechanisms.


Effects of an acidic polysaccharide procuced by Serratia piscatorum on immune responses in mice. I. mitogenicity and stimulation of plaque-forming cells (PFC) in vitro. An acidic polysaccharide of Serratia piscatorum, consisting of L-rhamnose, D-galactose and D-galacturonic acid, stimulated the primary IgM PFC response of spleen cell cultures against sheep erythrocytes. The polysaccharide (PS) caused dose-dependent stimulation of 3H-thymidine incorporation into DNA of spleen cell cultures and the maximum response was seen after about 48 hr. Nonadherent B (ATXBM) cells were strongly reactive to PS, whereas adherent spleen cells were less reactive. Higher doses of PS suppressed the peak PFC response, but enhanced the earlier PFC responses. Lower doses of PS stimulated the PFC responses significantly throughout the period of PFC production. The optimal dose (0.1 mug/ml) of PS increased the PFC responses in mixed cell cultures containing spleen cells and either B cells, T cells activated with a different antigen, or hydrocortisone-resistant thymus cells of syngeneic origin. However, this dose of PS interfered with the enhanced PFC response of spleen cells due to addition of antigen-primed T cells. Since these characteristic activities of PS were like those of lipopolysaccharides (LPS), this acidic polysaccharide may be useful for further elucidating the modes of LPS action.


DNP-Lys-ficoll: a T-independent antigen which elicits both IgM and IgG anti-DNP antibody-secreting cells. The 2,4-dinitrophenyl-lysyl derivative of Ficoll (DNP-Lys-Ficoll) was prepared and examined for immunogenicity. This antigen elicited large numbers of DNP-specific plaque-forming cells (PFC) of the IgM and IgG2 class in the spleens of C57BL/6 mice. Similar responses were observed in congenitally athymic (nu/nu) mice and in their littermates indicating that DNP-Lys-Ficoll is a T-independent antigen. The responses of nu/nu mice included a large number of IgG2 DNP-specific PFC, indicating that IgG responses can be initiated in the absence of mature thymus-dependent (T) lymphocytes. Cell transfer studies confirmed the T independence of the response and indicated that priming with DNP-Lys-Ficoll induces only a very meager degree of memory. Because they can be obtained in large quantities and in relatively pure form, DNP-Lys-Ficoll and other hapten conjugates of Ficoll should prove most valuable in the delineation of the mode of activation of precursors of antibody-secreting cells by T-independent antigens.


Repopulation with IgA-containing cells of bronchial and intestinal lamina propria after transfer of homologous Peyer's patch and bronchial lymphocytes. Transfer of 50 million rabbit allogeneic lymphocytes from either bronchus-associated lymphoid tissue (BALT) or Peyer's patches into 1000 R x-irradiated recipients results, 6 days later, in predominant repopulation of gut and bronchial lamina propria, as well as spleen with IgA-containing cells. After repopulation with BALT or Peyer's patch cells, lymphoid follicles in both gut and lung showed peripheral cellular membrane type of fluorescence with fluorescein-conjugated anti-IgA antisera only. Six days after x-irradiation alone, little evidence of repopulation was seen and immunofluorescent qualitative observations of gut and lung, and quantitative data in the spleen, confirmed these findings. After transfer of 50 million lymph node cells, very few immunoglobulin-containing cells were seen in the gut or bronchial lamina propria. These results suggest that there may be a common mucosal immunologic system, and that repopulation of gut and lung lamina propria may be through the organized lymphoid tissue therein.


Regulation of the immune response: production of a soluble suppressor by immune spleen cells in vitro. The addition of ovalbumin-immune spleen cells (Ova ISC) to sheep erythrocytes-immune spleen cells (SRBC ISC) in Mishell-Dutton-type cultures resulted in a dramatic reduction of PFC to SRBC and was dependent upon the addition of soluble Ova at low concentrations of Ova ISC. The suppressing cells in the Ova ISC were shown to be irradiation sensitive, depleted by anti-theta antiserum and complement treatment, and did not absorb to glass bead columns. Ova ISC-induced inhibition also occurred in culture chambers across a cell-impermeable membrane and a soluble inhibitor was recovered in chambers opposite the Ova ISC. This suppressor factor was sensitive to trypsin treatment and to heating at 80 degrees C, but not to 70 degrees C, for 30 min. The molecular weight, as determined by sucrose gradient analysis, was between 55,000 and 60,000 daltons. This suppressor factor appears to be distinct from a T-cell "helper" factor which was found to be sensitive to heating at 70 degrees C for 30 min. We propose that this suppressor factor participates in the termination of most immunologic responses and is responsible for the antigenic competition phenomenon.


Unilateral renal disease in the rat. I. Clinical, morphologic, and glomerular mesangial functional features of the experimental model produced by renal perfusion with aminonucleoside. Unilateral renal perfusion with the aminonucleoside of puromycin (60 mg. per kilogram) was used to produce unilateral renal disease in rats characterized by marked proteinuria, hypoalbuminemia, and hypercholesterolemia. Urine albumin excretion increased from 0.21 plus or minus 0.16 mg. per 24 hours prior to perfusion to 126 plus or minus 30 mg. on the fourteenth day after perfusion. If the perfused kidney was removed after 10 days, urine albumin excretion immediately decreased to normal, whereas marked proteinuria continued after contralateral nephrectomy. Immunofluorescent studies revealed abundant protein reabsorption droplets (beta1C and albumin) in proximal tubules of aminonucleoside-perfused kidneys but not in contralateral kidneys thus indicating that the increased proteinuria was of unilateral origin. Less marked proteinuria was observed following unilateral renal perfusion with lower doses of aminonucleoside. Glomerular mesangial function was studied 10 days after renal perfusion. Renal specimens were obtained 12 hours after intravenous injection of 37.5 mg. per 100 Gm. of body weight of aggregated human IgG and evaluated by immunofluorescent microscopy. Glomerular mesangial staining for human IgG in aminonucleoside-perfused kidneys was markedly increased when compared to contralateral kidneys. In contrast, mesangial staining in kidneys perfused with saline was equal to that of contralateral kidneys and proteinuria following perfusion with saline was not increased. These studies provide further evidence that increased proteinuria following administration of aminonucleoside to rats is the result of a rapid direct on the kidney and that alterations of glomerular mesangial function are related to renal factors rather than changes in systemic milieu.


Oxime derivatives of erythromycin: inhibitors of Rous sarcoma virus reverse transcriptase activity and focus formation. Bovine adenovirus type 3 (BAV-3), strain WBR-1, quantitatively transforms hamster embryo carcass cells with a maximum efficiency of 4-7 X 10-4 p.f.u./focus-forming units (f.f.u). This frequency is signigicantly inhibited by the presence of 1-8 mM of Ca++. The transformed cells are highly tumourigenic in hamsters and possess T- and tumour-specific transplantation antigens. BAV-3 is one of the most oncogenic of the adenoviruses and an ideal model virus for the study of transformation.


Occurrence of polyamines in coliphages T5, phiX174 and in phage-infected bacteria. The polyamine spermidine and the diamine putrescine have been detected in coliphages T5 and phiX174. Polyamines were identified by thin-layer chromatography and mass-spectrometry of dansyl derivatives, as well as by ion-exchange chromatography. In phiX174 phages, polyamines were sufficient to neutralize 0.5% of DNA phosphates. The polyamine content of T5 phages depended on growth media and purification procedures, but at least 1% of DNA phosphates were neutralized by polyamines. After infection, an increase in cellular polyamine was noticed. This increase paralleled variations in ornithine decarboxylase activity.


Electrostimulation of the neuropathic bladder. Intravesical electrostimulation offers promise in management of neurogenic bladder in children with myelocele. In the past 2 yr, we carried out about 500 treatments in 25 children aged 2 wk to 13 yr. After repeated stimulation, the starting intravesical pressure increases considerably in all cases; however, this was not always accompanied by clinical improvement. Our early results are encouraging, especially after repeated 10-day courses of electrostimulation; bladder contractions increase slowly and micturition begins to appear. Seventeen of 25 patients showed significant improvement, in two patients no improvement was observed. The remaining six have not been treated long enough to evaluate.


The effects of endotoxemia and bacteremia on gastrointestinal drug absorption in mice and rats. Endotoxin [lipopolysaccharide (LPS)] from four Gram-negative bacteria injected i.v. delayed absorption of drugs administered in solution by gastric tube to mice and rats. Salicylate and guinine absorption was delayed at LPS doses from 50 to 400 mug/kg. Salicylate absorption was delayed by LPS when drug was given by gastric tube, while LPS did not affect drug levels when salicylate was given i.p. or intraduodenally. Bethanechol prevented the LPS effect and LPS pretreatment also protected against delayed absorption. LPS- treated rats retained more drugs in their stomachs after 30 minutes and their plasma salicylate levels were lowered. Everted intestinal sacs from LPS-treated rats transferred salicylate as well as controls. Thus, LPS delays gastrointestinal drug absorption solely by retarding gastric emptying. Escherichia coli urinary tract infection did not reproduce LPS delay of drug absorption, but the effects of systemic bacteria were similar to those of endotoxemia.


A calcium ionophore stimulating the secretion of catecholamines from the cat adrenal. 1. Experiments were performed on perfused cat adrenal glands to examine the effect of a calcium ionophore A-23187 in the secretion of catecholamines. 2. Ionophore (1-10 muM) caused a dose-dependent release of catecholamines and the output was about 100-fold greater at 10 mum than at 1 mum. 3. Release of catecholamines by the ionophore was dependent on the calcium concentration of the perfusion medium. Omission of calcium blocked the response to the ionophore while excess calcium facilitated it. 4. Magnesium antagonized the secretory response to the ionophore. Excess calcium overcame the inhibitory effect of magnesium. 5. The ionophore did not modify release of catecholamines by induced splanchnic nerve stimulation. 6. The results suggest that the ionophore, like depolarization, introduces calcium into the chromaffin cell to cause release of catecholamines.


Diurnal fluctuations of testosterone and LH in the ram: effect of HCG and gonadotrophin-releasing hormone. To examine a possible relationship between the release of LH and increasing testosterone levels, blood samples were collected at 2-hr intervals for 24 hr from six mature rams with indwelling jugular cannulae. Although high levels of LH often preceded increases of testosterone, a consistent time relationship between these two hormones was not observed, nor was a diurnal rhythm established for either hormone. The following day, two rams were each injected intravenously with saline, 500 i.u. HCG, or 100 mug synthetic gonadotrophin-releasing hormone (Gn-RH) respectively. Immediately after the injection, blood was collected every 15 min for approximately 4 hr. After Gn-RH, the plasma LH rose 25- to 50-fold within 12 min and was elevated for more than 3 hr. A twofold rise of plasma testosterone followed this increase of LH and testosterone remained high until the end of the experiment. After HCG treatment, the level of testosterone rose threefold within 30 min and did not decline during the experiment, but there was no effect on the LH level. Saline treatment did not influence levels of LH or testosterone. It was concluded that daily fluctuations of testosterone and LH may occur independently, and no pattern is common to all rams. Treatment with Gn-RH results in a rise in both the testosterone and LH levels, but only testosterone is affected by HCG.


Somatostatin analogs. Relative importance of the disulfide bridge and of the Ala-Gly side chain for biological activity. Four analogs of ovine somatostatin (SRIF, PSOMATOTROPIN RELEASE INhibiting factor), the sequence of which is H-Ala-Gly-Cys-Lys-Asn-Phe-Phe-trp-Lys-Thr-Phe-Thr-Ser-Cys-OH, have been synthesized by the solid-phase methodology. The compounds were assayed and were found to possess the following somatotropin release inhibiting potencies relative to pure synthetic somatostatin in vitro and in vivo, respectively: [Ala3,14]somatostatin, 0.6 and 2.0%; [SMe-Cys3,14]somatostatin, 4 and 0.6%; [NAc-Cys3]somatostatin, 39 and 105%; [des-Ala1-Gly2]somatostatin, 65 and 71%. The dihydrosomatostatin analogs [NAc-Cys3-H2]somatostatin and [des-Ala1Gly2-H2]somatostatin after two purifications by gel filtration were assessed to be at least 80% homogeneous and had respectively 99 and 89% of somatostatin potencied in vivo. Structure-activity relationships are discussed.


Cyclopenta[f]isoquinoline derivatives designed to bind specifically to native deoxyribonucleic acid. 2. Synthesis of 6-carbamylmethyl-8-methyl-7(5)H-cyclopenta[f]isoquinolin-3(2H)-one and its interaction with deoxyribonucleic acids and poly(deoxyribonucleotides). 3-Ethoxy-8-methyl-5,6-dihydro-7H-cyclopenta[f]isoquinolin-5-one (2) was converted to 6-carbethoxymethyl-3-ethoxy-8-methyl-5,6-dihydro-7H-cyclopenta[f]isoquinolin-5-one (6) through an oxalyl derivative. Treatment of 6 with ammonia gave the corresponding amide 7 which on sodium borohydride reduction and subsequent dehydration yielded 6-carbamylmethyl-3-ethoxy-8-methyl-7(5)H-cyclopenta[f]isoquinoline (9). The analogous ester 10 was similarly obtained from 6. Numerous attempts to dealkylate the 3-ethoxy group of 9 or 10 failed. However, 6 coould easily be dealkylated on heating with 25% hydrochloric acid in a sealed tube.The ester, 6-carbethoxymethyl-8-methyl-5,6-dihydro-7H-cyclopenta[f]isoquinoline-3(2H),5-dione (11), so obtained was converted to the corresponding amide 12 which on reduction with sodium borohydride and subsequent dehydration afforded the desired compound, 6-car-bamylmethyl-8-methyl-7(5)H-cyclopental[f]isoquinolin-3-(2H)-one (1). 1 was found to be mildly cytotoxic againstL5178Y mouse leukemia cells in culture.1 was also found to bind to native calf thymus DNA. 1 inhibited RNA synthesis by a DNA-dependent RNA polymerase and a higher inhibition of RNA synthesis was observed when poly(dG-dC) was used as a template than when poly(dA-dT) was used. A significant increase of thermal transition temperature of calf thymus DNA and poly(dG)-poly(dC) was observed in the presence of 1. The accumulated evidence demonstrates that 1 interacts weakly with calf thymus DNA and interacts preferentially with poly(deoxyribonucleotides)-containing GC pairs.


Chemistry of cephalosporin antibiotics. 30. 3-methoxy- and 3-halo-3-cephems. The exo-methylene group in esters of 7-acylamido- and 7-amino-3-methylenecephams was ozonized to give 3-hydroxy-3-cephems. Conditions are described to effect a selective N-acylation of a 3-hydroxy-3-cephem nucleus ester. Vilsmeier reagents converted 7-acylamido-3-hydroxy compounds to 3-halo-3-cephem derivatives. Diazomethane converted the 3-hydroxy compounds to 3-methoxy-3-cephem derivatives. Removal of the ester-protecting group at the C4-carboxyl afforded a select group of cephalosporins with direct halo and methoxy substitution at C3. A number of these compounds are potent antibiotics.


Pseudosymmetry in the structure of luteinizing hormone-releasing hormone. Studies on a series of novel analogs. Pseudosymmetry in the LH-RH structure is described. Eleven analogs of LH-RH (SMALLER THAN Glu-His-Trp-Ser-Tyr-Gly-Leu-Arg-Pro-Gly-NH2) have been synthesized by the fragment condensation method and the repetitive excess mixed anhydride method. Multiple substitutions have been made in the LH-RH sequence, which retain the pseudosymmetry of the LH-RH molecule, while presenting fewer problems of synthesis than the corresponding residues in the natural decapeptide. Thus Trp3, Ser4, Tyr5, Gly6, Leu7, and Arg8 residues were replaced by amino acids having similar properties to the residues that they replace. In all but one of the peptides the Gly10-NH2 residue was replaced by ethylamide, while in the remaining peptide, 1-methyl-5-aminomethyltetrazole (AMT-Me) was substituted at position 10. The compounds were assayed in vitro and in vivo. The following analogs had in vivo and in vitro activities in the range 1-28 percent relative to LH-RH: I, smaller than Glu-His-Phe-Ala-Tyr-Gly-Leu-Arg-Pro-NHEt; II, smaller than Glu-His-Phe-Gly-Tyr-Gly-Leu-Arg-Pro-NHEt; VII, smaller than Glu-His-Phe-Ala-Tyr-Gly-Phe-Arg-Pro-NHEt; IX, smaller than Glu-His-Phe-Ala-Tyr-D-Ala-Leu-Arg-Pro-NHEt; XI, smaller than Glu-His-Phe-Gly-Tyr-Gly-Leu-Arg-Pro-AMT-Me.


Specific and nonspecific antitumor immunity. I. Description of an in vitro assay based on inhibition of DNA synthesis in tumor cells. As in vitro assay of cell-mediated antitumor immunity based on the inhibition of tumor cell DNA synthesis (IDS) was devised. It was reasoned that both cytolytic and cytostatic antitumor effects could be measured in a quantitative yet generalized manner with this approach. By the use of microculture techniques and simplified methods for the determination of tritiated-thymidine incorporation by all cells in individual cultures, normal and immune effector (E) cell populations were compared in their ability to inhibit the DNA synthesis of a fixed initial number of various target tumor cells. Doubling dilutions of E cells were used to titrate the antitumor effects of normal and immune cells at many E/T (effector to target) ratios. Under conditions of alloimmunization, significant immunologically specific IDS effects could routinely be detected at an E/T ratio of less than 1 or 0.1:1, and under certain conditions at 1:100 or less. Results were highly reproducible with respect to the individual E cell donors, replicate cultures, and repeat experiments. The effects were proportional to visually determined cell destruction and independent of obvious culture artifacts. The IDS method was compared with the 51Cr release technique under various experimental conditions. The results demonstrated that decreases in E/T ratio and/or the addition of excess nonimmune cells to immune effector populations had a similar effect in both assays, which was to decrease the magnitude of the immune cell activity. Addition of excess normal cells reduced the activity of immune cells to a level below that of an equal number of immune cells tested at the same E/T ratio without added nonimmune cells. Both assays detected primarily a T lymphocyte-mediated lytic event when effectors generated by the described alloimmunizations were used. The IDS assay also detected a weak non-T-cell activity in anti-theta plus complement-treated alloimmune spleen. The possibility that this represented antibody-dependent cell-mediated cytotoxicity was raised by the finding that normal spleen ceels plus antitarget antibody had significant activity in the IDS system. The sensitivities of the two methods were compared and the potential of the IDS method was evaluated.


Specific and nonspecific antitumor immunity. II. Macrophage-mediated nonspecific effector activity induced by BCG and similar agents. The recently described inhibition of DNA synthesis (IDS) assay, which measures antitumor effector (E) cell function by the quantitation of decreases in tritiated thymidine incorporation of target tumor cells, was used to analyze the nonspecific effector activity of peritoneal exudate cells (PEC) from mice infected intraperitoneally with BCG. These PEC could inhibit growth of and then kill all tumor target (effector to target) cells tested at E/T ratios as low as 1:1. This activity was not due to alterations in media, nor could any activity be shown for cell-free supernatants prepared from active cells. The principal cell type mediating this effector function was the "activated" macrophage-no activity was found in lymphoid or polymorphonuclear leukocytes. Direct effector to target contact was necessary for the cytotoxic reaction. The time course of these effects and comparative 51Cr release data were reported. The removal of the adherent nonspecific effectors from PEC of mice immunized to both BCG and a specific syngeneic tumor revealed a specific cytotoxicity of the remaining lymphoid cells. These results indicated that nonspecific effector activity by "activated" macrophages induced by BCG infection could be a potent antitumor mechanism, at least in vitro, and the IDS assay provided an accurate, reproducible, and quantitative method for measurement of the function of such E cells.


Differential cytotoxicity of tumorigenic and nontumorigenic strain-2 guinea pig cells as mediated by syngeneic phytohemagglutinin-stimulated peritoneal exudate cells. Phytohemagglutinin (PHA)-stimulated peritoneal exudate (PE) cells from strain-2 guinea pigs were more cytotoxic in culture to syngeneic tumorigenic cells than to syngeneic nontumorigenic cells. Cytotoxicity was measured by the release of 3H-thymidine from prelabeled target cells. Tumor-producing guinea pig fetal cells transformed in culture by chemical carcinogen released up to 70 percent of their label in the presence of PHA-stimulated PE cells. Non-tumor-producing cells, regardless of their morphologic characteristics, were less affected by PHA-stimulated PE cells. Nontumorigenic cultures included untreated early passage and long-term cultures previously treated with a carcinogenic or noncarcinogenic chemical. Differential cytotoxicity to tumorigenic cultures were best distinguished from nontumorigenic cultures when 0.5-1 times 10-6 PE cells and 50-100 mug PHA were incubated with 1 times 10-4 3H-thymidine-labeled target cells for 48 hours.


In vivo and in vitro tests of inhibitory effect of progesterone on cell-mediated immunity in rats bearing a syngeneic uterine adenocarcinoma. Growth inhibition or stimulation of target adenocarcinoma cells in rats sensitized with spleen cells from syngeneic tumor-bearing rats was significantly suppressed in colony inhibition assays when the spleen cells were treated in vitro with 0.8 mug progesterone or more/ml medium. In addition, when tumor-bearing rats were treated with 1 mg medroxyprogesterone acetate weekly in vivo, the inhibiting action of the spleen cells from rats with regressed tumors was also suppressed. Progesterone thus suppressed immune spleen cells in vivo and in vitro.


Mouse mononuclear cell chemotaxis: description of system. The mononuclear cell chemotaxis assay was adapted for use with normal mouse peritoneal cells. Mouse peritoneal macrophages responded well to endotoxinactivated mouse serum and to chemotactic factors produced by mouse spleen cell cultures stimulated with mitogens or specific antigen. The assay was quantitative, reproducible, and applicable to several mouse strains.


Self-screening for significant bacteriuria. Evaluation of dip-strip combination nitrite/culture test. A self-administered dip-strip device was used to screen for urinary tract infection in female subjects. Fifty-two cases of significant persistent bacteriuria were detected among 2,250 subjects by simultaneous use of pourplate quantitative cultures. The dip-strip culture test had good reliability in detecting Gram-negative organisms. Repeated nitrite tests, performed on first-morning specimens and read by the patient, also had good reliability in detecting Gram-negative bacteria. No false-positive test occurred. The device is effective in screening out contaminants, thus decreasing the need for repeated testing.


Treatment of persons exposed to rabies.

Treatment of persons exposed to rabies. Several clinical and epidemiologic criteria have been formulated by the Center for Disease Control in advising physicians on the treatment of persons exposed to possibly rabit animals. When deciding whether or not to institute rabies prophylaxis, the physician must consider (1) the type of exposure, (2) the animal species involved in the exposure and the regional epidemiology of rabies, (3) the circumstances surrounding the exposure, and (4) the treatment alternatives and complications.


Psoas abscess localization by gallium scan in aplastic anemia. Gallium 67 scanning is an effective method of detecting inflammatory lesions, especially abscesses. A 10-year-old boy with aplastic anemia and severe leukopenia and granulocytopenia had a psoas abscess diagnosed by gallium scan. The patient died with Candida spesis 18 days after bone marrow transplantation. At autopsy, a chronic psoas abscess with Candida was found. The gallium scan offers a clinically effective and noninvasive means of evaluating suspected infection in the granulocytopenic patient.


Lymphocytic choriomeningitis virus in man. Serologic evidence of association with pet hamsters;. Laboratory evidence of recent or current lymphocytic choriomeningitis (LCM) virus infection was obtained in 60 patients. Twelve had diagnosis of central nervous system (CNS) infection: four of meningoencephalitis and eight of meningitis. Thirty-four patients had a grippe-like syndrome. Fifty-nine had had contact with pet hamsters. All of the 24 patients whose pets were studied had been exposed to one or more hamsters with serologic evidence of past LCM virus infection. The data implicate pet hamsters as a source of LCM in man. A continuous effective control of LCM virus in pet hamsters appears impractical. At present, the only feasible way to prevent further cases is the physician's special attention to the possibility of rodent contacts of patients with CNS disease and early laboratory confirmation of suspected cases of human LCM virus infections.


Difficulties in obtaining kidneys from potential postmortem donors. Disease outcome and kidney disposition of 86 patients referred as potential postmortem kidney donors were followed up over a one-year period to determine factors that led to "organ wastage." Six patients died before fulfilling the electorencephalographic criteria for death; another six were referred too late, leaving insufficient time to contact the relatives; and in 16 patients, permission was refused by the next of kin. In eight cases, no relatives could be traced and, finally, 14 patients died wtthout fulfilling our criteria of acceptability. Organs were obtained from only 22 donors--25.5% of the total referrals. Any data presenting the number of potential postmortem kidney donors must be considered in thp light of factors incorporating the ease or difficulty with which kidney grafts can be obtained. An awareness of these factors is necessary for maximum utilization of potential kidney donors.


Decisive factors in the tolbutamide controversy. No increased mortality trend attributable to tolbutamide is shown by an analysis of variance on logit-transformed data from the University Group Diabetes Program (UGDP) study. The UGDP's controversial finding of an increased rate with mortality subgrouped by "cardiovascular" causes is confirmed by the Biometric Committee's report, with reservations that failed to include overriding decisive factors. The basic problem is that inspected data set up the hypothesis (the increased cardiovascular mortality), and that the same data were used to test the hypothesis, so that resulting probability values no longer have the usual meaning. The problem was compounded by multiple testing of the data without adjusting the probability levels. When cardiovascular deaths were redefined as myocardial infarcts and sudden deaths, in an attempt to test a proposed etiologic inotropic hypothesis, no significant increase in cardiovascular mortality was found.


[Extracorporeal attachment of the allo-and xenokidneys to recipients' body for temporary decrease of the level of antibodies and complement activity]. Data given in our investigation put questions important for clinical aspects of transplantation on efficacy of perfusional immunosorption for subsequent kidney transplantation with a temporarily reduced level of preexistent antibodies, on the character of evolution of the secondary response under the same conditions, on the level of immunodepression required in treating such patients etc.


[Hemodynamics in patients with circulatory insufficiency depending on the activity of the rheumatic process]. In 384 rheumatic patients, including 344 with mitral defect of the heart central hemodynamics, phasic structure of the left ventricle systole and renal hemodynamics were studied. With the help of the sought out algorythm and the computer technique qualitative information on the activity of the rheumatic process, expressed in terms of plausability proportions for each patient, was obtained. This was followed by a search for a correlation between the values of these proportions and the parameters of the cardiac function. An inverse correlation was found only relative to the stroke index and the ejection rate and merely in patients with mitral defect and circulatory insufficiency of the IIB-III stage. No essential difference was found between the values characterizing the hemodynamics, the duration of the left ventricle systole phases recorded in the groups of patients with active and inactive rheumatism, but at equal stages of ciruclatory insufficiency.


[Additional gadget for new techniques of artifical respiration with the Bennett repirator PR 2, particulary suitable for use in children (author's transl)]. A new gadget for the Bennett PR 2 repirator is described which in modified form can also be used with other types of apparatus. It makes possible new techniques of artificial respiration like IPPB with PEEP or compensated PEEP, the gasp respiration with CPAP or CPAP by itself, in a simple way. In neonates one may do without the often problematical assisted respiration when weaning from the respirator. Further it is now possible to achieve sufficient warming and humidification of the gas mixture by using an auxiliary gas flow in the expiratory phase.


Experimental oliguric acute renal failure: protective effects of renomedullary autotransplants. An acute circulatory renal failure (ARF) was induced in 18 rabbits by temporary ischemia of the remaining kidney 8 days after unilateral nephrectomy and subcuteaneous autotransplantation of renomedullary tissue.--Mortality in the postischemic course was 50% in treated animals but 100% in the control group (n = 18) without autotransplantation. In the postischemic period plasma urea concentration was significantly lower (p smaller than 0.005) in the surviving transplanted animals and excretion of sodium and water significantly higher (p smaller than 0.005) as compared with the control group. Plasma renin values which were significantly lower than thos of the control(p smaller than 0.005) had decreased significantly even as compared with the initial values. These results indicate that hormonal substances are produced in interstitial cells of renomedullary autotransplants exerting a distinct protective effect against experimental acute renal failure. Decreased plasma renin activity may point to an inhibition of circulating and/or intrarenal renin by lipids originating from the transplants. Changes in sodium and water excretion indicate effects of circulating prostaglandins


[5-Aminoacridine hydrochloride for fixation of human blood basophils (author's transl)]. 5-aminoacridine hydrochloride (0.4 percent in 50 percent aqueous ethanol) proved to be a useful fixative for the preservation of human blood basophils pretreated with methanol-formaldehyde (9:1 V/V). Leaching of the water-soluble basophil granules or other artificial cell alterations common to fixatives in current use were not observed. The organic compound used did not induce any chemographic artifacts in nuclear tracers, in contrast to most of the other fixatives hitherto applied. 5-aminoacridine hydrochloride is therefore particularly suitable for autoradiography of the human blood basophils.


Technic for serial bone sampling in canine skeletal labeling studies. A technic was described for repetitive bone sampling in beagle dogs. The procedure has provided ideal samples for quantitative histologic technics following 135 biopsies.


Colitis cystica profunda in rhesus monkeys. Spontaneously occurring colitis cystica profunda, characterized by the presence of non-neoplastic glands and mucin-containing cysts in the submucosa of the large intestine, was observed post mortem in 4 of 28 rhesus monkeys (Macaca mulatta) but in none of 20 squirrel monkeys (Saimiri sciuresu) necropsied during the same period of time. An analogous lesion in the stomach was present in 2 of the monkeys with the colonic condition. The submucosal glands and cysts resulted from extension of the mucosa through the muscularis mucosae, and inflammation was considered to have played a primary role in this process. The cause of the intestinal inflammation was not determined, and there was no known exposure to toxic chemicals, including pesticides and polychlorinated biphenyls. Colitis cystica profunda affecting man and other animals has been described infrequently in the literature, but the importance of differentiating it from intestinal adenocarcinoma has been emphasized.


A report of fourteen spontaneous tumors of the guinea pig. Fourteen guinea pig tumors were received by the Purdue University Animal Disease Diagnostic Laboratories over a period of 5 yr. Among them were 2 mammary gland adenocarcinomas, a mammary gland adenoma, a malignant mixed tumor of the mammary gland, a Schwannoma, 2 limpomas, an inflammatory polyp of the ear canal, a uterine fibroma, 3 trichoepitheliomas, an undifferentiated carcinoma, and a histiocytic lymphosarcoma. The pathologic features of these neoplasms were presented in this report.


Hexachlorophene retinopathy in rats.

Hexachlorophene retinopathy in rats. The primary effect of hexachlorophene on rat retina is disruption of the disc membranes of photoreceptor outer segments and irreversible destruction of their cell bodies. The neurons of the ganglion cell layer of the retina also become affected, probably secondary to optic nerve lesions present in hexachlorophene intoxication. The early and probably reversible changes of the discs are vacuolation and vesiculotubular degeneration. Vacuolation in the discs results from separation of their inner aspects. This lesion is analogous to the separation of myelin lamellae at the intraperiod line, also produced by hexachlorophene.


Characteristic immunohistochemical and ultrastructural glomerular lesions in Nude mice. Kidney glomerular lesions were studied by light microscopy and immunofluorescence in 17 congenitally athymic Nude mice and 25 of their phenotypically normal littermates. The 3-month-old mice had glomerular deposits of total IgG, IgG2, IgM, and C3, but IgG1 was consistently absent and IgA was present in only 30 per cent of cases. Conversely, the 6-month-old littermates showed no deposits. However, the 9- and 12-month-old littermates had glomerular deposits of all of the immunoglobulins and C3. Kidney tissue from five Nude mice was studied by electron microscopy. In three of these five mice the mesangial and subendothelial deposits contained characteristic double layered lamellar structures approximately 130 A wide. Antinuclear antibodies were found in the serum of 3 or 10 Nude mice and 1 of 12 littermates. Different hypotheses on the origin of the characteristic lamellar structures are proposed. The significance of the early development of autoimmunity and glomerular lesions in Nude mice is discussed.


The expressive portion of the NSST compared to a spontaneous language sample. This study was undertaken to determine the relationship between syntactic structures produced on the expressive portion of the NSST and those produced in a spontaneous language sample. The NSST was administered to 12 children previously diagnosed as delayed in language. In addition, spontaneous language samples were collected by a speech clinician and by the child's mother. The children ranged in age from four years one month to five years 11 months. We found that 30 percent of those syntactic structures incorrectly produced on the NSST were correctly produced spontaneously in the language sample. Furthermore, the sample obtained by the clinician was significantly richer in terms of number of structures produced correctly than the sample collected by the mother. Overall results indicate that an item analysis of the expressive portion of the NSST does not present an accurate representation of the child's language performance and therefore cannot be interpreted beyond its stated purpose, namely that of a screening instrument.


Encephalopathy and fatty infiltration of the viscera (Reye-Johnson syndrome): a 17-year experience. Reye-Johnson syndrome was found in 17 patients in a retrospective study of 235 children with acute encephalopathy seen at the Mayo Clinic in the period 1955 through 1971. Eight of the nine patients under 4 years of age developed the syndrome prior to 1968; eight children 10 to 15 years of age acquired the disorder from 1968 through 1971. Seven patients were admitted during the month of February. Prodromal symptoms preceded the encephalopathy in 13 patients. Eight patients had seizures. Progressive deterioration with brainstem signs led to death in 15 patients. Electroencephalographic findings correlated well with the clinical course and eventual outcome. However, no correlation was found between seizure activity and the electroencephalogram. Autopsy findings in 14 cases included cerebral edema, tonsillar herniation, hypoxic neuronal degeneration, and fatty inflitration of the liver and kidneys.


A review of the research on general health status indexes. During the mid-1960's, recognition of the spiraling cost of health care motivated Congress to enact several major pieces of legislation designed to underwrite efforts to improve the delivery of health services. The increased level of federal fiscal participation in the health service system has forced greater consciousness of the need for better accountability of the effectiveness and efficiency of the allocation of the dollar. Demands were articulated for precision tools which could evaluate the imput to output linkage between need and response; however, the tools were nascent and had limited applicability. Cost-effectiveness and cost-benefit analysis are two procedures that have since been applied with varying levels of success. A third tool, also developed as an outgrowth of the desire for a more accurate characterization of the planning concerns of an efficient/effective health service system, is the general health status index. The purpose of this article is to provide the reader with a comprehensive review of the literature on general health status indexes. Common objectives and constraints are presented, as well as a discussion of the expanding role of general health status indexes.


An assessment of institutional review committees in human experimentation. A study of the functioning of an institutional review committee, when combined with the Barber et al. survey data on 300 institutions, allows for a useful provisional assessment of the strengths and weaknesses of existing procedures for protecting human research subjects. The evidence shows that there is an important role for such committees; however, most committees are relatively permissive. While on committees' performance showed that such committees can have an impact on proposed research, the absence of effective monitoring procedures and lack of feedback from research subjects limits the impact of the review procedure on the actual conduct of research. The question is also raised whether the review procedure, because of its legitimizing functions, may have some regressive consequences for the protection of human subjects.


Cell proliferation kinetics in tumors after treatments. Analysis of data on cell reproductive death, cell proliferation kinetics, tumor volume responses and tumor eradication probability after single and fractionated doses of radiation given to experimental tumors, can yield several conclusions which may be relevant for the interpretation of clinical data: 1. considerable differences are observed among various cell types with respect to intrinsic radiosensitivity, but no specific differences are demonstrated for cells from tumors as compared to cells from normal tissue; 2. cell survival curves measured by in vitro cloning techniques for cells irradiated in an experimental rat rhabdomyosarcoma are consistent with the observed probability of tumor eradication, and 3. after a sufficiently large dose of radiation and after two weeks of fractionated treatments, important changes in cell proliferation kinetics have been observed with respect to cell cycle, cell production rate and cell loss rate, which may significantly influence the time of recurrence as well as the probability of attaining tumor eradication.


Carcinogenesis of laryngeal carcinoma.

Carcinogenesis of laryngeal carcinoma. Experimental models have been developed for the induction of carcinoma of the larynx and for the study of its pathogenesis. The hamster has been the animal of choice. Polynuclear hydrocarbons, administered intratracheally, induce mostly squamous cell carcinomas. Diethylnitrosamine given systemically induces papillary tumors; some other N-nitroso-compounds given topically or systemically also induce laryngeal tumors, including carcinomas. Cigarette smoke inhalation induces preneoplastic and early neoplastic lesions of the larynx, including some invasive carcinomas. In vivo and in vitro methods have been developed for the morphological and biochemical study of target tissues in respiratory epithelial carcinogenesis to identify critical pathogenetic steps and their inhibition. These methods are now applicable to the in vitro study of human laryngeal epithelium and its susceptibility to cancer induction and prevention.


Indirect laryngoscopy.

Indirect laryngoscopy. Indirect laryngoscopy is one of the procedural methods used for achieving a histopathologic diagnosis of cancer of the larynx. A chronologic historical summary of the development of mirror laryngoscopy is presented. The details of the procedure employed for obtaining a biopsy with the aid of topical anesthesia is discussed.


Post-laryngectomy vocal rehabilitation using expired air and an external fistula method. The advantages and problems of fistula speech in post-laryngectomy vocal rehabilitation are discussed. A pilot study of laryngectomees has shown the practical advantages and low risk of a primary one-stage external vocal fistula construction at the time of laryngectomy, allowing very early fistula speech. These results indicate the need for an intensive program to develop a definitive surgical procedure and prosthesis, with a view to applying the method to all types of laryngectomees.


Medial conchal excision in otoplasty.

Medial conchal excision in otoplasty. The most common cartilaginous deformities in protruding ears include an inadequate antihelical fold and an enlarged concha. We have employed medial conchal excision to correct deep conchas in 25 patients, all of whom were pleased with the postoperative result. Obvious wrinkling of the anterior skin occurred in four patients, and several patients displayed slight distortion of the helical crus. Medial conchal excision does not impede management of the antihelical fold with mattress sutures or by other means. We consider the risk of minor alterations of the concha justified if even slight distortion of the more conspicuous lateral auricle can be avoided.


Treatment of hypertension with an antihypertensive agent possessing vasodilator activity. Administration of the vasodilator agent, prazosin, in dosages from 3-0 to 7-5 mg per day, significantly reduced diastolic and systolic blood pressure in a group of 14 patients with mild or moderate hypertension. Nine of these patients had a lowering of diastolic blood pressure which was at least 10 mm Hg greater than that caused by placebo. Side effects, chiefly dizziness or lassitude, occurred in over half the patients, but were mild and of short duration and did not necessitate suspension of treatment. The antihypertensive effect of prazosin was similar to that produced by methyldopa or propranolol given in comparable doses. If prazosin and propranolol were given concurrently, blood pressure fell to a level which was significantly lower than that associated with the use of either of these agents alone.


[Season and psychiatric disease (author's transl)]. Clinical experience shows that certain psychiatric patients have to be hospitalized more frequently during certain periods of the year. We compared the data of the hospitalisation of 17268 psychiatric patients, hospitalized over a period of 13 years (1956-1969) with the time of the year. Schizophrenics are hospitalized mostly during the warm period, least during the cold period, regardless of their sex. The same can be said about the diagnostic subgroups (paranoics, catatonics, hebephrenics, schizophrenia simplex) and the periodic depressions and depressions of involution. Reactive and neurotic depressions and depressions of exhaustion, neurotics (crisis during puberty, neuroses of character, obsessional and anxiety neuroses), arteriosclerotics and psychopaths do not show an even pattern of distribution. Male alcoholics, too, do not show a maximum of admissions. Female alcoholics are admitted more during the warm periods, less often during the cold periods. Drug addicts, too, show a minimum in winter, an even level over the rest of the time of the year. It is suggested that the patterns of admissions for certain psychiatric patients are to be explained by the different sensibility of meteorological factors.


[Balkan-nephropathy, a particular form of interstitial nephritis (author's transl)]. Because of epidemiological, clinical, pathomorphological, and etiological criteria the Balkan-nephropathy is suggested to be a particular form of chronic interstitial nephritis with super-imposed pyelonephritis in about 30 p.c. of the patients. A basic scheme illustrates the origin and the development of the endemia as well as etiology and clinical course of the disease. Another scheme shows pathogenesis and pathomorphogenesis of the nephritis. This analysis about the characteristics of the endemic Balkan-nephropathy allows for the clarification of the triad: endemic occurrance, familial susceptibility, and mosaik like morbidity. The following important aspects of the disease are given: rarely occuring hypertension, facultative leukuria, and bacteriuria, smooth nephrocirrhosis. Prophylactic and therapeutic prospects are given.


The protein topography of the E. coli 30S ribosomal subunit: a preliminary model E. coli/30S subunit/ribosome/spatial arrangement of proteins. A three dimensional model is presented which shows the apatial arrangement of 20 of the 21 proteins of the 30S ribosomal subunit of Escherichia coli. The model fulfills several purposes: (a) It summarizes currently available structural and functional data on ribosomal proteins; (b) It suggests an interesting correlation between stoichiometry and function. Functional proteins are both clustered and fractional; (c) It can be evaluated in relationships or point out critical experiments by which it can be tested.


Isocitrate dehydrogenases and oxoglutarate dehydrogenase activities of baker's yeast grown in a variety of hypoxic conditions. The activities of isocitrate dehydrogenase (NAD), isocitrate dehydrogenase (NADP) and oxoglutarate dehydrogenase have been investigated in Saccharomyces cerevisiae grown in a variety of aerobic and hypoxic conditions, the latter including oxygen deprivation, high glucose concentration, addition of inhibitors of mitochondrial protein synthesis, respiratory inhibition by azide, and impaired respiration mutants. All hypoxic conditions led to a marked decrease of oxoglutarate dehydrogenase and significant decreases of the two isocitrate dehydrogenases. According to its kinetic properties, the NAD-isocitrate dehydrogenase will not be operative in hypoxia "in vivo". From these and other related facts it is concluded that hypoxic conditions in yeast generally lead to a splitting of the tricarboxylic acid cycle and that glutamate synthesis in these conditions takes place through the coupling of the NADP-linked isocitrate and glutamate dehydrogenases.


The adrenal medulla: a model for studies of hormonal and neuronal storage and release mechanisms. We have observed that phospholipids and protein of the catecholamine (CA) storage granules, i.e. the chromaffin granules, interact in an in vitro system to form liposomal particles, which in many respects resemble the intact matrix of the bovine chromaffin granule. A model has been suggested which consists of an aqueous phase, containing the acidic chromogranins and intact dopamine-beta-hydroxylase (DBH) ATP and CA, embedded in a liquid crystal of the matrix phospholipids. Ca2+ may play a significant role in the sequence of functional transitions of such an organelle, not only in the accumulation of Ca2+, as during the secretory phase of the intact cell, but also as the agent inducing a separation of the outer membrane bilayer from the matrix phase to be released, as during exocytosis. Furthermore, a liposome model of the matrix may also tentatively explain the occurrence of intact matrices in the interstitium of stimulated glands. Recent evidence for the identity between chromogranin A and DBH subunits have been summarized and a possible role for the inactive subunits in the ionic binding of ATP and CA in the aqueous phase of the matrix is discussed. A role of Ca2+ and cyclic AMP in the mediation of beta-adrenergic modulation is postulated on the basis of our recent work on acetylcholine-induced release of CA from perfused and stimulated bovine adrenals. We conclude that such a beta-adrenergic modulation is secondary to that of the cholinergic response. Hence, this activation is able to enhance the output induced by mild cholinergic stimulation although insufficient to evoke a CA release by itself.


Effects of p-fluorophenylalanine on the induction of mutations in bacteriophage T4. I. 5-Bromouracil mutagenesis. The amino acid analogue rho-fluorophenylalanine (PFPA) was found to have no mutagenic activity in the gamma system of bacteriophage T4. However, under standard conditions for 5-bromouracil (5-BU) mutagenesis, PFPA depressed the induced frequencies for both forward and reverse mutations. When the folate antagonist sulphanilamide (SU) was omitted from the mutangenic treatment medium or when it was replaced by Trimethoprim (TM), another folate antagonist, this depressive effect was abolished. It was proposed that PFPA alleviated the inhibitory action of SU.


Enterotoxigenic Escherichia-coli-associated diarrheal disease in Apache children. A search for intestinal enterotoxigenic Escherichia coli was made in 59 Apache children hospitalized with 64 episodes of acute diarrhea. Esch. coli isolates from acute-phase and convalescent-phase specimens of small-bowel fluid and stool were tested in three currently recognized models: the adult-rabbit ileal loop; infant rabbit; and the adrenal-cell assay. Enterotoxigenic strains were isolated from 10 children during acute diarrheal episodes (16 per cent); none were isolated from convalescent-phase specimens. None of 64 "enteropathogenic" serotypes of Esch. coli from 43 children with diarrhea, however, caused fluid production in the ileal-loop model. These results suggest that enterotoxigenic Esch. coli may be the cause of considerable diarrhea in this population and that the term "enteropathogenic" as applied to serotypes of Esch. coli needs to be redefined.


Management of heparin therapy: Controlled prospective trial. Among 100 consecutive patients receiving heparin in therapeutic dosage, major bleeding occurred in 21, and minor bleeding in 16. Two patients died from bleeding, and two had recurrent pulmonary embolism. Major bleeding occurred in 21% when therapy was regulated with whole-blood clotting time and in 20% when heparin was given without clotting tests. In a subsequent prospective trial patients received heparin by intermittent intravenous injection with or without laboratory control according to the partial thromboplastin time or continuously by intravenous infusion. Recurrent thromboembolism occurred once in each group. Major bleeding was seven times more frequent with intermittent injection than with continuous infusion. Control with the partial thromboplastin time did not prevent major bleeding in patients receiving intermittent injections. With continuous infusion, one-fourth less heparin was required than with intermittent injections. Administration of heparin by continuous infusion appears safer than intermittent injection with or without laboratory control and is no less effective for prevention of thromboembolism.


Trilobite eyes and the optics of Des Cartes and Huygens. The thick lenses in the aggregate eyes of a group of trilobites were double structures designed to eliminate spherical aberration. The shape of the optically correcting interface is in accord with constructions by Des Cartes and Huygens and is dictated by a fundamental law of physics. Trilobites may have evolved such sophisticated eye-lenses to maximise optic neurone response in a dimly lit environment.


Nasal infection of Alcaligenes bronchisepticus (Bordetella bronchiseptica) and lesions in newborn rabbits. The mode of experimental infection with Alcaligenes bronchisepticus (Bordetella bronchiseptica) of pig and rabbit origin, and lesions in the respiratory organs were examined in three groups, A, B and C, of newborn rabbits. Groups A and C were free from the organism and agglutinating antibody and inoculated with the organisms of pig and rabbit origin, respectively. Group B had maternal antibody and was inoculated with the organism of pig origin. Establishment and persistence of infection with the organism were certified in the nasal cavities, trachea, or lungs of groups A and C 3 days after inoculation or later. Late establishment of infection occurred in trachea and lungs of group B. Agglutinating antibody was detected in groups A and B mostly 14 days after inoculation or later. Ventral turbinate atrophy occurred in groups A and B mostly 10 days after inoculation or later. Histologically, it was hypo-osteogenesis caused by degeneration of osteoblasts and proliferation of fibroblast-like cells in the osseous tissue. Catarrhal inflammation in the nasal and tracheal mucous membranes, and bronchopneumonia with peribronchiolitis developed commonly in all the groups. The fluorescent antibody technique revealed antigen of the organism of pig origin on the nasal mucosa, mostly of the dorsal and ventral meatus, and on the tracheal and bronchiolar mucosa in groups A and B.


Pharmacologic approach to the maintenance of urate homeostasis. A reduction in the serum urate concentration in hyperuricemic subjects can be achieved by increasing the renal excretion of uric acid, by inhibiting its synthesis, or by a combination of both modalities. The three most commonly used hypouricemic drugs are probenecid, sulfinpyrazone and allopurinol. Each drug has been considered in detail with regard to its mechanism of action, metabolism, diverse metabolic effects, side effects and interaction with other drugs. In addition, guidelines for the use of these drugs in hyperuricemic subjects are proposed.


Stimulatory effect of prostaglandin E2 on LH release in the rat: evidence for hypothalamic site of action. The intravenous administration of prostaglandin E2 (PGE2; 100 mug/rat) to immature male and female rats increased the serum level of lutenizing hormone (LH). This effect was prevented by the prior administration of an antiserum to the hypothalamic gonadotropin-releasing hormone. LH release from rat pituitaries in vitro was not stimulated by PGE2 (10 mug/ml). It is inferred that the stimulatory effect of PGE2, on LH release is not a direct one on the pituitary gland, but is exerted at the level of the hypothalamus.


Variation of the pituitary response to LH-releasing hormone (LH-RH) during a 24-hour period in male, diestrous female and androgenized female rats. The pituitary response to LH-RH was studied at 8 a.m., 4 p.m. and 12 p.m. in normal male rats, female rats on day 1 of diestrus and female rats injected with testosterone propionate on the 2nd day of life. Androgenized rats responded to LH-RH with a greater release of LH than did female diestrous and male rats. In the 3 groups the lowest response to LH-RH was observed at 12 p.m., and the highest at 8 a.m., with the exception of androgenized rats which responded with a similar magnitude of LH release at 8 a.m. and 4 p.m. The release of FSH after the injection of LH-RH was studied only at 4 p.m. and only normal male rats responded with a significant FSH release.


Treatment of adenocarcinoma of the endometrium. The evidence concerning those factors related to prognosis in endometrial carcinoma has been reviewed and age, histologic differentiation of the tumor, depth of myometrial invasion and extent of disease have been found to be definitely correlated with survival. The development of different treatment methods has been traced and various modern treatment techniques have been discussed. On the basis of these prognostic indicators and reported experience with alternative methods of therapy, a plan of management for patients with endometrial carcinoma has been proposed. Although we believe this is a logical method with proven effectiveness, we wish to emphasize the importance of individualized therapy based on an understanding of the clinical-pathological findings.


Gynecologic malignancies in immunosuppressed organ homograft recipients. Immunosuppressed organ homograft recipients have a 5 to 6% incidence of de novo malignancies at some time after transplantation. Gynecologic cancers were encountered in 21 of 224 patients (9%) with these tumors. The predominant lesion was carcinoma of the cervix (18 cases), of which 16 were intraepithelial and 2 were invasive. Gynecologic malignancies have also been encountered in non-transplant patients who were treated with immunosuppressive agents or cancer chemotherapy. All such individuals require gynecologic examination before commencement of treatment and at regular intervals thereafter so that malignancies may be diagnosed at an early stage and treated effectively. Most neoplasms respond well to conventional cancer therapy, but high-grade malignancies may necessitate reduction or cessation of immunosuppressive therapy as well.


Relation of lichen sclerosus et atrophicus of the vulva to development of carcinoma. One hundred and seven patients with lichen sclerosus et atrophicus (LS&A) of the vulva were studies to determine the malignant potential of the LS&A. Five patients had coexisting invasive carcinoma of the vulva or perineum with the LS&A, and 1 patient had coexisting intraepithelial vulvar carcinoma on the clitoris. None of these, however, was known to have LS&A prior to the biopsy for carcinoma of the vulva. The high association of carcinoma and LS*A is probably a result of selection of 2 unusual lesions sent for consultation and evaluation. Squamous hyperplasia in the vulva occurred in association with LS&A in 37 (35%) patients, but only 6 patients had areas of dysplasia coexisting with LS&A. These areas of dysplasia, like the 5 invasive carcinomas, occurred in an area of the vulva where the LS&A was minimal or absent. Follow-up data were obtained on 92 patients with LS&A. Only 1 developed carcinoma of the vulva, which occurred 12 years after identification of the LS&A. When carcinoma arises in the vulva in a patient with vulvar LS&A, it tends to arise in areas of minomal LS&A or isolated areas of relatively normal vulvar skin. This study did not provide evidence of carcinoma arising from LS&A. Five of the 92 patients developed 6 malignant neoplasms in other sites, including carcinoma of the endometrium (3 patients), lung (1 patient), and simultaneous carcinomas of the colon and cervix (1 patient).


Responsibility of the obstetrician to the fetus. II. Influence of prepregnancy weight and pregnancy weight gain on birthweight. The diet of pregnant women has been restricted in various ways since earliest history. Dietary restriction may have severely deleterious effects on the fetus. Our study revealed a positive correlation of prepregnancy weight and pregnancy weight gain to term infant birthweight. Their influences are independent and additive. It is of the utmost importance to the fetus and the future of the human race that the diet of pregnant women contain the caloric value and essential nutrients recommended by the National Research Council.


Enchancement of deficient pituitary response to luteinizing hormone releasing hormone in patients with primary amenorrhea. Although the absence of pituitary response to the luteinizing hormone releasing hormone (LHRH) test has been considered proof of a lesion primarily localized at the pituitary level, the possibility exists that an absent pituitary response may represent only the effect of a chronic deficiency of hypothalamic secretion. To verify this hypothesis, 4 patients with primary amenorrhea, hypogonadotropic hypogonadism, and deficient or absent responses to a 25 mug LHRH rapid IV test were treated with 400 mug LHRH infused in 7 hours during each of 3 successive days. The finding that patients with deficient LH responses to a rapid LHRH test became normally responsive to a second equivalent test after a slow and prolonged treatment with the decapeptide suggests that, in these patients, besides a lesion at the pituitary level, a primary defect at the hypothalamic or higher centers may also be suspected.


[The graphic test "the enchanted family" and its application in educational counselling and paediatric clinics (author's transl)]. Projectional tests using pictures, drawings, story-telling and puppets induce children to exhibit their conflicts within the family. Among such drawing tests, "The Enchanted Family" asks the child to put the members of a family under the spell of a magician, without any limits being set on the child's imagination in the choice of objects to be drawn. The psychological content is then underlined by the child telling a story about the casting of the spell. Four thousand children and juveniles, of which 1562 had behavioural disturbances or were neurotically or psychosomatically ill, were examined with this test and 1225 of these were statistically evaluated for the formal aspects of their drawings. A group of healthy school children were evaluated as controls. In addition to the formal results, the depth-psychological results of the tests offered valuable pointers to the individual conflict situations of the test subjects, in particular in relation to the relationships within the family, the projections and identifications in "key situations" of the neurotic family behaviour patterns. This was demonstrated in individual case studies. The symbolism in the choice of animals receives specific interpretation. The use of this test in educational advisory practice and psychotherapy is recommended.


Skin and soft tissue injuries of the hand in children. Three pediatric hand injury subtypes and their management have been presented. Finger tip injuries, while often minor and self-healing in children, may require surgical repair if the nailbed is disrupted or if there has been significant skin or pad loss from the tip. The decision between local repair and skin graft or pedicle reconstruction depends on the nature and extent of the injury. Multiple digit injuries should be carefully evaluated and manged with a view toward retention of digit length and restoration of function. Immediate closure of all wounds, while desirable, is not necessary. Minor hand burns are quite easily managed but burn injuries more severe in extent and/or depth must be treated with careful attention to detail. Splinting and elevation of the hand, early incisional decompression, the institution of early and diligent active motion and expeditious wound closure with skin grafts where full thickness loss has occurred will hasten the time of healing, minimize deformity and assist in the recovery of normal hand function.


A review: new thoughts on growth.

A review: new thoughts on growth. There is a critical point in development when the size of an animal, arising from its previous plane of nutrition, determines its appetite thereafter, and hence its rate of growth and dimensions at maturity. A small size at this critical time, brought about by undernutrition, is not followed by "catch-up" growth, however liberal the diet. A full diet produces catch-up growth only if the undernutrition, whatever its cause, has occurred after this critical period is over. It can, moreover, only restore a young animal to its percentile channel of growth, and its ability to do this after long periods of undernutrition becomes progressively limited by the animals chronologic age when the catch-up growth became possible.


[Determination of intracapillary HbO2 saturation with a cryo-microphotometric method, applied to the rabbit myocardium (author's transl)]. We succeeded in determining the O2 saturation of Hb in capillaries of the rabbit myocardium with a cryo-microphotometric method. Myocardial samples (2-3 mm) were removed in situ with a pair of nitrogin-cooled copper tongs, and rapidly frozen in Freon 13. The samples were sectioned into 10-12 mum slices in a cryotome at about minus 60 degrees C. Hemoglobin absorption spectra were measured on the capillary sections of the frozen slices at minus 100 degrees C in a vacumm-isolated microscope cooling chamber which we developed for the UMSP 1 (C. Zeiss, Oberkochen). The spectra were subdivided into three basic components (oxygenated Hb, desoxygenated Gb, and desoxygenated dehydrated Hb) with a weighted multi-component analysis (Lübbers and Wodick, 1969). The basic components were measured in Hb solutions. The accuracy of the method was tested both with Hb solutions inserted into glass capillaries, and Hb droplets. O2 saturations of the Hb solutions were measured at room temperature. Subsequently, both test solutions were frozen, HbO2 saturation measured in the glass capillaries at low temperatures agreed well with those recorded at room temperature. HbO2 saturation of the sectioned hemoglobin droplets was found to be systematically increased with low Hb32 saturations as compared with the records made at room temperature. The systematic error was determined and the intracapillary HbO2 saturations were corrected accordingly. Measurements on samples of the rabbit myocardium showed that the histogram of capillary HbO2 saturations has a maximum at saturations of 20-30%. The lowest saturation values were found to be between 0 and 10%, but these values were recorded less frequently. The arterial HbO2 saturation in the femoral artery was about 98%.


Study of the role of the acceptor stem in the interactions between tRNAs and aminoacyl-tRNA synthetases. Several studies have clearly demonstrated that the end of the acceptor stem was a very important area determining the aminoacylation properties of tRNAs. However the attempts to measure the contribution of this region to the binding of tRNAs to aminoacyl-tRNA synthetases have led to contradictory results. We report here the stepwise degradation of yeast tRNA-Phe and tRNA-Val from their 3' terminus, up to the seventh nucleotide : the affinity of each of the degraded-tRNA for their cognate aminoacyl-tRNA synthetase was compared to that of intact tRNA and it was found that these affinities are not significantly decreased when compared to those of the intact tRNAs.


In vivo and in vitro effects of rifampicin and streptolydigin on transcription of Kluyveromyces lactis in the presence of nystatin. Rifampicin and streptolydigin, if used in conjunction with nystatin, depress the growth of Kluyveromyces lactis. The incorporation of labeled leucine into protein is inhibited by nystatin whereas the incorporation of labeled uracil into RNA is inhibited by rifampicin in nystatin-treated cells. In order to study the mechanism of inhibition of RNA synthesis we purified by DEAE-Sephadex column chromatography four forms of RNA polymerase from K.lactis cells. The general properties of these enyzmes are similar to those of Saccharomyces cerevisiae and of other eukaryotic RNA polymerases. In particular, enzymes IA, IB and III are more active with poly[d(A-T)] template and Mn-2+ than with native or denatured calf thymus DNA. Enzyme II shows optimal activity with denatured calf thymus DNA and Mn2+. When challenged with native calf thymus DNA all enzymes prefer Mg-2+ as a divalent cation whereas with denatured calf thymus DNA all enzymes are more active with Mn-2+. Enzyme II is inhibited by lambda-amanitin but no enzyme is sensitive to rifampicin and streptolydigin. The inhibition of growth and uracil uptake observed when rifampicin is added to nystatin treated cells is probably not caused by a specific inhibition of transcription.


Synthesis of pppGpN type dinucleotide derivatives: the 5' end sequence of some RNAs. A rapid and simple synthesis of pppGpN type /N equals C, U or A/ diribonucleotide derivatives is described by coupling guanosine 2', 3'-cyclic phosphate 5'-triphosphate with the appropriate ribonucleoside in the presence of ribonuclease T-1.


Primary sequence of the 16S ribosomal RNA of Escherichia coli. Recent progress in the nucleotide sequence analysis of the 16S ribosomal RNA from E. coli is described. The sequence which has been partially or completely determined so far encompasses 1520 nucleotides, i.e. about 95% of the molecule. Possible features of the secondary structure are suggested on the basis of the nucleotide sequence and data on sequence heterogeneities, repetitions and the location of modified nucleotides are presented. In the accompanying paper, the use of the nucleotide sequence data in studies of the ribosomal protein binding sites is described.


Location and characteristics of ribosomal protein binding sites in the 16S RNA of Escherichia coli. Specific binding sites for five proteins of the Escherichia coli 30S ribosomal subunit have been located within the 16S RNA. The sites are structurally diverse and range in size from 40 to 500 nucleotides; their functional integrity appears to depend upon both the secondary structure and conformation of the RNA molecule. Evidence is presented which indicates that additional proteins interact with the RNA at later stages of subunit assembly.


Interpreting cardiac catheterization data. Part 2. Data obtained by cardiac catheterization, properly interpreted, are an extremely useful supplement to information obtained from the medical history, physical examination, electrocardiography, chest x-ray examination, and other noninvasive diagnostic techniques. Elevations of pressure in the cardiac chambers and great vessels and corresponding patterns of pressure curves are discerned in the presence of various pathologic conditions affecting the heart. Blood samples are taken during cardiac catheterization for measurement of cardiac output and to detect intracardiac shunting. Attempts have been made to estimate the magnitude of shunts from abnormal dye-dilution curves. Exercise stress is often used during cardiac catheterization to evaluate overall cardiovascular performance. Angiocardiography gives a permanent graphic record of structural abnormalities. Myocardial lactate metabolism provides a means of evaluating the adequacy of coronary blood flow.


Problems of aging: sex in the aging.

Problems of aging: sex in the aging. For the aged and aging of today, sex is not taboo. With the change in attitudes of younger people toward sex, the elderly are now seeking enrichment of their lives through continued sexual experience. Physicians with knowledge of the physiologic, endocrinologic, and sociologic aspects of sexuality can help to relieve the loneliness and isolation of older people by giving appropriate encouragement and counsel.


Evidence for binding protein-independent substrate translocation by the methylgalactoside transport system of Escherichia coli K12. Three genes, mgl A, B, and C, are required for active transport of substrate by the methylgalactose permease of E. coli K12. We report here that only two of these genes are required for substrate translocation, as seen by the ability or inability of isogenic mgl mutants (referred to as Tra+ and Tra minus, respectively) to grow on methyl-beta-D-galactopyranoside, supplied as sole carbon source. Individual mutants of both the Tra+ and Tra minus classes exhibited no detectable intracellular accumulation of methyl-beta-D-galactopyranoside; thus, the Tra+ phenotype cannot be explained by the mutants' levels of residual active transport. The phosphotransferase (Pts), the beta-galactoside (LacY), and the arabinose (Ara E and Ara F) transport systems are not required for substrate translocation by Tra+ cells. The Tra+ phenotype was identified with mutants defective in the mgl B, locus of the galactose-binding protein, by genetic complementation; the Tra minus phenotype was observed with both mgl A and mgl C mutants. The conclusion that the galactose-binding protein is not required for substrate translocation was supported by direct assays of the mgl mutants' binding protein activity. Mutants capable of translocation all showed reduced galactose-binding protein activity; mutants incapable of translocation exhibited binding protein activity equal to that of the mgl+ parent.


Methionine and formylmethionine specific tRNAs coded by bacteriophage T5. By RNA-DNA hybridization, as well as chemical and chromatographic analysis, evidence is provided that the bacteriophage T5 codes for the synthesis of two isoacceptor methionine transfer RNA species, tRNA-Met and tRNA-f-Met. Because of the differences in chromatographic properties of T5 phage and host methionine tRNAs, the phage tRNA species are readily distinguishable.


Nature of R-factor replication in the presence of chloramphenicol. Covalently closed circular deoxyribonucleic acid molecules of RSF1030, a nonconjugative R-factor, initiate and complete rounds of semiconservative replication in the absence of protein synthesis long after the bacterial chromosome has ceased its replication. RSF1030 replication under these conditions is sensitive to the inhibitor of ribonucleic acid synthesis, rifampicin. The product of this replication, a covalently closed DNA molecule, shows, in contrast to those molecules produced during the replication in a logarithmically growing culture of Escherichia coli, a transition to the open circular form upon treatment with ribonucleases of alkali. Analysis of the product resulting from alkali treatment indicates that there is a single break in one strand of the original circular duplex. This alkali-sensitive site occurs with equal probability in either of the complementary strands. These results are interpreted as a requirement for an RNA primer for the initiation of RSF1030 DNA synthesis and as showing that its removal from the covalently closed molecule is inhibited in the absence of protein synthesis.


Spectator-ion effect on the passage of ions through membranes. In this paper, we investigate the interplay between geometric and dielectric factors in influencing the image force acting on an ion passing through a membrane, for a system having the approximate dimensions of Escherichia coli. We also study the effect of one ion in a membrane on the passage of a second ion through the membrane, by calculating the radial and angular forces experienced by the second ion due to the presence of the "spectator ion." Our conclusions follow from numerical studies on expressions obtained by solving (exactly) Laplace's equation for the model assumed in this paper. The conclusions are: (i) small changes in the dielectric constant of the membrane are far more significant in determining the image force acting on an ion in a membrane than dramatic changes in the dielectric character of the regions interior and/or exterior to the cell; (ii) a spectator ion in a membrane situated near a boundary may influence in a significant way the passage of a second ion through the middle third of the membrane. We suggest that this latter result should be taken into account in discussing the mechanism of ion migration across membranes.


Mutations simultaneously affecting endonuclease II and exonuclease III in Escherichia coli. We studied mutants of E. coli originally identified as being deficient in either endonuclease II (deoxyribonucleate oligonucleotidohydrolase, EC 3.1.4.30) or exonuclease III [deoxyribonucleate (double-stranded) 5'-nucleotidohydrolase, EC 3.1.4.27] activity. Twelve independently derived mutants were tested, including three new endonuclease II mutants. Deficiency of one enzyme was always accompanied by deficiency of the other. Furthermore, temperature-sensitivity of one activity was always accompanied by temperature-sensitivity of the other, and the enzymes were co-purified. The results suggested a physical association between exonuclease III and endonuclease II, which may be of advantage in the excision-repair of DNA. A thermolabile endonuclease II was purified from one of the new mutants, indicating that it had an altered structural gene. This mutation, and all similar ones mapped by genetic transduction, was located between the pncA and aroD genes on the E. coli chromosome. One mutant had a prolonged generation time, an increased sensitivity to the alkylating agents methyl-methanesulfonate and mitomycin C, and a decreased plating efficiency for bacteriophage lambda, but no marked sensitivity to ultraviolet or gamma-irradiation. Its enzymatic and biological abnormalities were simultaneously revertible, suggesting they were caused by a single mutation. These results suggested a role for these enzymes in normal cell growth processes and in the repair of alkylation damage.


Quantitation of the sensory response in bacterial chemotaxis. A quantitative assay for the stimulus-response relationship in bacterial chemotaxis has been developed by measurement of tumble frequency. Application of the assay has shown an additive relationship between changes in receptor occupancy and recovery times. Tumble suppression is related to the change in receptor occupancy and not to its rate of change. The results can be explained in terms of varying levels of a tumble regulator.


Preferential and cooperative binding of histone I to chromosomal mammalian DNA. There is a strong preferential binding of histone I to lymphocyte DNA as compared to Escherichia coli DNA when large DNA fragments (2 times 10-6 daltons) are used. The binding of histone I to lymphocyte DNA and to E. coli DNA is cooperative. The distribution of preferential binding sites has been investigated on fragmented DNA. Most of the 2 times 10-6 dalton fragments were found to have at least one preferential histone I binding site, whereas most of the 2 times 10-5 dalton fragments have none.


Immunosuppression in vitro induced by leukemia virus-infected splenocytes (38544). Immunization of dispersed spleen cells from normal mice in vitro with SRBC was suppressed by simultaneous incubation of the spleen cell cultures with splenocytes from mice previously infected with FLV. Cell-free virus preparations alone did not suppress the antibody response. In contrast, relatively small numbers of splenocytes from infected mice, even when present at a ratio of 1-500 normal spleen cells, significantly suppressed the in vitro immune response to SRBC. Viable leukemic splenocytes were necessary for immunosuppression although the leukemic cells did not have to be in direct contact with the normal spleen cells. Specific anti-FLV serum, when added to the leukemic splenocytes or to normal spleen cells separated from infected cells by cell-impermeable membranes, prevented immunodepression.


Effect of a long-acting estrogen on the pituitary response to LH-releasing hormone (38582). The effect of Quinestrol, an estrogenic substance of long-lasting activity, on the pituitary responsiveness to LH-RH was studied in ovariectomized rats.  Quinestrol administered as a single 200 pg-dose significantly augmented the pituitary response to LH-RH 36 hr, 9 days, and although not significantly, also at 24 days after its oral administration.  No effect could be detected 36 days after its administration.  At a 20 pg-dose Quinestrol significantly augmented the pituitary response to LH-RH only at the 36 hr-period studied, this effect not being apparent in later time periods.


An in vivo study of an antimicrobial mouth rinse on supragingival and subgingival plaque and calculus formation. An antibiotic mouth rinse (CC10232) was used twice a day for one week in human subjects in a supervised double blind clinical and histological study. Nylon strips were placed supra and subgingivally for one week and then sectioned, stained and examined. Results showed that the rinse containing CC-10232 reduced the amount of plaque and reduced the amount of mineralization in 4 of 5 subjects.Also, no spirochetes were found in subjects who utilized this rinse.