A modified rosette inhibition test in the early diagnosis of renal allograft rejection. The rosette inhibition test has been employed in the follow-up of 30 renal transplant patients using a technique which enables highly accurate marking of T-lymphocytes. The minimal inhibitory concentration (MIC) of anti-lymphocyte globulin (ALG) - that is, that concentration of ALG causing 25% inhibition of rosette formation-was higher than 1/16,000 in 32 (97%) out of 33 separate determinations made two to six days befor rejection became clinically evident, and lower than 1/16,000 in 323 (92%) out of 351 determinations after which no clinical evidence of rejection developed. The results presented in this paper indicate that this modified test is a useful tool either to predict the occurrence of or to confirm the diagnosis of rejection.


Proteinuria as diagnostic marker after human kidney transplantation. Molecular weight analyses of urinary proteins in 34 patients following cadaveric kidney transplantation were performed by SDS-PAA-electrophoresis in order to diagnose transplant complications. A micromolecular 'tubular' proteinuria (mw 70-10,000) was found in all post-operative urines. Later on during clinically normal periods the patients exhibited an unphysiological proteinuria of mw 70-40,000. Recurrence of tubular proteinuria was associated with rejection episodes and acute kidney failure. Twelve patients developed a macromolecular glomerular proteinuria (mw greater than 60,000), caused by recurrent glomerulonephritis, glomerular rejection disease or renal vein thrombosis. Steroid treatment reduced the glomerular permeability for macromolecules above mw 65,000.


Cellular and humoral immunity after clinical renal transplantation. Cellular and humoral responses against donor lymphocytes were studied in ten kidney-transplant patients, nine of whom had well functioning grafts. No(T)cell-mediated cytotoxicity against donor cells was demonstrated. Specific anti-donor antibodies were found in two recipients with well-accepted grafts. A single immunological factor responsible for a favourable clinical course was not demonstrated. Neither complete T nor B cell tolerance against donor cells had developed, and a well-tolerated graft could coexist with antibodies directed against donor cells.


Minimising the risks of treating acute allograft rejection. The risks of treating allograft rejection are primarily related to high-dose steroid therapy. To determine when the possible benefit of anti-rejection therapy might not justify the risks, we analysed 20 severe rejection (SAR) episodes for indices of reversibility. Prior renal function was similar in all patients. Ccr fell to 10 ml/min or less, but degree of renal dysfunction was not predictive of reversibility, nor were time since transplant, oliguro/anuria, proteinuria, or hypertension. The only consistent finding was that function began to improve in reversible rejection 3.8 +/- 1 days after beginning therapy. Our rejection treatment, based on this finding, is to use gram doses of IV prednisolone, up to three times in five to seven days. Among 41 patients with 45 grafts so treated, there was no fatality or gastrointestinal haemorrhage. Other complications (fistulae and/or infections) were related to total dose and frequency, to intensive therapy during severe renal dysfunction or to urinary leaks. Limitation of the period of high-dose steroid therapy was associated with reduced morbidity and mortality in renal allograft recipients.


Terminal renal failure due to oxalosis in 14 patients. The present status of regular dialysis and renal transplantation in patients with end-stage renal disease secondary to primary hyperoxaluria is reported. Clinical studies include one personal case with an 18-month period of follow-up and data concerning thirteen patients treated in 10 centres in Europe which have been collected through a cooperative survey carried out with the assistance of Registry of the EDTA. On January 1 st, 1974, mean survival of patients with oxalosis treated by RDT was 30.4 months (range 6 to 102 months). Five cadaveric renal transplants have been performed in four patients; two patients are surviving with grafts functioning for 18 and 45 months. Dialysis and/or transplantation should be performed in patients with oxalosis early enough to prevent ischaemic, cardiac and neuromusclar complications which occur at the end-stage of the disease. Evidence for blood coagulation disorders, particularly chronic consumption coagulopathy, should be investigated for with adequate laboratory methods and long-term heparin therapy instituted if necessary. No convincing reports concerning the efficiency of the various drugs which have been tried out to reduce the biosynthesis of oxalic acid in patients with oxalosis have been issued to this date.


Assessment of renal osteodystrophy following renal transplantation. Serial histological studies in patients after successful renal transplantation indicate that with restoration of adequate renal function osteomalacia invariably improves with symptomatic relief in bone pain. Histological changes of osteitis fibrosa resolve more slowly and radiological changes may persist longer, occasionally in the absence of confirmatory histological evidence of secondary hyperparathyroidism. For accurate and sensitive follow-up a combination of biochemistry, histology and radiology is desirable.


A controlled trial of cyclophosphamide in the treatment of proliferative glomerulonephritis. Cyclophosphamide was administered orally, in a dose just sufficient to depress the white-cell count to 3000-4000 per mm3 (mean 1.5 mg/kg/day), to 27 patients with proliferative glomerulonephritis for 12 months; 26 patients acted as controls. Cyclophosphamide conferred no benefit as judged by mortality, morbidity, renal function (serum creatinine and creatinine clearance) or proteinuria. The side effects of cyclophosphamide included permanent amenorrhoea in five of seven menstruating women. Since no controlled trial has yet shown that any immuno-suppressive drug benefits proliferative glomerulonephritis we question whether such drugs should be administered in this disease except in the course of planned prospective trials.


Complement deposition in glomerular diseases. Biopsies from 400 patients affected by glomerular diseases, both "primary" and secondary to systemic diseases, have been studied by immunofluorescence. Staining was performed for immunoglobulins fibrogen and C1q, C4, C3 and C3A. C1q, C4 and C3 were positive in a high percentage of cases in focal glomerulosclerosis, membranoproliferative glomerulonephritis, lupus nephritis and essential cryoglobulinaemia glomerulonephritis. C1q and C4 were very rarely present in focal proliferative glomerulonephritis and rheumatoid purpura glomerulonephritis. C3A was found frequently only in acute glomerulonephritis. Results are discussed with reference to their diagnostic value and to information about mechanisms of complement activation.


Drug induced hypersensitivity nephritis. Drug-induced hypersensitivity nephritis may show several histological and clinical patterns. In most of these microscopic vascular involvement of the kidney seems to be very frequent. On immunofluorescence, deposits of C3 in mesangium and in arterioles were observed in almost all cases, independently of histological features on light microscopy. The pointing out of clinico-histological relationship seems to be the best rational approach to diagnosis of these conditions.


DNA replication in vitro starting with an intact phiX174 phage. Conversion of the single-stranded DNA in the intact phiX174 phage particle to the duplex replicative form (RF) has been demonstrated in lysates form phage-sensitive cells. The conversion is resistant to rifampicin and requires participation of both a "membrane" fraction of the lysate and a multienzyme replicative system. The lipopolysaccharide phage receptor, while essential, does not replace the membrane fraction. Clear, nonsedimentable extract fractions prepared with a certain nonionic detergent can replace the membrane fraction. Purification of the activity in these extracts by adsorption to polypropylene film yields a fraction with a 5-fold increase in activity relative to lipopolysaccharide and 50-fold increase relative to protein. The low buoyant density (1.03 g/cm3) suggests a high phospholipid or detergent content in this fraction.


Restriction endonuclease analysis of mitochondrial DNA from grande and genetically characterized cytoplasmic petite clones of Saccharomyces cerevisiae. Digestion of grande mitochondrial DNA (mtDNA) BY EcoRI restriction endonuclease gives rise to nine fragments with a total molecular weight of 51.8 x 10(6). HindIII digestion yields six fragments with a similar total molecular weight. Specific restriction fragments can be detected despite the fact that yeast mtDNA consists of a heterogeneous distribution of randomly broken molecules. Digestion patterns of 10 genetically characterized petite clones containing various combinations of five antiobiotic resistance markers indicate that the petite mtDNA predominantly represents deletion of the grande genome. The petite mtDNAs contained up to seven EcoRI restriction fragments which comigrate with grande restriction fragments, and at least one fragment that did not correspond to any in the grande. Some strains contained multiple fragments with mobility different from that of grande; these fragments were usually present in less than molar concentrations. The genetic markers were associated with individual sets of restriction fragments. However, several internal inconsistencies prevent the construction of a definitive genetic fragment map. These anomalies, together with the digestion patterns, provide strong evidence that, in addition to single contiguous deletion, other changes such as multiple deletion and heterogeneity of mtDNA populations are present in some of the petite mtDNAs.


Neutron scattering measurements of separation and shape of proteins in 30S ribosomal subunit of Escherichia coli: S2-S5, S5-S8, S3-S7. Neutron scattering measurements done on E. coli 30S ribosomal subunit specimens in which specific pairs of proteins were deuterated have enabled us to estimate the distances between the labeled proteins. The distances between centers of gravity of three protein pairs have been determined: S2-S5 (105 A), S3-S7 (115 A), and S5-S8 (35 A). A method for extracting shape information about these proteins from the neutron scattering profiles is demonstrated. The method shows that S5 and S8 are compact and S2 is extended.


Yeast manno-protein biosynthesis: solubilization and selective assay of four mannosyltransferases. Using appropriate yeast strains and exogenous acceptors, we have devised specific assays for four mannosyltransferase activities involved in biosynthesis of the carbohydrate outer chain of yeast mannoproteins. The assays utilize GDP-[14C]mannose as the donor and unlabeled oligosaccharides as the acceptors, the products being neutral radioactive oligosaccharides one mannose unit larger than the acceptors. The multiglycosyltransferase system from Saccharomyces cerevisiae was solubilized in Triton X-100 and urea and purified 100-fold. Free mannose is an acceptor for the alpha1 leads to 2-mannosyltransferase, the major product being alpha[14C]Man leads to 2Man. The alpha1 leads to 6-mannooligosaccharides serve as acceptors for both the alpha1 leads to 2- and alpha1 leads to 6-transferases, but the tetrasaccharide alphaMan leads to 3alphsMan leads to 2alphaMan is a specific acceptor for the latter enzyme and yields (see article). When reduced, this same tetrasaccharide serves as the acceptor for an alpha1 leads to 3-mannosyltransferase from Saccharomyces chevalieri, yielding a pentasaccharide with two terminal 1 leads to 3 linkages. Assay of the alpha1 leads to 3-transferase in S. cerevisiae utilizes reduced alpha1 leads to 2-mannotriose as the acceptor, the product being alpha[14C]Man leads to 3alphaMan leads to 2alphaMan leads to 2Mannitol. The multienzyme system works in concert to make "mannan" in a cell-free in vitro system.


Role of leucyl-tRNA synthetase in regulation of branched-chain amino-acid transport. The regulation of the transport of leucine, isoleucine, and valine in Escherichia coli B/r was studied in a mutant with a complete deletion of the leucine biosynthetic operon and a temperature-sensitive leucyl-tRNA synthetase [L-leucine:tRNALeu ligase (AMP-forming), EC 6.1.1.4]. Under conditions of excess leucine and a functional leucyl-tRNA synthetase transport activity was repressed. Shifting the culture to a temperature at which the activation of leucine to an appropriate tRNA species became growth-rate-limiting led to a large increase in the high-affinity transport of leucine, isoleucine, and valine (system LIV-I) while the uptake of histidine and proline was unchanged. A similar increase was observed for branched-chain amino-acid binding protein activity. The temperature change did not alter the transport activity for any of these substrates or the level of the binding proteins in an isogenic strain with a normal leucyl-tRNA synthetase. The increase in transport activity observed in the mutant was prevented by inhibitors of protein and RNA synthesis and probably represents an increase in the differential rate of synthesis of the protein(s) required for transport. These experiments demonstrate that the repression of branched-chain amino-acid transport involves the interaction of leucine with its aminoacyl-tRNA synthetase and its cognate leucyl-tRNA species.


Methylation of a membrane protein involved in bacterial chemotaxis. A protein methylation reaction involved in chemotaxis of Escherichia coli has been identified. The involvement of this reaction in chemotaxis in indicated by four lines of evidence. (a) The methylation reaction is altered in several classes of generally nonchemotactic mutants and is coreverted with the chemotaxis defects. (b) The methylation level of the protein is affected by chemotactic stimuli. (c) The transferred methyl group is derived from methionine and is labile, in accord with the known fact that chemotaxis requires a continuous supply of methionine. (d) Methylation is abnormal in various mutants having defective or missing flagella.


Polypeptide chain initiation in eukaryotes: initiation factor MP in Artemia salina embryos. The activity of IF-MP, a polypeptide chain initiation factor that forms a ternary complex with eukaryotic initiator Met-tRNA  and GTP and promotes binding of the initiator to 40S ribosomes, is very low in undeveloped Artemia salina embryos but increases over 20-fold following resumption of development upon hydration of the cysts. The factor is present in both the ribosomal salt wash and high-speed-supernatant. Its specific activity is 50 times higher in the wash but its total activity is only about twice as high in the wash as in the supernatant. As is true of IF-MP from other eukaryotic sources, the A. salina factor is specific for eukaryotic Met-tRNAi and sensitive to SH-reagents, and its activity is GTP dependent.


Chitin synthetase zymogen is attached to the yeast plasma membrane. Pretreatment of yeast protoplasts with concanavalin A, according to the method used by G. A. Scarborough for Neurospora (J. Biol. Chem. 250, 1106-1111, 1975), reinforced the plasma membranes, and helped to maintain their integrity during subsequent lysis of the protoplasts. After purification by centrifuging on a Renografin density gradient, practically intact membranes were obtained. Previous labeling of the protoplasts with 125I or with [3H]concanavalin A resulted in recovery of the radioactivity in the membrane fraction. The bulk of the chitin synthetase (chitin synthase; UDP-2-acetamido-2-deoxy-D-glucose:chitin 4-beta-acetamidodeoxyglucosyltransferase; EC 2.4.1.16) recovered in the gradient was also found In this fraction; in the zymogen form. About 20% of the activity sedimented in a plasma-membrane-free fraction at lower density. Glutaraldehyde inactivated chitin synthetase when it was added to a lysate, but not when applied to intact protoplasts. It is concluded that chitin synthetase is so oriented in the membrane that it is only accessible from the inside of the cell. These results confirm our previous hypothesis that the chitin synthetase zymogen is associated with the plasma membrane, a basic assumption for the explanation of localized activation of the enzyme and initiation of septum formation.


Colony hybridization: a method for the isolation of cloned DNAs that contain a specific gene. A method has been developed whereby a very large number of colonies of Escherichia coli carrying different hybrid plasmids can be rapidly screened to determine which hybrid plasmids contain a specified DNA sequence or genes. The colonies to be screened are formed on nitrocellulose filters, and, after a reference set of these colonies has been prepared by replica plating, are lysed and their DNA is denatured and fixed to the filter in situ. The resulting DNA-prints of the colonies are then hybridized to a radioactive RNA that defines the sequence or gene of interest, and the result of this hybridization is assayed by autoradiography. Colonies whose DNA-prints exhibit hybridization can then be picked from the reference plate. We have used this method to isolate clones of ColE1 hybrid plasmids that contain Drosophila melanogaster genes for 18 and 28S rRNAs. In principle, the method can be used to isolate any gene whose base sequence is represented in an available RNA.


Cerebellar cell surface antigens of mouse brain. Reaggregated cells from 6- to 8-day-old mouse cerebella have been used to raise antibodies in rabbits. The interaction of these antibodies with cerebellar cell surface components was assessed by cytotoxicity of 51Cr-labeled cerebellar cell cultures and indirect immunofluorescence. A quantitative comparison of the relative amount of antigen on cells from other mouse tissues, brain regions, cerebella of various aged mice and mutant mice, and other animal species, as well as several clonal cell lines of nervous system origin, was made. A fixed subthreshold concentration of antiserum was adsorbed with increasing numbers of dissociated cells or amounts of particulate tissue prior to incubation with complement and 51Cr-labeled cerebellar target cells. Mouse thymus, spleen, liver, and heart tissue possess negligible adsorbing capacity, whereas kidney and sperm gave some adsorption. Of the brain regions examined, only cerebellum removed all immunofluorescence and cytotoxic activity, whereas other regions removed less than 90%, suggesting the possibility of cerebellar specific antigens on certain cell types. Only mouse and rat cerebellum gave measurable adsorptions, and this capacity decreased with increasing age. Although cerebellar mutants (stagger, weaver, and nervous) possessed similar adsorptive capacity, glioma and neuroblastoma clonal cell lines differed measurably in their adsorption; only the mouse neuroblastoma clones displayed significant adsorption of the antiserum.


Mechanism of dissociation of ribosomes of Escherichia coli by initiation factor IF-3. Initiation factor IF-3 clearly can cause dissociation of ribosomes by binding to 30S subunits and thus shifting the spontaneous equilibrium, but it theoretically may also do so by binding to 70S ribosomes. Previously reported experiments with differentially labeled ribosomes and subunits seemed to eliminate the latter mechanism, but these experiments neglected a substantial decrease in the specific activity of the added subunits resulting from net dissociation of the ribosomes by IF-3. The present experiments eliminate or correct this effect. The results exclude direct action on 70S ribosomes as a significant mechanism of dissociation by IF-3.


Identification of a soluble protein that stimulates peptide bond synthesis. A soluble protein factor was isolated, free of elongation factor (EF)-T and EF-G, based on its ability to stimulate the synthesis of peptide bonds using ribosomal bound 70S-AUG-N-formyl-[35S]methionyl-tRNA complex and added puromycin as substrates. Over 90% of this activity was found in the ribosome-free cytoplasm of Escherichia coli extracts. Otherfeatures such as molecular weight, purification properties, and catalytic activities distinguish this factor from ribosomal proteins and known activators of translation. The factor requires all components needed for peptide bond synthesis and is inhibited by antibiotics known to specifically block the peptidyl transferase activity of ribosomes. The factor increases the binding affinity of the ribosome for the aminoacyl-tRNA analog puromycin about 10-fold. We suggest that this extraribosomal factor modulates the intrinsic activity of ribosomes to catalyze peptide-bond synthesis, and regard it as a new factor required for peptide chain elongation, which we call EF-P.


Enzymatic induction of DNA double-strand breaks in gamma-irradiated Escherichia coli K-12. The polA1 mutation increases the sensitivity of E. coli K-12 by killing by gamma-irradiation in air by a factor of 2.9 and increases the yield of DNA double-strand breaks by a factor of 2.5. These additional DNA double-strand breaks appear to be due to the action of nucleases in the polA1 strain rather than to the rejoining of radiation-induced double-strand breaks in the pol+ strain. This conclusion is based upon the observation that gamma-irradiation at 3 degrees did not affect the yield of DNA double-strand breaks in the pol+ strain, but decreased the yield in the polA1 strain by a factor of 2.2. Irradiation of the polA1 strain at 3 degrees followed by incubation at 3 degrees for 20 min before plating resulted in approximately a 1.5-fold increase in the D0. The yield of DNA double-strand breaks was reduced by a factor of 1.5. The pol+ strain, however, did not show the protective effect of the low temperature incubation upon either survival or DNA double-strand breakage. We suggest that the increased yield of DNA double-strand breaks in the polA1 strain may be the result of the unsuccessful exision repair of ionizing radiation-induced DNA base damage.


Quaternary constraint in hybrid of aspartate transcarbamylase containing wild-type and mutant catalytic subunits. Unusual quaternary constraint in the regulatory enzyme, aspartate transcarbamylase (aspartate carbamoyltransferase or carbamoylphosphate:L-aspartate carbamoyltransferase, EC 2.1.3.2) from Escherichia coli, was demonstrated with a hybrid composed of one inactive "catalytic" subunit from a mutant strain and one active catalytic subunit and three regulatory subunits from the wild-type strain. The hybrid had a high affinity for three molecules of the bi-substrat analog, N-(phosphonacetyl)-L-aspartate, compared to the six strong binding sites in the wild-type enzyme and none in the mutant. However, the Vmax of the hybrid was only about 25% that of the wild-type enzyme. In addition, the hybrid exhibited a very low apparent affinity for the substrate, aspartate [Michaelis constant (Km) about 90 mM], as compared to the wild-type enzyme (apparent Km of 7 mM). No homotropic effect was observed for the hybrid in the absence of nucleotides as contrasted to the cooperativity of the wild-type enzyme; also, large changes in the Vmax of the hybrid were caused by the addition of the nucleotide effectors, CTP and ATP, which do not affect the Vmax of the wild-type, but influence only the cooperativity and the apparent Km. Although the hybrid undergoes a ligand-promoted conformational change analogous to that of the wild-type enzyme, this transition required a 20-fold higher concentration of the substrate analog, succinate. It appears that the "paralysis" of the wild-type catalytic subunit in the hybrid can be attributed to subunit interactions which constrain the molecule in a low-affinity state.


Structural properties of pyruvate carboxylases from chicken liver and other sources. Varieties of pyruvate carboxylase [pyruvate: CO2 ligase (ADP-forming), EC 6.4.1.1] obtained from the livers of several species of vertebrates, including humans, all show the same basic structure. They are composed of large polypeptide chains of molecular weights ranging from 1.2 to 1.3 X 10(5) for the different varieties of the enzyme. The native form of the enzyme appears to be a tetramer with a molecular weight of about 5 X 10(5). In the case of pyruvate carboxylase from chicken liver each polypeptide chain contains a biotin moiety, thus supporting the thesis that the tetramer contains four identical polypeptide chains. Pyruvate carboxylase from yeast appears to be basically similar to those from the vertebrate species and has a tetrameric structure. Each protomer contains a single polypeptide chain with a molecular weitht of 1.25 X 10(5). In contrast, pyruvate carboxylase from two bacterial species, Pseudomonas citronellolis and Axotobacter vinelandii, appears to be a dimer with a molecular weight (2.5 X 10(5)) about half that of the animal and yeast species. As a further difference, each of the protomers of the bacterial enzymes contain two polypeptides of 6.5 and 5.4 X 10(5) molecular weight in case of the Pseudomonas enzyme. The larger of the two polypeptides contains the biotin moiety. The functional units of the bacterial enzyme thus appear to contain two polypeptides while that of the liver and yeast enzymes is made up of a single chain. Neither of these arrangements corresponds with those of other biotin enzymes whose structure has been extensively studied (acetyl-CoA carboxylases from liver or Excherichia coli, and transcarboxylase from Propionibacterium).


Identification of a region in 23S rRNA located at the peptidyl transferase center. A photolyzable derivative of dipeptidyl-tRNA, p-azido-N-tBoc-Phe-[3H]Phe-tRNA, bound reversibly to 70S ribosomes in the presence of poly(U), becomes, when irradiated, covalently attached to components of the 50S ribosomal subunit. Most of the reaction occurs within the 23S RNA, while ribosomal proteins are only weakly labeled. Reversible binding as well as the covalent reaction are reduced in the absence of poly(U) or in the presence of several antibiotics specific for the 50S ribosomal subunit. There are apparently few sites (or perhaps a single site) of reaction on the 23S RNA that are exclusively located within the 2000 nucleotides from the 3 terminus of the molecule. Part of the 23S RNA within this region must therefore be closely associated with the peptidyl transferase center of the ribosome.


Biochemical construction and selection of hybrid plasmids containing specific segments of the Escherichia coli genome. Using a poly(dA-dT) "connector" method, a population of annealed hybrid circular DNAs was constructed in vitro; each hybrid DNA circle containing one full-length molecule of poly(dT)-tailed DNA from E1 colicinogenic factor (Col E1) fragmented by EcoRI endonuclease annealed to any one of a collection of poly(dA)-tailed linear DNA fragments of the entire E. coli genome. This annealed, but unligated, hybrid DNA was used to transform several different auxotrophic mutants of E. coli, and by direct selection, bacterial clones were isolated which contained specific hybrid plasmids. In this manner, bacterial strains containing Col E1 hybrid plasmids carrying the entire tryptophan operon or the arabinsoe and leucine operons were isolated. The methods described should allow the molecular cloning of any portion of the E. coli genome by selection from a pool of DNA molecules containing at least several hundred different hybrids representing the entire bacterial genome.


Guanosine 5'-diphosphate 3'-diphosphate (ppGpp): positive effector for histidine operon transcription and general signal for amino-acid deficiency. Maximal expression of the histidine operon of Salmonella typhimurium in a coupled in vitro transcription-translation system is strongly dependent upon addition of guanosine 5'-diphosphate 3'-diphosphate (ppGpp). This requirement for ppGpp is exerted at the level of transcription through a mechanism distinct from the his-operon-specific regulatory mechanism. In vivo derepression of the his operon is markedly defective when histidine starvation is imposed on a relA mutant--unable to rapidly increase synthesis of ppGpp--growing in amino-acid-rich medium. Increased sensitivity of relA mutants to growth inhibition by a number of amino-acid analogs suggests that ppGpp is generally important in adjusting expression of amino-acid-producing systems. Analysis of these findings leads us to propose that ppGpp is a positive effector in a system that enables the cell to balance endogenous amino-acid production with environmental conditions of amino-acid availability, and to compensate efficiently for transient changes in these conditions. We propose a unifying theory of the role of ppGpp as the general signal molecule (alarmone) in a "super-control" which senses an amino-acid deficiency and redirects the cell's economy in response.


Structure of yeast phenylalanine transfer RNA at 2.5 A resolution. The x-ray analysis of the monoclinic form of yeast tRNAPhe has been taken to a resolution of 2.5 A by the method of isomorphous replacement. The model proposed at 3 A has been confirmed and extended to reveal additional features of the tertiary structure and of the stereochemistry. An extensive hydrogen bonding network is described involving specific interactions between bases and the ribose-phosphate backbone. The structure of a G-U base pair has been solved.


Two stages in lymphocyte mediator production by differential susceptibility to blockade using niridazole. Sera from guinea pigs given niridazole, an anti-schistosomal compound, have been shown to reversibly block the production of antigen-induced migration inhibitory factor by sensitized guinea pig lymph node cells. Since niridazole itself has no effect in vitro, the blockade of production of migration inhibitory factor is probably due to drug metabolites in the serum. We report here further studies on the mechanism of this drug-induced suppression of cellular hypersensitivity; the data show that niridazole active serum does not block the production of migration inhibitory factor once it has been initiated. Indeed, if niridazole active serum is added a little as 60 sec after the addition of antigen, the lymphocytes will produce migration inhibitory factor. These results suggest the presence of at least two stages in production of migration inhibitory factor after the addition of antigen to lymphocytes. The first, lasting less than 60 sec, is susceptible to blockade by niridazole active serum; the second is not. The elucidation of the mechanism of this blockade should lead to further understanding of the early events after antigen triggering of sensitized lymphocytes.


Association of salmonella mutants with germfree rats: site specific model to detect carcinogens as mutagens. An association of the histidine auxotroph of Salmonella typhimurium (strain TA1538) within the gastrointestinal tract of otherwise germfree Sprague-Dawley rats is maintained during periods of observation lasting as long as 7 months. The bacteria are found at levels exceeding 10(7) per g in the forestomach and at levels greater than 10(8) per g in the lower bowel and in the feces. Only approximately 10(4) bacteria per g are found in the posterior stomach and in the upper small intestine. The association of the salmonella mutants is maintained when the bacterial association is increased by the addition of other bacteria characteristic of the gastrointestinal flora. Carcinogenic amines, which cause strain TA1538 to revert to histidine independence in Ames' in vitro assays, increase the number of revertants in the feces when fed to the salmonella-associated rats. In contrast, the number of revertants in the feces does not increase when the rats are fed structurally related compounds which are not mutagenic to the bacteria in vitro and for which no evidence of carcinogenicity exists. Sacrifice of rats after feeding the carcinogen 2-nitrofluorene indicates that the number of revertants is increased in the cecum and colon as well as in the feces. The apparent proximity of the bacterial mutagenic response to the location of the tumor response in the colon suggests that the rat associated with the histidine auxotroph may provide a useful model for further investigation of the possible association between bacterial mutagenesis and carcinogenesis within the gastrointestinal tract. In addition, with this model it may be possible to evaluate selectively the effects of various constituents of the flora on the activation of compounds provoking the revertant response.


Role of methionine in bacterial chemotaxis: requirement for tumbling and involvement in information processing. Chemotactic responses are mediated by modulation of the frequency of tumbling. Studies with methionine auxotrophs of wild-type Escherichia coli and four mutants which tumble continuously show that methionine or one of its metabolites is involved in the tumbling process. Following removal of methionine, the wild type and two mutants, after various periods of time, became unable to tumble. The presence of constant levels of chemical attractants considerably shortened these periods in the three strains and eliminated tumbling in another mutant. This effect of attractants considerably shortened these periods in the three strains and eliminated tumbling in another mutant. This effect of attractants implies that methionine or some derivative of methionine is also involved in transducing chemical stimuli to bacterial responses.


Induction of error-prone repair as a consequence of DNA ligase deficiency in Escherichia coli. DNA ligase deficiency is shown to induce generalized mutator activity in E. coli. This mutator activity is unaffected by 3 mug/ml of chloramphenicol but is abolished both in lig-recA double mutants and by incubation with 20 mug/ml of chloramphenicol. Dna ligase deficiency is also shown to reactivate ultraviolet light-irradiated phage lambda and T7 and to increase both spontaneous and ultraviolet light-induced mutagenesis in phage lambda, all of which are abolished in lig-recA strains. Interaction occurs between the molecular events of mutagenesis induced by ultraviolet irradiation and those induced by DNA ligase deficiency. These observations suggest a common pathway, coordinately expressed with the inducible repair mode, that is responsible for mutagenesis.


An x-ray study of valgus ankles in spina bifida children with valgus flat foot deformity. Radiological examination of the ankles of spina bifida children with flail lower limbs and valgus flat foot deformity has revealed a high incidence of abnormal valgus tilt of the ankle-joint. A study of ankle X-rays of spina bifida children before and after extra-articular subtalar fusion in which the bone graft is removed from the ipsilateral tibia has shown that the valgus tilt of the mortice may increase after this procedure.


Improved rapid method to check electrode localizations in the brain. A modification of known rapid methods to check electrode localization in the brain is described: the essential point consists in immersing the brain, after fixation in 4 percent Formalin, in pure heptane at -30 degrees C for 5 hr. Unstained sections, cut with the freezing microtome, are placed uncovered on glass slides and photographed (in an enlarger, as if they were negatives) either wet, to obtain  a contrast resembling Weil staining, or dry, to obtain a picture corresponding to Nissl staining.


[Physical methods in the treatment and prevention of deep phlebitis of the leg]. By the term "physical methods" the author envisages primarily walking, wearing an elastic support, and rest with the legs raised. Physical methods for the prevention and cure of phlebitis were worked out by two French surgeons between the two wars but have been rapidly replaced by coagulant treatment. Now these methods have been reduced, in most cases, simply to a "fight against haemostasis" by means of verbal instructions and with no relation to the original methods : in many cases the methods are not known to the younger generation of physicians because they have not been taught them. Several factors are leading to renewed interest in these methods : on the one hand the undeniable dissatisfaction with anticoagulant therapy, and on the other hand the many experiments that, in the last 15 years, have led to an understanding of the mode of action of the physical methods. These experiments are reviewed in the present article. From the practical point of view, improvements in materials have led to improvements in the range of bandaging techniques. The authors looked back at the original publications, that is to say to the publications of Chalier and of Nard, who described methods, which have been much referred to, that were quite exacting. The different types of bandaging for the prevention and cure of thrombosis are illustrated by numerous pictures. In the curative treatment of phlebitis, there are three essential indications for the use of physical methods : contraindications for anticoagulants, their failure, and the prevention of sequelae. In the prevention of phlebitis, the raising of the legs when seated, a factor in a quasi-experimental stasis, must give way to mobilization - very early and very frequent walking. It is the opinion of specialists in phlebitis, who have used these methods over many years, that the physical methods, which are also physiological, are a valuable complement to biological methods. Their effectiveness is, however, a function of the rigour with which they are applied : --as regards degree : the support must be applied in the correct dosage, as, for example, must heparin and digitalin ; --as regards staff : the patient and his associates must collaborate closely, and nursing staff are indispensable ; --as regards skill : the faith of the physician alone can overcome the doubts or scepticism of others.


[Brain tumor diagnosis using 3-detector-gamma-encephalography]. The probability of diagnosis of brain tumours by means of 3-detector-gamma-encephalography (Hg 197-Neohydrin) is higher than that of the scintigraphic procedures so far available. Above all, the diagnostic accuracy of foci with low storage rates and space-occupying processes of the infratentorial region is improved. The short duration of the examination allows the method to be applied as a screening test.


[Report on research into the methods of group psychotherapy]. An attempt has been made by the present authors to arrive at a better understanding of and describe, the process of group therapy and its dynamics by means of an intensive and multidimensional study of a group of hospitalized neurotics undergoing psychotherapeutic treatment. The records of twenty group sessions, which were obtained from tape recordings, were analyzed by Hill's method with regard to their contents. Also, sociometric records were made of selected sessions, and we analyzed all of the various sessions and studies with regard to their latent manifestational contents. The results thus obtained are presently being evaluated. It appears that processes of group therapy are characterized by changes and by what may be called "nodal points"; what is suggestive of this is the noncasual coincidence of parameter variations observed when different methods of investigation were used. It is resonable to assume that interventions made at such points will increase the effectiveness of therapy.


[The position of concentrated relaxation in a training program for the psychoprerention of myocardial infarction]. After a summarised presentation of the institutional framework and of the aims of a  training programme developed from psychotherapeutic and social psychological techniques, the method of concentrated relaxation is described in detail and its especial function in the first phase of training is explained. Through prompt realization results being made available through identification being made easier by the assigning into groups, through the stimulation of independent activity and the creation of an initial awareness of the problem, concentrated relaxation becomes the upholding element of this first phase, the aim of which is the increasing of motivation towards further participation in training in this relatively unsusceptible group.


The sexual significance of the axillae.

The sexual significance of the axillae. The present paper will review the existing material on the relationships between the axillae and sexuality, present examples of the relationship from clinical practice, everyday life, art, anthropology, mythology, and literature, and consider the relevant human and primate physiological knowledge.


The significance of depersonalization in the life and writings of Joseph Conrad. Through reference to his letters and fiction, this paper attempts to demonstrate how Conrad made use of depersonalization in order to cope with the childhood loss of his parents and to avoid, whenever possible, psychotic regression. Genetic and dynamic aspects of depersonalization are noted along with the relationship between dream and depersonalization.


Nostalgia: a 'forgotten' psychological disorder. Nostalgia, a psychopathological condition affecting individuals who are uprooted, whose social contacts are fragmented, who are isolated and who feel totally frustrated and alienated, was first described in the 17th century and was a problem of considerable interest to physicians in the 18th and 19th centuries. By the 20th century it seemed to have disappeared, but reappeared under other labels.


The effect of diazepam and fentanyl on mental, psychomotor and electroencephalographic functions and their rate of recovery. Ten healthy male subjects received diazepam (10 or 20 mg), fentanyl (0.1 or 0.2 mg) or a placebo intravenously at weekly intervals according to a latin square design. They were tested on a battery of psychological and electroencephalographic tests at 0.5, 2, 6, and 8 hrs following injection. Fentanyl had little effect on memory while diazepam reduced the ability to learn without increasing forgetting of material alread acquired. By the 2nd hour post injection, only the low dose of fentanyl had no residual effect. Recovery was complete by the 6th hour for all treatments according to the psychological tests except for the lagging effect of high dose of diazepam on memory. The electroencephalographic effects of diazepam persisted beyond the end of the testing sessions while those of the high dose of fentanyl recovered by the 8th hour. Thus in the dosages tested, diazepam had more intense and prolonged effects than fentanyl.


Effect of ECT and imipramine treatment on the concentration of 5-hydroxyindoleacetic acid (5HIAA) and homovanillic acid (HVA) in the cerebrospinal fluid of depressed patients. The influence of probenecid administration on 5HIAA and HVA concentrations in the CSF of depressed patients, was studied before and after treatment with imipramine or ECT. The average increase of the two metabolites in the CSF after probenecid was similar in the untreated depressed patients and in the same patients improved after both imipramine or ECT treatment. The treatment determined a significant increase in the CSF concentration of the acid metabolites also before the probenecid administration.


The effect of lithium treatment on manic symptoms and levels of monoamine metabolites in cerebrospinal fluid of manic depressive patients. Clinical effects, levels of 5-hydroxyindoleacetic acid (5-HIAA) and homovanillic acid (HVA) in cerebrospinal fluid (CSF) and lithium levels in serum were examined in 13 manic depressive patients acutely admitted because of a manic or hypomanic episode. Patients were examined before and 12 days after the beginning of lithium treatment. Manic scores were significantly reduced during treatment. The levels of 5-HIAA as well as HVA increased significantly during treatment. The HVA to 5-HIAA ratio was significantly reduced, indicating a more pronounced change in 5-HIAA than in HVA. The 5-HIAA and HVA levels before as well as after 12 days of treatment were significantly correlated. No significant correlation was found between manic scores and monoamine metabolites in CSF or between lithium level in serum and reduction of manic scores or elevation of monoamine metabolites in CSF in the relative small number of patients studied.


Smooth-pursuit eye movements, and diazepam, CPZ, and secobarbital. This study examined the effects on smooth-pursuit eye tracking of single doses of CPZ (0.667 and 1.334 mg/kg), diazepam (0.071, 0.142, and 0.284 mg/kg), and secobarbital (100 mg). Only the barbiturate significantly affected the ability to follow a moving target with smooth-pursuit eye movements. In repeated testing of a single subject, 130 mg of secobarbital disrupted smooth-pursuit movements at least until 24 hrs after ingestion.


Divided attention performance of cannabis users and non-users following cannabis and alcohol. The effects of delta9-tetrahydrocannabinol (delta9-THC) and alcohol, and their combination, on divided attention performance were compared for cannabis users and non-users of both sexes. Performance by all subjects was significantly impaired following 2.6 and 5.2 mg delta9-THC but not at blood alcohol concentrations of 48 and 96 mg/100 ml. The combined effect of the 2 drugs depended upon prior experience with cannabis. A synergistic action occurred in non-users while an antagonistic effect occurred in the group of users. Differences in the alcohol effects between users and non-users provided evidence of cross-tolerance between cannabis and alcohol.


A study of abrupt lithium withdrawal.

A study of abrupt lithium withdrawal. Twelve patients were abruptly switched from lithium to placebo as part of a double-blind cross-over study. In contrast to other drugs effective in mood disorders, lithium produced no withdrawal syndrome.


The effect of adrenaline on human platelet MAO activity. Platelet monoamine oxidase (MAO) activity was determined before and after the subcutaneous administration of adrenaline to nine healthy volunteers. Significant increases were found 15 min and 1 hr after adrenaline in the enzymatic activity with benzylamine acting as substrate. Increases were also found in all but two samples in the activity towards tyramine. Such increases may be part of a general response to "stress", and, if so, need to be taken into account when interpreting changes in platelet MAO activity in psychiatric patients.


Prediction of response to chlorpromazine treatment in schizophrenics. A dose of 50 mg of chlorpromazine (CPZ) was  given to 6 untreated schizophrenic patients and 8 healthy volunteers at 7:00 a.m. before breakfast. Blood samples were taken 3, 6, 9 and 24 hrs after for the analyses of CPZ and its metabolites by gas chromatographic techniques. In the cases of schizophrenic patients, the CPZ treatment was continued. Serum drug levels were monitored and clinical response assessed. The drug levels in serum of another group of patients already under long term treatment were also determined. Although wide inter-patients variations in serum drug levels after a single dose administration were observed, the CPZ level in the patients decreased faster than in the normal subjects. Patients showing high levels of the metabolites such as demethylated CPZ and CPZ sulfoxide after a single dose of CPZ tended to achieve poorer clinical improvement in CPZ therapy, agreeing with the results that poor responders to long term CPZ treatment revealed relatively high levels of the metabolites of CPZ compared with CPZ level. The results indicate that the study of a single dose administration prior to initiating treatment with CPZ can be used to determine how an individual patient would respond to CPZ therapy and be a valuable tool in the rational pharmacotherapy of schizophrenic patients.


Insulin antibodies and the control of diabetes. Seventy-two insulin-treated diabetic patients were classified on the basis of a clinical evaluation of their control of diabetes. There were 39 stable patients, 23 unstable patients and 10 patients of intermediate degree of control. Four insulin resistant patients were also studied. Serum insulin antibodies were measured in each patient and the concept of insulin buffering by its antibody was developed. Most unstable patients had low concentrations of insulin antibody. Twenty-four of the 39 stable patients had a significant concentration of insulin antibody and 15 patients had low levels of antibody. The insulin resistant patients had hugh levels of antibody. All unstable patients had low antibody buffering and all insulin resistant patients had high antibody buffering. Although many stable patients had buffering antibodies others lacking antibody required a low insulin dose and their stability of diabetic control was attributed to residual pancreatic function.


Studies on the nature and causes of hyperlipidaemia in uraemia, maintenance dialysis and renal transplantation. Fasting serum triglyceride and cholesterol measurements, and lipoprotein characterization by ultracentrifugation, were performed in four groups of patients with chronic renal disease (uraemic, short- and long-term haemodialysis and renal transplant recipients) and the results compared with those obtained from age- and sex-matched control subjects. Basal insulin and growth hormone levels, and serum creatinine and albumin concentrations were measured in, and detailed dietary histories taken from patients in each group. The predominant lipid abnormalities were hypertriglyceridaemia and increased very low density lipoproteins (type IV hyperlipoproteinaemia) in both uraemic and haemodialysis patients. Following renal transplantation, a different pattern of hyperlipidaemia was found. Hypercholesterolaemia was more common and hypertriglyceridaemia less common than in the uraemic and haemodialysis group. The lipoprotein abnormalities were increased low density and/or very low density lipoproteins, with types IIa IIb and IV hyperlipoproteinaemia occurring equally frequently. In uraemic and haemodialysis patients, the proportion of carbohydrate in the diet was high, and may have played a role in the genesis of hypertriglyceridaemia. There was a positive correlation between relative body weight and serum triglyceride in the long-term dialysis group. In renal allograft recipients hypertriglyceridaemia could be attributed, at least in part, to obesity, prednisone dosage and the degree of impairment of graft function. The aetiology of hypercholesterolaemia in the transplant recipients was unclear. Neither basal insulin nor growth hormone levels were elevated in any patient group. Uraemic hypertriglyceridaemia is a clearly defined and well documented metabolic abnormality which is not corrected by dialysis. Post-transplantation hyperlipidaemia however, is a condition of variable presentation and multifactorial aetiology.


Structural specificity in the lethal and mutagenic activity of furocoumarins in yeast cells. Using monofunctional (Angelicin) and bifunctional furocoumarins (Psoralen and 8 Methoxypsoralen) plus 365 nm light it is shown that both damages, the induced monoadducts and/or crosslinks in DNA, provoke lethal and mutgenic effects in haploid and diploid cells of Saccharomyces cerevisiae. Bifunctional furocoumarins are about 20 times more effective in cell killing than Angelicin. Diploid cells are always more resistant than haploid cells. Dark repair (agar haolding) increases survival. This effect can be at least in part correlated to the release of bound material from DNA in dark repair conditions. Bifunctional psoralens (10 mug/ml) are at least 10-fold more effective in inducing nuclear gene black mutations (his- to HIS+) than Angelicin (10 mug/ml) plus 365 nm light or 254 nm ultraviolet light. In contrast cytoplasmic "petite" (delta-) mutations are about as frequently induced by Angelicin plus 365 nm light as by 254 nm UV light. Bifunctional furocoumarins are less effective. The frequency of cytoplasmic "petite" mutations per survivors decreases during dark repair conditions more efficiently after Angelicin than after Psoralen plus 365 nm light treatment.


Studies on the energy metabolism during the respiratory process by baker's yeast. Microcalorimetry, in combination with conventional methods for determining metabolic activity, opens the possibility to study the efficiency with which ATP, produced as a result of metabolic activity, is utilized by the cell for energy-requiring synthetic reactions. Using commercial baker's yeast as a test organism and glucose, ethanol, acetic and lactic acids as substrates, the fate of the ATP produced by the respiratory process was studied by measuring oxygen consumption (using the Warburg technique) and the corresponding heat development (using the LKB Flow-Microcalorimeter). From these data heat development per mm3 oxygen consumed was calculated. Values obtained should fall within a heat production range that can be calculated from the combustion heat of the process (maximum heat development) and maximum energy conservation, assuming full participation of ATP in energy-requiring synthetic reactions (minimum heat development). It was found that during the respiratory process of "resting" cells of baker's yeast, regardless of the substrate used, heat development was close to the maximum value inherent with substrate oxidation. Consequently, practically all ATP, produced as a result of the respiratory process, is de-phosphorylated under heat development and thus is not (or very inefficiently) utilized for energy-requiring synthetic reactions. In accordance with this conclusion it was found that addition of 2-4-DNP, a powerful uncoupler of phosphorylation from the respiratory process, did not result in an appriciable increase in heat development. Even in the presence of an assimilable N source, allowing unrestricted growth, initially only a very small percentage of the ATP produced is utilized for synthetic processes. A gradual improvement of this poor economic ATP utilization was observed during the prelogarithmic growth phase. As a possible explanation of this wasteful aerobic metabolism of baker's yeast and its restricted ability to utilize ATP for synthetic processes was mentioned the exceptional low content of messenger RNA, typical for a baker's yeast subjected to a ripening process before harvesting.


Influence of energy metabolism on the repair of x-ray damage in living cells. IV. Effects of 2-deoxy-D-glucose on the repair phenomena during fractionated irradiation of yeast. Inhibition of repair of sublethal and potentially lethal damage was observed in respiratory-deficient mutants of yeast during fractionated X-irradiation in the presence of equimolar concentrations of 2-deoxy-D-glucose and glucose in the growth medium. In the wild-type cells, on the other hand, an enhancement of repair of the potentially lethal damage was obtained under similar conditions. These results suggest, by analogy, that in higher organisms also, 2-deoxy-D-glucose may differentially inhibit the repair of radiation damage in hypoxic tumor cells while enhancement of repair processes could be expected in normal tissues.


Effect of irradiation on immune responses. The radioresistance of antibody-mediated immune response is lowest when radiation is given before antigen, and rises steadily with time after antigen stimulation to reach a maximum when serum antibody is at a maximum, suggesting that antibody-producing cells are highly resistant. Irradiation affects the antibody-mediated response by 1) lengthening the period between stimulation and production of detectabel levels of serum antibody, 2) decreasing the rate of increase in serum antibody levls, and 3) decreasing the maximum concentration of serum antibody. Irradiation affects the cell-mediated response by inhibiting immunization and delayed hypersensitivity reactions when administered before antigen. Because the cell-mediated response involves nonlymphoid cells whose precursors are also radiosensitive, irradiation following stimulation may also produce temporary suppression.


Nonspecific immunotherapy of malignant tumors. At present, nonspecific immunotherapy of malignant tumors seems to be the most promising among immunotherapeutic modalities. Potent nonspecific immunostimulants, Bacillus Calmette-Guerin (BCG) and Corynebacterium parvum, exhibit an antitumor activity in experimental animals, which is commonly manifested by reduced tumor growth and sometimes by complete regression of tumors. Antitumor effectiveness of these bacteria is largely related to tumor immunogenicity and host immunocompetence. Recently, BCG has frequently been used for clinical immunotherapy and has provided therapeutic benefit in many instances, particularly when combined with chemotherapy, radiotherapy or surgery. Clinical experience with C. parvum is so far limited.


HL-A histocompatibility antigens and their relation to disease. Table 14 summarizes the data presented in this review. The table lists the various diseases, along with whatever HL-A-antigen associations may be present, and the ranking that is based on the accumulated confidence of the associations; also, it lists the individual antigens and those disease states in which the incidence of the various antigens is increased ro decreased. The Table should expand rapidly in future years. There are a number of problems involved in this area of research: (1) There is a scarcity and lack of stability of good reagents, as well as the general difficulty of HL-A serology. (2) Many studies are retrospective on cells that may be abnormal. We have mentioned the changing sensitivity of lymphocytes to HL-A antibodies in disease. Increased sensitivity of weak antibodies present in the HL-A antisera may create the false impression of increased frequencies. (3) What control population one selects is also of the utmost importance. One method of internal control is to include in the controls related and unrelated individuals, all tests being run at the same time, employing the same reagents, and being run by the same technician. (4) In some disease states, notably Hodgkin's disease and SLE, autoantibodies present may interfere with the HL-A antisera reactions. All of this is compounded by the fact that the lymphocyte is constantly and rapidly shedding and replacing the HL-A antigens; the rate of turnover may change in patients, thus introducing an additional problem. Finally, there is a need for a standardization of statistical tools and for the reporting of both positive and negative results [133]. The concern for a significant quantity of test data and the problems of evaluating statistical data bring out many views. Boswell, in The Life of Samuel Johnson, noted: "I recollect nothing passed this day except Johnson's quickness, who, when Dr. Beattie observed, as something remarkable which happened to him, that he had chanced to see both No. 1 and No. 1000 of the hackney-coaches. The first and the last, 'Why Sir' (said Johnson) 'there is an equal chance for one's seeing those two numbers as any other two.'" A partial solution to these problems may be offered by the evaluation of the LD antigens [49, 63, 64]. In any event, HL-A typing offers an unique opportunity for the grouping of related diseases, as similar clinical findings with related distributions of HL-A antigens may indicate disease relationships not previously considered [27].


Laboratory tests for diagnosis of autoimmune diseases. 1. Antimitochondrial antibody titers of 1:160 are practically diagnostic of primary biliary cirrhosis [71]. Serum antimitochondrial antibody titers of less than 1:16 are seen in 10% of cases of primary biliary cirrhosis. The antimitochondrial antibodies are usually absent in jaundiced patients with extrahepatic obstruction, drug sensitivity, and viral hepatitis. 2. Anti-smooth-muscle antibodies are noted in the various autoimmune liver disorders, viral hepatitis, infectious mononucleosis, malignancy, and intrinsic bronchial asthma. The smooth muscle antibody test helps in the differential diagnosis of lupoid hepatitis vs. systemic lupus erythematosus. The anti-smooth-muscle antibodies are usually absent in systemic lupus erythematosus. 3. The antinuclear antibody is frequently positive in the autoimmune liver diseases. In cases of chronic aggressive hepatitis associated with a high titer of antinuclear antibody the prognosis is usually grave. 4. The presence of antimicrosomal liver and kidney antibody is indicative of chronic aggressive liver disease, which is different from the classic lupoid hepatitis [95, 97]. 5. Hepatitis-B-antigen assay should be performed routinely to exclude viral hepatitis, type B. Heterophile antibody tests should done when the possibility of infectious mononucleosis must be considered. 6. Serum immunoglobulin determinations are of secondary importance in the laboratory diagnosis of autoimmune liver disorders. There is usually a polyclonal elevation of the major immunoglobulin in most chronic parenchymal liver diseases[48].


Value of exercise testing for screening asymptomatic men for latent coronary artery disease. Treadmill exercise testing identifies a group of men at high risk for coronary atherosclerotic heart disease. However, the predictive value and sensitivity limitations are obvious. An abnormal electrocardiographic response does not absolutely predict the presence of coronary atherosclerotic heart disease, and a normal response does not rule out this possibility. Thus in appropriate instances when the minimal risk of coronary angiography is justified this procedure can be used to determine the anatomic correlation of exercise-induced functional ST-segment changes.


Risk factors in breast cancer.

Risk factors in breast cancer. Various factors have been found to be predictors of the relative risk of breast cancer (Table 2). Epidemiologic variables influencing breast cancer risk include age, marital status, geographic location, racial or ethnic extraction, and socioeconomic status. The risk of developing mammary carcinoma is increased with advancing age, among unmarried women, in the United States and Europe, and among women of higher socioeconomic classes. Conversely, a decreased breast cancer risk is observed among fertile married women in Asian countries, among Oriental women, and in lower socioeconomic classes. Reproductive history plays an important role in determining breast cancer risk. The risk of developing mammary carcinoma is increased by an early menarche and decreased by delayed first menses. A late natural menopause increases breast cancer risk while an early oophorectomy offers protection. Hormonal factors are thought to play important roles in the etiology of breast cancer, but the contributions of estrogenic and androgenic influences to mammary neoplasia have not been delineated. Certain estrogen fractions have been implicated as mammary carcinogens, while certain adrenal androgenic steroids have been shown to be promotors of breast cancers. Chronic cystic mastitis is associated with an increased breast cancer risk. A positive family history increases the risk of developing mammary carcinoma and a past history of breast cancer markedly increases the possibility of subsequent breast neoplasia.


Prostaglandin E2 on the electroencephalogram. Present study was prompted by the report from another center on the occasional occurrence of convulsions and abnormal electroencephalogram (E.E.G.) patterns in women aborted with intra-amniotic prostaglandin F2alpha (PGF2alpha). Fifty four subjects were investigated by means of an E.E.G. taken before and after initiation of PGE2 administration. They included pregnant and non-pregnant patients, nearly half (23) of whom were known epileptics. One seizure was observed during PG administration in a man with daily psychomotor attacks who had not taken his anticonvulsants on the day the test was performed. PGE2 caused no alteration of the E.E.G. in subjects with a normal control tracing; in those with an abnormal E.E.G., a deterioration was seen in one and an improvement in three. It is concluded that PGE2 is not epileptogenic at doses required for termination of pregnancy.


Laminaria augmentation of intra-amniotic PGF2 for midtrimester pregnancy termination. In our hands, intra-amniotic PGF2alpha 40 mg for midtrimester pregnancy termination had a mean infusion to abortion interval of 29.4 hr. However, pretreatment of 230 patients with laminaria tents inserted 14-18 hr before PGF2alpha infusion resulted in a dramatically reduced time to abortion (14.3 hr mean) with a low incidence of gastrointestinal and other side effects. Laminaria tents inserted at the same time as PGF2alpha infusion in 26 patients also resulted in reduced time to abortion (18.6 hr mean). In the laminaria pretreated group, the infusion to abortion interval was indirectly related to the number of laminaria inserted and not to the nulliparous or parous state. Although we have made significant strides in shortening the abortion interval in the hospital, retained placentae and blood loss persist as problems related to the use of prostaglandin for abortion.


Induction of abortion with intra-amniotic or intra-muscular 15(S)-15-methyl-prostaglandin F2alpha. In order to evaluate the efficacy and acceptability of 15(S)-15-methyl-prostaglandin F2alpha (15-me-PGF2alpha) for pregnancy termination, we induced 30 abortions with single intra-amniotic injections of 2,5 mg of 15-me-PGF2alpha and 25 abortions with intra-muscular 15-me-PGF2alpha administered 200 mug initially and 300 mug every third hour until 30 hrs or abortion. Abortion occurred within 30 hrs in 97% of cases in the intra-amniotic group, with a mean abortion time of 17,6 hrs and in 80% in the intramuscular group, with a mean abortion time of 15.0 hrs. Neither parity nor gestational age was significantly related to the abortifacient efficacy of 15-me-PGF2alpha. No serious complications occurred. Vomiting (83-84%) and diarrhoea (23-92%) were the most common complaints. Uterine contractions were more painful if induction was effected with intra-amniotic rather than intramuscular injections. 15-me-PGF2alpha appears to be an effective and practicable abortifacient which can be used intra-amniotically or intramuscularly according to the ease of amniocentesis.


The effect of prostaglandin F2beta on expiratory flow rates. Prostaglandin F2beta (PGF2beta), a stereoisomer of F2alpha was administered by ultrasonic nebulization to eight patients with bronchial asthma and four normal subjects in increasing doses up to 200 mug maximum dose. Maximum expiratory flow (MEF) and forced vital capacity (FVC) were analyzed at 5, 15, 30, 60 and 120 minutes after administration of aerosol. All expiratory flow rates were reduced after 5 minutes. Some increase in terminal flow rates was observed after 60 minutes. We conclude that PGF2beta in not an effective bronchodilator at this dose level.


Decreased inhibition of platelet aggregation by PGE1 in children with cystic fibrosis and their parents. PGE1 inhibited ADP-induced platelet aggregation in children with cystic fibrosis and their parents to a much lesser extent than in normal controls. We suggest that this may be a reliable test for heterozygote carriers of cystic fibrosis.


The effect of indomethacin on plasma renin activity in man under normal conditions and after stimulation of the renin angiotensin system. 1) The influence of oral indomethacin on basal and stimulated plasma renin activity in normal human subjects was determined. 2) Indomethacin lowers the basal plasma renin activity in man. 3) The response of the plasma renin activity after indomethacin to physiological and pharmacological stimuli is maintained at a lower level. 4) There is no evidence from our experiments that major changes in the sodium balance are responsible for the effects observed.


Antagonism of the effects of furosemide by indomethacin in normal and hypertensive man. Furosemide and the prostaglandin synthetase inhibitor, indomethacin, were administered singly and in combination to four normal subjects and six patients with essential hypertension in order to determine whether the antihypertensive, natriuretic and other effects of furosemide could be altered by inhibition of prostaglandin synthesis. In all subjects indomethacin treatment alone resulted in a significant elevation of blood pressure and a fall in plasma renin without any change in sodium excretion. Furosemide alone resulted in a significant blood pressure fall with a rise in plasma renin and urinary aldosterone with a marked increase in urinary sodium loss. These effects were either obviated or blunted by addition of indomethacin. The results are compatible with hypothesis that the antihypertensive and natriuretic effects of furosemide might be mediated at least in part by prostaglandin synthesis. In addition, the effects of indomethacin should be considered when using this drug in hypertensive patients and in subjects requiring diuretic therapy.


Treatment with reserpine of patients resistant to tricyclic antidepressants. A double-blind trial. The literature concerning the therapeutic effects of the administration of reserpine to patients who fail to respond satisfactorily is discussed briefly. A double-blind study was conducted on 14 patients; eight were given 5 mg of reserpine i.m. and six were given 2 ml of normal saline on 2 successive days. The administration of the tricyclic antidepressants the patients had been taking, was continued. The Hamilton Depressive Rating Scale was administered on the day before treatment was commenced, and repeated on the fourth day. Statistical analysis revealed that the patients who received reserpine showed a highly significant improvement of a good quality. The mean fall in the Hamilton rating for the placebo group was 6 points, and in the reserpine group it was 18.87. The therapeutic significance of the findings is discussed.


Myofibrillar abnormalities following cardiac muscle cell injury. A review is presented of morphological aspects of myofibrillar alterations which occur in cardiac muscle cells following various types of injury. Emphasis is placed on the association between specific patterns of alterations involving the structure or the orientation of myofibrils and diverse forms of myocardial injury.


Different morphological types of myocardial cell death in man. The evolutive histological stages, the frequency, and the eventual association of the different types of myocardial cell death have been studied in the following human material: acute infarction, sudden "coronary" death, accidental death, pheochromocytoma, transplanted hearts, "stone" heart syndrome, thrombotic thrombocytopenic purpura, and alcoholic cardiomyopathy. Three distinct main histological types of myocardial cell death are recognizable: Coagulation necrosis, the fundamental lesion in infarcts in which the myocardial cell loses its capability to contract and dies in an atonic state with overdistension due to the intraventricular pressure. No early myofibrillar damage is seen. Coagulative myocytolysis, found in all the present cases, always seen in the outer zone of an early infarct and in the surrounding normal myocardium at any stage of the repair process in most of the acute infarcts and in most cases of sudden death. The myocardial cell dies in a hypercontracted state, with early myofibrillar rhexis, and anomalous irregular cross-band formations. This tetanic death is similar to that seen in pheochromocytoma and in experimental catecholamine-induced necrosis. Colliquative myocytolysis, in which edematous vacuolization with dissolution of myofibrils is the main early finding, without hypercontraction, anomalous bands, and myofibrillar rhexis. This pattern, likely related to the low-output syndrome, was often seen in the preserved subendocardial and perivascular muscle fibers of acute infarct cases, in some transplanted hearts, and in all the alcoholic hearts. The different clear-cut morphological patterns of these three types of myocardial necrosis suggest a different pathogenesis and that different pathogenetic mechanisms may act in the same disease.


Evaluation of lung function indices for bronchodilator trials. Results of a cross-over study of fenoterol. In 10 patients with airway obstruction, spirographic indices and maximal expiratory flow rates were measured before inhalation of fenoterol and at different time intervals, for 5 h, following the inhalation of 200 mug of this substance. 10 min after inhalation of fenoterol, there was a statistically significant increase in all lung function indices. A further increase was observed later. 3 h after inhalation of fenoterol, all indices were still significantly higher than control values. No side effects were observed. At all time intervals, the increase of the forced expiratory volume in 1 sec (FEV1.0), peak expiratory flow rate (PEFR) and maximal expiratory flow rate at 50 and 75% of the vital capacity reached a similar level of statistical significance. It is concluded that for the trial of the bronchodilator drugs, any of these indices may be used, and for practical purposes FEV1.0 and PEFR are best suited.


Objective evaluation of antitussive agents under clinical conditions. A new method for objective assessment of cough under normal or pathological conditions is described. Thoracic coughing can be discriminated from any other pressure wave because of its relatively high frequency. This method was applied in a double blind crossover trial in 18 patients with respiratory disease.


Production of MIF-like supernatants by rheumatoid arthritis lymphocytes stimulated by immunoglobulin G. Patients with rheumatoid arthritis (RA), patients with positive tuberculin (PPD) skin-tests and controls were studied. The lymphocytes from these groups were cultured in serum-free medium to obtain cell-free supernatants. These lymphocyte cultures were pre-incubated with the appropriate antigen or reconstituted after removal of the cells. Supernatants from RA lymphocytes stimulated in vitro by IgG induced an inhibition of the leucocyte migration, as well as the supernatants from tuberculin-sensitized lymphocytes. However, supernatants from non-RA lymphocytes or tuberculin-unsensitized lymphocytes did not show such an inhibition. These MIF-like supernatants have been studied by Sephadex G-100 gel filtration. A MIF activity has been found for PPD and IgG supernatants between the chymotrypsinogen (MW 23,000) and the lysozyme (MW 17,000). This seems to agree with the classical region where MIF can be usually isolated.


Experimental arthritis produced by injection of mediators of delayed hypersensitivity. Synovitis was produced in the rabbit knee by repeated intraarticular injection of a preparation of mediators of cellular immunity. The mediators were prepared by incubation of KLH with lymph node cells of animals previously immunized with KLH in Freund's adjuvant. Following three intraarticular injections, a chronic synovitis resulted in which hyperplasia of the lining layer and infiltration of the sublining layer occurred. The cell types in the sublining layer were predominantly histiocytes and fibroblasts. These experiments demonstrate that mediators of cellular immunity may produce a chronic inflammatory reaction when injected repeatedly into normal joints. They indicate that the cellular immune response may play a role in the development of the synovitis of immunologically induced arthritides.


The origin of rheumatoid arthritis.

The origin of rheumatoid arthritis. The origin of rheumatoid arthritis (RA) is in our opinion a bacterial infection. The infection gives rise to changes in the macrophages, with release of enzymes, etc., and secondarily abnormal immune processes occur. In favor of this opinion is, among other things, the similarity with rheumatic fever, which is caused by streptococci group A, as well as experience gained in connection with experimentally provoked arthritis. In experimental arthritis, produced by streptococci group B (Svartz), there appears in rats the same type of joint disease as in human RA and, besides, a rheumatoid factor (RF)-like macroglobulin, which cannot be distinguished by available methods from human RF macroglobulin. A 7 S hemagglutinating RF (RF II) was also produced in animals, as well as some other immunoglobulins. The RF II has a much weaker hemagglutinating capacity than the usual RF macroglobulin which for comparison could be termed RF I. The streptococci B used in our investigations were mostly isolated from the nasopharynx of RA patients.


Studies on the production of MIF and mitogenic factor using highly purified human T and B lymphocytes. Human lymphocytes were separated into highly purified populations using an immunoadsorbent column technique. It was previously reported that both T and B cells exhibited increased 3H-thymidine incorporation in response to PHA, Con A and pokeweed mitogens, whereas only T cells showed increased incorporation in response to specific antigen. In the present studies, the cellular basis of MIF and mitogenic factor production was studied. Both T and B cells produced MIF in response to antigen. The MIF produced by both T and B cells elutes from Sephadex G-100 columns in the same fraction. Studies using BUdR and light suggest that the T cell which produces MIF is also a proliferating cell, whereas the B cell producing MIF is not. Only T cells produce mitogenic factor in response to antigen. The mitogenic factor produced, however, causes both T and B cell populations to increase 3H-thymidine incorporation. The present studies indicate that antigen induced mitogenic factor production and increased 3H-thymidine incorporation are properties of T cells per se, whereas antigen-induced MIF is made by both T and B cells.


Lumbar traction: a double-blind controlled study for sciatica. A double-blind control study of lumbar traction for sciatica has been carried out. Although there is a tendency for traction to produce improvement in pain and straight-leg raise the extent does not achieve statistical significance. Changing 'control' patients to 'treatment' seemed to produce worthwhile relief of pain for all who were not already improving. It is suggested that a large trial using more discriminating criteria might delineate a group of patients susceptible to help by traction.


Sinus arrhythmia in man: influence of tidal volume and oesophageal pressure. The effect of tidal volume (VT) and of the intrathoracic pressure (Poes) on the respiratory sinus arrhythmia (RSA) was studied in healthy subjects. They breathed into a spirometer with a VT of 1, 1.5, and 2 1, at a standardized, slow respiratory rate, 6-min-1 (A). Poes was varied by (B) adding a negative inspiratory pressure (NIP) of 5 cm of water and by (C) intermittent positive pressure ventilation (IPPV) at identical VT and respiratory frequency. In a separate study (D), intermittent negative pressure ventilation (INPV) was induced by applying negative pressure on the thorax. In A, increasing VT provoked an augmented RSA by a more marked tachycardia as well as bradycardia. On increasing the amplitude of Poes in B, RSA was somewhat more marked due to a lower minimum heart rate. When comparing respiratory cycles that had similar Poes but a different VT, the larger VT caused a slight increase in the RSA amplitude due to a more marked deceleration of the heart rate. IPPV almost abolished RSA, whereas INPV did not reduce the arrhythmia. It is concluded that pulmonary stretch reflexes to a minor extent contribute to RSA, whereas the hypothesis of a central nervous origin does not gain support. Cardiovascular reflexes remain the main possible cause of RSA.


The effect of physical training on the sympathoadrenal response to exercise. The urinary excretion of catecholamines was measured in six healthy male volunteers at rest and during a fixed amount of work before and after physical training. It was found that, although training resulted in a significantly lower heart rate during exercise, the output of catecholamines was unaltered, indicating that the total activation of the sympathoadrenal system by exercise was similar before and after training. A similar heart rate study before and after training was also made during beta-adrenergic receptor blockade. Under these conditions the heart rate during exercise was not significantly changed by training. It is suggested that physical training reduces the sensitivity of the beta-receptors of the heart.


Solid-phase cobalamin assay using cobalamin-binding protein from dog stomach. Ninety-five samples from 42 animals were studied for the presence of a cobalamin-binding protein fulfilling the criteria of occurring in major quantities and being homogeneous regarding size and binding constant. The binder from dog stomach thus found was made insoluble by coupling to bromoacetyl-cellulose and used for solid-phase assay of serum cobalamins. Equilibrium between free and bound radioactive cobalamin was unaffected by centrifugation of the samples, thus allowing the straightforward use of the Scatchard equation for calculation of results. The precision of the method was 0.05 to 0.10 at concentrations above 100 pmolX1(-1), the sensitivity was about 30 pmolX1(-1), the accuracy could be based on aqueous solutions of cyanocobalamin, and the reference interval was as for the Lactobacillus leichmannii method, i.e. 160-480 pmolX1(-1).


Experimental gingivitis in young dogs.

Experimental gingivitis in young dogs. The aim of the present study was to analyze and express in quantitative terms some of the structural alterations which develop in an initially normal gingiva during a phase of continuous plaque accumulation. Four beagle dogs were used. The animals had from birth been twice daily subjected to meticulous mechanical tooth cleaning. When the dogs were 10 months of age their gingiva were in excellent health as evaluated by Gingival Index and Gingival Exudate measurements. Gingival tissues were harvested from the premolar and molar regions in the right jaws. The tooth cleanings were then terminated and plaque allowed to accumulate. Clinical examinations were performed and gingival biopsies sampled after 4, 7, 14, 21 and 28 d. The composition of the gingival biopsies was analyzed in a sampling microscope. After 4 d of plaque accumulation significant amounts of gingival exudate could be sampled. The exudation then gradually increased during the following weeks. Biopsies representing day zero did not contain any inflammatory cell infiltrates. However, after 4 d of the experiment leukocytes were found in the collagen-poor connective tissue immediately beneath the junctional epithelium. The size of the infiltrated connective tissue (ICT) gradually increased during the experiment. The volumetric density of collagen in the noninfiltrated connective tissue (NCT) was always much higher than in ICT. In ICT, however, this density parameter remained rather constant throughout the study. On days 4 and 7 neutrophilic granulocytes constituted 60-70% of the leukocyte population. On day 28, however, the infiltrate comprised mainly mononuclear leukocytes, especially plasma cells, neutrophils at that time occupying only a small fraction of the infiltrate.


Peritonitis fibroplastica incapsulata with superadded post-operative starch powder peritonitis. Peritonitis fibroplastica incapsulata is not generally accepted as a distinct syndrome. However, characteristic pathological alterations can be identified at laparotomy and by histological examinations. The aetiology of the disease is unknown. In the case reported a second disease arose, i.e. the peritoneal reaction to corn starch powder in the course of the surgical treatment of the peritonitis fibroplastica.


Acute abdominal complications of coeliac disease. Two rare complications of coeliac disease are described in patients who presented as acute abdominal emergencies. One of the patients had both oesophageal and small intestinal obstruction produced by an ulcerative process involving these portions of the gastro-intestinal tract. The other, a patient with long standing dermatitis herpetiformis, perforated his small intestine at a site involved by both a lymphoma and partial villous atrophy.


Haematopoietic defects of W/WV mice studied with the spleen colony, agar colony, and diffusion chamber techniques. Bone marrow progenitor cells from anaemic W/WV mice were compared with normal +/+ cells utilizing the spleen colony, the agar colony and the diffusion chamber techniques. Spleen colony formation from W/WV cells was markedly defective, and more so for erythroid than for granuloid colonies. The progenitor cell concentration was apparently normal as measured by the two other techniques. The concentration of circulating progenitor cells also seemed to be normal. On the other hand, the cell formation per progenitor cell was subnormal in all three assay systems. The initial proliferative response of W/WV spleen colony-formers and agar colony-formers to short-term diffusion chamber culturing was apparently normal. The incorporation of 3H-thymidine, related to the number of proliferative granulocytes present in the chambers, also seemed to be normal. The results indicate that the W/WV defect is not limited to the multipotent stem cells. A possible interpretation is that it is the capacity for continued self-renewal of immature cells that is defective.


Ultrastructural study of bone morrow-derived granulocytic colonies in diffusion chambers in rats. An ultrastructural study of diffusion chamber granulocytic colonies is reported. The colonies were derived from normal rat bone marrow cells and the chambers were inserted into the peritoneal cavity of lethally irradiated rats. The colonies were processed en bloc for electron microscopy enabling observation of cellular relationship to be made. Ultrastructural analysis of colonies disclosed normal maturing cells at all stages of maturation, with the exception of occasional granulocytes on neutrophil type that presented narrow strips of chromatin ('nuclear blebs'). The cells in colonies generally occurred in close apposition to one another and to occasional macrophages. This organization possible enhanced transmission of factors of maturation. Advantages of diffusion chamber haematopoietic culture are discussed; among the most important are the occurrence of fibroblasts originating from implanted marrow cells and the local formation of fibrin within the chambers.


Immunofluorescence microphotometry for the detection of platelet antibodies. III. Demonstration of autoantibodies against platelets. After a survey of the literature dealing with the demonstration of platelet autoantibodies by immunofluorescence techniques, the results are given of a study in which immunofluorescence microphotometry was used for this purpose. The serum of 58, the platelets of 34, and the megakaryocytes of 2 patients with thrombocytopenia were investigated. In 21 of 52 sera (40%) in which the presence of platelet autoantibodies could be expected, positive results were obtained that could not be due to isoantibodies, either because the patients had not been pregnant and had not received blood transfusions or because the reactivity of the serum with the patient's own platelets was demonstrated. The platelets of 28 patients with thrombocytopenia not due to a platelet defect or decreased thrombopoiesis were investigated. In the platelets of 15 (54%) of these, significant differences in fluorescence were found with anti-immunoglobulin conjugate as well as with anti-IgG, -IgA, -IgM, or -complement reagents. It was concluded that in these patients in vivo sensitization of the platelets with autoantibody was demonstrated. In two patients an indication of the in vivo sensitization of the megakaryocytes was also obtained.


Correction: mouse spleen cells cultured in homologous serum can indeed make primary antibodies to sheep erythrocytes. Contrary to what I have reported in a previous article, I now present data that prove that spleen cells from various strains of mice can make primary antibodies to sheep erythrocytes in syngeneic adult serum. The reasons for this dichotomy of data are not clear. The present results indicate that it is possible to obtain an antibody response in the absence of demonstrable mitogens or polyclonal activators, suggesting activating signals only between antigen-specific cells. Primary IgG formation in vitro was demonstrable in cultures with normal mouse serum but not in fetal-calf-serum-substituted cultures. Since antigen has never induced antibody formation in vitro under serum-free conditions, it is now deduced that normal adult serum, in addition to containing suppressor molecules that restrain general lymphocyte proliferation, also contains material absolutely essential for antigen-induced specific cell proliferation to occur. These latter substances work even at very high dilutions.


Experimental murine leprosy. IX. Antibodies against Mycobacterium lepraemurium in C3H and C57BL mice with murine leprosy and in patients with lepromatous leprosy. Sera from C3H and C57BL mice infected with Mycobacterium lepraemurium (MLM) and from human leprosy patients were examined for antibodies against MLM by a crossed immunoelectrophoresis (CIE) technique. Altogether antibodies against six or seven MLM antigens were found in the mouse sera. After a small inoculum of MLM, C3H mice produced more antibodies than C57BL mice. After a large inoculum both strains produced about the same amount of antibodies but showed qualitative differences in their response patterns. A serum pool from patients with lepromatous leprosy contained antibodies against six MLM antigens; five of these were identical with the antigens against which antibodies were found in infected mice. C57BL mice that had lost their delayed-type hypersensitivity to MLM during the course of a disseminated infection showed a fairly strong antibody response to three antigens and a weak response to three others. Since almost the same spectrum of antibodies, although in lower titres, could be demonstrated in C57BL mice with intact delayed-type hypersensitivity to the bacilli, these antibodies did not seem to interfere with the expression of cell-mediated immunity.


IgG rheumatoid factor in dental periapical lesions of patients with rheumatoid disease. To detect "hidden" IgG rheumatoid factor in tissues from dental periapical lesions, 26 rheumatoid and 14 control patients were examined by the direct immunofluorescence technique for binding of FITC-labelled IgG before and after pepsin digestion. Whereas free rheumatoid factor was detected in only 1 rheumatoid tissue before digestion with pepsin, this tissue as well as 8 other rheumatoid tissues strongly bound heat-aggregated IgG after the digestion procedure. Six of these 9 tissues also bound native IgG. In no control tissue was free rheumatoid factor detected and in only 1 was "hidden" rheumatoid factor revealed after pepsin digestion. Hence, presence of IgG rheumatoid factor correlated positively with the presence of rheumatoid disease, and evidence was established that certain features of rheumatoid inflammation occur in dental periapical lesions of many patients with rheumatoid disease.


Occurrence of amyloid in the teeth-supporting tissues of patients with rheumatoid diseases. An immunohistochemical study. An investigation was carried out to determine whether amyloid could be detected in the dental periapical lesions or gingival buccal fold, or in both, of patients with rheumatoid disease but in whom amyloidosis had not been diagnosed. Tissue from the dental periapical lesions of 36 rheumatoid and 23 control patients, as well as from the gingival buccal fold of 11 of the rheumatoid and 11 of the control patients, were examined by the direct immunofluorescence technique and by polarization microscopy of sections stained with Congo red. Amyloid was observed almost 5 times more often, or in 19% of the dental periapical lesions of rheumatoid patients: it was detected by immunofluorescence in 7 rheumatoid patients and 1 control patient, and by polarization microscopy in 6 of these 7 rheumatoid patients as well as in the 1 control. Rectal biopsies performed on these 8 patients were positive in only 1 of the rheumatoid patients. Amyloid was not detected in any of the gingival biopsies. Serum samples from the rheumatoid and the control patients were tested for the presence of the nonimmunoglobulin amyloid fibril-related serum component, protein ASC. Nineteen of the 36 rheumatoid patients, including the 7 whose dental periapical lesions contained amyloid, had protein ASC in their serum.


Treatment of chronic articular effusions with 90-yttrium (90Y). In an open, controlled trial, radioactive 90Yttrium was injected in doses of 3-6 mCi into 40 joints with chronic effusions in patients suffering from rheumatoid arthritis and other rheumatoid diseases. The processing in a computer was carried out by the punch card method. Intra-articular administration of 90Y resulted in a significant improvement of five objective criteria. In our study we have paid particular attention to the clinical and statistical differentiation of the effects of systemic, and especially of basic therapy, from the effects of topical intra-articular therapy. At the time of the last check-up examination, 43% of the patients were free of any effusion. The treatment was well tolerated. Skin necrosis occurred in only one single case. Intra-articular treatment with radioactive 90Yttrium represents a valuable contribution to the therapeutic arsenal for the treatment of the chronic articular effusions when all other methods of treatment failed.


The value of roentgen irradiation in the treatment of painful degenerative and inflammatory musculoskeletal conditions. A double-blind study. A double-blind trial was carried out to study the effect of roentgen radiation treatment in 104 patients presenting 127 painful disorders of the joints and muscles. 64 disorders received genuine treatment and 63 had sham treatment. Improvement occurred in 59% of the genuinely treated group and in 65% of the placebo group. The results were about the same 2 weeks and 6 weeks after termination of treatment. Thus there was no significant difference between the groups.


Prognosis of post-neonatal respiratory distress syndrome (RDS) treated with positive end-expiratory pressure ventilation (PEEP). Thirty-six patients with respiratory distress syndrome (RDS) were treated with mechanical ventilation with positive end-expiratory pressure (PEEP). In 16 patients the RDS was the result of direct pulmonary injury due to chest trauma (group A), and in 20 patients the RDS followed non-direct injury of the lungs (group B). Fifteen patients died. At the moment of death the RDS had disappeared. No difference in mortality existed between groups A and B. Four patients died from causes unrelated to the RDS, one patient died from an avoidable error in the treatment. The ultimate outcome did not seem to be related to age, use of mechanical ventilation or PEEP, or occurrence of complications (e.g. a pneumothorax, which appeared to be related rather to the chest trauma). Of probably prognostic significance was the presence of a combination of massive aspiration and RDS. Of the 12 patients who suffered from this combination, nine died. PEEP ventilation was more unsuccessful in raising PaO2 appreciably in these patients than in others. The combination of massive aspiration and RDS posses a therapeutic dilemma. PEEP ventilation is invaluable in the treatment of RDS. Interruption of the PEEP within the first 1-2 days may sometimes result in massive recurrence of the RDS. Endotracheal suctioning which is a prerequisite for the treatment of massive aspiration, may under these circumstances be virtually impossible within this period. A compromise, including PEEP ventilation for as short a period as possible (usually no longer than 2 to 3 days) without interruption, followed thereafter by intensive physiotherapy with endotracheal suctioning, may succeed in saving some of the patients.


Function and homeostasis of copper and zinc in mammals. Recently there has been great interest in the determination of levels of trace elements in biological systems. The goals of many researchers in this field have been: understanding the roles of micronutrients in biochemical processes and the evaluation of biological mechanisms that maintain tissue concentrations at relatively constants levels. The biochemical and physiological functions of the micronutrients copper and zinc have been reviewed with emphasis on factors, both endogenous and exogenous, associated with the maintenance of homeostatic levels in mammalian sera. Understanding the mechanisms affecting homeostasis will provide a background necessary for the application of data on serum trace minerals in the diagnosis and prognosis of disease states. The general roles of copper and zinc in animal nutrition may be understood by evaluating physiologic changes associated with deficiency states of these essential elements. Deficiencies are associated with antagonisms and interactions from other elements and from chelating organic compounds as well as with primary deficiencies due to insufficient dietary levels. Biochemical and physiochemical properties of copper and zinc biomolecules are discussed with primary emphasis on the forms of these metals in serum. Also discussed in detail, are the effects of disease, radiation exposure and environmental factors on serum and tissue copper and zinc levels.


Bone resorption restored in osteopetrotic mice by transplants of normal bone marrow and spleen cells. Capacity to resorb bone and calcified cartilage was restored permanently in mice with inherited osteopetrosis by the intravenous administration of cell suspensions prepared from spleen and bone marrow of normal littermates. Beginning near active growth plates as early as 2 weeks after transplantation, replacement of the abnormal spongiosa continued until medullary cavitites were fully expanded.


Mefloquine (WR 142,490) in the treatment of human malaria. Mefloquine hydrochloride, a new 4-quinolinemethanol, was administered as a single oral dose to 47 volunteers infected with malaria. Treatment resulted in rapid clearence of fever and parasitemia. No recrudescence of parasites was observed after treatment of chloroquine-sensitive infections of Plasmodium falciparum. More significantly, in nonimmune persons with chloroquine-resistant infections, 1 gram of mefloquine cured 10 of 12 patients and 1.5 grams cured all 8 patients who received this dose of the drug. The marked activity of a single dose of mefloquine against chloroquine-resistant strains of Plasmodium falciparum suggests that this agent may be more useful than currently available drugs are for the treatment of drug-resistant malaria.