[Topography of the optic thalamus, caudate and lenticular nuclei of the human brain in frontal section (an anatomical-statistical study applied to stereotaxis)]. Topographic coordinates of the thalamus, caudate and lentiform nuclei of the human brain in relation to the medial-sagittal plane and inferior-medial part of the corpus callosum were studied in 70 preparations. The parameters under study are characterized by mean values of the variants and square deviations. Detailed tables of these values are given which may be employed in stereotaxical calculations for all coordinates, for men and women separately, for the right and left hemispheres, brachy- and mesencephaly. Statistically reliable differences of coordinates found for 3 of 13 parameters studied were not regular. The necessity to identify the above subgroups in topometrical investigations of the human brain is under doubt.


[Morphologic and applied aspects of mitotic pathology]. The author presents a classification and descriptions of various forms of pathology of mitosis. Changes in the mitotic regimen following administration of some drugs and under the effect of extreme factors are considered. Data on changes in the number and character of pathological mitoses in viral infection and radiation damage are discussed. Particular attention is given to the analysis of shifts in the mitotic regimen in various benign and malignant hyperplasia. It is shown that malignization (precancer and cancer of the larynx, endometrium, cervix uteri and stomach) is characterized by a rise of the mitotic activity, detection of division in metaphase and by a drastic increase in the number of pathological mitoses. These indices are used in the differential diagnosis of neoplastic processes and for early detection of possible malignization pf precancer hyperplasia.


[Detection of antinuclear autoantibodies by the indirect Coon's method]. A variant of the indirect method of fluorescent antibodies for revealing antinuclear autoantibodies and simultaneously for identifying the tissue- and organ-specific autoantibodies is suggested. As substrate, cryostatic sections of the rat's liver, heart, kidney which were fixed for 3 minutes in 96 degrees ethanol were used. Detection of autoantibodies is performed with the use of pure labeled autoantibodies to human IgG. The method described makes it possible to obtain easily compared and reproducible results.


[Pathologic anatomy of experimental listeriosis]. The authors present a survey of the Soviet and foreign literature and findings of their own experimental studies. On the basis of these data the pathologo-anatomic picture of listerosis in laboratory animals (white mice, guinea-pigs and rabbits) is given in dynamics and histogenesis of focal changes in this disease in elucidated. The most typical feature of listerosis in animals is lesions of the kidney where focal changes in the form of granulems could be detected macroscopically at an early period and with great consistency. Several stages in its histogenesis may be discerned: I. focal necroses of hepatic cells associated with their invasion with lister Listeria; 2. appearance of cellular elements around the foci of necroses with subsequent formation of granulemas consisting mainly of leucocytes and lymphoid cells; 3. development of necrobiotic changes in the central areas of granulemas with concomitance of exudative processes; 4. organization of necrotic foci with subsequent scarring.


[Intestinal localization of shigellae in dysentery and experimental shigellosis]. The investigation of 53 section cases of dysentery and 18 biopsy specimens of the large intestine in acute dysentery in children showed that intrapithelial distribution of Shigella was not always regular. In studies of experimental Shigellosis on isolated loops of the intestine 459 segments of the intestine of 51 rabbits were investigated. The results obtained showed that Shigella multiplied mainly in the lumen of the intestine. The increase in number of Shigella in enterocytes was by 8-9 orders lower than that in the content of the ligated segment, whereas the number of enterocytes with Shigella was many times less than the total number of damaged cells. This confirms the conclusion that intraepithelial multiplication of Shigella is of no considerable significance in pathogenesis of dysentery.


Familial neurological disease associated with spongiform encephalopathy. In a family in whom susceptibility to neurological diseases was transmitted in autosomal dominant fashion, the diseases affecting different family members ranged from subacute and chronic dementias to various motor system abnormalities without dementia. The propositus suffered a typical clinical course of Creutzfeldt-Jakob disease. Neuropathological observations revealed spongiform encephalopathy. A first cousin had a chronic dementia; no spongiform changes were present at autopsy. Both patients had PAS-positive, eosinophilic plaques throughout the brain. Muscle biopsy of the propositus revealed some changes suggestive of "ragged-red" myopathy. The heterogeneity of disease and the inheritance pattern in this family suggests that general susceptibility to neurological disease is a genetic trait.


Myoclonus in Alzheimer disease. A confusing sign. Myoclonus in association with dementia of later adult life has been considered almost pathognomonic of Creutzfeldt-Jakob disease. However, myoclonus may also be seen with Alzheimer disease, and when the myoclonus occurs as an early manifestation of Alzheimer disease, distinction from Creutzfeldt-Jakob disease may prove difficult.


The properties of four dental cements.

The properties of four dental cements. Tests on 4 cements showed no significant difference in the retentive property of zinc phosphate and polycarboxylate cements but significant differences existed between these and two zinc oxide eugenol (modified) materials. Polycarboxylate cement was the only material which fractured partially or wholly within the cement film and the zinc oxide eugenol modifications mostly adhered to the inlay.


Bases for gold inlays and crown restorations. Modified zinc oxide-eugenol and calcium hydroxide cements are frequently used as bases beneath restorations. Investigation reveals that the bond strength between different types of dement may be less than that between different consistencies of the same type of dental cement. In some clinical situations, the choice of the type of cement as a base forming material beneath inlays and crowns should be made bearing in mind the type of luting material to be used.


Turkey meningo-encephalitis: a general review. Turkey meningo-encephalitis (TME), a neuro-paralytic disease of the adult turkey caused by an Arbovirus, was described in 1960 in Israel, and not yet reported elsewhere. The seasonal outbreaks caused a high morbidity and a mortality up to 80%. A tendency toward spread has been found in the last two years. The TME virus was attenuated sucessfully by adapting it to a new host, the Japanese quail, and a vaccine prepared with this attenuated virus is effective in immunizing turkeys to the disease.


Efficacy of pralidoxime iodide and obidoxime dichloride as antidotes in diazinon-poisoned goslings. The antidotal efficacy of pralidoxime iodide and obidoxime dichloride was investigated in goslings poisoned by a supralethal dose of the organophosphorus insecticide diazinon. Various doses of both drugs were administered by intramuscular injection when the poisoned birds were unable to walk. Pralidoxime at 100 mg/kg brought about a complete and speedy clinical recovery. Fifty mg/kg induced recovery in 4 of 6 poisoned goslings, and 25 mg/kg successfully trated only 1 of 6 birds. Obidoxime at 25 mg/kg showed no therapeutic properties whereas 50 and 100 mg/kg delayed the death of some birds by several hours. At 100 mg/kg, all goslings had transient signs of intoxication, which precluded the use of this compound as an antidote at higher doses. The mode of action of these antidotes in diazinon-poisoned goslings is discussed.


Double blind trial of L-dopa in chronic schizophrenia. A double blind study in 28 patients with chronic schizophrenia was carried out comparing L-dopa (up to 1250 mgm daily) with placebo (both groups continuing to receive regular neuroleptic medication) over a six week period. Assessments by the psychiatrists and psychologist using Rockland and Pollin Rating Scale showed differential improvement of insignificant proportions but the nurse's ratings showed clearly significant improvement in the subject group.


A clinical trial of electrosleep therapy with a psychiatric inpatient sample. The study assessed the effectiveness of electrosleep therapy in the treatment of depression, anxiety, and sleep difficulties in a small, heterogenous sample of psychiatric inpatients. A double-blind format was employed, one group receiving active treatment while the other received simulated treatment. The results showed active electrosleep to be no better than placebo in bettering quality of sleep or in lessening symptoms of depression or anxiety.


Isolation of Yersinia (Pasteurella) pseudotuberculosis from the Palm dove (Streptopelia senegalensis). Yersinia pseudotuberculosis was isolated from a sick Palm dove (Streptopelia senegalensis) picked up near a turkey farm in Nir-Banim, Israel. Clean birds and a guinea pig inoculated with the isolate died of the infection, or were killed in extremis. Y. pseudotuberculosis showing the same cultural characteristics as the original isolate was recovered from these animals. This is the first reported case of this infection from Israel.


Chicken dermatitis and loss of feathers from Candida albicans. An epidemic of dermatitis affecting the skin of the back and thighs of chickens in Israel is described. The causal organism was shown to be Candida albicans.


Air operations and circadian performance rhythms. This paper reviews experimental results and pertinent data from the literature on circadian behavioural rhythms and their modifications through various factors. It relates them to the operation of aircrews "round the clock" and on transmeridian routes and discusses some possibilities of an appropriate scheduling.


Heat stroke: a review.

Heat stroke: a review. Heat stroke is a complex clinical picture caused by extreme elevation of body temperature and is especially prevalent in hot climates. The danger of heat stroke has apparently always accompanied unacclimatized man on his way through arid zones, and was often the cause of man's fatal adventures in the desert. Large numbers of unacclimatized urban dwellers have suffered when the urban areas have been involved in heat waves. Heat stroke has also been a major problem in hot industrial environments. This paper is a review of pertinent literature on this subject.


Conversion of pepsinogen into pepsin is not a one-step process. By incubation of pepsinogen with pepstatin at pH2.5, the first 'active' protein generated on activation is trapped in an inactive complex. The first activation peptide liberated has been identified as residues 1-16 from the pepsinogen sequence. This suggests a sequential mechanism rather than a one-step formation of pepsin.


Editorial: Electrical activity and excitation-contraction coupling in mammalian ventricular muscle. The modern view of the mammalian ventricular action potential is that Na-ions are responsible for depolarization, the plateau is maintained by an inward Ca current and repolarization is due to the inactivation of this inward Ca current against a background outward K current. The electrical activity spreads over the surface and T-tubules of the cell and the inflow of Ca-ions, and possibly also the electrical signal, cause, a further release of Ca from internal stores, the lateral cisternae of the sarcoplasmic reticulum (SR). This released Ca, by triggering the splitting of ATP, induces contraction. The released Ca is pumped back into the longitudinal SR and, as the Ca concentration is reduced, relaxation occurs. The Ca in the longitudinal SR is transported back to the storage site in the cisternae. This completes the cycle, release, uptake, transport back to the releasing site. On the basis of this scheme, the action of various drugs is briefly discussed.


Substrate-binding ability of Escherichia coli ribonucleic acid polymerase in relation to its protein composition. Interaction between Escherichia coli RNA polymerase and its substrates, the nucleoside triphosphates, was studied by gel-filtration and dialysis-rate-measurement techniques. 2. The holoenzyme bound variable amounts of ATP and GTP. There was no correlation between substrate-binding ability and enzyme activity of different enzyme preparations. 3. The core enzyme bound a maximum of 0.1 mol of ATP/mol of enzyme. The dissociation constant of this interaction was of the order of 1 X 10(-5)M. The core enzyme did not bind GTP. 4. A protein of mol.wt. 60000, which was eluted in the first fraction during phosphocellulose column chromatography of the holoenzyme, bound appreciable amounts of ATP. The dissociation constant of this interaction was of the order of 3 X 10(-5)-5 X 10(-6)M. 5. Evidence presented shows that this protein, and not the sigma factor, is responsible for the observed variation in the ATP-binding ability of the holoenzyme.


Analysis of enzyme induction in bacteria. The theoretical relations between the induced initiation and accumulation of lac mRNA and its translation are derived, taking the kinetics of repressor-operator dissociation and enzyme maturation into account. These relations are used to evaluate observed data on lac induction and to estimate a number of parameters that characterize the transcription and translation of the beta-galactosidase gene in the bacterium Escherichia coli B/r growing at three different rates (0.7-2.1 doublings/h).


Gamma-ray spectrometry data collection and reduction by simple computing systems. The review summarizes the present state of the involvement of relatively small computing devices in the collection and processing of gamma-ray spectrum data. An economic and utilitarian point of view has been chosen with regard to data collection in order to arrive at practically valuable conclusions in terms of feasibility of possible configurations with respect to their eventual application. A unified point of view has been adopted with regard to data processing by developing an information theoretical approach on a more or less intuitive level in an attempt to remove the largest part of the virtual disparity between the several processing methods described in the literature. A synoptical introduction to the most important mathematical methods has been incorporated, together with a detailed theoretical description of the concept gamma-ray spectrum. In accordance with modern requirements, the discussions are mainly oriented towards high-resolution semiconductor detector-type spectra. The critical evaluation of the processing methods reviewed is done with respect to a set of predefined criteria. Smoothing, peak detection, peak intensity determination, overlapping peak resolving and detection and upper limits are discussed in great detail. A preferred spectrum analysis method combining powerful data reduction properties with extreme simplicity and speed of operation is suggested. The general discussion is heavily oriented towards activation analysis application, but other disciplines making use of gamma-ray spectrometry will find the material presented equally useful. Final conclusions are given pointing to future developments and shifting their centre of gravity towards improving the quality of the measurements rather than expanding the use of tedious and sophisticated mathematical techniques requiring the limits of available computational power.


[Electrophoretic mobility of peripheral lymphocytes and Hodgkin's erythrocytes. Correlation with some clinical, hematological and immunological parameters of the disease]. In 32 patients with Hodgkin's disease the electrophoretic mobility of peripheral blood lymphocytes and, at the same time, some clinical, hematological, and immunological parameters of the disease were determined. The mean mobility of lymphocytes was normal; nevertheless, the lymphocytic mobility of 8/32 patients was significantly decreased. No correlation with clinical, hematological, and immunological parameters of the disease was detected. However, the functional deficiency of hodgkinian T lymphocytes seems to play a  role in their abnormal electrophoretic behaviour. In 9 out of these 32 patients the electrophoretic mobility of peripheral erythrocytes was also determined. The average mobility was significantly (P less than 0.05) decreased. No correlation with clinical, hematological, and immunological parameters nor with electrophoretic mobility of lymphocytes was detected.


Effects of E. coli O 127 endotoxin on regenerating rat liver. The Authors investigated the effect produced by endotoxin upon regenerating rat liver. The animals were divided into three groups after hepatectomy. The first group of animals received physiological solution, the second group received 0.5 mg of E. coli endotoxin soon after hepatectomy and the last group received the same quantity of endotoxin 22 hours after hepatectomy. To estimate hepatic regeneration we used: percentage of liver regeneration and mitotic activity. It was noted that the percentage of hepatic regeneration and mitotic activity were higher in the two groups of treated animals than in the control group. Mitotic activity and hepatic regeneration were higher in the animals treated 22 hours after hepatectomy than in the animls of second group. These results lead us to conclude that E. coli O 127 endotoxin is mitogenic also in vivo.


[Immunopathology of nephropathy secondary to anaphylactoid purpura]. With the purpose of contributing to the study of the pathogenesis of the nephropathy of anaphylactoid purpura (NPA), investigation was made of the presence and extension of immunoglobuline deposits, complement factors and fibrinogen in renal biopsies of 15 patients with NPA, correlating the findings with glomerular lesions seen at the light microscope. Fibrin and IgA deposits were found in all biopsies in mesangium, while C3 was detected only in 5 cases with potentially progressive lesions: 3 with PEEF, one with PEED and one with MP, being negative in PSF and PE cases, which are potentially reversible. The extension of deposits was diffuse or segmentary, without the existence of a precise correlation with the different morphological types. It is concluded that the immunopathologic pattern found in NPA is quite characteristics, different from that of postinfectious acute glomerulonephritis and that there seems to exist relation between findings of C3 with progression of the glomerular lesion.


[Simplification of methods for the study of beta hemolytic Streptococcus in faryngeal exudate]. A procedure of possible epidemiological application is described. The material is taken from pharynx in infants in an attempt to control the serious problem of rheumatic fever in our environment. The investigation is carried out in two steps: in the first, the samples are inoculated in a selective medium impregnated in filter paper strips, from where they are transferred to blood agar plates where 15 to 20 inoculations may be practiced; with this, unnecessary waste of individual plates is avoided, as done following conventional methods. The equipment may be easily adapted for direct takings.


Prediction of inspired oxygen concentration within a circle anaesthetic system. Fresh gas flows of nitrous oxide, oxygen and halothane at 6, 3, 2 and 1 litre/min were introduced into a circle absorber system. Spontaneous respiration and IPPV were studied and a regression of inspired on delivered oxygen concentration % was calculated. The difference between delivered and inspired oxygen concentration % was increased by decreasing the fresh gas flow and by decreasiing the proportion of oxygen in that flow, especially during IPPV. Circuits designed to allow a maximum overflow of alveolar gas provided a greater inspired oxygen concentration. The patients' height and weight were related to the scatter of inspired values observed at 1 litre/min of fresh gas flow with IPPV.


Immunogenicity of a rat leukaemia of spontaneous origin (SAL). The SAL rat leukaemia, which resembles acute myeloblastic leukaemia, appeared initially to be non-immunogenic since resistance to an i.p. challenge with as few as 100 cells could not be obtained using stimulation of the RES or by immunization with SAL cells exposed to x-rays, nitrogen mustard, iodoacetate or glutaraldehyde. However, immunization with SAL cells exposed to low doses of mitomycin-C slowed the growth of the challenge inoculum. Cells treated with high doses of mitomycin-C did not immunize. The results are interpreted in terms of rapid shedding of a tumour-specific antigen from the membrane of SAL cells.


Cross reactivity of an alloantigen present on normal cells with the tumour-specific transplantation-type antigen of the acute myeloid leukaemia (SAL) of rats. Resistance can be induced in the syngeneic host (August rats) to a myelogeneous leukaemia of spontaneous origin, called SAL, by immunization with allogeneic cells derived form both normal and malignant tissues obtained from the Hooded rat strain. Serological experiments support the conclusion that the antigen involved-referred to as "Ho-SAL"-has the properties of a tumour specific transplantation-type antigen for SAL cells but is a widely expressed alloantigen found in both normal and malignant cells derived from Hooded rats. Antisera to it can be raised in Wistar rats.


Smooth muscle associated antigen in astrocytes and astrocytomata. Four human and 4 rat astrocytomata and mammalian adult brain and spinal cord were examined by indirect immunofluorescence with human serum containing smooth muscle antibody. Cryostat sections of astrocytomata showed staining of the tumour cell cytoplasm and processes while in normal adult brain and spinal cord the entire astrocyte stained. Impression film and tissue culture monolayers of astrocytomata showed staining of cell processes and a fine, filamentous network in the cell body. The reaction with astrocytoma tumour cells was stronger than that with the corresponding normal astrocytes. Specificity of the staining reaction was established by its prevention on neutralization absorptions of the serum with extracts or homogeneous of smooth muscle. The presence of smooth muscle-associated antigen in astrocytes and astrocytomata is indicative of contractile protein providing a mechanism of cell movement in vivo.


Pancreatic ischaemia; sensitivity and reversibility of the changes. In the rat, pancreatic clamping producing warm ischaemic times ranging from 5 to 90 min gives rise to changes similar to those of an haemorrhagic pancreatitis. The severity of the changes is proportional to the time of ischaemia. After 1 to 1 1/2 h clamping 95 per cent of the glandular changes are reversible, and at 2 months the pancreas appears normal apart from localized areas of fibrosis. The islets of Langerhans remain morphologically normal even after 90 min ischaemia. The implications for islet cell transplantation are discussed.


Investigation of the effect of K antigen in Escherichia coli urinary tract infections by use of a mouse model. Urinary infection could be produced in mice by the inoculation of Escherichia coli into the bladder, provided that sutures had first been inserted into the bladder wall to act as foreign bodies. While the bladder was almost always infected, thekidneys were involved less often. The frequency of kidney infection was directly proportional to the K antigen of the infecting strain of E. coli. The significance of K antigens in relation to host defence mechanisms and tissue invasion is discussed.


The effect of cytotoxic drugs on neutrophil phagocytosis in vitro and in patients with acute myelogenous leukaemia. The in vitro effects of a range of concentrations of cyclophosphamide, doxorubicin, actinomycin D, cytarabine and methotrexate on neutrophil phagocytosis of C. albicans was studied. The reduction in phagocytic index (PI) was inversely proportional to the dilution of the drug and there was some inhibition of phagocytosis at all dilutions of all drugs. In patients with acute myelogenous leukaemia (AML), in vivo experiments showed that remission chemotherapy of doxorubicin or daunorubicin together with cytosine arabinoside increasingly inhibited phagocytosis over the period studied. The importance of these findings in the chemotherapy of malignant disease and the possible mode of action of cytotoxic drugs are discussed.


Toward an understanding of the formylation of initiator tRNA methionine in prokaryotic protein synthesis. I. In vitro studies of the 30S and 70S ribosomal-tRNA complex. Formation of the 30S-tRNA initiation complex of Escherichia coli with nonformylated initiator tRNA is stimulated by all three initiation factors and is messenger dependent, whereas the complex formation involving the 70S ribosomes is strongly inhibited by initiation factors when the nonformylated species is used. When the 30S-Met-tRNAfMet complex is first formed and the 50S ribosomal subunit added subsequently, there is no significant inhibition by initiation factors and the nonformylated initiator tRNA is puromycin reactive. This leads to the conclusion that the formylation of the methionyl initator tRNA is only obligatory when polypeptide synthesis is initiated by nondissociated 70S ribosomes.


Toward an understanding of the formylation of initiator tRNA methionine in prokaryotic protein synthesis. II. A two-state model for the 70S ribosome. The 70S ribosomes can select the proper initiator tRNA between Met-tRNAfMet and fMet-tRNAfMet. Experiments on binding and on formation of aminoacylpuromycin, as a function of magnesium, potassium, or initiation factors, suggest a two-state equilibrium for 70S particles, involving a minor, active conformation and a major one which is not readily active. The formyl group would act as a specific trigger to select the active conformation. Experimental results are interpreted following this simple model and equilibrium parameters, together with kinetic constants of the peptidyltransferase activity, are presented.


Incorporation of noncomplementary nucleotides at high frequencies by ribodeoxyvirus DNA polymerases and Escherichia coli DNA polymerase I. The fidelity of DNA synthesis with synthetic homopolymer templates by two ribodeoxyvirus DNA polymerases and E. coli DNA polymerase I was examined by nearest neighbor frequency analyses. The experiments were designed to favor the incorporation of noncomplementary nucleotides, and the reactions were carried out only for short periods of time. All incorporations were template dependent. The frequency of incorporation of noncomplementary nucleotides next to complementary nucleotides by all three of these DNA polymerases significantly varied, depending on the conditions, from almost none (less than 0.2%) to 100% of the incorporation of the complementary nucleotide. In general, there was more incorporation of noncomplementary nucleotides in the presence of Mn2+ than in the presence of Mg2+ and with ribohomopolymer templates than with deoxyribohomopolymer templates. With a heteropolymer RNA template, the infidelity of DNA synthesis by one of the ribodeoxyvirus DNA polymerases was also increased by the presence of Mn2+ in the DNA synthesizing reaction. These findings indicate that, under appropriate conditions, any DNA polymerase has the potential to make a significatn number of errors in DNA synthesis and that altered conditions for DNA polymerase action might play a role in spontaneous mutation.


The effect of cations and membrane permeability modifying agents on the dark kinetics of the photoelectric response in isolated chloroplasts. The kinetics of the photoelectric response induced by saturating light pulses were studied in isolated chloroplasts of Peperomia metallica as a function of K+- and Mg2+-concentrations in the medium in the absence and presence of ionophores for K+ and divalent cations. The dark decay of the potential generated in the light is found to be accelerated upon an increase in K+- or Mg2+-concentrations in the presence of valinomycin and A23187. An acceleration of the decay phase in the flash-induced response is also observed immediately after preillumination of the chloroplast. It is concluded that the dark kinetics of the potential decay after short and long light exposures are controlled by two different processes with rate constants of about 20 and 0.2s-1, respectively.


Characterization of a replication mutant of the bacteriocinogenic plasmid Clo DF13. In a previous paper (Kool, A.J. and Nijkamp, H.J.J. (1974) J. Bacteriol. 120, 569--578) the isolation of a mutant of the bacteriocinogenic plasmid Clo DF13-Rep3, has been described. It was observed that cells harbouring the wild type plasmid synthesize more plasmid DNA cells harbouring the wild type plasmid. This paper deals with the characterization of the nature of this plasmid-specific mutation. The following properties of the Clo DF13-Rep3 mutant plasmid could be observed: 1. The plasmid-specific mutation did not lead to a significant change in the sedimentation value of Clo DF13 DNA. 2. The specific rate of Clo DF13-Rep3 DNA synthesis (expressed as the number of plasmid DNA molecules synthesized per min) is on average seven times the specific rate of wild type Clo DF13 DNA synthesis. 3. Also chromosomeless minicells, harbouring the Clo DF 13-Rep 3 plasmid, contain about seven times more plasmid DNA as wild type Clo DF13 harbouring minicells. 4. The replication time of the Clo DF13-Rep3 plasmid is approx. 90 s at 30 degrees C and does not differ significantly from the replication time of the wild type plasmid. 5. The Rep3 mutation did not alter the dependence of Clo DF13 plasmid replication on the dnaA and dnaC gene products. 6. The plasmid-specific mutation is cis-dominant over wild type. The data presented in this paper indicate that this mutant plasmid is not affected in the elongation but in the initiation of plasmid DNA replication.


Methylated nucleosides in polyadenylate-containing yeast messenger ribonucleic acid. Yeast messenger RNA was found to be methylated. A calculation of the specific methylation showed that the average yeast messenger RNA molecule contains only two methylated nucleosides which occur in one alkali stable oligonucleotide. Similar to other eukaryotic messengers, the 5' terminus of yeast messenger RNA is blocked by 7-methylguanosine, linked through a di- or triphosphate bridge to a ribosemethylated nucleoside. Contrary to the messengers of high eucaryotic organisms, no additional base methylated constituents were found.


Regulation of nitrate reductase at the transcriptional and translational levels in Escherichia coli. Nitrate reductase from Escherichia coli is induced by nitrate and derepressed by oxygen removal after a lag phase. Elimination of inducer, shift to aerobic conditions and addition of actinomycin D causes the decline in the rate of its synthesis, which eventually may stop. Kinetic analysis of the sensitivity of the biosynthetic process to oxygen, chloramphenicol, actinomycin D and rifampicin gave results which we interprete as evidence that oxygen (and possibly nitrate) affect simultaneously both the transcriptional and translational processes.


Kinetic processes in Escherichia coli membranes and cells. A laser photolysis study using derivatives of pyrene. Pyrene and several derivatives of pyrene are used to investigate photo-induced kinetic processes in whole cells and membranes extracted from Escherichia coli. A mutant of E. coli was used which, under appropriate growth conditions, produced a complete or incomplete lipopolysaccharide in the outer membrane. The pyrene derivatives used were: pyrene sulfonic acid, pyrene butyric acid and the ester of pyrene butyric acid and 10-hydroxydecanoic acid. The pyrene chromophore was excited by the ultraviolet pulse from a Q switch, frequency-doubled, ruby laser. The lifetimes of the pyrene fluorescence in the presence of the quenchers O2, thallous ion (T1+), I-and CH3NO2 were measured and tabulated as second order rate constants. For the most part the quenching rate constants were much lower than the corresponding values observed in simple nonviscous solution, e.g. ethanol. This is interpreted as being due to the location of the probe within the membrane. The membrane inhibits the movement of the quenchers to the excited state. Cell membranes containing complete lipopolysaccharide showed significantly lower quenching rates for the probes pyrene and pyrene sulfonic acid than cell membranes with incomplete lipopolysaccharide. From an amalysis of the kinetic data it is suggested that pyrene and pyrene sulfonic acid are located near and under lipopolysaccharide and close to membrane proteins. On the other hand, no effect of lipopolysaccharide composition was observed for the probes pyrene butyric acid and pyrene butyroyl decanoic acid. This may suggest that these probes are located primarily in the lipid part of the membrane. A simple model for the outer membrane of E. coli is suggested that accounts for the observed laser-induced kinetic processes.


The altered fibrous form of vitreous collagen following solubilization with pepsin. Collagen occurs in the extracellular matrix of the bovine vitreous as fibers which have a fairly uniform diameter of approximately 195 A and exhibit an indistinct axial periodicity. Following treatment with pepsin approximately three quarters of the collagen was rendered soluble and by gel electrophoresis and comparison with calf skin collagen was shown to be composed of alpha1 chains, a high molecular weight alpha chain component, beta, as well as other high order components. No alpha2 chains were detected. The amino acid composition of the pepsin soluble collagen was different from that of other collagens composed only of alpha1 chains which suggests that it is composed of either a distinct type or mixture of alpha chains. When fibers were reconstituted from the pepsin solubilized collagen they differed markedly from the native fibers and exhibited a pronounced axial periodicity (approximately 640 A) and had diameters up to 1500 A. The difference between the reconstituted and native fibers suggests that the presence of the peptides cleaved by pepsin may be one of the factors which determines the particular fibrous form of collagen in the bovine vitreous.


Amino acid sequence homology in 30 S ribosomal protein S19 from Bacillus stearothermophilus and Escherichia coli. The amino therminal sequence of 30 S ribosomal protein S19 from Bacillus stearothermophilus has been determined. Comparison with the corresponding ribosomal protein from Escherichia coli reveals substantial sequence homology in the first thirty residues and provides further evidence for conservation of genetic information which specifies the primary structure of ribosomal proteins in these taxonomically dissimilar organisms.


Membrane-associated reactions in ubiquinone biosynthesis. 2-Octaprenyl-3-methyl-5-hydroxy-6-methoxy-1,4-benzoquinone methyltransferase. The O-methylation of 2-octaprenyl-3-methyl-5-hydroxy-6-methoxy-1,4-benzoquinone, which has been previously postulated to be the final reaction in the biosynthesis of ubiquinone was demonstrated in vitro using cell extracts of Escherichia coli. S-Adenosyl-L-methionine was active as the methyl donor for the reaction. The enzyme concerned, S-adenosyl-L-methionine: 2-octaprenyl-3-methyl-5-hydroxy-6-methoxy-1,4-benzoquinone-O-methyltransferase, was partially purified and shown to have a molecular weight of about 50 000 and to require a divalent metal and dithiothreitol for optimal activity in vitro. The methyltransferase was absent from extracts from ubiG- mutants suggesting that the ubiG gene is the structural gene coding for the methyltransferase. The enzyme, although not firmly membrane-bound, showed some affinity for the cell membrane in broken cell preparations and could utilize the benzoquinone substrate when the latter was free or bound to the cell membrane, with about equal efficiency. It is concluded that in vivo, the methyltransferase reaction probably occurs at the internal surface of the cytoplasmic membrane.


A gene controlling the synthesis of non specific alkaline phosphatase in Saccharomyces cerevisiae. Recessive mutants defective in the formation of non-specific alkaline phosphatase (EC 3.1.3.1) could be selected by staining colonies on a plate with p-nitrophenylphosphate after treatment with chloroform vapour. Since no complementation was observed among the nine mutants so far tested, all the mutations might occur in the same locus, phoH. The non-specific alkaline phosphatase was repressible, although a significant basal level of the enzyme activity was observed in the repressed condition.


Uridine phosphorylase from Escherichia coli. Kinetic properties and mechanism. Type I and Type II uridine phosphorylases (uridine: orthophosphate ribosyltransferase EC 2.4.2.3) are distinguished by their pH optima (Krenitsky et al. (1965) J. Biol. Chem. 240, 1281-1286). A Type I enzyme was partially purified from Escherichia coli. The crossing pattern of the initial velocity analysis indicated that the catalytic mechanism involved the sequential addition of substrates to the enzyme. Product inhibition by uracil or by ribose 1-phosphate was linear competitive with uridine or with concentrations of phosphate below 3 mM. This indicated that the sequence of substrate addition was random rather than ordered. At concentrations of phosphate above 3 mM, product inhibition by uracil was complex. The random mechanism of this Type I enzyme contrasts with the ordered mechanism of a Type II enzyme from rat liver (Kraut, A. and Yamada, E.W. (1971) J. Biol. Chem. 246, 2021-2030).


Release of certain ribosomal proteins from 70-S Escherichia coli ribosomes by mild ribonuclease digestion. A method for the release of some proteins from Escherichia coli (MRE 600)ribosomes is described, avoiding extraction with denaturing reagents. High-salt-washed, 70-S ribosomes were treated with pancreatic ribonuclease which led to the release of 12 proteins of the larger ribosomal subunit. Separation of released protein was first attempted by gel filtration and by fractionation with (NH4)2SO4. The number and type of the released proteins were identified by sodium dodecyl sulphate-polyacrylamide gels and two-dimensional gel electrophoresis. The method should prove of use in the large scale purification of proteins L1, L7, and L25.


Outer membrane of Salmonella typhimurium. Transmembrane diffusion of some hydrophobic substances. The outer membrane, which is composed of lipopolysaccharide, phospholipids, and proteins, is a layer of the cell wall of Gram-negative bacteria, and apparently acts as a penetration barrier for various substances. It had been shown by other workers that "deep rough" mutants of Salmonella typhimurium, whose lipopolysaccharides lack most of the saccharide chains, were much more sensitive than the wild type strain to certain antibiotics and dyes, but not to others. We found that the former group of agents are usually hydrophobic and the latter group mostly hydrophilic. All hydrophilic antibiotics had molecular weights lower than 650, and one of them was shown to diffuse through the outer membrane of 0 degrees C. In contrast, some hydrophobic antibiotics had molecular weights in excess of 1200, and the rate of diffusion of one of them was shown to be extremely dependent both on temperature and on the structure of lipopolysaccharide present. These data and results presented elsewhere suggest, but do not necessarily prove, that most hydrophilic antibiotics diffuse through aqueous pores, whereas hydrophobic antibiotics and dyes mainly penetrate by dissolving into the hydrocarbon interior of the out membrane. In contrast to the outer membrane of deep rough mutants, that of the wild type strain and less defective rough mutants was unusual among biological membranes in that it was practically impermeable to hydrophiobic agents. It is proposed that the difference in hydrophobic permeability between the two types of strains is due to radical differences in the organization of the outer membrane, more specifically to the presence or absence of exposed phospholipid bilayer regions.


Preparation of erythrocyte ghosts by a glycol-induced osmotic lysis under isoionic conditions. A procedure has been developed for obtaining haemoglobin-free, erythrocyte ghosts under ionic conditions approximating that of the cell cytoplasm. Haemolysis was effected by incorporating glycol into cells suspended in the isoionic medium and then diluting with a large volume of glycol-free medium. The ghosts were of uniform spherical shape throughout the preparative procedure and were impermeable to macromolecules. Analysis of polypeptides by sodium dodecyl sulphate-gel electrophoresis at each stage of preparation and comparison with ghosts prepared under hypo-ionic conditions served to distinguish membrane components from those of cytoplasm.


Neutron scattering for the analysis of membranes. The advantageous use of neutron scattering techniques for the determination of membrane structures is described. Constituents of biological membranes show much larger differences in their scattering factors for neutrons than for X-rays, permitting the assignment of chemical groups to features in the Fourier map. Deuteration of particular components further enhances this difference and can be used to phase neutron data similar to the heavy atom technique of protein crystallography. Methods of contrast enhancement using H2O and 2H2O exchange, as well as secific deuterations, are outlined with examples from studies of sciatic nerve myelin artificial membranes and retinal rod outer segments.


Selenium and cancer: a review.

Selenium and cancer: a review. The essential trace element selenium retards the growth of certain chemically induced tumors in animals. The addition of subtoxic amounts of this element in form of selenite to the supply water lowers the incidence of spontaneous mammary tumors in female C3H mice significantly without affecting the health and life-span of the animals. Arsenic, a selenium antagonist, administered in form of arsenite in the supply water, also lowers the tumor incidence at dosage levels of 10 ppm, but those animals which develop spontaneous mammary tumors under these conditions demonstrate dramatically enhanced tumor growth rates. The results of initial epidemiological studies suggest that the human cancer mortality is lower in areas providing an adequate dietary intake of selenium as estimated from the selenium content in grains and forage crops in various regions of the United States, or the dietary selenium intakes as calculated from food consumption data in various countries.


Comparative study of the 16S RNA's of Escherichia coli and Proteus vulgaris. We have studied the primary structure of 16S ribosomal RNA from Proteus vulgaris. The oligonucleotides containing methylated bases appeared to be the same as those of Escherichia coli, with one exception. We have also studied the base composition of the oligonucleotides obtained after T1 ribonuclease digestion of 16S RNA. On the basis both of their position on the fingerprint and of their pancreatic ribonuclease analyses, approximately 25 appeared to differ from those found in the E. coli T1 fingerprints. From the isolation of large fragments arising from the action of endogeneous endonucleases, we have concluded that the RNA sequences of both species are very similar. We have shown that the 5' and 3' extremities of 16S RNA are mostly conserved. It appears that the regions which are known to interact with ribosomal proteins in E. coli (particularly S8 and S15) are also less modified. It is noteworthy that the sequence modifications which have been observed are clustered and often correspond to regions of heterogeneity in E. coli 16S RNA.


Sequence studies on the 5S RNA of Proteus vulgaris: comparison with 5S RNA of Escherichia coli. We have studied the sequence of 5S ribosomal RNA of Proteus vulgaris. Although several doubts remain, it seems that no more than 8 per cent of the nucleotides differ from those of Escherichia coli 5S RNA. Of the ten bases differing from Escherichia coli 5S RNA sequence, three changes take place in one of the six positions which are known as intercistronic mutation points in Escherichia coli 5S RNA. We can conclude that they are "hot spots" of mutation.


Development of bacteriophage Ha2, a phiX174 derivative,  in Escherichia coli strains carrying a thermosensitive mutation in the dnaG gene. Ha2 is a derivative of HaHb, a phiX174 mutant able to grow on several Escherichia coli K 12 strains which are insensitive to phiX174 wild type. Ha2 was isolated after nitrous acid mutagenesis and selected as being able to give large plaques in equal number at 42 degrees C as well as 30 degrees C when plated on Escherichia coli C and CR34. Hosts carrying a thermosensitive mutation at the dnaG locus are unable to support the replication and maturation of Ha2 at the restrictive temperature. The first steps of Ha2 development: attachment, eclipse and penetration, are not affected by the dnaG mutation. The viral DNA penetrates the cell as single-strands, which are probably attached to a viral protein component. The following steps of viral replication depend on the presence of an active dnaG gene product: no formation of parental RF; no synthesis and replication of progeny RF were observed in the mutant strains at 42 degrees C. The synthesis of viral single-stranded DNA as well as phage formation are lowered after a shift to the restrictive conditions, suggesting that the dnaG gene product is also involved at these stages.


Rearrangement of mitochondrial DNA molecules during the differentiation of mitochondria in yeast. I.-Electron microscopic studies of size and shape. Size and shape of purified mitochondrial DNA was analyzed by electron microscopy as a function of mitochondrial differentiation. The mitochondrial DNA was extracted at fourth growth stages corresponding to different steps of mitochondria repression and depression. It was heterogeneous both in form and length. The size of linear molecules ranged from 1 mu to 25 mu but most of the molecules could be assigned into four Gaussian subpopulations with mean lengths of 2.2 mu to 4.0 mu, 6.0 mu and 10.0 mu. The circular molecules were all open and sized varied from 0.5 mu to 10 mu. Their length repartition was congruent with a logarithmic Gaussian distribution. The relative proportion of the different classes of molecules changed according to the stage of the growth cycle: during the repression most of the mitochondrial DNA molecules were short: the population of 2.2 mu was predominant. The longest linear molecules were observed during derepression where the populations of 4.0 mu and 10.0 mu were only found as well as the highest proportion of circular molecules. At the stationary phase the mitochondrial DNA became short again and the circles disappeared completely. The mitochondrial DNA extracted from a cytoplasmic "petite" was composed of linear and circular molecules. The linear molecules ranged from 0.1 mu to 32 mu and most of them could be assigned to two subpopulations of 1.3 mu and 4.2 mu. The circular molecules which accounted for 11 percent had contour lengths of 0.7 mu and 1.5 mu. The physiological meaning of the change in the relative proportion of different classes of mitochondrial DNA is discussed.


Rearrangement of mitochondrial DNA molecules during the differentiation of mitochondria in yeast. II. - Labelling studies of the precursor product relationship. The length distribution in sucrose sedimentation gradient of the newly-synthesized pulse-labelled mitochondrial DNA has been established at an early stage of depression in wild type yeast (Saccharomyces cerevisiae). This stage corresponded to the beginning of mitochondrial differentiation. The radioactive DNA was longer (mean lengths 5, 10 and 22-25 mu) than the preexisting cold DNA (mean length 6.5 mu with two shoulders at 4 mum and 10 mum and one minor peak at 2-2.5 mum). These date confirm that the mean size of the different length populations of linear yeast mitochondrial DNA are under physiological control. Chase experiments were undertaken as follows. The yeast cells were uniformly prelabelled under anaerobiosis. Therefore the mitochondrial DNA molecules were short. Respiratory adaptation was performed in a cold medium and the lengthening process was induced. The specific activities of the long molecules made up during the respiratory adaptation did mot markedly differ from that of prelabelled DNA (decrease of specific activity less than 18 per cent). Molecules as long as 40 mum were also recorded. This lengthening seems to proceed through a non reciprocal exchange of polynucleotide stretches between preexisting molecules. We call it rearrangement. It occurs during the differentiation of mitochondria. Much of the mitochondrial DNA is maintained whereas a small amount of DNA is synthesized. This hypothesis is favoured by recent genetical and physical studies on mitochondrial recombination in yeast.


[Transamination of L-aspartate and L-phenylalanine in Escherichia coli K 12]. At least four separate enzymes are found to catalyze the transamination between phenylalanine and alpha-ketoglutarate in E. coli K 12, one of them being the aspartate aminotransferase. The Km of the latter enzyme for alpha-ketoglutarate is 0.3 or 0.035 mM according to the acceptor aminoacid being phenylalanine or aspartate respectively. The double specificity of aspartate aminotransferase in E. coli is however clearly shown by thermal inactivation studies using various effectors or different temperatures, and by the finding of an active transamination between aspartate and phenylpyruvate in the absence of ketoglutarate. This reaction shows the usual ping-pong type of mechanism, which implies that both substances are substrates for the same protein. Contrary to the phenylalanine-alpha-ketoglutarate reaction, which is probably of little importance in vivo when catalyzed by this enzyme, the direct ketoglutarate-free transamination between aspartate and the aromatic alpha-ketoacid is likely to represent a physiological function in regulating, at least partially, the balance between biosynthetic pathways for aromatic aminoacids and aspartate, for instance by maintaining similar ratios between the aminoacid and its ketoacid partner in both cases. For the sake of clarity it is proposed that the name "transaminase A", first devised by Rudman and Meister, be used for aspartate aminotransferase only, knowing that the specificity of this peculiar enzyme behaves as an accessory agent in the transamination of the aromatic compounds.


Coding origin of isoaccepting tRNA in yeast mitochondria. Valyl-, leucyl- and tyrosyl-tRNA of yeast mitochondria were fractionated by reversed phase chromatography. Each of the tRNA contained multiple isofunctional species. Some of them specifically hybridized to mitochondrial DNA from (see article) strain. These species were absent in a petite colonie mutant lacking mitochondrial DNA. Three valyl-, one leucyl- and one tyrosyl tRNA were found to be products of mitochondrial genes.


Histochemical changes in the blood cells of schizophrenic patients under pimozide treatment. Chromatin structure and nucleohistone pattern were investigated histochemically in the neutrophils of 11 schizophrenics and 16 healthy controls. Compared to controls, all schizophrenic parents prior to medication showed a distinctly different histochemical pattern consisting of increased concentration and abnormal distribution of nucleohistones. This pattern has been attributed to an increase of arginine-rich histones in schizophrenics. Pimozide administration exerted a normalizing effect on the nucleohistone distribution pattern. These findings further support our view that genomic expression abnormalities may be related to schizophrenic illness.


A new method for measuring simultaneously the phagocytic and bactericidal capacity of human leukocytes. A new technique for simultaneously measuring the phagocytic and bactericidal capacity of human leukocytes is proposed. The method uses 14C labelled bacteria and is based on the principle that only viable intra-cellular bacteria incorporate 3H-thymidine. Phagocytosis is measured by the ratio intra-cellular 14C/extra and intra-cellular 14C and the bactericidal capacity of leukocytes by the difference between the 3H-thymidine incorporation of the ingested and non-ingested bacteria. Results in normal subjects and in a case of chronic granulomatous disease show the validity of the method which is easier and quicker than the methods previously used.


Sustained oscillations and threshold phenomena in an operon control circuit. A genetic regulatory model involving a positive feedback (via induction) and a negative feedback (via catabolite repression) is analyzed and applied to the problem of the lac operon regulation in E. coli. Damped and sustained oscillations of the limit cycle type are found along with threshold phenomena corresponding to multiple limit cycles or to multiple steady states, for values of the parameters compatible with experimental data. A comparison with the observations of Knorre and Goodwin is outlined.


Factors affecting risks of congenital malformations. II. Effect of maternal diabetes on congenital malformations. The effect of maternal diabetes on the risk of congenital malformations was investigated in 23,695 pregnancies of white mothers, inclucing 339 patients of the Joslin Clinic, and in 24,742 pregnancies of Negro mothers, drawn from the prospective Collaborative Perinatal Project. Of these, 372 mothers had gestational diabetes and 567 had overt diabetes (before and during pregnancy). Pregnancy outcomes studied included stillbirths and live births. Among core women (excluding the Joslin Clinic cases), the frequencies of diabetic pregnancies were 1.31% and 1.18% for white and Negro mothers, respectively; in both groups, approximately two thirds of these pregnancies had gestational diabetes. There was no increase in malformation risk in the pregnancies of mothers with gestational diabetes over that of nondiabetic mothers in either racial group. However, the risk of malformation for white mothers with overt diabetes was double that of nondiabetic mothers for both major and minor categories of malformations. The incidences of major and minor types of malformations in the pregnancies of white mothers with overt diabetes were 17.94% and 10.94%, respectively, compared to the corresponding incidences of 8.34% and 6.25% for the white nondiabetic group. In Negro mothers with overt diabetes, a smaller increase of risk was seen only in major malformations; the incidences were 13.64% and 8.45% for the diabetic and nondiabetic groups, respectively. The increased risks for malformations were distributed generally throughout the organ systems. Multiple malformations occurred more frequently in the overt diabetic than in the nondiabetic group, suggesting that maternal diabetes must act adversely an an early stage of fetal development. Two cases with the caudal regression syndrome were observed in children of diabetic mothers, whereas none was found among births from nondiabetic mothers. Insulin (or analog) therapy of diabetes neither decreased nor increased the risk of malformation in the fetus. However, duration of diabetes had a significant effect on the malformation risk: the longer the mother had the disease, the higher was the incidence of malformations in the fetus. Paternal diabetes did not contribute to increase in risk. These observations suggest that maternal diabetes per se, through its adverse effects on maternal metabolism, is the responsible factor for the increase of malformations in the offspring.


[Morphological changes in the internal organs in chronic streptococcal infection]. A histological and histochemical study was made (for a period of from 24 hours to 27 weeks) of the internal organs of albino mice after a single intraperitoneal injection of the L-forms of beta-hemolytic streptococcus, group A. The following progressive pathological process (myocarditis, hepatitis, pyelonephritis) developed against an intense allergic background with a resultant systemic lesion of the tissues.


[Algorithm for distinction of EEG tracings by means of a computer]. The authors describe machine algorhythm for the drawing of two-dimensional histograms of the EEG in the amplitude-wave frequency coordinates constituting a curve. EEG in its coding is presented by the extremums with the fixation of the moments of their appearance. Usefulness of the algorhythm work is confirmed by examples.


[Isolation under the influence of tetracycline of L-forms of Menchikov's vibrio and the NAG vibrio and their biological properties]. Stable L-forms were for the first time obtained under the effect of tetracycline on the Mec thnikov vibrio and NAG vibrio. The process of conversion of the L-forms under the effect of tetracycline was the same as under the action of penicilline. Three types of the L-forms were obtained: stable tetracycline-resistant L-forms, stable tetracyclin-superresistant and tetracycline-dependent L-forms. Under the reversion of the unstable L-forms strains with a typical complex of biological properties and atypical revertants were obtained.


Chediak-Higashi syndrome: reversal of increased susceptibility to infection by bone marrow transplantation. Transplantation of normal bone marrow to mice with the Chediak-Higashi syndrome (CHS) resulted in normal granulopoiesis and a reversal of their increased susceptibility to challenge with intravenous Candida albicans. These findings suggest that (1) the leukocyte defect in CHS can be reversed by marrow transplantation and (2) the mechanism for increased susceptibility to infection in these animals is due to a bone-marrow-derived cellular defect. Because of similarities between murine and human CHS, bone marrow transplantation might be considered as a mode of therapy in selected cases of the human disease.


Treatment of advanced non-Hodgkin's lymphomas with favorable histologies: preliminary results of a prospective trial. From July 1971 to August 1975, 63 previously untreated patients with stage IV non-Hodgkin's lymphomas with favorable histologies were prospectively randomized to three treatment programs: cyclophosphamide, vincristine, and prednisone alone (CVP); split course CVP and total lymphoid irradiation (CVP-TLI); or single alkylating agent (SA) therapy. More than 95% of all patients responded to therapy, and pathologically documented complete remissions were achieved in 78.3% of CV, 65% OF CVP-TLI, and 55% of SA patients (p greater greater than 0.2). The actuarial probability of obtaining a complete remission was the same (greater than 80%) for SA patients as it was for those receiving CV or CVP-TLI, but the time required to achieve a complete remission was more prolonged for SA patients (up to 40 mo). Only six (14.3%) complete responders have relapsed; the others have remained relapse-free for periods of 1-35 mo. There have been no statistically significant differences noted among the groups in terms of the probability of disease-free survival or survival, and 82.7% of all patients are alive at 30 mo (84.6% CVP, 73% CVP-TLI, and 90% sa). all three treatment programs have thus been highly effective in achieving excellent responses and prolonged disease-free survivals in patients with stage IV non-Hodgkins lymphomas with favorable histologies. Over the 4-yr period of study, single agent therapy has been associated with as good or better overall survival when compared to the more aggressive treatment programs (CVP and CVP-TLI).


Specific release of neutrophillic- and eosinophilic-stimulating factors from sensitized lymphocytes. Mitogen-stimulated lymphocytes recently have been shown to release colony-stimulating activity (CSA), a stimulator of granulopoiesis in vitro. Whether CSA release is a result of specific antigen-lymphocyte interactions has been investigated by determining the ability of spleen lymphocytes isolated from Trichinella spiralis and Bacille Calmette Guerin (BCG) infected mice to release CSA. Lymphocytes were incubated with different antigens to obtain conditioned media (CM). Conditioned media prepared from Trichinella-sensitized lymphocytes incubated with Trichinella antigen (CM-1) resulted in a fourfold increase in the number of colonies from murine marrow cultured in methylcellulose as compared to controls. The addition of Trichinella antigen to either nonsensitized or BCG-sensitized lymphocytes did not stimulate CSA release. Similar results were obtained with lymphocytes from BCG-infected mice. Liquid cultures stimulated with CM resulted in an increase in 3h-thymidine incorporation and cell numbers. Using CM-1 to stimulate marrow from Trichinella-infected mice resulted in a three- to fourfold increase in the number of eosinophils present after 4 days. All other CMs tested stimulated only neutrophil production...


[Topography of the neurons producing LRF in primates]. Specifically immunoreactive perikarya have been found in the hypothalamus of normal monkeys, using antisera to synthetic LRF. These perikarya are mainly localized in the medio-basal hypothalamus. The majority of their axons form a "tubero-infundibular LRF tract", with a very complex preterminal pattern. Some specifically immunoreactive axons seem to belong to "extra-hypophyseal LRF pathways", having in part telencephalic or mesencephalic terminations.


[Evolution of the homotypic graft of the presumed cardiac area of the quail in the chick]. Employing quail cells as biological labelers, we could easily follow the evolution of the presumptive cardiac area of the quail in the chick blastoderm. If the embryos are operated on in stage 5, the cardiac area fuses completely to that of the host embryo forming a large part of the corresponding half in the definitive heart. On the other hand, in earlier stages the grafted cardiac area contributes only to the formation of island of cells in the resultant heart.


Brain concentrations of biogenic amine metabolites in acutely treated and ethanol-dependent rats. 1 Mass fragmentography was used to measure whole brain concentrations of some of the major metabolites of tyramine, octopamine, dopamine and noradrenaline in acutely treated and in ethanol-dependent rats. 2 Treatments with ethanol, either acutely or chronically, failed to alter significantly brain concentration of p-hydroxphenylacetic and p-hydroxymandelic acid (metabolites derived from tyramine and octopamine respectively). The effect on catecholamine metabolites was marked and therefore suggests that ethanol is selective in its effect on central metabolism of biogenic amines. 3 Acute ethanol treatment significantly increased brain concentration of homovanillic acid (HVA), 3,4-dihydroxyphenylacetic acid (DOPAC) and 3-methoxy-4-hydroxyphenylglycol (MHPG). Vanilmandelic acid (VMA) was not affected. All four metabolites (HVA, DOPAC, MHPG and VMA) were increased in the brains of rats rendered dependent on ethanol while still intoxicated (blood ethanol levels above 200 mg/dl). In ethanol-dependent rats undergoing ethanol withdrawal syndrome (no ethanol present in blood), the brain concentrations of HVA and DOPAC were normal while those of MHPG and VMA continued to be elevated. 4 From the decline in the concentrations of HVA and DOPAC after 50 mg pargyline/kg in control rats and rats acutely treated with ethanol, it was concluded that ethanol has no effect on the transport of phenolic acids across the blood brain barrier. 5 No reversal in the metabolism of catecholamines from an oxidative to a reductive pathway, analogous to that produced by ethanol in the periphery, could be established in the brain. 6 The increase in catecholamine metabolite concentrations after ethanol treatment, either acute or chronic, were interpreted as manifestations of increases catecholamine turnover.


Evaluating signs and symptoms: comparison of structured interview ans clinical approaches. Are research interview techniques adequate in assessing signs and symptoms? This question is investigated by obtaining two sets of interview schedule ratings on 49 patients, one by a research psychiatrist applying the interview and one by the patient's psychiatrist using all available information. The latter was considered a clinical standard with which a cross-sectional research interview could be contrasted. These two data sets were subjected to several types of analysis commonly undertaken with research interview ratings. Results indicated that the research interview adequately represents symptom data, but is seriously lacking in the assessment of observed behaviour. The effect of this difference depends on the goals of the study and the nature of the data analysis. If overall group findings are desired, or if analysis relies primarily on symptom data, results with a research interview may be similar to results based on a far more extensive evaluation. On the other hand, if conclusions are to be drawn on individual patients, or if data analysis relies heavily on observed behaviour, then data derived from research interviews are questionable.


The painful prostate.

The painful prostate. A clinical diagnosis of chronic prostatitis was made on 105 adult males who were subsequently admitted and investigated by Stamey localisation techniques, psychological questionnaires, urine flow studies, cysto-urethroscopy and prostatic biopsy or transurethral prostatectomy. From the Stamey localisation studies and cultures of the tissue obtained at transurethral prostatectomy a diagnosis of bacterial prostatitis was made in 50%, of which half were Staphylococcus albus and half were well recognised urinary pathogens. Other significant pathology was found in 25% and, particularly of note, were 2 patients who presented with chronic cystitis (biopsy negative) and subsequently developed carcinoma of the bladder. Also in this group were 5 unsuspected strictures and 5 patients with poor flow rates but normal endoscopy. Investigations in the remaining 25% were all negative except for a significantly higher incidence of neuroticism when compared with the other groups and controls.


Results of 250 consecutive cadaver kidney transplants. The results of 250 cadaver kidney transplants performed at this hospital between May 1968 and December 1974 were analysed. A functioning transplant was defined strictly as one that maintained the recipient in good health with a serum creatinine below 442 mumol/1 (5 mg/100 ml) without any need for dialysis. The proportions of kidneys functioning after one, two, and three years were 40-4%, 33-9%, and 31-1% respectively, the corresponding survival rates of patients being 62-6%, 57-4%, and 43-8%. The primary failure rate overall was 21-6%, while the failure rates for first, second, and third transplants were 18-1%, 39-9%, and 66-7% respectively. Half of the primary failures were attributed to the use of cadaver kidneys with abnormal vasculature or long ischaemic times or originating from non-ventilated donors. Of the initially successful transplants 49% were subsequently lost due to rejection (53%) or death of the patient with a functioning transplant (46%), and of the secondary losses 58% occurred within three months of transplantation. HLA matching of donor and recipient for two or more antigens was associated with a significant increase in transplant survival--46% at three years as opposed to 9-5% at three years for kidneys with poorer matches.


Streptokinase in central retinal vein occlusion: a controlled clinical trial. Forty patients with central retinal vein occlusion were allocated at random either to a treatment group given streptokinase followed by anticoagulatns or to a control group given no specific treatment. The two groups, which were each of 20 patients, were broadly similar in respect of clinical and laboratory values and similar in their initial visual acuity. At follow-up ("final" vision) the visual acuity in the treated group was significantly better than in the untreated group. Only one treated patient developed thrombotic glaucoma compared with four controls. Streptokinase may, however, have been responsible for vitreous haemorrhage (and permanent loss of vision) in three patients and hence probably has only a limited role in the treatment of central retinal vein occlusion.


Islet-cell, thyroid, and gastric autoantibodies in diabetic identical twins. Sera from 54 pairs of identical twins, 29 discordant and 25 concordant for insulin-dependent diabetes, and 11 pairs of concordant non-insulin dependent identical twins were examined for pancreatic islet-cell antibodies (ICAs). ICAs were found in 10 of the 29 diabetic discordant and eight of the 50 concordant twins (difference not significant P greater than 0-05). Six out of nine twins tested within one year of onset of diabetes were positive, whereas nine out of 29 tested after one to 10 years and three out of 41 tested after 10 years were positive. Only one of the 22 non-insulin-dependent twins had ICAs. Repeat ICA testing in five pair of insulin-dependent twins and in the siblings of one pair showed that ICAs may be present in people with normal glucose tolerance' may precede clinical diabetes by several years; and may decline in titre or disappear with increasing duration of disease. Thyroid or gastric autoantibodies, or both, were found in 36 out of 108 insulin-dependent twins and three out of 22 non-insulin dependent twins (difference not significant P less than 0-05). Only four twins had both ICAs and thyrogastric antibodies. There were no significant associations between autoantibodies and HLA histocompatibility types. As ICAs are more common in the diabetic than the non-diabetic twins of the discordant pairs they must be associated with juvenile onset diabetes. ICAs may appear some years before the onset of diabetes, but their prevalence declines with increasing duration of diabetes. The factors determining the production of ICA differ from those for thyroid and gastric autoantibodies.


T lymphocytes in kidney allograft recipients. The spontaneous sheep erythrocyte (E) rosette test was used on 340 occasions to measure T cell levels in 28 renal allograft recipients. The E rosette counts were reduced by high-dose steroids but usually returned towards normal under maintenance treatment with azathioprine and low-dose prednisone. Unexpectedly, rejection crises were more often associated with a decrease in E rosettes before steroid treatment (12 cases) than with an increase in E rosettes (5 cases). Our results show the need for caution in using the E rosette test and more generally B and T cell markers for monitoring anti-graft immunity in renal allograft recipients.


Causes of failure to harvest cadaver kidneys for transplantation. Fifty-two possible donors of cadaver kidneys were referred to the Nuffield Transplantation Surgery Unit, Edinburgh, in 12 months. Only 12 (23%) yielded kidneys, while a further 12 were medically unsuitable as donors. Refusal by relatives to allow cadaver nephrectomy was the largest avoidable loss of potentially transplantable kidneys. A similar but unavoidable loss occurred through sudden death of the possible donor.


Therapeutic experience with fludrocortisone in diabetic postural hypotension. Fourteen patients with diabetic postural hypotension were treated with fludrocortisone for a mean 12 months (range 6-30 months). The mean daily dose of fludrocortisone was 0.2 mg (range 0.1 mg-0.4 mg). Standing systolic and diastolic blood pressures increased significantly (P less than 0.001) after treatment with fludrocortisone and the postural hypotension decreased significantly (P less than 0.001). Thirteen patients noted considerable symptomatic improvement. Fludrocortisone should be used cautiously in patients with congestive cardiac failure or the nephrotic syndrome.


Role of the kidney in regulating plasma immunoreactive beta-melanocyte-stimulating hormone. An analysis of the factors that influence the increase in plasma immunoreactive beta-melanocyte-stimulating hormone (beta-MSH) concentration in chronic renal failure showed that: (a) the increase correlated with the increase in serum creatinine concentrations; (b) beta-MSH was not cleared from the plasma by haemodialysis; (c) beta-MSH concentrations increased with length of time on dialysis and increased further after bilateral nephrectomy but there was no further increase with time; (d) beta-MSH levels decreased to normal after renal transplantation; and (e) beta-MSH was excreted in urine only when plasma levels rose to well above those of chronic renal failure (in Nelson's syndrome). These findings suggest that the kidney regulated plasma beta-MSH by a non-excretory mechanism and is the major site of beta-MSH metabolism.


Demonstration of extracellular material at the surface of pathogenic T. pallidum cells. Pathogenic T. pallidum cells possess and extracellular layer when observed in vivo and in vitro after exposure to ruthenium-red. The extracellular layer is partially removed from a pre-fixed cell by repeated washing in vitro. Non-pathogenic treponemes examined in this study do not possess an extracellular layer. It is hoped that the data presented herein will cause our colleagues to take another look at the methods and techniques used for preparing pathogenic T. pallidum cells for practical end-point objectives.


Growth and subculture of pathogenic T. pallidum (Nichols strain) in BHK-21 cultured tissue cells. The growth and nine subcultivations of the experimental Nichols strain of pathogenic Treponema pallidum were successfully accomplished in cultured baby hamster kidney tissue cells (BHK-21) using serum-free media. The number (motile and non-motile cells occurring extracellulary) of cell generations generally increased with each subcultivation, the largest increases (greater than 3-0) occurring in subcultures 4, 5, 7, 8, and 9. Also, the number of motile cells decreased with each subcultivation. Virulent organisms were demonstrated in subcultures 1, 4, 5, 7, and 8, and their numbers estimated with the use of standards established by the animal inoculation titration of counted numbers of organisms freshly harvested from experimental infections; the estimated number of virulent organisms was higher than or equal to the counted cultivated treponemes injected, which may be attributable to uncounted virulent spirochaetes occurring intracellularly.


Two-day treatment of trichomoniasis in the female. Comparison of metronidazole and nimorazole. A comparison has been made of the efficiency of a 2-day course of metronidazole (Flagyl) with that of a similar course of nimorazole (Naxogin) in the treatment of trichomoniasis. Of the 105 consecutive patients treated, 72 were finally included in the study (38 on metronidazole and 34 on nimorazole). Follow-up tests indicated an overall cure rate of 84-3 per cent. in those given Flagyl and 85-3 per cent. in those given Naxogin. Consorts were treated in just over 55 per cent. of cases in both groups. An attempt has been made to classify the recurrences as either 'primary' treatment failures or re-infections. Although both drugs were effective in the majority of cases, 'primary' treatment failure appeared to be commoner in the group receiving metronidazole. It is emphasized that the total dose of metronidazole was substantially lower than that recommended by the manufacturers.


Experimental syphilis vaccines in rabbits. I. Differential protection with an adjuvant spectrum. This study shows that 1 per cent. glutaraldehyde fixation of unwashed Treponema pallidum, Nichols pathogen, preserves the integrity of the outer envelope as well as the ruthenium-red (RR) staining extracellular slime layer. Since other researchers wash their treponemal suspensions before preparing their vaccines, it is likely that the vaccine preparations used in this study contain antigens not tested elsewhere. In an attempt to eliminate the requirement of large numbers of injections to achieve any protection, the rabbits in this study were injected with glutaraldehyde-fixed T. pallidum (GFTP) only once, with or without one of a spectrum of adjuvants, and 5 months later were challenged intradermally or intratesticularly with freshly harvested pathogenic treponemes. Data of time of lesion appearance and severity of lesions reveal a differential protective effect of the various vaccine preparations when compared to the response of non-vaccinated controls. Vaccines which included phytohaemagglutinin (PHA) or alumina C gel (ALC) as adjuvants provided some degree of protection, whereas vaccines which contained the adjuvants incomplete Freund's, zymosan, complete Freund's, polyadenylic-polyuridylic acid, or no adjuvant at all produced enhanced infections. The differential protection data indicate that various portions of the immune mechanism are either suppressed or are not stimulated by T. pallidum antigens alone, but can be made to respond with a minimum of vaccine injections.


Ribosomal RNA: the message or matrix for ribosomal proteins. The known nucleotide sequence of Escherichia coli 16S ribosomal RNA has been converted to amino acid sequences in all possible ways, and compared to known ribosomal protein sequences. The degree of similarity is precisely what one would expect by chance alone, providing additional evidence that ribosomal proteins cannot be coded for by ribosomal RNA.


Relationship between ppGpp levels and rates of protein and RNA synthesis in Escherichia coli. When amino acid starvation is ended in stringent (relA+) strains of escherichia coli, the rates of RNA and protein synthesis as well as their accumulation return to normal more slowly in spoT- PSTRAIns than in the spoT+ strains. The level of ppGpp accumulated declines more slowly in the spoT- strains than in the spoT+ strains. Thus, there is an inverse relationship between ppGpp levels and the rates of RNA and protein synthesis. The slow resumption of protein synthesis in the spoT- relA+ strains could therefore be explained in terms of the limited synthesis of mRNA species coding for the bulk of cellular proteins.


The action of the ionophores, X-537A and A-23187, on smooth muscle. The cation ionophore X-537A in the concentration range of 10(-6) to 3 X 10(-5) M produced contractions in the rat and guinea-pig vas deferens. No contractile effect was produced in either of the vasa deferentia preparations by the ionophore A-23187 in the concentration range of 10(-7) to 5 X 10(-5) M. In contrast, X-537A had no contractile effect on the guinea-pig ileal longitudinal smooth muscle while A-23187 produced a dose and [Ca2+] dependent contraction. The contractile effect of X-537A in the vasa deferentia preparations is abolished by phenoxybenzamine or prior reserpine treatment and is therefore attributed to the release of norepinephrine. The effect of A-23187 in the intestinal smooth muslce is attributed to a direct Ca2+ transporting action since its contractile effect is unaffected by histamine, acetylcholine, or 5-hydroxytryptamine antagonists.


Computer-aided diagnosis of gastroenterologic diseases in Sherbrooke: preliminary report. To assess the diagnostic accuracy of a computer-aided-diagnosis system when implemented in different parts of the world, an automated system, which had established its reliability in Leeds, England, was transferred to Sherbrooke, Quebec. In this preliminary study two retrospective series, comprising 104 patients with acute abdominal pain and 101 patients with dyspepsia, were drawn from the files of the Centre Hospitalier Universitaire in Sherbrooke. The history and physical-examination sheet was analyzed, coded and tested against the Leeds data base on a WANG 2200 computer, and the results were compared with the final Sherbrooke pathologic diagnosis. Overall the computer made a correct diagnosis in 78.8% of cases of acute abdominal pain and 70% of cases of dyspepsia. Computer diagnoses of appendicitis were correct in 97% of cases and the system recognized 91% of the actual appendicitis cases. Similar figures for cholecystitis were 91% and for peptic ulcer, 87%. However, the "pick-up" rate by the computer of pancreatitis was only 25%. It is concluded that geographical differences in disease presentation will probably not impair the validity of the computer method used in this study. A comparison of various diagnostic methods and levels of competence will await a prospective trial of this method.


The buccal smear: Reassessment of its usefulness. Over a 7-year period 43 patients who underwent sex-chromatin and cytogenetic studies in the investigation of a disorder related to reproductive function were found to have abnormalities of the sex or autosomal chromosomes that could not have been detected by routine buccal smear. Therefore, testing for sex chromatin is of no value to the clinician, because full chromosome analysis must be performed irrespective of the findings from the buccal smear. However, the sex-chromatin test is an aid to the cytogeneticist in interpreting the chromosome analysis. In addition to those with amenorrhea and oligospermia or aspermia, persons with hypospadius and those to be treated with fertility drugs should undergo cytogenetic studies.


Results of a randomized study comparing DTIC with TIC mustard in malignant melanoma. This prospective randomized Eastern Cooperative Oncology Group (ECOG) study (1071) was designed to compare a new and promising cytotoxic agent TIC Mustard (triazeno imidazole carboxamide mustard, NSC 82196) with DTIC (dimethyl triazeno imidazole carboxamide, NSC 45388) in the treatment of inoperable melanoma. One hundred and seventy-eight patients were randomized to receive either DTIC (150 mg/m2/day X 5) or TIC Mustard (800 mg/m2/day X 5). Of this group 145 patients were evaluable for tumor response at the completion of the study. Objective responses were seen in 15/79 (19.0%) DTIC patients and 4/66 (6.1%) TIC Mustard patients. Adjustment of crude response rates yielded final response rates of 18.2% for DTIC patients and 5.8% for TIC Mustard. These differences were significant at the p less than or equal to .03 level. Median response duration was 15 weeks for the DTIC responders and 4 weeks for the TIC Mustard responders. Responders and nonresponders did not differ significantly in any of the standard prognostic categories. However, responders had a significantly longer median survival (47.5 weeks) compared to that for nonresponders (17.8 weeks). Toxicity was tolerable for either drug and no deaths were ascribed to either. We conclude that TIC Mustard has limited usefulness in the treatment of malignant melanoma and is less effective than DTIC.


Nonspecific immunotherapy by Corynebacterium parvum: phase I toxicity study in 12 patients with advanced cancer. Corynebacterium parvum, a non-specific immunopotentiator, was administered intravenously to 12 patients with advanced cancer at 2, 3, and 4 mg/m2 dose levels in combination with radiation therapy. One dose of C. parvum was given every 7 days for a total of 4 doses in 21 days. Symptoms and signs developed by these patients for a period of 3 to 6 hours during and shortly after the i.v. infusion of the first dose of C. parvum were moderately severe in nine patients and mild in three patients. For the second, third, and fourth doses of C. parvum, patients had fewer and less intense reactions and were given their treatments on an outpatient basis. There was no added morbidity to the patients' tolerance to either palliative or radical dose levels of radiation therapy. Changes in renal, hepatic, hematologic, and immunologic functions were minimal. At the above dose levels, the use of C. parvum to stimulate the reticuloendothelial system in humans by the intravenous route can be safe and well tolerated provided the side effects are appreciated and symptomatic treatments administered.


Association of cadmium with renal cancer. Sixty-four cases of renal cancer in white males were compared with controls (197 cases of nonmalignant diseases of the digestive system and 72 cases of colon cancer) for past exposures to cadmium. Controls were also white males, and were group-matched to the cases on age for the analyses. Data on the three main sources of exposure to cadmium--diet, cigarette smoking and occupation--were obtained by interview. The results showed a significant association of renal cancer with exposure to cadmium, and favored a synergistic effect between occupational exposure and smoking. The relative risk for men who both smoked and worked in high-risk occupations was more than four times that for men who did neither. The apparent synergism, however, suggests that the agent in cigarette smoke contributing to this association may not be cadmium.


Identification and subcellular localization of a sarcoma-associated antigen(s) in a human cell line. The present investigation was designed to demonstrate and identify the subcellular localization of sarcoma-associated antigen(s) (TAA) in an established human neurogenic sarcoma line (T cell line). Indirect immunofluorescence was used to screen sera from patients with sarcoma, nonsarcoma neoplasias, and from presumably normal blood bank donors. The positive sera were submitted to a series of absorptions to remove possible nonspecific cross-reacting antibodies. The target cells were then studied with electron microscopy, utilizing the indirect immunoperoxidase technique to determine the subcellular localization of the sarcoma-associated antigen(s). Findings indicate that sarcoma-bearing patients have circulating antisarcoma antibodies directed to antigen(s) localized at the surface membrane of T cells. These antibodies pertain to the IgM or IgG immunoglobulin class. The exact nature of the sarcoma-associated antigen(s) identified in this study is not known at the present time. However, the results obtained strongly suggest that these substances may represent a new type of tumor-associated antigen(s).


Impairment of rosette-forming T lymphocytes in patients with primary intracranial tumors. The percentage of T lymphocytes that form rosettes (RFC) with sheep erythrocytes (E rosettes), cutaneous delayed-type hypersensitivity, and in vitro lymphocyte transformation was measured in 15 patients with primary intracranial tumors. The ability of T lymphocytes  to  form E rosettes was significantly impaired. These patients also exhibited impaired ability to become sensitized to dinitrochlorobenzene and humoral suppression of PHA-induced lymphocyte blastogenesis. The hypothetical role of antibody(s) to possible shared antigenic determinants on brain and T cells is discussed.


Malignant disease and tracheobronchial epithelial multinucleation. Multinucleation of noncancerous ciliated tracheobronchial epithelial cells seen in smears from 412 patients suffering from malignant tumors originating from a wide variety of organs was found to be 2.03 times more frequent than in a control group without prediagnosed malignant disease, matched by age (decades), sex, and smoking habit (p less than 0.0005). Multinucleation involving at least 3% of cells was seen four times more frequently in patients with invasive tumors without known metastases than in controls. Excessive smoking habit in control females as well as site of origin and stage of tumor influenced statistical significance, otherwise unaffected by age, sex, and smoking habit in males. A prospective study is being planned in which incidence and degree of tracheobronchial epithelial multinucleation will be used in conjunction with biochemical tests for the diagnosis of occult cancer.


Monitoring of immunologic status of patients receiving BCG therapy for malignant disease. BCG immunotherapy in a standard regime was administered by scarification to 26 selected patients with controlled malignant disease, 14 with lung cancer and 12 with melanoma. All were followed for 12 months after the first BCG administration or until death. During the first 3 months, when BCG was given weekly, immune reactivity as determined by skin tests and in vitro lymphocyte responses to phytohemagglutinin and recall antigens was enhanced in all patients except those in whom recurrence or extension of malignancy subsequently occurred. Patients who had received prior radiation therapy for lung cancer also did not manifest significant immunoenhancement. During the following 9 months when BCG was administered at increasing intervals, immune responses were maintained except in those patients who experienced recurrence of malignancy, and those who discontinued BCG therapy. The response to PHA was predictive of a favorable clinical course during the following 9 months, and was significantly impaired in advance of the clinical recurrence of malignancy. Tests of cell-mediated immunity, particularly the in vitro response to HA, are valuable in assessing the efficacy of BCG immunotherapy, prognosticating clinical progress, and predicting the recurrence of malignancy.


Carcinoma arising in a branchial cleft cyst. A patient is presented who was found to have invasive squamous cell carcinoma arising in the epithelial lining of a lateral cervical cyst which had been present for more than 40 years. Radical neck dissection was performed, and metastases were found in a single cervical lymph node. A critical review of cases of branchiogenic carcinoma reported over the past quarter-century yielded no more than three others which meet the criteria for diagnosis of this entity established by Martin, Morfit, and Ehrlich in 1950.


Combination chemotherapy with cyclophosphamide (NSC-26271), cytosine arabinoside (NSC-63878), and methotrexate (NSC-740) in advanced solid tumors. Forty patients with advanced solid tumors of diverse primary sites received a combination of cyclophosphamide (1 gm/m2), cytosine arabinoside (300 mg/m2), and methotrexate (80 mg/m2) given intermittently at 2-3-week intervals. Eight of the 40 patients received citrovorum factor rescue. The major limitation of therapy was suppression of bone marrow elements. Only minimal nonhematologic toxicity was encountered. Granulocytes appeared the most sensitive. The first course of treatment produced median nadir granulocyte and platelet counts of 1200 and 100,000 cells/mm3 respectively. Subsequent courses were tolerated with no evidence of increasing myelosuppression. Objective antitumor responses were noted in five of 16 patients with lung cancer and in eight of 14 women with breast cancer with a median duration of 8 months.


Cyclophosphamide (NSC-26271) maintenance therapy after a second remission of childhood acute lymphoblastic leukemia: comparative clinical trial (standard dose versus intermittent high dose versus cyclophosphamide plus cytosine arabinoside (NSC-63878)). Children with acute lymphoblastic leukemia who had experienced only one relapse were reinduced into remission using a 6-week induction course of prednisone and vincristine. One hundred fifty-one children who achieved a second complete marrow remission were randomly assigned to one of three cyclophosphamide treatment groups for maintanence. Forty-one children received standard-dose cyclophosphamide (3 mg/kg/day), 55 received intermittent high-dose cyclophosphamide (10 mg/kg/day for 4 days out of 14), and 55 received a combination of oral cyclophosphamide (3 mg/kg/day) plus cytosine arabinoside (3 mg/kg/week im). The standard-dose cyclophosphamide regimen resulted in a remission maintenance time of 109 days and was the least toxic of the three maintenance regimens. Giving cyclophosphamide on an intermittent high-dose schedule or combining it with cytosine arabinoside did not increase the remission maintanence time (105 days).


Guanazole (NSC-1895)--a phase I clinical study. Two dose schedules of guanazole were used in this phase I clinical study: intermittent prolonged 5-day infusion and intermittent iv bolus twice weekly. Ninety-seven treatment observations were analyzed for toxic effects resulting from the prolonged infusion and 42 from the twice-weekly bolus schedule. The main toxic effect was bone marrow suppressions, the frequency and severity of which were intensified by prior chemotherapy or radiotherapy and repetition of guanazole therapy. The leukocyte count was affected more than the platelet count. Partial responses were observed in four patients: two with lung carcinoma, one with prostate carcinoma, and one with melanoma. Further phase II clinical studies of guanazole are indicated.


Treatment of small cell carcinoma of the lung using methyl-CCNU (NSC-95441) combined with cyclophosphamide (NSC-26271) and vincristine (NSC-67574) in a 3-week schedule. Twenty-six patients with small cell carcinoma of the lung were treated with a combination of methyl-CCNU (75 mg/m2 orally), cyclophosphamide (750 mg/m2iv), and vincristine (1.4 mg/m2iv) once every 3 weeks and followed for 2-56 weeks (mean, 24 weeks). An average of seven treatments were given per patient. Myelotoxicity was mild to moderate with no white blood cell count (wbc) less than 1000 cells/mm3 and no platelet count less than 25,000 cells/mm3. Six patients (23%) had a wbc of 1000-2000 cells/mm3 and two (8%) had a platelet count of 25,000-75,000 cells/mm3. Sixty-eight persons of the projected dose of methyl-CCNU was given. Fourteen of 22 patients with measurable disease (54%) responded. Of 14 patients who had received no prior treatment 64% responded with a median survival duration of 40 weeks. Complete responses occurred only in patients without prior radiation therapy or chemotherapy. We conclude that methyl-CCNU may be given with an acceptable level of toxicity in an every 3-week schedule and that the combination of cyclophosphamide, methyl-CCNU, and vincristine warrants further evaluation in the treatment of small cell carcinoma of the lung.


Combination chemotherapy for acute nonlymphoblastic leukemia in adults. Between January 1973 and February 1975, 77 adults with acute nonlymphoblastic leukemia were treated with a combination of daunorubicin, cytosine arabinoside, 6-thioguanine, prednisone, and vincristine in university-affiliated and private institutions. After 31 patients were treated (regimen 1) the doses of all drugs were significantly increased (regimen 2). Regimes 1 and 2 yielded CR rates of 59% (17 of 29 patients) and 70% (32 of 46 patients) respectively. With regimens 2 the mean number of courses and the median number of days to CR decreased from 3 to 1.4 and from 46 to 29 respectively. Failure to achieve CR was due to persistent leukemia during regimen 1 and fatal infections during regimen 2. With regimen 2 ten of 20 patients (50%) greater than 50 years had CR compared to 22 of 26 patients (85%) less than 50 years. CR rates were similar in community and university institutions.


Phase I study of corynebacterium parvum in patients with solid tumors. Nineteen patients with various solid tumors were treated with Corynebacterium parvum for 10 consecutive days at doses ranging from 0.5 to 6 mg/m2. Major toxic effects included rigors and cyanosis, hypertension, headache, nausea, and vomiting. Toxicity was maximal during the first 3 days of treatment and decreased or even disappeared when, on subsequent days, increasing doses of the vaccine were given. Objective tumor regressions were observed in four patients.


Ultrastructure of lymphocyte tumor cell interaction with localization of cell-bound antibody by ferritin labeling. Splenic lymphocytes derived from Walker carcinoma-bearing rats were harvested and incubated with Walker carcinoma cells growing in tissue culture. The sequence of events leading to target cell death was studied by phase microscopy and scanning and transmission electron microscopy. The sensitized lymphocytes adhere to the tumor cells by multiple cytoplasmic appendages, but no ultrastructural changes are seen at this interface. After 1 hr these lymphocytes release cytoplasmic components consisting of membrane-lined vesicles, cell membranes, endoplasmic reticulum, and cytoplasmic material. This material adheres closely to the surface of the tumor cells and is subsequently seen within the cytoplasm of the tumor cell. The tumor cells then undergo degenerative changes and cell death occurs in 24 to 36 hr. The lymphocyte-derived material appears to contain immunoglobulin components as determined by specific ferritin labeling.


The effect of Mycobacterium bovis (Bacillus Calmette-Guérin) on macrophage random migration, chemotaxis, and pinocytosis. Macrophage random migration, chemotactic responsiveness, and pinocytosis were studied in the guinea pig after Bacillus Calmette-Guérin (BCG) administration. Oil-induced peritoneal exudate cells were evaluated for random migration and chemotaxis in modified Boyden chambers. Pinocytosis was measured by the in vitro uptake of colloidal 198Au. There was a parallel increase in random migration and chemotaxis after an i.p. dose of 1.0 X 10(7) COLONY-FORMING UNIts of BCG. This was seen as early as Day 4, sustained through Day 21, and absent by Day 44. A number of different strains and preparations of BCG vaccine exerted a similar augmentation of macrophage mobility. In parallel assays, aliquots of macrophages from BCG-treated animals showed increased pinocytosis, first noted at Day 14, peaking at Day 28, and no longer measurable at Day 44. These alterations in macrophage function following BCG administration may in part contribute to the antitumor effect of BCG adjuvant therapy.