Effects of variations in renal function on the clinical pharmacology of bleomycin administered as an iv bolus. The clinical pharmacology of bleomycin administered as an iv bolus has been studied in a homogeneous group of patients receiving a single regimen containing bleomycin, vinblastine, and cis-dichlorodiammineplatinum (II). These studies demonstrated that in patients with creatinine clearances greater than or equal to 35 ml/minute, the serum (or plasma) terminal elimination half-life of bleomycin was approximately 115 minutes. In patients with creatinine clearances less than 25-35 ml/minute, the terminal elimination half-life increased exponentially as the creatinine clearance decreased. The volume of distribution was approximately 20 liters, and was unaffected by changes in the creatinine clearance. The microbiologic assay and radioimmunoassay employed gave equivalent results.


Twice weekly 5-azacytidine infusion in dissmeinated metastatic cancer: a phase II study. A phase II study of 5-azacytidine given twice weekly as a rapid iv infusion was performed on 116 patients with different metastatic cancers of refractory lymphomas at a dose of 150 mg/m2 twice weekly  x 6. Ninety-one patients were evaluable. Dose modifications were carried out depending on previous treatment status. Nausea and vomiting was a major side effect; significant granulocytopenia was observed in 35 patients. Responses were observed in only four patients. Our results indicate little effectiveness of this drug. The severe toxicity prevented escalation to potentially more effective dose levels.


A joint produce of the genes gag and pol of avian sarcoma virus: a possible precursor of reverse transcriptase. A virus-specific protein of approximately 180,000 daltons has been identified in cells transformed by avian sarcoma virus. The protein, designated P180, includes immunological determinants of both viral core proteins and reverse transcriptase. Its tryptic peptides represent essentially the sum of those of the precursor of the core proteins (Pr76gag) and reverse transcriptase. Thus P180 must arise from the uninterrupted translation of gag and pol. The kinetics of its formation and decay suggest that P180 is the precursor of reverse transcriptase.


[Immunopathological aspects of nucleolar activation. 1. Changes of nucleolar activation during the course of primary immune response]. During the primary immune response induced by the administration of sheep erythrocytes in mice, nucleolar activation was observed in macrophages, lymphocytes as well as in plasmacytes. The first maximum (4.6%) was observed on day 3 in macrophagic cells. Maximal activation of plasmoblasts (6.6%) and plasmacytes (5.9%) was observed on day the lymphoid series the first maximum in the occurrence of cells showing specific immunological activatin was as follows: large lymphocytes on day (6.5%), medium-sized lymphocytes on day 7 (6.6%) and, ultimately, small lymphocytes (6.3%) on day 8. The study verified the possibility of using nucleolar staining for estimating its functional morphology and thus following the changes of specific immunological activation during the primary immunological response.


Hydatidosis: a global problem of increasing importance. This review of recent literature reporting the occurrence of hydatid disease due to Echinococcus granulosus and E. multilocularis throughout the world emphasizes the global nature of the problem and the threat of its spread into those countries currently free from it. Attention is drawn to the urgent need for measures to prevent the importation of infected livestock and this would require the development of techniques for pre-mortem diagnosis and differentiation of hydatidosis and cysticercosis of animals. There must also be increased awareness of the possible occurrence of biological strains of the parasite which may be of greater or lower infectivity for man. In the absence of information on infectivity, studies concerning the prevalence of the disease may be meaningless.


Antigenic variation in African trypanosomiasis: a memorandum. After reviewing the present knowledge on antigenic variation of the trypanosomes of the Trypanosoma (Trypanozoon) brucei species, this Memorandum discusses the relevance of this phenomenon to the possible development of new tools for trypanosomiasis control.As antigenic variation is related to protective immunity and immunopathology, it is of crucial importance for the feasibility of vaccine development and for treatment principles. It is also of interest as a model for understanding antigenic variation occurring during infections with Plasmodium knowlesi, Babesia, and others. Recent methods will permit in depth studies on the antigenic repertoire, the significance of basic antigens, and on the homogeneity of trypanosome populations. For epidemiological purposes, characteristic patterns of variation can be used for strain typing.As regards the basic mechanism of variation, a better insight is required on the molecular structure of the variant antigens. Various methods have so far indicated that they are glycoproteins with a long polypetide chain with 600 amino acids and 15-30 monosaccharide units.The process of variation may be generated by pre-existing genetic information, recombination, or mutation.The stimulus to change variants probably derives, directly or indirectly, from the host immune response, but may also be associated with other environmental factors.The possible relation to acquired resistance, innate immunity, and host specificity, as well as the differences in severity of infection occurring amongst the same host species, are outlined. Histopathological and serological findings are considered in the light of the effect antigenic variation may have on the development of immunopathological lesions.A series of recommendations is included.


[Use of a new process of metallic shadowing by cathodic vaporization for scanning electron microscopy of tegumental products of insects]. In scanning electron microscopy, the recent process, not yet much used, of coating subjects with gold by cathodic sputtering, allows one in biology and especially in entomology, to visualize microreliefs, habitually masked, when the old technique called evaporating technique, was used. This process effectively allows one to deposit a very much thinner layer of metal and, because it is performed at room temperature, prevents artifacts caused by the high temperature necessitated by the other technique, whose previous results nevertheless remain generally correct.


[Retrograde axoplasmic transport of serotonin in central mono-aminergic neurons]. Following an injection of 3H-5 HT in the neostriatum of the Rat, the tracer is transported by axoplasmic retrograde flow to the cell groups containing mono-aminergic neurons which are known or thought to have afferences to this structure: substantia nigra, dopaminergic group A 8 and n. raphe dorsalis.


A kinetically based logical approach to the chemotherapy of head and neck cancer. The application of some basic principles derived from studies of the cell cycle and proliferative kinetics of normal and malignant cells has provided a rational basis for designing cancer treatment protocols. Using this approach in advanced head and neck cancer it is possible (a) to increase the response rate, (b) to reduce toxicity and (c) to reduce in-patient hospital stay time. Seventy-one patients with advanced carcinoma of the head and neck were randomized for treatment between two combination schedules, one with and the other without adriamycin. Responses (more than 50% tumour regression) were 74% overall with 70% responding to the combination without adriamycin and 82% responding to the schedule containing it. The increase in response rate seen with adriamycin is not statistically significant. Prior radiotherapy significantly reduced the likelihood of response to chemotherapy. These results have major implications for adjuvant chemotherapy and suggest a possible way of increasing the survival time in this group of diseases.


Toward a curriculum for the profoundly retarded, multiply handicapped child. An approach to formulating programmes for the profoundly retarded child is described. It is suggested that the basis for programming should be an analysis of the child's ability to operate on, and find out about, his environment. This analysis can be approached by asking questions about blocks to development, needs and preferences, socialization and communication and play and sensori-motor coordination.


Synchronous VBM and radiotherapy in the treatment of squamous cell carcinoma of the head and neck. Since April 1974, 60 patients with squamous cell carcinoma of the head and neck region, of poor prognosis and generally in advanced stages, were treated with the combination of a cytotoxic regimen--VBM (Vincristine, Bleomycin and Methotrexate) and radical radiotherapy. The essential feature of the combination is the administration of pulses of VBM synchronous with a course of fractionated external radiotherapy in order to achieve potentiation of radiotherapy. On average 4-5 pulses of VBM were given during treatment, combined with radiotherapy on a Cobalt unit. The selection, preparation and management of the patients are described. Intense mucositis and intercurrent infection provide the main problems during treatment and close management is essential. Late complications have not been a serious problem. The crude actuarial survival rate at 24 months is 61%. The probability of survival without any recurrence to 24 months following initial treatment is 46%. Local control was achieved by the initial treatment in 43 patients. These results suggest that potentiation of radiotherapy and an increased therapeutic ratio has been obtained by the addition of VBM to radiotherapy and there is a possibility that the occurrence of distant metastases has been reduced or postponed.


The assessment needs of pre-school children with handicaps of language development. An outline of the paediatric assessment needs of children with delayed or deviant language development has been given based on the experience and findings of the research language team at the Wolfson Centre.


Identification of nucleolus organizer regions (NORs) in normal and neoplastic human cells by the silver-staining technique. Silver nitrate has been used to demonstrate the chromosomal location of ribosomal cistrons in nine tissue-culture lines derived from human tumors of various pathological origins. Control individuals have a particular modal number (range 7--10) of D- and G-group chromosomes stained with silver. In the controls, 96.2% of the D- and G-group chromosomes that have a stalk show silver staining, while no relationship can be seen in acrocentric chromosomes without stalks. The tumor cells, whose modal chromosome numbers range from 42 to 68, possess variable numbers of acrocentrics (11--18). The number of chromosomes stained with silver, however, remained at control levels (range, 6--9). These data indicate that, in humans, silver staining may not identify all NORs that contain structural ribosomal genes.


Concealed (proximal) Wenckebach phenomenon with distal 2:1 exit block in the ectopic-ventricular junction. The findings in two patients with interpolated ventricular extrasystoles showing 2:1 exit block are reported. In these patients the blocked impulses appear to penetrate into the ectopic-ventricular junction (or reentrant pathway) to a varying extent, and the coexistance of a distal 2:1 exit block and a proximal (concealed) Wenckebach phenomenon in the ectopic-ventricular junction is suggested.


Differential staining of Chironomus thummi giant chromosomes by treatment with acridine orange after mild acid hydrolysis. The fluorescence of Chironomus thummi giant chromosomes stained by acridine orange after mild acid hydrolysis (1N HCl at 37 degrees) has been studied. After very short hydrolysis as well as in control preparations (untreated by HCl) all chromosome regions show green fluorescence. After long hydrolysis (10 min) all chromosome bands fluoresce red. Intermediate time of hydrolysis (2 min) give in all transcriptionally inactive bands including centromeric ones red fluorescence whereas transcriptionally active puffing regions are green. The possible mechanisms of differential staining of individual chromosome regions are discussed. It is suggested that transcriptionally active chromosome regions are less susceptible to the action of acid or that the difference in chromatin stainability after acid-AO treatment is due to the difference in chromatin packing. The applicability of this method to the study of functional states of chromatin, at least in giant chromosomes, is discussed.


Suppression of quinacrine banding of human chromosomes by mounting in organic media. When A-banded human chromosomes mounted in water are transferred to an organic mounting medium, the chromosomes show uniform bright quinacrine fluorescence. This change is reversible. It is inferred that quinacrine is bound uniformly along the chromosomes, and that Q-banding is a consequence of a non-uniform distribution along the chromosomes of chemical groups, probably proteinaceous, which affect the fluorescence efficiency of the bound quinacrine.


[Combined doxorubicin and bleomycin treatment of metastasising thyroid carcinoma: results in 21 patients (author's transl)]. The effectiveness of combined cytostatic treatment with doxorubicin and bleomycin was analysed in 21 patients with metastasising thyroid carcinoma which had progressed despite both surgical and radiotherapy. Tumour histology (anaplastic carcinoma in 50%), age and general condition of all patients pointed to a poor prognosis. Significant success (full or partial remission) occurred in eight patients. It is possible that these results can be improved if chemotherapy is started earlier and other cytostatic drugs are used in case of failure of treatment.


[Treatment of Sudeck's syndrome with calcitonin (author's transl)]. Ten patients with Sudeck's syndrome were treated with porcine calcitonin. If this hormone, which inhibits bone absorption, is given no later than the first or in the transition from first to second stage, the spontaneous burning pain and, after some weeks, the oedema and increased warmth disappear. Calcitonin is as effective as corticosteroids. But its range of application is wider, because it has fewer side effects and can be administered particularly where corticosteroids are contra-indicated. But it is ineffective in stage III. Synthetic salmon calcitonin is now available, and more effective than porcine, lasts longer and is the drug of choice in Sudeck's syndrome.


Daily rhythm and regulation of AIB transport in rat liver. The active transport of AIB in rat liver slices shows a daily rhythm with a maximum at 18(00) and a minimum at 10(00). The rhythmic increase of transport activity is inhibited by cycloheximide. At the time of low transport rate, cycloheximide does not affect AIB transport. During the diurnal decrease of AIB transport activity, after its maximum, cycloheximide partially diminishes the transport rate. 5-azacytidine and alpha-amanitin stimulate AIB transport. The stimulation is prevented by simultaneous administration of cycloheximide.


Distribution and excretion of chlordecone (Kepone) in the rat. Rats received a single, oral, 40-mg/kg dose of 14C-labeled chlordecone in a corn-oil solution. Initially the highest levels of radioactivity were found in the adrenal gland, liver, lung, and fat. While levels declined steadily in all tissues during the course of the study (182 days), the ratio of liver content to that of other tissues increased considerably. The blood half-life was 8.5 days for the first 4 weeks, 24 days for the next 8 weeks, and 45 days for the final 14 weeks, The amount excreted in the feces was 12.7% for the first 24 hr, 2.9% for the second, and 3.3% during the third 24-hr period. By 84 days 65.5% of the dose had been excreted by this route. Total urinary excretion of radioactivity for 84 days was 1.6%. These results indicate that chlordecone is well absorbed and distributed throughout the body, has a long half-life, and disappears more slowly from the liver than from other tissues. The majority of a dose is eliminated slowly in the feces with very little appearing in the urine. The findings are consistent with the expected pharmacokinetics of a chlorinated hydrocarbon, although there was less of a tendency to localize in fat than anticipated.


N1--P2 component of the auditory evoked potential during alcohol intoxication and interaction of pyrithioxine in healthy adults. The auditory evoked potential was used to assess the effect of alcohol intoxication (1 g/kg) and pyrithioxine (7 mg/kg) on 9 adult subjects. Its components in the latency range 50--250 msec (N1--P2) were studied for 6 g 30 min, during a constant level of alertness. Four periods were considered: alcohol alone, alcohol plus pyrithioxine, pyrithioxine plus alcohol and placebo. With alcohol alone the N1--P2 amplitude was small in the first part of the test and large in the second part as compared to placebo values. Pyrithioxine antagonism was greatest after alcohol had been resorbed. The placebo period indicated that amplitude changes were not due to long-term habituation, when the subject was kept alert.


Limbic spindles: genuine cerebral activity or artifact? A periodic spindling activity recorded in clinical EEG laboratories from nasopharyngeal (NP) leads has been interpreted as expression of genuine cerebral rhythms originating in the limbic system. Evidence is here presented to suggest that such activity is indeed an artifact. Genuine spindling occasionally occurs in NP leads but this is intimately related to sleep spindles occurring also in other surface electrodes.


Some peculiar changes in the pattern of respiration connected with REM sleep. A preliminary report. In the course of polygraphic studies of night sleep the authors recorded respiration through the right and left nostrils by means of two thermoelements. They observed a peculiar and unexpected phenomenon: during the REM sleep phase of the 3rd sleep cycle of 4 healthy persons with 6 full night recordings, respiration through the left nostril stopped, whereas it increased both in frequency and amplitude through the right nostril. This type of respiration continued until awakening. In 2 patients with narcolepsy-cataplexy and in 2 others with idiopathic hypersomnia (8 nights recorded) the same phenomenon was observed with the difference that respiration disappeared on the right side and was preserved on the left side. Furthermore, these changes occurred earlier than in healthy persons. The above changes could be explained by congestion of the venous plexi of the nose.


Sleep telemetry in the rat: I. a miniaturized FM--AM transmitter for EEG and EMG. The article describes a miniature 2-channel FM-AM transmitter for recording EEG and EMG in unrestrained, small animals. Field changes during head movements yield a signal which can serve as a measure of motor activity.


Sleep telemetry in the rat. II. Automatic identification and recording of vigilance states. An identification system for the vigilance states of the rat is described which uses as inputs the cortical EEG, neck muscle EMG and motor activity, and which allows concomitant monitoring of feeding and drinking behaviour. State identification and data recording are performed in an on-line and an off-line stage which are designed to accommodate a large number of data for computer processing.


Quantitative analysis of intracerebral recordings in epilepsia partialis continua. A 14-year-old female with epilepsia partialis continua was explored stereo-electroencephalographically (SEEG). SEEG, EEG and EMG were recorded synchronously on a 32-channel machine and stored on magnetic tape for off-line analysis. The beginning of the myoclonus was used as trigger for the analysis of the intracerebral activity, which was analysed by averaging. Thereby the generating potentials of the jerks became evident. They had different maxima and latencies relative to the facial and hand muscles: that for m. orbicularis oculi was located in the precentral gyrus, the beginning of its positive deflection was 17 msec earlier than the muscle action potential; that for the thenar muscles had a latency of 24 msec, appeared at first in the premotor cortex and with a slight delay, but with greater amplitude in the corona radiata and capsula interna. Stimulation of the lateral area 4 elicited myoclonus which corresponded to the spontaneous one in distribution and latency. Stimulation of the thalamic VL nucleus had no effect. During deep sleep the frequency of the myoclonus was diminished. REM sleep was preceded and followed by a definite increase of jerking. The pattern, topography and latency of the generating potentials in waking and sleeping were very similar. In this way quantitative evidence of the neocortical origin of Epc is given and therefore a precise delineation of the epileptogenic focus.


The effects of ablations on primary and secondary epileptic discharges in commissure-sectioned rhesus monkeys. Nine monkeys underwent division of the corpus callosum, anterior commissure, massa intermedia, and posterior commissure. At the same operation, in seven of these animals aluminium hydroxide was applied to the left posterior parietal-prestriate cortex. Monthly EEG recordings were taken from all animals. All seven animals with epileptogenic implants gave evidence of primary abnormal discharges (i.e. from the ipsilateral hemisphere) and secondary (i.e. from the contralateral hemisphere) discharges. The secondary events were of two types: transmitted, i.e. synchronous with primary events; independent, i.e. asynchronous with primary events. After intervals varying from 4 to 22 months all seven monkeys underwent wide ablation of the posterior parietal cortex: on the left in four animals, on the right in three animals. EEG recordings were taken for a further 6 months. All recordings were quantitatively analysed, the number of primary, transmitted secondary and independent secondary events being counted separately. This analysis indicated the following: (1) Primary and transmitted secondary discharges ceased after primary ablations but were unaffected by removal of the secondary cortex. (2) Independent secondary discharges persisted after removal of the primary focus but were abolished by secondary ablations. Possible mechanisms for the development of transmitted and independent secondary discharges are considered.


Contingent negative variation and alpha attenuation responses in children with different abilities to concentrate. In three paralleled groups, each of seven children (age, 11 years) with reliable high, average and low ability to concentrate, measured by psychological tests, the contingent negative variation (CNV) and the concomitant alpha attenuation responses were studied in warned reaction time experiments. Stimuli were tone (S1) and patterned light (S2). In half of the trials, S2 was a square, in the other half a triagle, stimuli being projected in random order onto the fixation point. In two experiments the children had to react (a) to each type of S2, and (b) selectively to one type of S2. Significant group differences were found. In comparison to the children with low ability to concentrate, the children with average and especially those with high ability to concentrate showed: (1) stronger central occipital alpha attenuation responses to the warning stimulus, but no differences in the early CNVs; (2) more occipital alpha reduction and enhanced development of central negativity before the imperative stimulus; (3) task-specific modulation of these responses, i.e. larger pre-S2 rise in negativity in the simple reaction task, and stronger pre-S2 reduction of alpha amplitudes in the discriminative reaction task.


Phase of the theta wave in relation to different limb movements in awake rats. A significant relationship was observed between the moment of self-initiated pressing or releasing of a lever and the phase of the hippocampal theta wave recorded concurrently in rats. In addition, the phase of the theta wave at which lever pressing was most likely to occur was opposite to that at which lever releasing was most likely to occur. These findings imply that, in rats, sensorimotor integration occurs not continuously, but intermittently and rhythmically, in phasic relation to hippocampal theta activity.


Rhythmical activity of the rat's tongue in sleep and wakefulness. Nine chronically implanted rats were used to study rhythmical activity of suprahyoidal muscles controlling tongue motility. This muscle group exhibited a fixed, regular rhythm of 5--8 c/sec during PS, not during SWS, resembling that observed when the awake rat drank, ate or groomed. In PS the tongue rhythm occurred less frequently than did eye movements and phasic nasolabial muscle activity; when it did, it was associated with such eye movements 80% of the time and 20% of the time before or after an episode of eye movements. A respiratory-related suprahyoidal EMG was observed in one rat to precede the onset of the diaphragm's EMG. Mechanisms for entraining phasic activity of extraocular, nasolabial and suprahyoidal muscles in PS are discussed.


The 3'-Terminal nucleotide sequence of encephalomyocarditis virus RNA. Poly(A)-containing encephalomyocarditis virus RNA functions as an excellent template for cDNA synthesis in vitro with an RNA-dependent DNA polymerase in the presence of an oligothymidylate primer. Under appropriate conditions, discrete transcripts of increasing chain length were obtained, suitable for sequence analysis. A limited cDNA fragment of 36 nucleotides, primer (dT)10 included, was synthesized when dGTP was omitted from the reaction mixture and its primary structure was elucidated using direct DNA-sequencing methods. The complement corresponds to the 3' end of encephalomyocarditis RNA. The hexanucleotide (5'-3')(A-A-U-A-A-A) found in this sequence is also present in all 3' non-coding regions of poly(A)-containing eukaryotic mRNAs studied until now, in nearly identical positions relative to the poly(A) tail. The possible biological significance of this structural homology is discussed.


Modifications of serum glycoproteins the days following a prolonged physical exercise and the influence of physical training. Eight male subjects (mean age 24.1 +/- 2.6 years) performed at intervals of 2 weeks successively a 3 h and two 2 h runs of different running speed. The days following the running there were moderate elevations of C-reactive protein, haptoglobin, alpha-1-acid glycoprotein, coeruloplasmin, transferrin, alpha-1-antitrypsin and plasminogen. There were small or no changes of albumin, alpha-2-macroglobulin and hemopexin. The elevations of the "acute phase reactants" were examined in three male subjects following a 2 h run before and after an endurance training period of 9 weeks. This demonstrated a decreased acute phase response after training as illustrated by the changes of C-reactive protein, haptoglobin and alpha-1-acid glycoprotein in spite of higher posttraining running speeds. Well-trained athletes have elevated levels of the serum protease inhibitors alpha-1-antitrypsin, alpha-2-macroglobulin and C1-inhibitor. These antiproteolytic glycoproteins might limit exercise-induced inflammatory reactions.


Noradrenaline innervation of the spinal cord studied by the horseradish peroxidase method combined with monoamine oxidase staining. The origin of the spinal cord noradrenaline (NA) has been investigated by means of the horseradish peroxidase (HRP) method, combined with monoamine oxidase staining (Glenner) to identify the NA neurons. Following the injection of HRP to the various levels of rat spinal cord, cervical to sacral cord, A1-3, 5-7 NA neuron groups were labeled with HRP. They showed almost the same distribution pattern regardless of difference in the injected segment. Labeled NA neurons in A6 were concentrated in the ventral division of the locus coeruleus, which continued to the labeled NA neurons in the subcoeruleus area. The HRP positive neurons in the pons outnumbered those of the medulla oblongata. As the NA neurons described above were considered to be the source of NA in the forebrain, such as the hypothalamus and preoptic area, the possibility that the same NA neurons might innervate both the forebrain and spinal cord has been presented.


Axonal transport in the electromotor nerves of Torpedo marmorata. Studies on the axonal transport of cholinergic cell components were made on the electromotor nerves of Torpedo marmorata. Choline acetyltransferase was rapidly accumulated at ligatures on Torpedo nerves, both in vivo and in segments incubated in vitro. In vivo accumulation was maximal approximately one month after nerve interruption. Orthograde transport (both in vitro and in vivo) is calculated to have a velocity of 50--140 mm/day, if, as double-ligature experiments suggest, only about 15% of the axoplasmic enzyme is mobile. A small retrograde accumulation of the transferase was demonstrated. Lactate dehydrogenase did not accumulate but a slight reduction of its activity at ligatures was observed. In contrast to mammalian cholinergic nerves, no accumulation of esterase was observed. ACh accumulation proximal to a cut was apparent and may result in part from local synthesis in the presence of elevated levels of its synthesizing enzyme. Measurements have been made on the activity of choline acetyltransferase in the brain and all parts of the "electric system". In view of these results it is difficult to see how the measured rate of axonal translocation is sufficient to supply the levels of the enzyme found within the electric organ. Within the electromotor cells, choline acetyltransferase is highly concentrated in the axon terminals.


The pontine projection to the flocculonodular lobe and the paraflocculus studied by means of retrograde axonal transport of horseradish peroxidase in the rabbit. The occurrence and distribution of labeled cells in the pontine nuclei were mapped following injections of small amounts of horseradish peroxidase (0.05-0.5 microliter, 50% suspension) in the flocculus, nodulus and the dorsal and ventral paraflocculus in adult albino rabbits. While no labeled cells were found in the pontine nuclei following injections in the nodulus, some were present following injections in the flocculus and a great number following injections in the paraflocculus. The projections onto the flocculus and paraflocculus are precisely organized. Following injections in the paraflocculus labeled neurons are arranged in four columns (E and G in the paramedian pontine nucleus, F in the peduncular and H in the dorsolateral nucleus). Following injections in the ventral paraflocculus labeled cells are present only in parts of column E and F, while columns G and H and parts of E and F project onto the dorsal paraflocculus. Following injections in the flocculus labeled cells occur in the rostral part of column E only. A comparison between the sites of termination of pontine afferents and the areas giving origin to floccular and parafloccular fibers shows that only few fibers mediating visual impulses end in these pontine areas, while they receive numerous fibers from gyrus cinguli and areas 18 and 19 of the cerebral cortex.


Specific and cross-reactive activation of rabbit peripheral blood lymphocytes by streptococcal vaccines. The ability of primed rabbit blood lymphocytes to respond in vitro to the homologous streptococcal group antigen depends on its presence in culture in the form of vaccine or cell walls thereof. These lymphocytes can also be stimulated in vitro by streptococcal vaccines with chemically related group antigens. The basis for this cross-stimulation apparently resides in shared rhamnose moieties. Activation of these lymphocytes was not achieved by vaccines from unrelated bacteria. There is also the suggestion that rabbits of different genetic origin differentiate between cross-stimulating antigens, probably at the level of antigenic determinants. The data support the view that recognition and response pattern of the immune system rely heavily on a network of antigens.


Synthesis of alpha-fetoprotein by human yolk sac tumor transplanted into nude mice. All nude mice bearing primary or secondary transplants of a human yolk sac tumor exhibited a high serum alpha-fetoprotein level. This finding clearly indicates the synthesis of alpha-fetoprotein by the human yolk sac tumor and supports an idea that human yolk sac tumor simulates yolk sac endoderm not only morphologically but also functionally.


Carcino-fetal proteins and gastric cancer: the site of alpha-fetoprotein synthesis in gastric cancer. Although several investigators have reported serum alpha-fetoprotein positive gastric cancer with or without metastasis to the liver, its site of production is still unclear. We studied on the site of alpha-fetoprotein synthesis in our cases which showed remarkably high level of serum alpha-fetoprotein, and clarified the presence of alpha-fetoprotein producing gastric cancer by means of direct immunofluorescent technique. However, we also knew the hepatocytes adjacent ot the metastatic lesions could also synthesize alpha-fetoprotein, although these hepatocytes were not known whether under regeneration or degeneration. Through this study, the other carcinofetal proteins such as carcino-placental alkaline phosphatase and CEA were examined using the sera or tumor tissues. Our results will support the idea that cancer is the disease of cell differentiation.


[Transfemoral catheter embolization of inoperable kidney cancer]. Ten patients with inoperable renal carcinoma underwent embolization of the renal artery. As embolic material homogenized autologous muscle was used. Besides conventional catheters introduced by the Seldinger technique also flow-directed balloon catheters were employed. The merely palliative purposes of embolization were staunching of otherwise untreatable hematuria in eight and reduction of tumor bulk in two cases. Bleeding could be stopped in all, tumor mass reduced in 6 patients as shown by control angiographies. There was always a recanalization of the renal arteries, the vascular tree, however, being much rarefied. Five patients died of the metastatic cancer within the first seven months after embolization, one patient three days after embolization due to phlegmonous retroperitoneal infection. Further complications consisted in flank pain, reversible rises of body temperature, blood pressure and serum creatinine levels. Thrombotic occlusion of deep veins occurred in two patients. The only true benefit of embolization for the patient consists in a relatively simple, fast and safe way to control an otherwise untreatable hemorrhage from inoperable renal carcinoma. Whether prolongation of survival can be reached remains doubtful in spite of a reduction of the tumor mass.


[Treatment of chronic hepatitis. A comparative study of the effect azathioprine and (+)-cyanidanol-3]. The clinical, biochemical and histological results of the treatment of 2 groups of 8 patients each with chronic hepatitis (persistent or aggressive) treated with azathioprine (100mg daily) or (+)-cyanidanol-3(1.5g daily) are compared. The duration of treatmant was 6 months, with monthly examination during this period. The clinical results were comparable in the 2 groups. Among the liver function tests, (+)-cyanidanol-3 appeared superior in the case of total bilirubin, transaminases and BSP retention and azathioprine was superior as regards reduction of gamma-globulin, IgG and IgM. These different results appear to correspond to their different mechanisms of action. The tolerance was superior in the (+)-cyanidanol-3 group, in which no side effects were observed, whereas in the azathioprine group, treatment had to be temporarily interrupted in 3 patients showing leukopenia and/or thrombocytopenia. We therefore believe that it can be asserted that treatment with (+)-cyanidanol-3 yields results similar to those obtained with azathioprine, but being a non-immunosuppressive therapy is devoid of the severe consequences produced by a decrease in immunity in day-to-day clinical practice.


[Immunological mechanisms for tumor prevention. Changes for immuno therapy]. Present knowledge about the immune response to cancer is reviewed briefly. Various mechanisms by which tumor cells can escape from immunological destruction are discussed. Immune therapy can be successful only, when new methods and details about immunological mechanisms are available.


Retroviruses and cancer.

Retroviruses and cancer. All RNA viruses that cause cancer under natural conditions fall into the "retro" category, meaning that the first step in their replication is the "reverse transcription" of RNA into DNA. This peculiarity of their biologic behavior has helped explain other intriguing features of these viruses and opened new directions for future research into the role of viruses in altering the infected cell's genetic material and in oncogenesis.


Suppression of reaginic antibodies with modified allergens. I. Reduction in allergenicity of protein allergens by conjugation to polyethylene glycol. The conjugates of ovalbumin (OA) and of the nondialysable constitutents of the aqueous extract of ragweed pollen (RAG) with polyethylene glycols of molecular weights of 6,000 or 20,000 (PEG6 or PEG20) were shown to be nonantigenic, nonallergenic and nonimmunogenic. Thus, the i.v. administration of OA-PEG and RAG-PEG conjugates into mice did not elicit antibodies to OA and RAG, respectively, and these conjugates were shown to suppress in an immunologically specific manner the capacity of these animals to mount primary as well as secondary IgE responses to sensitizing doses of dinitrophenylated OA or of RAG. Moreover, the Peg-modified antigens did not combine either in vitro or in vivo with IgE antibodies directed against the natural antigens. Hence, OA-PEG and RAG-PEG conjugates were incapable of triggering allergic reactions in animals possessing IgE antibodies to the unmodified antigens. These PEG-modified antigens were also shown to be tolerogenic.


Mechanism of histamine release induced by the ionophore X537A from isolated rat mast cells. X537A released histamine from isolated histamine-retaining mast cell granules incubated at 37 degrees C in Tris-sodium (150 mM) or Tris-potassium (150 mM), but not in Tris-glucose (300 mM). The release was depressed at 0 degrees C. In contrast, decylamine released all histamine bound to the granules irrespective of the presence of monovalent cations in the incubation medium of temperature. X537A did not release histamine from an artificial heparin-protamine complex when incubated in deionized water. The mechanism of histamine release by X537A can be explained by the ability of the ionophore to carry monovalent cations across cellular membranes, hereby making the ions available for exchange with histamine bound to the granular matrix. This mechanism can be distinguished from that of agents triggering an exchange between cations and bound histamine through a calcium- and energy-dependent exocytotic process on the one hand and through membrane lysis on the other. Based on the observation that the ionophore was able to carry histamine into the bulk of an organic phase, various possibilities exist to explain how histamine escapes from the cells following release from intracellular granular stores.


Ultrastructure of isolated human mast cells during histamine release induced by ionophore A 23187. In the presence of calcium, the ionophore A 23187 (10(-7) TO 10(-6) M) causes a dose-dependent histamine release from isolated human mast cells. The accompanying degranulation process is characterized by a formation of channels of fused mast cell granules and by an exocytotic extrusion of altered granule material. Simultaneously, large numbers of newly formed 70 A filaments occur. These filaments probably have a key function in secreting human mast cells.


Fc-rosette inhibition by pregnant women's sera and by rabbit anti-beta2-microglobulin. Some anti-HLA sera showed Fc-rosette inhibitory activity, which had little correlation with type-specific anti-HLA activity. Cytotoxic titers did not correlate with Fc-rosette inhibition rate and these antisera showed considerable inhibition of rosette formation even after absorption of anti-HLA activity with T lymphocytes. These results suggest that some anti-HLA sera contain B-cell-specific inhibitory activity against Fc-receptor like anti-Ia antibody in mice. Rabbit antiserum against human beta2-microglobulin showed specific inhibition of Fc-rosette formation. It was suggested that Fc-receptor or Ia-like antigen in human has a close relation with beta2-microglobulin.


Antigen-, anti-F(ab')2- and anti-IgE-induced histamine release from rat mast cells. The existence of IgE antibody molecules on peritoneal mast cells from rats immunized with dinitrophenylated ascaris extract was demonstrated by double antibody immunofluorescence staining and by histamine release induced by anti-IgE antibodies. Cross-linking of the IgE molecules, which are fixed to mast cells, by interaction with either the homologous antigen or with antibodies to the Fab or Fc regions of IgE, triggered in the presence of calcium ions a chain of intracellular reactions which involve cyclic nucleotide modulation and energy-requiring processes leading ultimately to the release of histamine from the granules of these cells. Although there was no apparent difference in the mechanism(s) underlying the reactions triggered by any of these three agents, the extent of histamine release caused by antibodies to the Fc region of the IgE was significantly lower than that induced by cross-linking of IgE molecules through their Fab regions by reactions with either anti-Fab antibodies or antigens.


HIDACSYS: computer programs for interactive scanning cytophotometry. A description is given of a combination of three programs developed for computer-assisted stage scanning cytophotometry and cytofluorometry of isolated, close-lying, or touching objects in different types of microscopical preparations. The advantages and limitations of the individual programs are discussed, as well as the local specimen conditions determining the optimal application range of each of the programs. The applicability of these programs was investigated by determination of the integrated absorbance values of Feulgen or gallocyanin-chrome alum stained chicken erythrocytes, human leucocytes, and skin biopsy cells in imprint preparations, as well as of guinea pig peritoneal granulocytes which had been submitted to a simultaneous coupling azo dye incubation for alkaline phosphatase activity.


[Peptidases. I. Histochemical investigations with 2-naphthylamides and hexazonium-p-rosanilin (author's transl)]. Using fresh frozen (with and without semipermeable membranes), freeze-dried or sections from aldehyde fixed material and hexazotized p-rosaniline for simultaneous coupling more than 20 different unsubstituted or substituted L-amino acid naphthylamides are split especially in the microvilli and/or stereocilia of the small intestine, kidney and epididymis from rats. Further sites of positive reactions can be revealed by L-alanyl, L-leucyl, L-lysyl, alpha,L-glutamyl, gamma,L-glutamyl, L-asparaginyl, N-benzoyl-L-arginyl, N-carbobenzoxy-L-arginyl and N-benzoyl-L-phenylalanyl 2-naphthylamide. Among the substituted and unsubstituted peptide 2-naphthylamides L-prolyl-L-arginyl 2-naphthylamide is not hydrolysed in visible amounts; L-arginyl-L-arginyl, L-alanyl-L-arginyl-L-arginyl, L-alanyl-L-leucyl-L-tyrosyl, L-histidyl-L-seryl, L-seryl-L-tyrosyl and L-glycy-L-phenylalanyl 2-naphthylamide are metabolized in the renal and intestinal brush border; the reaction pattern obtained with N-carbobenzoxy-L-glycyl-L-glycyl-L-arginyl 2-naphthylamide differs from that of N-carbobenzoxy-L-arginyl 2-naphthylamide. In addition L-glycyl-L-prolyl, L-leucyl-L-alanyl, L-lysyl-L-alanyl and L-alanyl-L-phenylalanyl-L-prolyl 2-naphthylamide are also split in the lysosomes of many organs and the secretion granules of gland cells.


Gas-liquid chromatographic determination of kepone in field-collected avian tissues and eggs. A procedure is described for determining Kepone (decachlorooctahydro-1,3,4-metheno-2H-cyclobuta [cd] pentalene-2-one) residues in avian egg, liver, and tissue. Samples were extracted with benzene-isopropanol, and the extract was cleaned up with fuming H2SO4-concentrated H2SO4. Kepone was separated from organochlorine pesticides and polychlorinated biphenyls on a Florisil column and analyzed by electron capture gas-liquid chromatography (GLC). The average recovery from spiked tissues was 86%. The analyses performed on 14 bald eagle carcasses and livers, 3 bald eagle eggs, and 14 osprey eggs show measurable levels which indicate that Kepone accumulates in the tissues of fish-eating birds. Residues were confirmed by GLC-mass spectrometry.


Plasma kallikrein activation and inhibition during typhoid fever. As an ancillary part of a typhoid fever vaccine study, 10 healthy adult male volunteers (nonimmunized controls) were serially bled 6 days before to 30 days after ingesting 10(5)Salmonella typhi organisms. Five persons developed typhoid fever 6-10 days after challenge, while five remained well. During the febrile illness, significant changes (P < 0.05) in the following hematological parameters were measured: a rise in alpha(1)-antitrypsin antigen concentration and high molecular weight kininogen clotting activity; a progressive decrease of platelet count (to 60% of the predisease state), functional prekallikrein (55%) and kallikrein inhibitor (47%) with a nadir reached on day 5 of the fever and a subsequent overshoot during convalescence. Despite the drop in functional prekallikrein and kallikrein inhibitor, there was no change in factor XII clotting activity or antigenic concentrations of prekallikrein and the kallikrein inhibitors, C1 esterase inhibitor (C1-INH) and alpha(2)-macroglobulin. Plasma from febrile patients subjected to immunoelectrophoresis and crossed immunoelectrophoresis contained a new complex displaying antigenic characteristics of both prekallikrein and C1-INH; the alpha(2)-macroglobulin, antithrombin III, and alpha(1)-antitrypsin immunoprecipitates were unchanged. Plasma drawn from infected-well subjects showed no significant change in these components of the kinin generating system. The finding of a reduction in functional prekallikrein and kallikrein inhibitor (C1-INH) and the formation of a kallikrein C1-INH complex is consistent with prekallikrein activation in typhoid fever. The correlation of these changes with the drop in platelet count suggests that a common mechanism may be responsible.


Serum alpha-fetoprotein levels in patients with acute and chronic liver disease. Relation to hepatocellular regeneration and development of primary liver cell carcinoma. Using a radioimmunoassay technique serum alpha-fetoprotein could be detected in healthy adults in concentrations of less than 20 microgram/l. Of patients with acute, viral hepatitis 43% exhibited a transient rise of serum alpha-fetoprotein, the peak occurring eight to nine days after the maximum recorded serum aspartate transaminase activity. Patients with hepatic damage due to paracetamol poisoning were also shown to have transiently raised levels, the peak occurring earlier than in subjects with viral hepatitis. Six subjects with fatal fulminant hepatitis were studied; the three with the more protracted illness were noted to have increased levels before death. Twenty of 163 cases of chronic liver disease also had raised serum alpha-fetoprotein concentrations. In four, primary liver cell cancer developed; in two of these the serum alpha-fetoprotein levels rose progressively, and in two it remained raised but at low levels.


Chlorinated pesticide residues in milk of Iranian nursing mothers. One-hundred-thirty-one samples of human milk were collected during October, 1974, to January, 1976, throughout the Tehran area. Sources included four maternity hospitals as well as individual nursing mothers outside of hospitals. The samples were collected 1 to 8 days after child birth from women 14 to 42 yr old and from all social strata. The samples were analyzed for chlorinated pesticide residues by gas-liquid chromatography. Insecticides 1,1,1-trichloro-2,2-bis(p-chlorophenyl)ethane (DDT) (with its metabolites), isomer of benzene hexachloride (gamma BHC), and dieldrin were detected in varying concentration in 101, 108, and 47 samples, respectively. The means and ranges were .024 (.001 to .333) ppm, .008 (.001 to .046) ppm, and (.001 to .028) ppm. These concentrations in human milk represented insecticidal ingestion by infants. The mean dieldrin exceeded the World Health Organization limit and may pose a health hazard. There was no significant relationship between economic status of donors and pesticide in the milk; however, milk from the older nursing mothers contained more DDT than that from young mothers.


Tannic acid-metal salt sequences for light and electron microscopic localization of complex carbohydrates. Use of tannic acid (TA), in sequence with ferric chloride, uranyl acetate or gold chloride resulted in staining of selective but sometimes different sites in paraffin sections. TA-uranyl acetate of TA-ferric chloride stained sites rich in complex carbohydrates, wherease TA-gold chloride stained the collagen of various connective tissues different shades of red-purple to gray-black. Applied to epoxy-embedded thin sections of tissues fixed with glutaraldehyde and not post-osmicated, TA-uranyl acetate and TA-ferric chloride imparted density to subcellular sites known to contain a high concentration of mucosubstances, such as secretory granules and cisternae of the Golgi complex of certain cells. TA-gold chloride proved unsatisfactory for ultracytochemistry because of its tendency to form globular precipitates on thin sections. The effect of blockage procedures at the light microscopic level indicated that vicinal glycols are not required for binding of TA to tissue sites. Electrostatic forces were shown to be of minimal significance, whereas hydrogen bonding appeared to play a part in both TA-tissue and TA-metal binding mechanisms.


Dual binding specificities in MOPC 384 and 870 murine myeloma immunoglobulins. Homogeneous murine myeloma immunoglobulins (IgA, kappa), M 384, and M 870, bind methyl alpha-D-galactopyranoside and phosphorylcholine at different subsites. Heterologous recombinant immunoglobulins of these two immunoglobulins with M 603 (a homogeneous IgA, kappa with known phosphorylcholine specificity) also bind phosphorylcholine.


Quantitative studies on the precursors of cytotoxic lymphocytes. IV. Specificity and cross-reactivity of cytotoxic clones. Murine cytotoxic lymphocyte precursor cells (CLP) appear to be specificity restricted, yet 2 to 4% of the total pool appears to be activated in a response against a single foreign H-2 alloantigen. The simplest model that provides enough CLP for all possible reactions is that H-2 antigens have cross-reacting determinants. Experimentally, we observed that activation of RNC-nu/+ (H-2k) LN cells with H-2b spleen cells activated 1200 to 1800 CLP per 10(6) LN cells capable of lysing H-2b target cells. Of these, 3 to 4% could also lyse H-2d target cells. In addition, a small number of clones (approximately 25/10(6) LN cells) were activated which could lyse H-2d but not H-2b target cells. However, the total number of such apparent nonspecifically activated clones is small since greater than 80% of all the CLP activated on culturing with H-2b alloantigens will lyse H-2b targets. The results are discussed in terms of specificity restriction and possible subpopulations of CLP.


Fragments Ba and Bb derived from guinea pig factor B of the properdin system: purification, characterization, and biologic activities. Functionally active guinea pig factor B was purified by a combination of chromatographic steps including Sephadex G-25, QAE A25, QAE A50, CM C50, and Sepharose 4B coupled with purified cobra venom factor. Purified factor B had a m.w. of 106,000 daltons and a single subunit structure. It was heat labile. After cleavage of native B with cobra venom factor coupled to Sepharose 4B in the presence of D, the resulting two fragments, the larger one (Bb) and the smaller one (Ba), were further purified. The m.w. of Bb and Ba was determined as 64,000 and 53,000 daltons, respectively, by SDS-PAGE. Neither of the fragments evoked a contraction of guinea pig ileum or histamine release from rat mast cells. Only the smaller fragment Ba (at a concentration of 120 nM) stimulated guinea pig peritoneal polymorphonuclear leukocytes to respond with increased movement. This activity as well as the antigenicity of Ba were heat stable, but were sensitive to trypsin digestion, whereas the antigenicity of Bb was heat labile.


Cellular basis of tolerance to serum albumin in adult mice. I. characterization of T suppressor and T helper cells. The surface markers and size of suppressor cells were determined in adult (BALB/c x C57BL/Ka)F1 mice which were tolerized with a single injection of deaggregated bovine serum albumin (BSA). Suppressor cells from the spleens of tolerazided donors were assayed in a cell transfer system in which graded numbers of cells were injected into irradiated syngeneic mice along with limiting numbers of T cells primed to BSA and an excess of B cells primed to DNP-BSA. Adoptive hosts were challenged with DNP-BSA in saline, and the anti-DNP response was measured. Suppressor cells were antigen specific as shown by the inhibitory activity of BSA-tolerant spleen cells on the response to DNP-BSA, but not to DNP-BGG. Suppressor cells were eliminated by in vitro treatment with anti-Thy 1.2, anti-Ly-2.2, anti-I-J subregion antisera and C, but not with anti-Ly-1 or anti-I-A subregion antisera. Neither unprimed nor primed helper T cells were detected in the spleen of tolerized donors after in vitro treatment with anti-Ly-2.2 antisera. Both helper and suppressor T cells from the spleens of primed or tolerized donors, respectively, showed a rapid sedimentation velocity (S greater than 3.7 mm/hr).


Antigenicity of the major polypeptides of hepatitis B surface antigen (HBsAg). The major polypeptides (P-1, P-2, and P-6) of HBsAg were isolated from purified preparations of 22-nm HBsAg particles, iodinated, and analyzed by double-antibody radioimmunoprecipitation assays for the presence of hepatitis B virus (HBV)-specific antigens. Each polypeptide fraction contained both group (a) and subtype (d) specific determinants in common by virtue of their immunoreaction with antiserum to native HBsAg and antisera to the other structural polypeptides. The antigenic and structural similarities of the HBsAg polypeptides establish that they are not each unique gene products of the HBV genome.


The distribution and relative immunogenicity of calf alpha-crystallin antigenic determinants on different subunits. In the native alpha-crystallin molecule, 45.9% of all reactive antigenic determinants were found to be located on SH-containing subunits. Of these, the majority (35.3%) were reaggregation dependent, and 10.6% were reactive on monomeric subunits. By contrast, only 10.9% of all antigenic determinants were located on SH-free subunits, and the ratio of aggregation-dependent determinants (4.4%) to those of monomeric subunits (6.5%) was reversed compared to SH-containing subunits. Among all antigenic determinants reactive in native alpha-crystallin, 44.1% were dependent on the presence of both types of subunits. These data indicate that the antigenic determinants requiring subunit interaction were formed from SH-containing and SH-free subunits in a ratio of 1:1. Direct analysis showed that in the alpha-crystallin molecule, the ratio of these subunits is 2:1. The experiments indicate that some conformations of subunits in the native molecule persist in separated subunits. The relative immunogenicity of each type of antigenic determinant expressed as the ratio of the percentage of the determinant reactive in the native calf lens alpha-crystallin to the percentage of corresponding antibodies induced by native alpha-crystallin was found to be close to 1.


Identification of a tumor-associated antigen of the guinea pig L2C leukemia by using syngeneic antisera. Inbred strain 2 guinea pigs immunized with L2C leukemia cells produced antibodies to L2C cells detected by 125I-protein A assay. L2C-associated tumor antigens were reacted with syngeneic antisera and analyzed by immunoprecipitation and SDS-polyacrylamide gel electrophoresis. These sera recognized idiotypic determinants on surface IgM molecules of L2C cells but did not recognize any determinants on normal strain 2 spleen cells. Thus, determinants on IgM molecular act as tumor-associated antigens in the L2C system and can be detected by syngeneic sera.


Expression of group b light chain allotypes in cottontail rabbits. Group b allotypic determinants (b4, b5, b6, and b9) were detected on cottontail IgG by several assays including immunodiffusion, radioimmune binding, and inhibition of radiobinding. The results indicate that cottontail IgG possess some but not all of the subspecificities present on domestic rabbit IgG. Several cottontail rabbits exhibited three of the four possible allotypic markers. In these instances, however, only two populations of IgG molecules (i.e., phenogroups) could be detected, each bearing one, two, or three of the allotypes. Five separate and distinctive phenogroups were identified. The results suggest that the phenogroups represent products of multiple allelic genes for the constant region of cottontail rabbit kappa light chain.


Human IgG3 allotypes, with special reference to a new allotype related to G3m(g) (G3m21). The IgG3 allotype described as L1 (Blanc et al., 1976) occurs on the CH3 region of G3m(g) proteins, in contrast to G3m(g) that is known to be present on the CH2 region. G3m(g) and L1 are, as a rule, present on the same gamma3 heavy chain, just like the G3m(b) subspecificities of the CH2 region, (b1) and (b4), with those of the CH3 region (b0), (b3) and (b5). Several families were investigated that showed inheritance of rare combinations of IgG3 allotypes. The data obtained are suggestive for notation of L1 as (g5), since L1 probably occupies a position antithetical to (b5). The relation of amino acid substitutions to allotypes and isoallotypes is discussed.


Quantitative studies of Gm allotypes. II. G1m(1), G3m(5) and G3m(21) in sera from healthy caucasoid blood donors, and in a family with the inheritance of a gene responsible for a weak Gm1,17;..;21 haplotype. The quantitative expression of three allotypes--G1m(1), G3m(5) and G3m(21)--has been studied in normal caucasoid sera. A gene dosage effect, previously described for all of these allotypes, is not noticed for G3m(5) in the present study. The different content of G3m(5) and G3m(21) IgG3 molecules in heterozygous Gm5/Gm21 sera has been verified: these contents are respectively 75% and 25% of the IgG3 content. The same allotypes have been studied in a family which shows the inheritance of a weak Gm1,17;21 haplotype. The gene responsible for this abnormality is probably a new regulatory gene, and is transmitted without the 'aimed' haplotype.


Combination of cholinesterase staining of nerves and stereoscopic viewing for three-dimensional study of skin innervation on whole mounts. A histochemical staining technique for cholinesterases is reported for the visualization of skin innervation on whole mounts in the chick. A method for realization of stereoscopic pictures showing the nerve fiber pattern in the full thickness of preparations is described. The combination of these 2 techniques allows an excellent three-dimensional demonstration of skin innervation.


Mechanism of densensitization in DNCB-contact sensitive guinea pigs. Contact sensitivity to dinitrochlorobenzene (DNCB) in guinea pigs could be rapidly suppressed by intravenous injection of dinitrobenzene sulfonic acid sodium salt (DNBSO3). This suppression is transient and antigen-specific. Macrophages from desensitized animals are not inactivated as shown by their ability to react, both in vivo and in vitro to lymphokines produced in a separate system. Therefore, effector lymphocytes are considered the target for the desensitizing antigen. Using an adoptive transfer system it was demonstrated that effector lymphocytes are inactivated by a direct effect of the hapten. Since this inactivation can be reversed by trypsin treatment, a receptor blockade of effector lymphocytes is proposed as the mechanism of desensitization of DNCB-contact sensitive guinea pigs. This does not exclude the possibility that additional mechanisms such as suppressor cells, compartmentalization or endogenous proliferation of lymph node lymphocytes may play an additional role.


Specific antigens of Lactobacillus acidophilus. Antigens specific for Lactobacillus acidophilus were investigated by double immunodiffusion in agar-gel. Antigenic materials were extracted from whole bacteria and some walls with cold trichloroacetic acid. Antisera were prepared by intravenous injection into rabbits of suspensions of whole organisms in solutions of bovine serum albumin, which had been heated and then washed. Four specific antigens were found as precipitinogens and denoted as antigens 11, 12, 13 and 14. Of 43 strains of L. acidophilus studied, 33 strains possessed antigen 11, six strains antigen 12, two strains antigen 13 and two strains antigen 14. Sugar compositions of wall preparations were analysed in an attempt to characterize the determinants of antigens 11 and 12. The walls contained glucose, galactose, hexosamine and sometimes glycerol, but no rhamnose was found. It was considered that alpha-glucopyranose was the major component of the determinant of antigen 11 since trehalose and maltose significantly inhibited the reaction between antibody 11 and its antigen; the determinant of antigen 12 was not clarified.


A quantitative micro-complement fixation method in studies of human wart viruses. This report offers a description of a quantitative micro-complement fixation method (Cikes, 1975) for detecting human wart virus antigens and their specific antibodies, and proof of the specificity of the reactions being detected. The increased sensitivity demonstrated by chromium-release measurement is compared to the results of visual interpretation of complement fixation.


Characteristics of human lymphoblastoid (Namalva) interferon. Interferon derived from the human lymphoblastoid cell line, Namalva, was fractionated by antibody affinity chromatography into two antigenically distinct interferon subspecies. At least 13% of the total Namalva interferon activity possessed the F antigenic determinant found on human interferon derived from fibroblast cultures, while the bulk of the Namalva interferon activity had the Le antigenic determinant characteristic for human leukocyte interferon. The separated Le and F subspecies of Namalva interferon differed in the degree of their heterospecific activities on bovine cells. The Le moiety resembled crude leukocyte interferon in that it was highly active in bovine cells. The F component of Namalva interferon showed a lower degree of activity in bovine cells, thus resembling crude fibroblast interferon. When analysed by sodium dodecyl sulphate-polyacrylamide gel electrophoresis and by isoelectric focusing, crude Namalva interferon qualitatively resembled crude leukocyte interferon.


Whipple's disease confined to the brain: a case studied clinically and pathologically. A 40 year old man developed seizures, intermittent fever, and progressive dementia ending in coma and death after four years. The cerebrospinal fluid showed variable pleocytosis and occasional elevation of protein. The necropsy revealed many lesions characteristic of Whipple's disease confined to the grey matter of the brain. The pathological changes were studied with the light and electron microscope. The findings permitted an understanding of the temporal sequence of changes in the lesions. Involvement of the brain in this condition is rare, but the disease is treatable and the diagnosis can be made by brain biopsy.


Prenatal diagnosis of hemoglobin H disease. Hemoglobin H disease was diagnosed prior to the twenty-second week of gestation in a pregnancy at risk for homozygous alpha-thalassemia using the technique of DNA-DNA hybridization. Fetal DNA was obtained from amniotic fluid fibroblasts obtained during the thirteenth week of gestation and grown in culture. The fetal fibroblast DNA was hybridized to radioactive alpha-globin cDNA. The number of alpha-globin genes present in the fetus was determined by comparing results of hybridization studies on the fetal DNA to similar studies on subjects with well-defined alpha-thalassemia syndromes and with normal subjects. The diagnosis of hemoglobin H disease was confirmed at birth by studies of the cord blood. This study confirms the ability of DNA-DNA hybridization techniques to distinguish the three-gene defect of hemoglobin H disease from the lethal four-gene defect of homozygous alpha-thalassemia.


[A neglected technique for reproducing slides (author's transl)]. Duplicating x-ray films is a matter of interest to all physicians, even if they are not radiologists. The impossibility of a direct reading is a major drawback of reproduction in the form of slides. By contrast, a transparency is an irreplaceable teaching tool. Contact printing of slides on counterpart film is a process within the reach of all departments of radiology. In one single step, this process gives a plate of 100 transparencies on counterpart film costing about 2.20 dollars.


[A simplified technique for reproducing slides (author's transl)]. By making use of the film of the substractive screen in contact printing, it is possible to reverse the films into negatives, and to obtain in this manner excellent slides at low cost.


Isolation, characterization, and properties of a labile hydrolysis product of the antitumor nucleoside, 5-azacytidine. The antitumor nucleoside, 5-azacytidine (5-AC), is best administered clinically by prolonged intravenous infusion to minimize toxic effects. In opposition to this administration technique is facile drug decomposition in aqueous formulations giving products of unknown toxicity. Analysis of 24-h-old water solutions of 5-AC with high-pressure liquid chromatography (HPLC) indicated a threefold mixture of 5-AC, N-(formylamidino)-N'-beta-D-ribofuranosylurea (RGU-CHO), and 1-beta-D-ribofuranosyl-3-guanylurea (RGU). Preparative HPLC allowed the isolation and subsequent identification of each component in the mixture, including RGU-CHO which until now has not been available for chemical and biological study. It was shown that RGU-CHO in water solution readily equilibrates to 5-AC and more slowly deformylates to give RGU irreversibly. The latter hydrolysis produce exhibited no pronounced toxicity when tested either in vitro or in vivo. Although RGU-CHO showed considerable antitumor activity against murine L1210 leukemia, hydrolysis studies indicated that all of the observed activity could be attributed to 5-AC formed by in vivo equilibration from RGU-CHO. Moreover, RGU-CHO seemed to impart to test animals a toxicity which was no greater than that anticipated from its ability to generate 5-AC.


Estrogen receptor and alpha-fetoprotein in human breast cancer: brief communication. Concentrations of estrogen receptor (ER) and alpha-fetoprotein were determined by dextran-coated charcoal assay and analyzed with Scatchard plots and radioimmunoassay, respectively, in cytosols of 72 human breast cancers. The values for ER ranged from 0 to 340 fmoles/mg cytosol protein. The concentrations of alpha-fetoprotein, which were low in all tumor cytosols examined, ranged from less than 0.1 to 1.1 ng/mg cytosol protein. No positive relationship was found between ER and alpha-fetoprotein concentrations. These results show that ER, but not alpha-fetoprotein, usually accounts for most of the high estrogen-binding capacity in cytosols of human breast cancers.


Particle--lamella complexes in a case of human benign prostate hyperplasia: brief communication. Particle--lamella complexes (PLC's), described for the first time, were found in glandular epithelial cells of the hyperplastic prostate tissues from a patient with transitional cell carcinoma of the urinary bladder. PLC's observed in this patient were similar to those seen in human hematopoietic neoplastic cells. They showed cylindroid forms and were composed of concentrically arranged lamellae and particles found in rows between these lamellae. PLC is closely related to rough endoplasmic reticulum (RER), and some PLC's were completely surrounded by RER. Particles approximately 25--30 nm in diameter were similar to ribosomes in size, shape, and electron density; lamellae approximately 10 nm thick appeared circular in cross sections and lamellar in longitudinal sections. Although the nature and function of PLC's are as yet unknown, the present observation indicated that PLC's are not a characteristic structure restricted to malignant tumors of hematopoietic origin.


Comparisons of the chemical and biologic properties of triaziquone and triaziquone-protein conjugates. Prepared with nonimmunospecific proteins were covalent conjugates of triaziquone [2,3,4-tris(1-aziridinyl)-p-benzoquinone] (hereafter referred to by the tradename, Trenimon). The bound Trenimon that absorbs maximally at 350 nm (epsilon = 8,200) was assayed by titration of the acid uptake during alkylation of thiosulfate ion and by the color produced during alkylation of 4-(p-nitrobenzyl)pyridine. Conjugates of Trenimon with nonimmune IgG were toxic to cells in culture, although no firm binding of conjugate to cell surface could be measured by fluorescein labeling. Inhibition of cellular pinocytotic activity with cytochalasin B had no effect on the cytotoxic response. Polyoma virus-transformed baby hamster kidney (BHK) cells that were threefold more resistant to the action of a conjugate than was the parent cell line were as sensitive as normal BHK cells when grown in the presence of dibutyryl cyclic AMP or when acted on in suspension by the conjugate. These conditions did not affect the response of the parent BHK line. Cysteine acted to protect both cell lines. The results suggest that Trenimon bound to nonimmmune protein reacted primarily with a component of the cell surface. The reaction did not appear to depend on a firm attachment of the conjugate to the cell.


Catalytically and noncatalytically treated automobile exhaust: biological effects in rats. Chronic exposure to catalytically treated or noncatalytically treated automobile exhaust significantly depressed the spontaneous locomotor activity (SLA) of rats. Exposure to H2SO4 alone or CO at comparable levels did not alter the SLA. Exposure to noncatalytically treated exhaust resulted in significant reductions in growth rate and food and water intake. However, these effects were not evident in the exposure to catalytically treated exhaust or in the control H2SO4 and CO exposures. Blood acid-base analyses indicated that exposure to either catalytically treated exhaust or H2SO4 elicits a metabolic alkalosis, while exposure to CO alone results in a metabolic acidosis. All acid-base parameters were within the normal range several weeks after the termination of exposure.


Isolation and characterization of an endogenous type C RNA virus of mink (Mv1Lu) cells. Cells of the established MvlLu mink line spontaneously released a reverse transcriptase-containing virus after long-term passage in tissue culture. By molecular hybridization, DNA of normal mink cells was found to possess extensive nucleotide sequence homology with a reverse-transcription product of the viral genome, demonstrating that the new isolate was an endogenous virus of mink origin. The mink virus shared antigenic determinants with the major structural proteins of known mammalian type C viruses. Double-antibody competition radioimmunoassays were developed by utilizing the purified major structural protein, p30, of the mink endogenous virus. The virus was shown to possess antigenic determinants unique from those of other known mammalian type C viruses. It exhibited a higher degree of immunological cross-reactivity with endogenous rat type C and horizontally transmitted feline leukemia viruses than with other mammalian type C viruses tested. The finding that mink cells can remain nonvirus producing for many cell generations argues that there normally exists some cellular restriction to endogenous virus expression in this species.


A replication-defective variant of Moloney murine leukemia virus. I. Biological characterization. We have studied the virus produced by a clone, termed 8A, that was isolated from a culture of murine sarcoma virus-transformed mouse cells after superinfection with Moloney murine leukemia virus (MuLV-M). Clone 8A produced high levels of type C virus particles, but only a low titer of infectious murine sarcoma virus and almost no infectious MuLV. When fresh cultures of mouse cells were infected with undiluted clone 8A culture fluids, they released no detectable pogeny virus for several weeks after infection. Fully infectious MuLV was then produced in these cultures. This virus was indistinguishable from MuLV-M by nucleic acid hybridization tests and in its insensitivity to Fv-1 restriction. It also induced thymic lymphomas in BALB/c mice. To explain these results, we propose that cone 8A is infected with a replication-defective variant of MuLV-M. Particles produced by clone 8A, containing this defective genome, can establish an infection in fresh cells but cannot produce progency virus at detectable levels. Several weeks after infection, the defect in the viral genome is corrected by back-mutation or by recombination with endogenous viral genomes, resulting in the formation of fully infectious progeny MuLV. The progeny MuLV'S that arose in two different experiments were found to be genetically different from each other. This is consistent with the hypothesis that, in each experiment, the progeny virus is formed clone 8A cells and assayed for infectivity by the calcium phosphate transfection technique. No detectable MuLV was produced by cells treated with this DNA. This finding, along with positive results obtained in control experiments, indicates that clone 8A cells do not contain a normal MuLV provirus.


Preliminary characterization of a temperature-sensitive mutant of Moloney murine leukemia virus that produces particles at the restrictive temperature. The isolation and preliminary characterization of a new temperature-sensitive mutant of Moloney murine leukemia virus, designated ts7, are reported. The infectivity of ts7, determined by a focus-forming unit assay, was reduced at least 100-fold when the virus was assayed at the nonpermissive temperature (39 degrees C) as compared with assay at the permissive temperature (34 degrees C). However, several lines of evidence indicated that the diminution of ts7 titer at 39 degrees C is not due to its inability to form virus particles at that temperature. The supernatant from ts7-infected cells grown at 39 degrees C showed significant infectivity when assayed at 34 degrees C; only small reductions in reverse transcriptase activity and fusion ability were observed when compared with supernatant from 34 degrees C ts7-infected cultures. That particles are produced at the nonpermissive temperature was confirmed by transmission electron microscopy of the supernatant from ts7-infected cells at 39 degrees C and by transmission electron microscope observations of mature particles trapped in the intercellular spaces of pelleted thin cell section. A possible explanation for the productivity at 39 degrees C of particles that are infectious at 34 degrees C but not at 39 degrees C is that the virus is heat labile at the nonpermissive temperature. Consistent with this hypothesis is the extreme heat lability of virus harvested at 34 degrees C. Such virus, when incubated at 39 degrees C, has a half-life one-sixth that of identical virus incubated at 34 degrees C, or that of wild-type virus at either temperature.


Classification of the New Jersey serotype of vesicular stomatitis virus into two subtypes. We propose a reclassification of five strains of the New Jersey serotype of vesicular stomatitis virus into two subtypes designated Concan and Hazelhurst. This subclassification into two subtypes is based on reciprocal differences in antibody neutralization of virion infectivity, nucleotide base sequence homology, oligonucleotide maps of virion RNA, and interference by defective-interfering particles.


[Continuous automatic ECG analysis using a computer with the cardiac signal directly led in from the patient (II). The diagnosis of heart rhythm disorders using a computer]. It is shown that appraisal and comparison of the duration of the R-R intervals in continuous surveillance of patients by means of electronic computers on the on-line regimen provides for automatic diagnosis of most types of disorders of the cardiac rhythm. The elaborated criterion of arrhythmic cardiac contraction (ACR-R), which takes into account not only the absolute value of the time between heart contractions but also the trend of the changes in the next R-R interval, provides a high percentage of revealed arrhythmic contractions. Disorders of the rate of cardiac contractions may be diagnosed by means of an electronic computer by comparison between the mean value of intervals of normal duration and the preset threshold values. Disorders of the rhythm may be diagnosed by means of an electronic computer by assessment and comparison of the arrangement of the combinations of short, normal, and long R-R intervals. The elaborated algorithms are described in detail and the block diagrams of the programs are shown.


[Factor VIII activity and factor VIII associated antigen in newborns (author's transl)]. Factor VIII activity and factor VIII associated antigen were determined in healthy term newborns. On the first day of life factor VIII activity was higher than in adults. The activity reached the adult level at about the tenth day. The factor VIII associated antigen was found higher than the activity and did not decrease in the first ten days. Studies of the factor VIII associated antigen of newborns by the two-dimensional immunoelectrophoresis showed the same pattern as compared to adults.


Demonstration of thymus-leukemia (TL) antigens on mitochondria of lymphoid cells by immunoelectron microscopy. The presence of thymus-leukemia (TL) antigens on the surfaces of mitochondria isolated from TL+ cells, e.g., RADA 1 leukemia cells, and TL+ normal thymocytes, has been directly demonstrated by immunoelectron microscopy. Reagents used were TL alloantiserum and a hemocyanin conjugate of rabbit antibody to mouse IgG. No hemocyanin labeling was observed on mitochondria obtained from TL- cells, e.g., thymocytes of TL- strains, splenocytes of either TL+ or TL- strains, and TL- leukemia cells. The concurrence of TL antigens on the plasma and mitochondrial membranes was shown by the ability of intact cells to absorb all reactivity toward mitochondria.


Prophylactic treatment of alcoholism by lithium carbonate. A controlled study. Lithium therapy has been shown to have a therapeutic influence in reducing the drinking and incapacity by alcohol in depressive alcoholics in a prospective double-blind placebo-controlled trial conducted over one year, but it had no significant effect on non-depressed patients. Patients in the trial treated by placebo had significantly greater alcoholic morbidity if they were depressive than if they were non-depressive.


Diagnosis of Mallory-Weiss lesions. A common cause of upper gastrointestinal bleeding. Mallory-Weiss lesions were considered to be the source of bleeding 21 (13.4%) of 157 unselected patients admitted to a general medical unit because of suspected upper gastrointestinal haemorrhage over a period of 30 months. They represented 16.7% of the 126 patients in whom there was ultimately good evidence of upper gastrointestinal blood-loss. In the total series of 200 suspected bleeding episodes the incidence was 11.5%. It is suggested that endoscopy of the upper gastrointestinal tract, peformed as early as possible after resuscitation, enables the diagnosis of the Mallory-Weiss lesion to be made, shows that it is a relatively common source of haemorrhage, and establishes whether bleeding has stopped, thereby helping to identify patients who can be managed without transfusion and those who are likely to require surgery.


Disturbed oxidative metabolism in organic brain syndrome caused by bismuth in skin creams. Two patients are described with an organic brain syndrome thought to be due to bismuth (Bi) absorbed from a skin cream. Both patients had intellectual impairment and memory loss punctuated by periods of confusion, tremulousness, clumsiness, difficulty in walking, and myoclonic jerks. A similar clinical picture has been reported from Australia and France in patients taking insoluble bismuth salts by mouth. Bi was found in cerebral venous blood in both patients and in the cerebrospinal fluid in one. It is suggested that bismuth can cross the blood/brain barrier and disturb oxidative cerebral metabolism, because increased lactate production was found with decreased consumption of oxygen and glucose and lowered cerebral blood-flow.


Multiple immune complexes and hypocomplementaemia in dermatitis herpetiformis and coeliac disease. Circulating immune complexes have been detected in 100% of 59 patients with dermatitis herpetiformis (D.H.), and in 100% of 27 patients with coeliac disease (C.D.). Three methods for detecting immune complexes were employed: radiobioassay, which gave an incidence of 77% in D.H. and 81% in C.D.; C1q binding activity, with which the incidence was 83% and 96%, respectively; and precipitation with 4% polyethylene glycol (69% positivity in D.H., 100% in C.D.). The immune complexes in D.H. and C.D. were compared with those in sera from 23 patients with systemic lupus erythematosus (S.L.E.). Multiple complexes of differing properties were found in D.H. and C.D. but not in S.L.E. The varying nature of the complexes in D.H. and C.D. may account for the damage to different tissues (skin, small intestine, reticuloendothelial system). Low third component of complement was found in 49% and low C4 in 20% of D.H. patients. C3 hypocomplementaemia was found in 26% of patients with C.D.


Variable adherence to normal human urinary-tract epithelial cells of Escherichia coli strains associated with various forms of urinary-tract infection. The ability to become attached to normal epithelial cells from the urinary tract was much greater in Escherichia coli bacteria isolated from the urine of patients with acute symptomatic pyelonephritis or cystitis than in those isolated from the urine of patients with asymptomatic bacteriuria. Attachment of the bacteria could be prevented by incubation in urine containing antibodies against the strain tested. The ability to attach to uroepithelial cells might be a virulence factor for E. coli strains which cause symptomatic urinary-tract infection.


Relation of e antigen to infectivity of hBsAg-positive inoculations among medical personnel. Hepatitis-B surface antigen (HBsAg)-positive blood which contained e antigen, when accidentally inoculated into medical personnel, resulted in hepatitis B or an anti-HBs response in 60% compared to 31% when e antigen was not detected in the inoculum. e antigen was detected in 74% of inocula sustained on chronic renal dialysis and transplantation units compared to 20% on other services and the resultant incidence of hepatitis B varied accordingly--i.e., 22% and 6% respectively. Tests for e antigen can identify the relative infectivity of groups of HBsAg carriers; technical improvements should result in valuable applications to individual cases.


Production of pancreatitis in rabbits by intestinal re-instillation of stimulated pancreatic secretion. Pathological changes reminiscent of acute pancreatitis in man were observed in rabbits as a result of the intestinal instillation of pancreatic secretion produced by continuous cholinergic stimulation. Both the cause and nature of the pathological changes suggest a bloodborne disease produced by the absorption of digestive enzyme. It is proposed that acute pancreatitis can be the consequence of the absorption of active digestive enzyme in quantities and at rates sufficient to overwhelm natural defence mechanisms.


Inactive renin in human plasma.

Inactive renin in human plasma. Human plasma contains renin, which is enzymatically active at neutral pH (active renin), and a non-dialysable factor, which has renin-like activity after treatment at low pH (inactive renin). In vitro activated plasma-renin and purified human renal renin showed identical enzyme-kinetic properties. Quantitative estimations of inactive renin in renal venous plasma from 5 patients with renal-artery stenosis demonstrated its release by the kidney. Acute stimulation of renin release by isoprenaline, tilting, or diazoxide in 13 normotensive individuals and in 9 patients with essential hypertension increased active plasma-renin and reduced inactive plasma-renin. Inactive plasma-renin was increased and active plasma-renin decreased during suppression of renin release by propranolol in 12 patients with essential hypertension. In 55 patients with various disorders, inactive and active plasma-renin were directly correlated. However, the concentration of inactive renin, for a given value of active renin, varied widely from patient to patient. These results indicate that so-called inactive renin is indeed physiologically related to active renin. They also suggest that inactive renin can be activated not only in vitro, but also in vivo. Different renin assays measure different relative amounts of active and inactive renin. This may call for reinterpretation of results obtained by various methods, especially in situations where changes in plasma concentrations of the two forms of renin are in opposite directions.


The rhythm of the normal human heart.

The rhythm of the normal human heart. The 24-hour cardiac rhythm was studied in 86 subjects (41 male, 45 female) aged 16-65 years, after exclusion of 15 additional volunteers with suspected abnormalities. The electrocardiogram was recorded continuously for two 24-hour periods. In this apparently normal population, 10 subjects (12%) had disturbances of rhythm which are widely believed to be of serious prognostic significance; they included frequent ventricular ectopic beats, R-on-T and multifocal ventricular ectopic beats, bigeminy, and ventricular tachycardia. Supraventricular tachycardia, infrequent ventricular ectopic beats, junctional rhythm, and second-degree heart block were also observed, and if these are included most of the subjects showed some disturbance of rhythm. Bradyarrhythmias and tachyarrhythmias were equally common in waking hours and during sleep. These disturbances were not confined to the older age-groups. Heart-rate but not the number of arrhythmias was significantly higher in smokers.


Coronary heart-disease after treatment of hypertension. Within a group of 1026 men aged 47-54, cause-specific death-rates and the incidence of non-fatal myocardial infarction and stroke in treatment group of 635 hypertensive men (casual systolic B.P. greater than 175 or diastolic B.P. greater than 115 mm Hg on two occasions) treated at a hypertension clinic were compared with those in a control group of 391 men (causal systolic B.P. greater than 175 or diastolic greater than 115 mm Hg on only one occasion) who remained mainly untreated during their 4.3 years of follow-up. The predicted risk of coronary heart-disease (C.H.D.) at entry, calculated by a multiple logistic function, was slightly higher in the treatment group. Total death-rate during follow-up was significantly lower in the treatment group (3.3%) than in the control group (6.1%). The difference in death-rate for C.H.D. was of the same relative order (0.8% versus 1.5%), as was the incidence of non-fatal myocardial infarction (2.8% versus 5.4%), although none of the differences reached statistical significance. However, the pooled incidence of fatal and non-fatal C.H.D. was significantly lower in the treatment group (3.6%) than in the control group (6.9%). The results suggest that antihypertensive treatment might be effective in preventing or postponing C.H.D. in middle-aged men.


Association of presenile cataracts with heterozygosity for galactosaemic states and with riboflavin deficiency. Red cells and the lens of the eye are non-nucleated cells; moreover, they have metabolic similarities. Cataracts develop in childhood in homozygotes for galactosaemic abnormalities, which can be detected by biochemical measurements in red blood-cells. It has not been determined whether heterozygotes for these defects are at greater risk for cataract development later in life. Similarly, riboflavin deficiecy for which the erythrocyte is a sensitive indicator, has been associated with cataracts in animals. Red-cell studies were carried out in 22 patients, aged under 50, with cataracts. Heterozygosity for galactokinase deficiency was detected in 5 patients, for galactose-uridyl transferase in 2, and evidence of an erythrocytic deficiency of riboflavin in 8. Even when Black subjects were excluded from analysis because of their high incidence of polymorphism for galactokinase, these findings are significantly different from those expected from population surveys and suggest that many patients with presenile cataracts have a biochemical abnormality which can be detected by examination of red blood-cells and which may be corrected by dietary restrictions or supplements.


Cardiorespiratory arrest and diabetic autonomic neuropathy. Twelve cardiorespiratory arrests in eight neuropathy are reported. Only one patient died at the time, but two others subsequently died suddenly at home. There was no evidence of myocardial infarction, cardiac arrhythmia, or hypoglycaemia at the time of arrest. In most of the episodes there was some interference with respiration, either by anaesthesia, drugs, or bronchopneumonia. Five of the episodes occured during or immediately after anaesthesia. It is suggested that the arrests were caused by defective respiratory rather than cardiovascular reflexes. Cardiorespiratory arrest appears to be a specific feature of diabetic autonomic neuropathy and may contribute to the mortality of this condition.


Common precursor molecule as origin for the ectopic-hormone-producing-tumour syndrome. When messenger R.N.A. (m-R.N.A.) extracted from various hormone-secreting tumours was injected into Xenopus eggs, the translation products in all cases proved to be a protein of molecular weight 65 00. Analysis by polyacrylamide-gel electrophoresis and specific precipitation reactions with antibodies showed a striking similarity between the various proteins. When translation products of m-R.N.A. from calcitonin-secreting medullary thyroid carcinoma (M.T.C( and the non-secreting anaplastic form of M.T.C. were incubating with specific enzyme systems (the microsomal fraction) from both types of tumour, enzymes from anaplastic M.T.C. had no effect on the translation products, whereas enzymes from differentiated M.T.C. degraded the translation products from both differentiated and anaplastic M.T.C. The results support the hypothesis that the primary gene product of all the different types of carcinoma cell studied is a single large protein (a hormone precursor or prohormone) containing different specificities. The specific enzyme system in each carcinoma cell probably selects the specific hormone liberated from this primary protein.


Polyamine interaction with pregnancy serum in suppression of lymphocyte transformation. Biogenic polyamines interacting with pregnancy serum elicit potent suppression of lymphocyte transformation in vitro. Within the assay limits, activity was first shown after about 15 weeks' gestation and reached its highest level at about 28 weeks. This level was maintained until term. It is thought that specific humoral amine oxidases were the cause. Fetal-cord serum and non-pregnancy serum were inactive. This system may have an immunoregulatory function in pregnancy.


Pool-priming: A means of generating T lymphocytes cytotoxin to tumour or virus-infected cells. It is proposed that cells cytotoxic for autologous or syngeneic tumour cells can be produced in vitro by sensitisation of lymphocytes to a pool of normal cells from 20 unrelated individuals. Restriction on molecules that can serve as cytotoxic determinants (C.D.), may explain why a random pool of cells from 20 people could present essentially all of the determinants (C.D.) may explain why a random pool of occur because of extensive cross-reactivity of antigens on tumour cells with normal alloantigens present in the stimulating pool.


Epidemic malathion poisoning in Pakistan malaria workers. In 1976, epidemic organophosphate insecticide poisoning due to malathion occurred among 7500 field workers in the Pakistan malaria control programme. In July, the peak month of the epidemic, it is estimated that there were about 2800 cases. In field studies low red-cell cholinesterase activities were associated with the signs and symptoms of organophosphate insecticide intoxication. Toxicity was seen with 3 different formulations of the insecticide and was greatest with the products containing increased amounts of isomalathion, a toxic malathion degradation product. Poor work practices, which had developed when D.D.T. was the primary insecticide for malaria control, resulted in excessive skin contact with and percutaneous absorption of the pesticide. Airborne malathion concentrations were very low. Implementation of good work practices and proscription of use of the 2 pesticide formulations most contaminated with isomalathion halted the epidemic in September. An extensive training programme and surveillance system for pesticide toxicity preceded 1977 spraying operations.


Colonic response to dietary fibre from carrot, cabbage, apple, bran. Approximately 20 g/day of concentrated dietary fibre from carrot, cabbage, apple, bran, and guar gum was added to the controlled basal diet of nineteen healthy volunteers. Faecal weight increased by 12% on bran, 69% on cabbage, 59% on carrot, 40% on apple, and 20% on guar gum. These changes in faecal weight were correlated with an increased intake of pentose-containing polysaccharides from the fibre. On the basal diet there were pronounced individual differences in faecal weight, and from these the response of subjects to the fibre preparations could be predicted. Addition of fibre shortened mean transit-time through the gut and significantly diluted an inert marker in the faeces. Diet-induced changes in colonic function may explain international differences in the prevalence of colonic disease, whilst personal variation in the response to dietary fibre may determine individual susceptibility to large-bowel disease within a community.


Osteomalacia after small-intestinal resection. Histological examination of bone from 25 patients with small-intestinal resection showed that 9 (36%) had osteomalacia, which was severe in 5 and mild in 4. The serum-alkaline-phosphatase concentration was raised in all patients with severe osteomalacia, but serum calcium, phosphate, and alkaline-phosphatase concentrations were normal in the 4 patients with mild disease, 2 of whom had symptoms. Osteomalacia was diagnosed radiologically in only 3 patients. Osteomalacia appears to be commoner in patients with small-intestinal resection than has previously been thought, and bone biopsy is essential if all cases are detected. Although high-dose parenteral vitamin-D therapy is usually effective in the treatment of osteomalacia after small-intestinal resection, our findings showed that oral vitamin-D metabolites and their analogues may also be effective. This has important practical advantages.


Rubella infection and diabetes mellitus. The incidence of diabetes mellitus was increased in patients with congenital rubella. Experimental congenital rubella infection in rabbits caused histological changes in the beta-cells of the pancreatic islets similar to those found in mice made diabetic by the M variant of the encephalomyocarditis virus. It is concluded that the diabetes seen in congenital rubella is due to viral infection of the pancreatic islet cells.


A role for purine metabolism in the immune response: Adenosine-deaminase activity and deoxyadenosine catabolism. We have investigated a new hypothesis for the association between adenosine deaminase (A.D.A.) deficiency and immunodeficiency--namely, that deoxyadenosine rather than adenosine (an equally effective A.D.A. substrate) is toxic to proliferating cells of lymphoid origin. This possibility was explored in mitogen-stimulated lymphocytes cultured with a potent A.D.A. inhibitor, E.H.N.A. (erythro-9[2-hydroxy-3-nonyl] adenine) to simulate A.D.A. deficiency. In this in-vitro system deoxyadenosine was inhibitory at much lower and more physiological concentrations (1 mumol/1), compared with adenosine (100 mumol/1).


Amitriptyline plasma-concentration and clinical effect. A World Health Organisation Collaborative Study. 54 patients in five centres participated in a study of the relationship between steady-state plasma-levels of amitriptyline (AT) and its active metabolite nortriptyline (NT) and therapeutic response. The participants were inpatients who, after a 7-12 day period of assessment, were rated greater than or equal to 16 on the Hamilton rating scale for depression. They were given 75 mg of amitriptyline for 3 days and then 150 mg daily for an active-treatment period of 6 weeks. Clinical ratings and plasma-samples were obtained at baseline then at 2, 4, and 6 weeks after starting therapy. Contrary to the findings of three previous trials, no important correlations were found between steady-state plasma-levels and therapeutic outcome or corrected side-effects. Corrected side-effects correlated negatively with therapeutic outcome. There seems little advantage in routine monitoring of AT and NT, since variations in plasma-levels do not account for the considerable variation in therapeutic outcome.