A review of the National Health Service's computing policy in the 1970s.

The health service computer policy is reviewed in this paper particularly the potential contribution of some systems to information gathering. The paper begins with a brief description of the computer applications thought suitable for the medical field in the late 1960s, and two views of the future that were published in 1968. Two reports on computing and information systems in Scotland are then described; the general philosophy and specific proposals on the use of population files are contrasted with the initial Department of Health and Social Services' (DHSS) experimental computer program. The subsequent changes in English policy are revealed in the reports of three reviews published by the DHSS. The present development of a master patient index in Tayside is noted and the potential applications in management and planning of information stemming from such systems are discussed. It is suggested that lack of work in this field is a major gap in the programme of activity in England.


Anencephalus, Spina Bifida, twins, and teratoma.

The twin pairs with spina bifida and or anencephalus collected from the literature by Rogers and Weatherall (1976) form the basis for an argument that the apparent rarity of dizygous twins concordant for these malformations may be due to the breakdown of the interamniotic partition and a subsequent fetus-fetus interaction. It is suggested that this may lead to complete or partial destruction of one twin. When cells survive they may form teratoma or patches of anomalous skin cover. The hypothesis that monozygous twins concordant for these defects may form double monsters is re-stated. The present hypothesis predicts that the incidence of pineal and intraspinal teratoma will vary in time and place with anencephalus and spina bifida, and that the scalp type hairs found over or around spina bifida may prove, in male infants, to have female chromosomes.


Area differences in the incidence of neural tube defect and the rate of spontaneous abortion.

In an attempt to corroborate the finding of Roberts and Lloyd (1973) of increased incidence of previous abortions in women living in those areas of South Wales with relatively low incidences of malformations of the central nervous system, we examined the data of the 1958 British Perinatal Mortality Survey. We also found evidence that the history of preceding abortion among all mothers in this survey was slightly more prevalent in areas where the rates of stillbirth and neonatal death from anencephalus or spina bifida were low, but the order of magnitude was much less than in the Welsh study.


Hypochondriacal states.

A brief historical introduction traces the evolution of the concept of hypochondriasis. It is suggested that the term should now be used only as a descriptive adjective when there is a morbid preoccupation with health or body. Social and cultural factors are outlined, as well as problems of measurement. The psychopathology, as formulated by Freud and others, is also described. Clinical aspects are discussed under the headings of general symptoms, pain, smell, bodily appearance, sexual, gastro-intestinal, cardio-respiratory, eyes, and ears, nose and throat. Psychiatric syndromes mentioned are: hypochondria as a possible primary state, personality disorders, phobic-anxiety state, neurashthenia, obsessional neurosis, hysteria, depression, paranoid psychosis and organic. In general, hypochondriacal symptoms seem to make the prognosis rather worse. Treatment is to be aimed at the primary condition, which is most commonly depression, anxiety state or conversion reaction.


Subacute sclerosing panencephalitis presenting as Leonhard's speech-prompt catatonia.

A woman aged 20, first presenting with what appeared to be hysterical blindness as part of the syndrome of hysterical pseudo-dementia, soon showed the picture of speech-prompt catatonia, one of the subtypes of chronic schizophrenia described by Karl Leonhard. However, within a short time the neurological, EEG and laboratory findings indicated that the condition was one of subacute sclerosing panencephalitis.


Parent-offspring resemblances in intelligence: theories and evidence.

A review of data on parent-offspring resemblances in intelligence is presented in the context of correlation, regression and variance predictions from the polygenic model and an environmental model. Consideration was given to reliability, test equivalence and long-term stability of IQ scores. Results indicate that much of the difference among offspring IQ scores is not directly attributable to parental IQ, and that some is due to other between-family variables. The magnitude of single-parent-offspring correlations was related to the degree of assortative mating present in samples. Evidence on whether parent-offspring resemblances in IQ are transmitted genetically or environmentally is on the whole lacking. A single study provides evidence for some degree of genetic transmission, but it is argued that the present polygenic model is inadequate.


Computer subtraction in regional cerebral blood-volume measurements using the EMI-Scanner.

A computerized subtraction technique has been described to measure regional cerebral blood volume (rCBV) using the EMI-Scanner in a group of 13 patients. Sodium iothalamte was injected intravenously (1-75 ml./kg) to increase the absorption of X rays in the cerebral circulation. Significant regional differences in CBV were shown, values in the frontal and temporal regions being lower than the mean hemisphere value (4-9 +/- 0-7) and higher in the occipital region. The left hemisphere showed a significantly higher CBV when compared with the right. Measurements of CBV in the cortex showed no regional variation, but the mean cortical value of 6-0 +/- 1-8 was significantly higher than the hemisphere mean.


Measurement of regional pulmonary oedema in man using radioactive water (H215O).

Regional extravascular lung water (rELW) has been measured in normal subjects and in patients with left heart diseases using a double-indicator dilution technique and external counting over the chest. Gamma-emitting radioisotopes were injected intravenously, 113Inm as a vascular non-duffusible indicator, and H215O as a freely diffusible indicator. Time activity curves were then recorded over the upper and lower zones of the lung in the supine position with external probes. rELW per unit of blood volume and rELW per unit of blood flow were increased in patients with raised left atrial pressure even in the presence of radiologically clear lung fields. There was a uniform distribution of these ratios between upper and lower zones in normals, whereas in patients rELW was preferentially distributed in the lower zones.


The limitations of 113Inm for plasma volume measurement.

Previous authors have claimed that 113InmCl3 is a valid tracer for plasma volume measurement. However, careful measurements in haematologically normal volunteers and in rabbits, using 125I-labelled human serum albumin as a reference tracer, show that the results obtained with 113Inm-chloride, -citrate or -transferrin consistently over-estimate the plasma volume and are probably no better than can be predicted from the height and weight of the subject.


Circumcaval ureter: a report of four cases in children with a review of the literature and a new classification.

4 cases of circumcaval ureter presenting in childhood are reported. A review of the literature reveals that most cases recieve attention only later in life at a time when ureteric changes are not so readily reversible. A study of the course of the ureter reveals that 2 forms can be distinguished: a common Type I with a slter reveals that 2 forms can be distinguished: a common Type I with a low loop and kinking of the proximal ureter producing obstruction and a rare Type II with a high loop where there is no kinking and no obstruction. Ureteric remodelling on the ordinary principles formulated for congenital obstructions can give good results.


Effect of nicotine chewing gum on smoking behaviour and as an aid to cigarette withdrawal.

In a double-blind, placebo-controlled, crossover trial the effect of 2-mg nicotine chewing gum was studied in 43 smokers when they were smoking as inclined and when they were trying to stop smoking. Although 70% of the smokers stopped smoking during treatment, only 23% were still abstinent after one year. The effect of the nicotine, though significant, was small compared with the overall reduction in smoking. When the subjects were smoking as inclined cigarette consumption was reduced by an average of 37% on the nicotine gum compared with 31% on placebo gum, while avergage carboxyhaemoglobin (COHb) levels were reduced by 26% and 15% on the active and placebo gums respectively. When subjects  tried to stop smoking there was a further considerable reduction in cigarette consumption, but no longer any difference between the two gums. Nevertheless, average COHb was still lower on the active gum. Plasma nicotine levels on the nicotine gum averaged only 10-7 ng/ml compared with 27-4 ng/ml after smoking. Better results could be expected with 4-mg nicotine gums.


Prophylactic antibiotic therapy and heart valve replacement.

Patients undergoing cardiac bypass for heart valve replacement maintained adequate blood concentrations of cloxacillin throughout the duration of bypass, provided their initial blood concentration was in the therapeutic range. Blood levels related to the time between the last preoperative dose of antibiotic and operation. Maximal values were achieved if an intraoperative bolus of drug was given.


Inhibition of human lymphoma cell-line colony formation by lymphocytes from patients with lymphoma and cancer hospital employees.

Inhibition of human lymphoma cell-line colony formation (ICF) was induced by peripheral blood lymphocytes (PBL) from patients with lymphoma and apparently healthy cancer hospital personnel. PBL from patients with non-lymphoma neoplasms and from normal blood bank donors did not elicit ICF. ICF was most marked when PBL were cocultivated for 24 hours in a ratio of 1000:I with target lymphoma cells that had been cultured for 24 hours before exposure. No significant ICF was observed when target cells consisted of human neurogenic sarcoma, melanoma, colon adenocarcinoma, or Chinese hamster cells. It is possible that ICF is elicited by PBL sensitized to a cross-reacting antigen present on the membrane of cultured lymphoma cells. This antigen may be synthesized by a transmissible etiologic factor.


Phase III comparison of the treatment of advanced gastrointestinal cancer with bolus weekly 5-FU vs. methyl-CCNU plus bolus weekly 5-FU. A Southwest Oncology Group study.

In a randomized and stratified study, 294 patients with advanced gastrointestinal cancer were treated either with 5-fluorouracil (5-FU) 400 mg/m2 weekly intravenously (i.v.) or 5-FU 400 mg/m2 i.v. weekly plus methyl-CCNU 175 mg/m2 orally (p.o.) every 6 weeks. The response rate in colorectal cancer with 5-FU was 9.5% while the two-drug treatment produced a response of 31.8% (p=.009). The  response in all gastrointestinal cancers to 5-FU was 10.6% as compared with29.3% for the combination (p=.012). All responses were partial. The two-drug regimen is more effective and more toxic than weekly 5-FU therapy.


Feasibility study of active immunotherapy in patients with solid tumors.

Forty-five immunocompetent patients with solid tumors were immunized with BCG, PPD, and tumor cells. The methods were practical, but the morbidity was significant, including painful draining ulcerations at vaccine sites, possible enhancement of tumor growth in three patients, and the discovery at autopsy of systemic tuberculosis in one patient. Various facets of cellular immunity were altered, namely: 1) a majority of the patients developed enhanced cutaneous reactions to the microbial skin-test antigens (particularly tuberculin) and tumor cells; 2) nine patients developed the equivalent of delayed hypersensitivity reactions or flares at all previous PPD and BCG inoculation sites following subsequent injection of these agents, which supports the concept of immunologic memory for these target antigens; 3) lesions resembling those of "spontaneous" regressed moles (halo-nevi) were observed at previous vaccine sites in 20 patients and generalized depigmentation occurred in three patients; 4) foreign body giant cells in tumor metastasis remote from BCG-PPD-tumor vaccine sites may indicate a cross-reactivity of microbial and tumor antigens; and 5) intralesional inoculation of the nonspecific agents (BCG, PPD, Varidase, and Mumps) resulted in dense mononuclear cell infiltration and complete regression of most of the injected lesions. Destruction of single or multiple lesions by local injections of antigens did not provide either significant regression of uninjected lesions or clinical benefit.


Familial erythrophagocytic lymphohistocytosis. Report of two cases and clinicopathologic review.

An unusual syndrome of hepatosplenomegaly and fever followed by rapid deterioration and death has been described in 38 children from 21 families. Pancytopenia, liver dysfunction, and bleeding developed prior to death from hemorrhage, sepsis, or lymphocytic meningitis. This report reviews the literature and adds a set of twins to the reported cases.


A novel nucleotide implicated in the response of E. coli to energy source downshift.

When E. coli cells are subjected to energy source downshift, the accumulation of RNA (and overall cell growth) is drastically restricted within 1 to 2 min. However, the identity of the primary metabolic signal for this adjustment is a mystery. Earlier studies, and further evidence presented here, show that there is no satisfactory correlation between the sudden adjustment of RNA accumulation and the kinetics of changes in the levels of prospective signalling compounds, such as glycolytic intermediates, ppGpp, ATP, or the three adenylate nucleotides. We have discovered an unusual nucleotide, which we call the phantom spot, whose level decreases dramatically within a minute of downshift, correlating well with the adjustment of RNA accumulation. Preliminary characterization of the phantom spot indicates that it is a triphosphate derived from the guanylate pathway, and suggests that it is a form of GTP with a modification of the imidazole portion of the purine ring. We postulate that this nucleotide serves as a regulatory facsimile of ATP, linking the rate of RNA accumulation and other anabolic processes to the overall rate of phosphorylation.


An electron microscopic study of malignant lymphomas; with special reference to undifferentiated type.

Nine cases of malignant lymphomas of undifferentiated type, which is difficult to classify whether they are derived from reticulum cell or lymphocyte by light microscopy, were collected and studied by electron microscopic and histopathological examinations, and calssified into two types from electron microscopic findings. Some characteristic features, including cellular size and shape, and quantity and quality of cytoplasmic and nuclear structures at the electron microscopic level, were compared between the two types of lymphomas with similarity to reticulum cell and to lymphoblastic cell. From the aspects of systemic and synthetic view, it is possible to classify whether these tumor cells correspond to the so-called reticulum cell or to lymphoblastic cell in malignant lymphomas of undifferentiated type, which was previously thought to be indistinguishable. In addition to these results, clinico- and histo-pathological analyses were also made, with short discussion.


[50 cases of acute malaria: symptomatic study, especially cardiac].

The authors have studied 50 records of patients who had presented an acute attack of P. falciparum malaria. Both sexes were equally implied. Young people were predominant. The distribution of cases was about the same in the whole year. The fever decreases on the second day and increases on the third day (300/0). Among the classical signs: relative rarity of hepatomegalia (100/0), splenomegalia (10 0/0), jaundice (140/0), nervous symptoms (100/0). Vomiting is rather frequent (30 0/0). From the cardiovascular point of view a relative bradycardia is observed in 16 0/0 of the cases, and a relative tachycardia in 100/0 of the cases; hypotension in 100/0 of the cases. Electrocardiographic signs are observed in 360/0 of the cases; they are aspecific, concerning mainly ST-T anomalias (22 0/0) and a QT lengthening (200/0). The cardiothoracic ratio is higher than 0.5 in 320/0 of the cases. From the pulmonary point of view the authors have observed symptoms contemporary of the attack: two asthma attacks, three radiologic anomalias reminding of viral pneumopathias. The biological symptoms are mainly transitory functional renal insufficiency in 18 0/0 of the cases. Protection due to AS heterozygosis seems to be confirmed in this study. The efficiency of intravenous quinin treatment is certain.


A focus of hyperendemic Plasmodium malariae-P. vivax with no P. falciparum in a primitive population in the Peruvian Amazon jungle.

Findings in a sample population in southeastern Peru with a very high rate of malaria infection, due to Plasmodium malariae and P. vivax with apparently no P. falciparum, are described. The proportion of persons with P. malariae in this sample population, as determined by slide examination, appears to be the greatest ever reported for any area before the introduction of control measures. Although very few P. vivax were found on stained slides, results of the indirect immunofluorescence test indicated that this species was probably as prevalent as P. malariae; the absence of P. falciparum was supported by results of serologic tests. Possible reasons for this focus of malaria with no P. falciparum are discussed.


[Filarial eosinophilic lung diseases, value of immunology (apropos of 9 cases)].

The study of nine cases of "eosinophilic lung" using specific immunological techniques indicates that the latter completes the geographical, clinical, radiological and hematological criteria of this syndrome. The search of circulating antibodies confirms the filarial etiology and individualises a remarkable immunological profile thus, suggesting a diagnosis in the case of occult filariases. The intensity of the immunological reactions brings a supplementary argument in favor of the hypothesis of a poor host-parasite relationship in the pathogeny of secondary manifestations to an infestation by W. bancrofti, B. malayi and other animal filariae such as B. pahangi.


[Evaluation of Plasmodium falciparum antigen of human origin using indirect immunofluorescence reaction in malaria].

The authors point out the use of P. falciparum antigens from man in the Malaria IFA test. In Malaria areas it is very easy to find them and although they are "coated" by antibodies they are quite valuable in significant titers. The use of P. falciparum from man is therefore very interesting for Malaria diagnosis in non endemic areas and very useful for Malaria surveys in endemic areas.


WHO collaborative evaluation of reference hepatitis B surface antigen and antibody reagents, subtype ad.

As a result of a WHO consultation in 1970 a guinea-pig antiserum, V801-501-058, was comprehensively evaluated by 11 collaborating laboratories in order to determine its usefulness as a reference reagent for the detection and assay of hepatitis B surface antigen (HB(s)Ag). The range of titres obtained were 1:64-1:256 by the immunodiffusion technique, 1:64-1:512 by counterimmunoelectrophoresis, 1:256-1:4096 by complement fixation, 1:6400-1:9600 by immune adherence haemagglutination, and <1:32 by platelet aggregation. The sensitivity of the guinea-pig antiserum for the detection of HB(s)Ag in serum and plasma samples was found to be equivalent to that of antisera obtained from other sources (man and baboon) with complement fixation and immune adherence haemagglutination, but it was slightly less sensitive with immunodiffusion and counterimmunoelectrophoresis. HB(s)Ag-positive reagent serum, which was used for the preparation of the immunogen, was found to have titres of 1:16-1:64 by immunodiffusion, 1:32-1:128 by counterimmunoelectrophoresis, 1:512-1:4096 by complement fixation, and 1:256-1:25 600 by immune adherence haemagglutination.


Antibody response in the intestinal secretions of volunteers immunized with various cholera vaccines.

The efficacy of various cholera vaccines in eliciting an intestinal antibody response was assessed in human volunteers who received oral live, oral killed, or parenteral cholera vaccines, or placebo. The intestinal immune response in terms of antibacterial and antitoxin antibodies was determined 2 and 4 weeks after immunization. By means of the mouse peritoneum opsonization assay and the infant mouse protection test, antibacterial activity could be detected in the intestinal secretions of volunteers who had been immunized either orally or by the parenteral route. Significant protective activity and duration of immunity were observed with the oral killed vaccine. The bacteriological data indicated the absence of significant intestinal colonization of the live attenuated strain after oral administration, and probably explains the observed lack of effectiveness of the oral vaccine compared with that of the killed vaccine. The predominant immunoglobulin class of intestinal antibody was found to be IgA. None of the vaccines used in the study elicited significant antitoxin activity in the intestinal secretions, as determined by the skin permeability neutralization test.


Sources and incidence of airborne Aspergillus fumigatus (Fres).

Specific surveys of the air for Aspergillus fumigatus were carried out in rural and urban situations over a 2-year period. Overall, low concentrations of spores were recorded with a higher incidence during the "winter" months. Counts in the open air and in a hospital ward showed similar fluctuations, the indoor counts being consistently lower. Plant debris in the form of compost heaps and stacks of hay and straw baled with a high moisture content in which self-heating occurs, produces large numbers of spores which may be liberated into the air causing high but localized counts if disturbed. The widespread distribution of decaying leaves following leaf fall represents a potential source of smaller concentrations of spores but over a much larger area. This availability of decaying plant debris with high water content fulfils the growth requirements of Aspergillus fumigatus and is the probable explanation of its winter seasonality.


A 12-month double-blind assessment of betamethasone valerate aerosol in the management of asthma.

A double-blind trial of the topically active corticosteroid, betamethasone valerate in aerosol form, in the control of chronic asthma is reported. The results show that this is an extremely effective therapeutic agent in non-steroid dependent but nonetheless moderately severe asthmatics. Patients were well controlled on 800 mug of betamethasone valerate daily and control was maintained over a 12-month period. This form of treatment has few undersirable side effects but there is probably an increased incidence of oropharyngeal and laryngeal candidiasis. In particular, adrenocortical suppression was not noted.


Enzyme-immunoassay.

The bases of the different enzyme-immunoassay techniques are described and their applications to the identification and quantification of antigens, haptens, and antibodies in biological fluids are discussed. Substances for which enzyme-immunoassays have been developed are listed. The enzymes used as labels, the methods of linking them to proteins, and the methods for separating free and bound labeled material are described. The reliability and practicality of the enzyme-immunoassay methods are reviewed.


An extraorally activated expansion appliance for cleft palate infants.

A new lever-action expansion appliance is described which is designed specifically for use in infants with cleft lip and palate. An extraoral control knob allows for easy activation, while the important anterior cleft areas are left clear for premaxillary repositioning and clinical assessment. Activation is registered by a positive clicking sound. Rapid expansion is made possible by the design of the appliance which is retained by stainless steel pins.


Indirect immunofluorescence staining of human thyroid by antibodies occurring in Yersinia enterocolitica infections.

In the diagnostic routine for tissue antibodies, using indirect immunofluorescence on cryostat sections of human thyrotoxic thyroid, rat stomach and kidney, ninety-six out of 48,388 sera showed a marginal staining of the membrane region of thyroid epithelial cells but no other reaction. Twenty-six of these sera were from patients with acute Yersinia enterocolitica serotype 3 infection but without signs of thyroid disease. Fifty of sixty-three sera with agglutinins against Y. enterocolitica serotype 3 and three out of four sera with agglutinins against Y. enterocolitica serotype 9 also showed this reaction on thyroid sections. It was due to antibodies, mostly of the IgG class, occurring in low titre, which react with intracytoplasmic antigens in thyroid, as staining of live thyroid epithelial cells was negative. The pattern of immunofluorescence on thyroid sections caused by these antibodies could not be distinguished from that caused by smooth muscle antibodies by appearance only. However, smooth muscle antibodies react also on other tissue sections and extracts of contractile proteins which absorb out these, did not change the reaction on thyroid of Y. enterocolitica sera. Absorption with sonicated Y. enterocolitica 3 and 9 antigens, but not with heat-killed whole bacteria, extinguished the reaction on thyroid. This indicates the presence of a cross-reactivity between antigens in these bacteria, different from the O antigen, and antigens in thyroid epithelial cells. Knowledge of this pattern of immunofluorescence on thyroid sections can be of diagnostic significance.


Clinical significance of antibodies to ovarian antigens; association with cancer of the genito-urinary tract.

Serum from 491 patients with cancer and from 151 patients of comparable age without recognized cancer was tested by indirect immunofluorescence for antibodies to ovarian antigens. Circulating antibody to the cytoplasm of rabbit ova was found in from 19 to 47% of patients with cancer of the ovary, endometrium, kidney, bladder or testis, or with lymphoma, and in only 3-3% of control patients. Antibodies to thecacell antigens were not more common in patients with cancer than in other patients, but within the group of cancer patients, such antibodies were, in all but one case, associated with cancer of the genito-urinary tract or with lymphoma. The anti-theca-cell antibodies observed produced a staining pattern indistinguishable from that obtained with the serum of patients with Addison's disease but were not, in the cancer patients, associated with antibodies to adrenal tissue. Tests for antibody to the cytoplasm of ova were more frequently positive in patients with progressive cancers than in patients successfully treated by surgery or radiation, and were seen in patients in whom cancer had recurred following removal of the organ of origin. These findings suggest that the antigen or antigens that evoke antibody to the cytoplasm of ova arise from tumour cells rather than from damage to normal tissue by surgery, tumour invasion or radiation.


Peripheral lymphocyte subpopulations in human falciparum malaria.

The concentration of circulating T, B, and 'null' lymphocytes was determined in thirty children and three adults with Plasmodium falciparum infections in West Africa. During infection, both percentage as well as concentration of T cells were decreased as compared to levels following treatment. The percentage but not concentration of B cells was increased. Both percentage and concentration of 'null' cells were increased in malaria. Patients with splenomegaly had the most severe alterations in T-cell number; no other historic or clinical parameter correlated with the degree or pattern or change in circulating lymphocyte subpopulations. These alterations were rapidly reversible after antimalarial treatment and presumably represent the sequestration of T cells in the spleen or other organs.


In vitro quantitation of cell-mediated immunity in guinea-pigs by macrophage reduction of nitro-blue tetrazolium.

In the cell-mediated immune (CMI) system lymphocytes from sensitized animals incubated with antigen manufacture and release lymphokines which activate the hexose-monophosphate shunt in macrophages. The rate-limiting enzyme of this activation is NADPH oxidase, the activity of which can be quantitated by the amount of nitro-blue tetrazolium reduced to formazan, a blue precipitate. Data is presented which demonstrates that lymphokine-activated macrophages can be microscopically quantitated, both in the direct and indirect assays, by counting the number of macrophages containing formazan precipitate. The indirect component of this assay correlates directly to the skin test diameter. Further, it correlates better to the skin test than another assay for CMI, the macrophages aggregation factor assay. The simplicity and reproducibility of this assay provides another method whereby lymphokine activation of physiological events in macrophages can be determined.


Membrane antigens shared by renal proximal tubules and other epithelia associated with absorption and excretion.

The distribution of shared antigens in specialized surface membranes of epithelia associated with absorption and excretion was studied using antisera against isolated epithelial brush borders of renal proximal tubules. Rabbits were immunized with a membrane fraction isolated from rat kidneys and the reactions of the resulting heterologous antisera with different rat organs were studied by immunofluorescence. The antisera reacted with the following structures: epithelial brush border of renal proximal tubules, bile canaliculi and bile duct epithelium of the liver, epithelial brush border of the intestinal villi, luminal parts of some epididymal tubules, allantochorionic epithelium, and apical parts of the exocrine epithelium of the pancreatic, salivary and lacrimal glands. Both quantitative and qualitative differences in antigen contents were suggested by absorption experiments.


The reactivity of spleen cells from malarious rats to non-specific mitogens.

The reaction of spleen cells from rats infected with Plasmodium berghei to non-specific mitogens has been measured. The cells have been stimulated in vitro by phytohaemagglutinin, concanavalin-A and by bacterial lypopolysaccharide. In addition the release of lymphocyte activating factor (LAF) by splenic macrophages has been assayed using a heterologous thymocyte culture. The reactivity of spleen lymphocytes from malarious rats is severly affected. The cells do not react either to the T cell-specific mitogens or to the B-cell stimulant. The reactivity of macrophages, as measured by the release of LAF, was not altered by the disease.


A comparative study of the immunohistological and serological response of intact and T cell-deprived mice to Trichinella spiralis.

Thymectomized, lethally irradiated CBA mice reconstituted with anti-theta-serum-treated bone-marrow cells (TxB) were infected with T. spiralis at the age of 11 weeks. Intact, age-matched T. spiralis infected and non-infected CBA mice served as controls. Sera were collected up to 26 days after infection and examined for the presence of total and class-specific antibodies by indirect immunoflourescence. Mesenteric lymph nodes, spleen and axillary lymph nodes were examined by conventional histopathology for the presence of pyroninophilic blast cells, plasma blasts and plasma cells. Immunoflourescence was applied to examine cells containing immunoglobulins of various classes. Antibodies against T. siralis were demonstrated both in intact and TxB mice from day 10 after infection onwards. The amount of antibodies was lower in the TxB than in the intact mice. This might indicate that besides thymus-dependent, also thymus-independent antibodies against Trichinella are formed. No difference was observed in the thymus-independent areas of the lymphoid tissues from both intact and TxB mice, with the exception of a lower increase in number of IgM-containing cells in T cell-deprived mice. A marked increase in pyroninophilic blast cells was found in the thymus-dependent areas of the intact mice after infection, whereas only a very limited increase was observed in the T cell-deprived mice. The data were interpreted as supporting the thymus dependency of host response against Trichinella.


The incorrect use of Chi-square analysis for paired data.

When results are classified in categories (for example, improved and unimproved, reactive and non-reactive) and the same patients are examined by two different treatments or two different tests, then the correct statistical analysis is by McNemars test. More often a Chi-square analysis is used; this is not only incorrect but also leads to erroneous conclusions.


Histone and DNA detection in swollen spermatozoa and somatic cells, by immunofluorescence.

A method of swelling spermatozoa and other cells, which leads to the exposure of nuclear antigens is described. By applying the indirect IFT on these swollen cells with sera containing antibodies to nuclear antigens, and by comparing the results to those obtained in other tests (measuring anti-nuclear antibodies), the following conclusions could be drawn: (a) By swelling human spermatoza, nuclear antigens of the sperm are exposed, and can be used for the detection of antibodies directed against them. (b) Heterlogous antibodies to histones F2al, FIa2 and F3 which can not be detected in the indirect IFT on rat liver cells, become detectable after swelling of these cells. (c) Mature human spermatozoa contain, in addition to double-stranded DNA and protamine, small amounts of histone F2b and F2a2. (d) In mature human spermatozoa histone F1 is absent.


The occurrence of antibodies against single-stranded DNA in the sera of patients with acute and chronic leukaemia.

One hundred and seventy-five sera from thirty-three patients with acute myeloid leukaemia, forty-two patients with chronic myeloid leukaemia and twelve patients with acute lymphatic leukaemia were examined by a radioimmunological technique for the presence of antibodies against single-stranded and double-stranded DNA. The levels of single-stranded DNA binding activity was significantly higher in all three types of leukaemia compared to those of healthy controls. In contrast, none of these sera exhibited a positive reaction with double-stranded DNA. In some cases the level of serum anti-DNA antibodies increased after the decrease of the leucocyte count. The presence of anti-DNA antibodies in leukaemic patients may have some biological significance.


Changes in intra-vascular complement and anti-treponemal antibody titres preceding the Jarisch-Herxheimer reaction in secondary syphilis.

Six patients with secondary syphilis and one control subject were observed over a period of up to 8 hr following the administration of either penicillin or erythromycin. Serial clinical observations were made and blood samples obtained for complement and serological analysis. The patients showed Jarisch-Herxheimer reactions (JHR) of varying intensity which were found to be preceded by and to parallel in degree certain changes in complement and syphilitic antibody titres. Falls in total haemolytic complement, in C4, C3, C6 and C7 and a marked drop in C1INH were observed. There was no change in total GBG/GGG or evidence of conversion of GBG to GGG. Associated falls occurred in the titres of the QFTA and the QTPHA antibodies but not of the QVDRL or QTPI antibodies. C3 conversion was found in the two patients that suffered severe reactions. Immune complexes were not detected and it is suggested that complement activation occurred in the extra-vascular body compartment. The significance of these changes in relation to other plasma enzyme systems and to the development of the full clinical picture of the JHR is discussed.


Interdependence of thymic and neuroendocrine functions in ontogeny.

The immunological blockade of the adenohypophysis of athymic nude mice bearing allogeneic skin grafts prevents the reconstitution of transplantation immunity when such animals grafted with thymus, and the grafts are permanently accepted. Newborn and adult athymic mice have markedly diminished levels of prolactin in blood and abnormally high levels of luteotropic hormone. Implantation of the thymus normalizes blood levels of these two hormones. These findings affirm the role of the thymus in the organization of the maturing brain for endocrine functions and identify prolactin as one of the hormones which play a major role in immune differentiation in early ontogeny.


Epidemic glomerulonephritis in Maracaibo. Evidence for progression to chronicity.

In 1968 an outbreak of 348 cases of acute poststreptococcal glomerulonephritis (AGN) was observed in Maracaibo, Venezuela. During the year, the epidemic had three peaks of incidence. Districts with better sanitation showed a lower incidence of disease than those with less adequate facilities. Endemic cases occur every year. Lowering of serum complement activity was observed in 96% and hypertension in 90% of the patients. The mortality rate in the acute phase during the epidemic was 1.31%. A history of antecedent infection was found in 39% of the cases. 70% of these infections were in the upper respiratory tract. During 1973-74, 120 of the patients (19 adults and 101 children) were reexamined. All but one had been completely asymptomatic. Sixteen patients (13.3%) had one or more of the following abnormalities (group A): low CCr, microscopic hematuria, proteinuria of 1 g/day or more and hypertension. One hundred and four patients (86.7%) were normal by all clinical and laboratory parameters tested (group B). The incidence of persisting disease, as judged by biochemical findings, was significantly higher (P less than .01) in adults (36.7%) than in children (8.9%). Percutaneous renal biopsies from 7 patients of group A, and 8 patients from group B, were studied by light microscopy and immune histology. All biopsies from group A patients had evidence of advanced glomerular disease by light microscopy and by immune histology. Seven biopsies from group B patients were also abnormal showing mild changes with corresponding immunologic findings. Only in one patient was the biopsy completely normal. Our studies indicate that significant numbers of patients progress towards chronicity after epidemic, poststreptococcal AGN. Such progression is more common in adults than in children.


Glomerular lesions in asymptomatic microscopic hematuria discovered on routine medical examination.

Renal biopsies from 145 patients with asymptomatic microscopic hematuria were studied with light microscopic, electron microscopic and immunofluorescence antibody techniques. The predominant lesions were a diffuse proliferative glomerulonephritis (mesangial hypercellularity) with focal epithelial crescents and focal segment and/or global sclerosis in many of them; and a minimal lesion with increased mesangial matrix and mild mesangial hypercellularity. Focal and segmental glomerulonephritis, diffuse mesangio-capillary and membranous glomerulonephritis were less common lesions. IgA deposition with other immunoglobulins was seen in over 50% of cases, with an IgA IgG-Beta1C-globulin combination being the common lesion. IgA secretory piece and HBs antigen were not found in the glomeruli and early complement components C1q and C4 were absent. Changes in the mesangium, basement membranes of capillary loops and mesangial osmophilic deposits reflect the pathogenesis of this disease. In addition to the above 145 patients, thirty-five cases of persistent microscopic hematuria classified as symptomatic, with a past history of "acute nephritis", lumbar pain and other complaints; and 11 patients with macroscopic hematuria, painless or associated with "acute nephritis" had similar glomerular lesions. Raised ASOT levels suggest the role of an upper respiratory infection in the exacervation or precipitation of this lesion. The IgA depositon may be associated with deposition of other antibodies in a picture of chronic glomerulonephritis, post-streptococcal or otherwise. 6 of the 145 patients with asymptomatic microscopic hematuria have gone into chronic renal failure in 3.5 years.


Kidney transplantation in primary oxalosis.

A 33 year old patient with primary oxalosis was submitted to cadaver kidney transplantation after 15 months treatment by hemodialysis. During the dialysis period, he developed complete heart block which immediately followed bilateral nephrectomy. The transplant functioned correctly and was found to excrete large amounts of oxalate. Death, which supervened 7 months after transplantation, was due to miliary tuberculosis. The patient's own kidneys and various organs examined post mortem showed extensive oxalate deposits, which were mainly observed in the graft, conducting system of the heart, ocular structures, spleen and pancreas. The problems of managing terminal uremia secondary to primary oxalosis are discussed.


Effect of haematological malignancies and their treatment on host defence factors.

Immunological factors are involved in all aspects of the lymphomas and leukaemias. The aetiology of these diseases is related at least in some cases to immunodeficiency, immunostimulation, autoimmunity and a dysregulation of the immune system. The majority of lymphomas and leukaemias are monoclonal proliferations of the B-lymphocyte series at different stages of maturation while some are derived from T lymphocytes and others have no recognisable B or T-cell markers. Each of the lymphoid malignancies has a characteristic and unique pattern of immunological deficiency, suggesting a unique aetiology. Hodgkin's disease and histiocytic lymphoma, the acute leukaemias and chronic myelogenous leukaemia have predominantly cell-mediated immune deficiencies, while lymphocytic lymphoma, chronic lymphocytic leukaemia, multiple myeloma, and the plasma cell dyscrasias have predominantly humoral immune deficiencies. There is a relationship between immunocompetence and prognosis and between immunocompetence and extent of disease in the lymphomas and leukaemias. Immunocompetent patients have a better prognosis and more limited disease than immunoincompetent patients. Therapy for these diseases profoundly suppresses host defence mechanisms, particularly those which are cell-mediated. Ability to resist or  recover from this immunosuppression is also associated with an improved prognosis. Lymphoma and leukaemia also induce a tumour-specific immune response in the tumour-bearing host and this also correlates with prognosis. These factors form a rational basis for immunotherapy and indeed lymphomas and leukaemias respond to active nonspecific immunotherapy with BCG and active specific immunotherapy with tumor cells resulting in prolongation of remission duration and survival.


Biological and clinical significance of the gut as a barrier to penetration of macromolecules. Practical implications with respect to breast feeding.

This review stresses the importance of the gut as an immunologic organ, and describes those factors in the gut which impede penetration of potentially harmful macromolecules, particularly the secretory IgA system. Because of the immaturity of this gut function in the young infant, breast feeding should be encouraged for the first six to nine months of life whenever possible.


Immediate information expected by the neonatologist from the placenta.

As the obstetrician attends to the mother and the pediatrician to the child, the placenta often tends to be ignored. Nevertheless, essential anamnestic information about the condition of a newborn infant, and especially of a premature, can be gained from careful scrutiny of the placenta and fetal membranes. This paper emphasizes the importance of gross examination of the placenta and membranes as a source of immediate information to the pediatrician within the delivery room.


Antihypertensive effects of oxprenolol and propranolol.

The antihypertensive effects of the beta blockers oxprenolol and propranolol were compared in a randomized double-blind study of patients with standing diastolic pressures (SDP) exceeding 99 mm Hg when receiving hydrochlorothiazide alone. After 3 wk of hydrochlorthiazide with placebo, the latter was replaced with oxprenolol (n= 12) or propranolol (n = 14), 20 mg three times daily. Beta blocker was increased subsequently to 40 and 80 mg three times daily if SDP exceeded 89 mm Hg. Nine oxprenolol and 7 propranolol subjects were hospitalized for 24-hr monitoring. With oxprenolol, standing pressure declined from 135 +/- 2 (SE)/104 +/- 1 MM Hg to 128 +/- 3/90 +/- 2. SDP declined to under 91 mm Hg in 7 of 12 subjects, and to from 91 to 95 in 3 subjects. With propranolol, findings were 138 +/- 3/106 +/- 2 to 123 +/- 3/89 +/- 3; in 7 of 12 to less than 91 mm Hg and from 91 to 95 in 4 subjects. Decrements in supine and SDP were slightly (4 mm Hg) greater for propranolol than for oxprenolol. Both drugs gave similar 24-hr blood pressure control. We conclude that oxprenolol and propranolol used to supplement hydrochlorothiazide provide comparable reductions in blood pressure and smooth control over a 24-hr period in most patients with hypertension.


Spironolactone and potassium canrenoate in normal man.

The pharmacological activity of single doses of the two aldosterone antagonists, potassium canrenoate and spironolactone, was examined in two studies in healthy volunteers. Both drugs were active in reversing urinary electrolyte changes induced by fludrocortisone in periods 2 to 16 hr after treatment. Potassium canrenoate was significantly less potent that spironolactone on a weight or molar basis, with best estimates of the relative potency potassium canrenoate: spironolactone of approximately 0.3:1. On a weight basis the two drugs yielded plasma levels of the metabolite canrenone which were approximately equivalent. The results indicate that canrenone is not the principal pharmacologically active metabolite of spironolactone. Our study suggests that a major part of the renal antimineralocorticoid activity of spironolactone may be attributable to minor sulfur-containing metabolites or their precursors having a high renal clearance that affords access to their site of activity via the renal tubular fluid.


Metaproterenol in children with chronic asthma.

Metaproterenol sulfate was given to 25 children with asthma in the form of a syrup in a continuous treatment course of 180 days. Dosage amounted to 10 to 20 mg metaproterenol four times daily, depending on the patient's age and weight. Double-blind crossover tests of pulmonary function were run against placebo at the beginning and after 3 and 6 mo of treatment. The peak expiratory flow rate responses to metaproterenol consistently exceeded the responses to placebo, the differences proving statistically significant at several intervals after administration. Adverse reactions were limited to instances of hyperactivity in one child and of mild tremors in another; laboratory values remained normal throughout the 6-mo period except for low normal fasting blood sugar values recorded in 2 patients at the end of the study. Pulse rate increases occurring after metaproterenol were not considered clinically important.


Metabolism of ethosuximide.

Twenty subjects, in a double-blind, controlled, rising dose study, were given ethosuximide either once daily or 3 times daily. Steady-state plasma levels and urinary throughput were proportional to dose and were equivalent whether the daily dose was given as a single or divided dose. This finding adds validity to consideration of the single daily dose regimen as a therapeutic possiblity. The metabolic principles should be considered both in patient management and in the treatment of overdosage.


A model to evaluate mild analgesics in oral surgery outpatients.

A model was developed to evaluate mild analgesics in an oral surgery outpatient clinic population. On a report form, patients recorded starting pain and then pain intensities, relief responses, and side effects hourly for 3 hr after drug administration. The treatments were randomly allocated to patients on a single-dose-only basis, and the double-blind technique was used. The first of two studies compared codeine 30 mg, aspirin 650 mg, codeine 30 mg with aspirin 650 mg, and placebo in 128 subjects. The second study compared codeine 60 mg, acetaminophen 600 mg, and codeine 60 mg with acetaminophen 600 mg and placebo in 160 subjects. Time-effect curves were generated for both pain relief and pain relief and pain intensity difference (PID). First-hour scores, peak scores, and total scores were statistically analyzed by parametric and nonparametric factorial analysis. Both aspirin 650 mg and acetaminophen 600 mg proved superior to placebo (p less than 0.01) for all measures of effect with both parametric or nonparametric analyses, while codeine 30 mg was not significantly superior to placebo in any analysis. Codeine 60 mg proved significantly superior to placebo for certain measures of effect when analyzed with the nonparametric model. There was no significant interaction between either aspirin or acetaminophen and codeine.


Octopamine neurons in lobsters: location, morphology, release of octopamine and possible physiological role.

Octopamine cells are found along second thoracic roots, where they serve as neurosecretory neurons capable of releasing octopamine at two distinct points: one into the hemolymph immediately before it enters the gills; one into the hemolymph immediately after it leaves the gills. The octopamine cells receive a cholinergic synaptic input. We presume that this input is from processes of peripheral sensory cells bringing information to the CNS. Octopamine can increase the strength of contraction of exoskeletal muscles and, at higher concentrations, can induce contractures in these muscles. These effects can be interpreted as a resetting of the level of ionized calcium within muscle fibers (the contracture) to a higher value or a possible enhanced entry of calcium ions during nerve stimulation (increased strength of contraction). The observed effects are of a prolonged duration, outlasting the time of application of octopamine by some 20-40 minutes. We do not know if this effect on muscle tension production is the normal physiological role of octopamine. Other possible roles will be explored in the future. The pathway involving the octopamine neurons in lobsters may provide a model neurohumoral system that can be studied and understood in detail from the level of sensory input to the level of behavioral output.


Transference: historico-philosophical note.

Transference as a term in philosophy has been used by Kant and Fichte from the end of the 18th century. By the end of the next one it became widely used. Freud's first "definition" of the term transference (1895) is, as far as daily use of it is concerned, the most precise one and in closet symphony with the early ones in philosophy. The later formulations of his, are dim and vague. But even in this respect they follow the path this metaphore has already passed in the works of Dilthey: from a specific descriptive notion to an all-encircling concept. These uncertainties of meaning, depleated its practical value. Further studies might be of, both, theoretical and practical importance, only if discipline will be applied in defining and testing its definitions. To proceeed further in scholastic disputations is senseless.


Reduced inspiratory effort during intermittent mandatory ventilation with PEEP.

The use of intermittent mandatory ventilation (IMV) and positive and expiratory pressure (PEEP) may demand the patient mount an inspiratory pressure equivalent to the pressure level of the PEEP for spontaneous breathing. During respiratory failure, ineffective inspiratory muscles may be unable to consistently meet such demands, especially if high levels of PEEP are used. A technique which reduces the required inspiratory effort was devised for use in patients being treated with IMV and PEEP. Using this technique, isovolume inspiratory time was dramatically reduced and less inspiratory effort was required. This maneuver may assist spontaneous breathing in patients with respiratory failure on high levels of PEEP.


Indoramin in the treatment of hypertension: a placebo controlled trial.

The effect of the alpha-blocker indoramin was studied in a 4-week double-blind comparative trial with placebo in 39 patients with mild to moderate essential hypertension. Dosage of indoramin was individually adjusted and ranged from 125 mg to 200 mg daily. Indoramin produced a significantly greater reduction in diastolic blood pressure than placebo, and 9 (56%) out of 16 patients attained diastolic pressures of 90 mmHg or less. Heart rate, haematology and blood biochemistry were unaffected by treatment with indoramin, and there were no E.C.G. changes. Nine out of 19 patients on indoramin complained of side-effects. These were generally not troublesome, although 3 patients withdrew because of severe tiredness or weight gain.


The effect of PEEP on oxygenating capacity in acute respiratory failure with sepsis.

We report an evaluation of the effect of postive-end-expiratory-pressure (PEEP) on improving pulmonary oxygenating capacity in the adult respiratory distress syndrome (ARDS), when the latter is associated with generalized gram-negative sepsis. Fifty-seven cases treated in our RICU with PEEP ventilation (April 1972 to January 1975) were retrospectively reviewed. Oxygenating capacity improvement was evaluated in terms of the changes in PaO2/FIO2 and AaDO2 (FIO2 = 1.0). Both the short term (2-3 hours from the initiation of PEEP) and the overall effects of PEEP were evaluated. A mean PEEP of 5.6 cm H2O initially increased PaO2/FIO2 by a mean of 94 torr and decreased AaDO2 (FIO2 = 1.0) by 105 torr in the 28 nonseptic patients. In the 29 septic patients, 5.1 cm H2O PEEP initially increased PaO2/FIO2 by 32 torr and decreased AsDO2 (FIO2 = 1.0) by 38 torr. The differences between the septic and nonseptic patients were statistically significant (P less than 0.001). Likewise, the long-term effect of similar levels of PEEP was in increasing PaO2/FIO2 by 142 torr and by 75 torr in the nonseptic and septic patients, respectively. The final reduction in AaDO2 (FIO2 = 1.0) was 163 torr and 87 torr in the nonseptic and septic patients, respectively. These differences between patient groups were also statistically significant (P less than 0.02). Mortality during PEEP was 15/29 and 3/28 in the septic and nonseptic patients, respectively. Overall mortality in the septic and nonseptic groups was 18/29 and 5/28, respectively. We conclude that ARDS with sepsis constitutes a more severe pulmonary insult than ARDS without sepsis, and/or that generalized sepsis creates a more prolonged pulmonary insult that makes it less amenable to PEEP. Thus, high levels of PEEP may be needed to treat ARDS associated with sepsis.


The selection of healthy volunteers for clinical investigation: the case for volunteer pools.

Discussions on the healthy volunteer in clinical investigation do not attempt to define normality. In 34 healthy volunteers, 1653 biochemical and haematological tests were performed. The incidence of abnormal results was 11%. Only 4 subjects had all tests within normal limits and when these repeated only 1 subject still had all results within normal limits. The authors recommend that a stable volunteer pool, with regular physical examinations and blood tests, would provide a large, serial data base for use in subject selection for clinical trials. Attention should be given to human error. Protocols should be realistic, while ensuring the safety of volunteers.


A comparative crossover study of two long-acting bronchodilator preparations.

A comparative crossover investigation was carried out in 18 patients with reversible airways obstruction to assess the bronchodilator effectiveness of aminophylline and salbutamol in long-acting tablet form. Patients received treatment for 4 weeks with either salbutamol 8 mg tablets in a dose of 2 tablets b.d. or aminophylline 225 mg tablets in a dose of 1 tablet b.d. increasing to 2 tablets b.d. after 1 week. They were then crossed over to the alternative preparation for a further 4 weeks. Peak expiratory flow rates (PEF) were measured at weekly intervals. Results showed that the aminophylline tablets produced a highly significant (p less than 0.002) improvement in PEF values compared with salbutamol tablets when both treatment periods were considered, and patients considered they obtained longer lasting relief with the aminophylline preparation.


A randomised controlled trial of an oral solution of prostaglandin E2 and oral oxytocin used immediately after low amniotomy for induction of labour in the presence of a favourable cervix.

A randomised controlled trial was carried out in 50 primigravidae and 50 multigravidae to compare the effectiveness in induction of labour after low amniotomy of prostaglandin E2, given as an oral solution, and oxytocin, given as buccal tablets. The results showed that in dosages recommended by the manufacturers, both oxytocic preparations were almost equally effective. With oral oxytocin, once labour had been established and dosage was left to the discretion of the staff, there appeared to be a potentially dangerous tendency to continue giving large doses despite adequate uterine contractions. The authors comment that this was probably the reason why oxytocin-treated multigravidae having normal deliveries within 24 hours had labours significantly shorter on average than those of other successfully induced patients.


Oxprenolol in the treatment of examination stress.

In a double-blind preliminary study in 32 students exhibiting symptoms of examination stress, treatment with 80 mg oxprenolol daily or 4 mg diazepam daily were found to be equally effective in relieving anxiety and tension, as assessed by both students and physician. Although students on diazepam became significantly more confident of success than those on oxprenolol, their results were worse than expected. In contrast, students on oxprenolol did not gain in confidence and they were significantly more successful than anticipated by their tutors.


Clinical course of 91 consecutive near-drowning victims.

Hospital records of 91 consecutive near-drowning victims were studied retrospectively. Eight-one (89 percent) of these patients survived. Patients who were alert on arrival at the emergency room survived, but those who were comatose and had fixed dilated pupils died. Other states of consciousness were unreliable predictors of survival. All patients with a normal chest roentgenogram on admission survived; however, values for arterial oxygen tension (PaO2) did not necessarily correlate with the chest roentgenograms. Values for arterial blood gas tensions and pH varied widely, as follows; PaO2, 25 to 465 mm Hg; arterial carbon dioxide tension (PaCO2), 17 to 100 mm Hg; pH, 6.77 to 7.50; and arterial bicarbonate level, 6.6 to 29.7 mEq/L. The ratio of PaO2 to the fractional concentration of oxygen in the inspired gas (FIo2), which was calculated to standardize PaO2 data for varying concentrations of inspired oxygen, ranged from 30 to 585 mm Hg. Only one patient with a ratio of PaO2/FIo2 greater than 150 mm Hg on admission subsequently died; this was a neurologic rather than a pulmonary death. Serum electrolytic concentrations and values for hemoglobin level and hematocrit reading neither predicted survival nor indicated that a threat to life existed. Steroid and prophylactic antibiotic therapy did not appear to increase the chance of survival. Observations on these patients are discussed in light of previous experiments in animals, and an approach to therapy is suggested.


Closure of a ventricular septal defect through the aortic valve: a note of caution regarding resultant narrowing of the aortic valve annulus.

Closure of ventricular septal defects through the aortic valve annulus has been described for a variety of cardiac anomalies. This technique is most appropriate when simultaneous aortic valve replacement is anticipated. A continuous suture through the patch material may produce a purse-string effect upon the aortic valve annulus. The appropriate size of the aortic valve prosthesis should be determined after the closure of the ventricular septal defect is completed to avoid selecting one which may be too large.


Relationships between in vitro susceptibility and efficacy in experimental mouse infection-protection assay of cefazolin and cephalothin using Escherichia coli strains.

The disc sensitivity and minimal inhibitory concentrations (MIC) of cefazolin and cephalothin were compared against a series of Escherichia coli isolates. These data were correlated with the mouse protective doses of the 2 cephalosporins in animals infected with E. coli strains selected according to their various degrees of in vitro sensitivity to the 2 cephalosporins. The overwhelming majority of E. coli strains showed a significantly higher degree of susceptibility and lower MIC values for cefazolin than for cephalothin. There has been found a good correlation between the inhibition zones and especially the MIC values and the ED50 results for both cephalosporins. Using E. coli clinical isolates, cefazolin was found to be superior to cephalothin not only in vitro experiments but also more potent in protecting the experimentally infected mice.


Rapid diagnosis of sporotrichosis by immunofluorescent method.

Histopathological examinations fungal cultures and direct immunofluorescent staining of the pus and skin biopsy microsections with fluorescein isothiocyanate-labelled specific antiserum were performed for 13 patients suspected to be infected with Sporotrichum schenckii. While histopathological examinations could not give useful information, the latter two gave more reliable results which could support the clinical diagnosis. The direct immunofluorescent staining test could be used as a method for rapid diagnosis of sporotrichosis.


New concepts in the formation, regulation of release, and metabolism of parathyroid hormone.

New information has elucidated many of the biochemical pathways in the formation, release and metabolism of parathyroid hormone (PTH). The hormone is biosynthesized in the parathyroid cells from two distinct precursors, or prohormones, that are modified by specific enzymic cleavages during the synthesis and intracellular transport of the hormonal polypeptide. Release of the hormone from the gland inversely depends on the extracellular calcium concentration, but is regulated over a much narrower range of calcium concentration than was realized previously. This new information points to a pattern of regulation that is more appropriate for homeostasis than was the pattern indicated by earlier studies. The persistence of a basal level of PTH secretion, despite sustained hypercalcaemia, suggests a possible mechanism for the abnormal secretion seen in states of hyperparathyroidism. The discovery of a calium-dependent degradative pathway for PTH in the parathyroid cell indicates that changes in the turnover of PTH may be one means by which calcium regulates the amount of hormone available for secretion. Of the multiple immunoreactive forms of PTH present in the circulation of man and animals, the predominant form in blood appears to be a large biologically-inactive fragment consisting of the middle and carboxy two-thirds of the hormone sequence. At times, smaller biologically-active fragments of PTH may also appear in blood. Most circulating fragments of PTH probably arise from peripheral cleavage of the intact, secreted hormone in kidney and liver, but some forms of the hormone, including prohormones, may also be secreted from the parathyroid gland. The heterogeneity of circulating PTH and the concomitant uncertainties regarding its precise character have introduced difficulties in the interpretation of immunoassay measurements. A further delineation of the pathways and regulation of PTH biosynthesis, secretion and metabolism should lead to the development of more-specific immuno-assays and result in improved diagnosis and management of patients with disorders of the parathyroid glands.


Structure and structure-function relationships in glycoprotein hormones.

Relationships between the sequences of thyrotropin (thyroid-stimulating hormone, TSH), lutropin (luteinizing hormone, LH), human choriogonadotropin (chorionic gonadotropin, hCG) and follitropin (follicle-stimulating hormone, FSH) are now well established. Each beta-subunit contains six disulphide bonds and considerable homology is seen when all four linear sequences are aligned with half-cystine residues in juxtaposition. Major questions about the tertiary structures of the subunits and their interactions to form active hormone remain. Determination of the disulphide bridges in both alpha- and beta-subunits has not yielded to usual methods and conflicting data about the alpha-subunit have been reported. Partial reduction of the beta-subunits of LH and TSH with subsequent labelling of the cysteines formed has shown that a single bond is first reduced. This bond is between positions 93 and 100 in LH-beta and the corresponding positions 88-95 in TSH-beta. Thus, as would be expected from the fact that interhormone hybrids can be made with the common alpha-subunits, the chemical data, though still limited, indicate similar tertiary structures for the different beta-subunits. To investigate whether other useful intermediates can be obtained after partial reduction, we have studied reduction and derivative formation in various conditions. Intact LH is more resistant to reduction than either its alpha- or beta-subunit but no intermediates have been observed which are not present after partial reduction of individual subunits. Preliminary experiments on the reoxidation of fully reduced alpha-subunit show that the reoxidized material will recombine with native beta-subunits to yield biologically active TSH or LH. Studies from this and other laboratories on chemical modifications of several amino acid residues of glycoprotein hormones and their subunits are also summarized.


Heterogeneity of the gastrins in blood and tissue.

The forms of gastrin which have been isolated from antral mucosa or Zollinger-Ellison tumour tissue (or both) and characterized chemically are as follows: little gastrin (G17) (LG); big gastrin (G34) (BG); minigastrin (G13); the NH2-terminal 1-13 fragment of G17. All these exist as pairs of peptides which have an identical amino acid sequence and differ solely in that the single tyrosyl residue present may be sulphated. The proportions of the pairs of each peptide show species variation where isolation has been accomplished (e.g. from hog, dog, cat, cow, sheep and man in the case of LG, and hog and man for BG). All these forms of the hormone have been identified immunologically in serum; LG and BG have been identified in duodenal mucosa. Two larger forms of the hormone have been identified immunologically in serum; component I (CI) and 'big big gastrin' (BBG). Material corresponding in size to BBG and CI has been identified in extracts of antral and jejunal mucosa and Zollinger-Ellison tumour. Neither BBG nor CI has been characterized chemically to date and their physiological significance is uncertain. Recent studies suggest that the heterogeneity of gastrins in serum and tissues may be considerably greater than is indicated by the list of components given above.


Molecular evolution of the polypeptide hormones.

Any biological function is at least bimolecular and its evolution therefore is at least dual, with variations in two lines of molecules. The hormone specificity results from a particular fit between the three-dimensional structure of the agent and that of the receptor but, because receptors are not known at the structural level, a discussion on the evolution of the polypeptide hormones is mainly limited to the possible progressive changes of the latter. As for other proteins (enzymes, oxygen carriers etc.) two degrees of complexity can be distinguished according to whether the hormone comprises one or several polypeptide chains. Protein assembly can bring new biological properties, each subunit playing a particular role. In this case, the 'internal' evolution (chain-chain interactions) overlaps the 'external' evolution (hormone-receptor contacts). The 'monomeric' hormones present the following problems: evolution of the prohormone and of the converting enzyme (for insulin), duplication and differentiation of two lines of hormones either by amino acid substitutions (neurohypophysial hormones and neurophysins) or by substitutions and size modifications (corticotropin and lipotropin), duplication and fusion leading to internal homology in the single polypeptide chain (somatotropin, prolactin, placental lactogen). The 'dimeric' hormones lead to several problems: successive duplications giving different subunits, selective associations between subunits, unequal rates of evolution of the subunits, the function of each subunit (lutropin, follitropin, thyrotropin, choriogonadotropin). An attempt is made to integrate the evolution of polypeptide hormones in the frame of the evolution of proteins.


Biosynthesis of insulin and glucagon: a view of the current state of the art.

It is now well established that insulin biosynthesis proceeds through a precursor molecule, proinsulin. This single polypeptide chain form has been identified as a ribosomal product in the microsomal fraction from islet tissues. The newly synthesized peptide chain, after folding and thiol oxidation, is transferred to the Golgi apparatus where it begins to undergo proteolytic processing to insulin and packaging into secretory granules. The secretion from the cells of significant amounts of newly synthesized material by exocytosis begins only one hour or more after biosynthesis and this process is regulated by several factors, including glucose. Foci of current attention discussed in this paper include (1) the possible existence of larger precursor forms than proinsulin, especially short-lived biosynthetic transients with extended NH2-termini analogous to the recently described immunoglobulin L chain and proparathyroid hormone precursors; (2) the large-scale production of insulin by chemical or genetic engineering approaches; (3) isolation of beta-cell plasma membranes; (4) regulatory mechanisms for the biosynthesis and secretion of insulin, the possible role of mRNA modification in this process, and effects of somatostatin on insulin biosynthesis and secretion; (5) studies on the secretion, metabolism and clinical usefulness of the proinsulin C-peptide; (6) finally, the biosynthesis of glucagon and other peptide hormones and the general significance of precursor forms.


Isolation of a biologically active messenger RNA: preparation from fish pancreatic islets by oligo(2'-deoxythymidylic acid) affinity chromatography.

RNA was extracted from the pancreatic islets of channel catfish in the presence of the ribonuclease inhibitor, diethyl pyrocarbonate (oxydiformate). High molecular weight RNA was observed on sucrose gradient analysis. enrichment of mRNA was achieved by oligo(2'-deoxythymidylic acid)-cellulose affinity chromatography. The mRNA fraction stimulated incorporation of [35S]methionine into protein up to 30-times the background in the wheat-germ cell-free system. Analysis by sodium dodecyl sulphate-polyacrylamide gel electrophoresis revealed two major proteins corresponding to molecular weights of 27 000 and 11 000. These proteins were not observed in the absence of mRNA or in the presence of mRNAs from other tissues. They were also synthesized in the ascites tumour cell-free system. No protein co-migrating with proinsulin or insulin was detected in either the ascites or wheat-germ cell-free systems. Pancreatic islet slices also synthesized the proteins of 27 000 and 11 000 molecular weight and smaller ones as well.


The treatment of pulmonary heart failure.

Treatment of acute pulmonary heart failure is usually achieved with rest, relief of alveolar hypoxia and diuretics. Apart from thromboembolism, emphasis is placed on prophylaxis and the active management of the pulmonary dysfunction, including regular functional assessment to guide therapy directed particularly at the relief of alveolar hypoxia.


Treatment of gastroenteritis in children.

Mortality and morbidity in gastroenteritis in children is the result of fluid loss, acid-base and electrolyte imbalance. Hence therapy should be aimed at preventing or correcting this imbalance. The use of intestinal antibiotics to treat the condition should not be a routine, but parenteral antibiotic therapy in the presence of septicaemia is mandatory.


Carbenoxolone: a review of its pharmacological properties and therapeutic efficacy in peptic ulcer disease.

Carbenoxolone sodium has been shown to accelerate the rate of healing of both gastric and duodenal ulcers, but its overall value in duodenal ulcer is probably less because of the high rate of natural remission of duodenal ulcers. Further studies are required to decide whether it should be used prophylactically to delay ulcer recurrence. Carbenoxolone may act by affecting both the proliferative activity of gastric epithelium and the differentiation of the epithelial cells to produce mucus (as well as favourably altering the physicochemical properties of mucus and by reducing peptic activity), factors which may be relevant ot the prevention of acute gastric ulcers. Some studies suggest that carbenoxolone adds to the effect of hospitalisation and bed rest on ulcer healing. Whether bed rest confers additional benefit to the drug's ulcer healing effect in outpatients is also uncertain. There is no evidence that accelerated healing by carbenoxolone is associated with improved overall prognosis. Carbenoxolone is of greatest benefit in accelerating the healing of gastric ulcers in patients for whom hospitalisation is not possible or desirable, but it should only be used in the ambulatory patient when careful and regular observation of serum electrolytes (particularly potassium), blood pressure and weight is possible and when it is known that the patient will attend regular follow-up. Patient must be educated in the proper use of the drug. If severe mineralocorticoid-like toxic effects such as sodium and water retention and hypokalaemia appear, as they do in a variable proportion of patients but most frequently in those receiving excessive doses, carbenoxolone should be stopped and the complication treated; they respond to thiazide diuretics and potassium supplements, and probably to amiloride given in conjunction with a low dose of a thiazide diuretic. Treatment with carbenoxolone can continue with concurrent diuretic therapy in patients with less severe side-effects. Optimum therapeutic effect in gastric ulcer with the least side-effects is achieved with a dosage of 100mg carbenoxolone tablets 3 times daily for the first week followed by 50mg 3 times daily thereafter, best taken before meals. A lower dosage is desirable in the elderly and in those with liver, cardiac or renal disease. Barium meal or preferably endoscopic examinations should be performed regularly and therapy continued until the ulcer is healed. Dosage for duodenal ulcer is 50mg 4 times daily, in special positioned-release capsules. These are best taken about 20 minutes before meals.


[The crisis of medicine or the antimedicine crisis].

In this lecture, Professor Michel Foucault makes an in-depth study of the problems currently afflicting medical institutions and the medical practice. He deals with the thesis set forth by Ivan Illich in his book Medical Nemesis--The expropriation of Health, as well as the 1942 Beveridge Plan, but goes even further back in history to discover the origin of the medical crisis common throughout the world--back to the XVIII century roots of the social practice of medicine. He also describes the phases through which medical activity has passed from then until now and deals with what he calls the political economy of medicine. Finally, he reaches the conclusion that what matters is not so much the present crisis of medicine, which he considers to be a false concept, but the discipline's historical model dating from the XVIII century and serving to determine to what extent it can be modified.


[Comparative study of the most common prosthetic aids].

The two most often used attachments and anchors were each submitted to permanent load in an alternating bending machine. Removing force, removing performance and mobility in a vertical direction were measured after permanent load and compared with each other. All compound elements showed signs of wear and tear. The removing force decreased by approximately 25%, in Bona anchors by 60%, the removing performance was reduced by 20% on the average, but by 75% in Bona anchors.


[Kinetics and stress distribution of supported free-end prostheses. I. Effect of the frame stability on the kinematics of the saddle and the stress on the edentulous prosthesis bed].

By means of inductive pressure and motion recorders, the influence of the stability of the framework, the extension of the saddle and type and location of anchorage on the kinetic properties of the denture and the distribution of load between edentulous base and abutment teeth was studied in three different free-end dentures. The findings are discussed with respect to the planning and technical design of dentures.


Tissue levels of luteinizing hormone-releasing hormone in the preoptic area and hypothalamus, and serum concentrations of gonadotropins following anterior hypothalamic deafferentation and estrogen treatment of the female rat.

Female rats were ovariectomized prior to anterior hypothalamic deafferentation (AHD) or sham AHD of the medial basal hypothalamus (MBH). LHRH in the MBH and the preoptic area (POA), and the blood concentrations of LHRH, FSH, and LH were measured following decapitation at the end of 30 days in experiment 1 and 28 days in experiment 2. Interruption of anterior neural links of the MBH resulted in a drastic reduction in the amounts of LHRH in the MBH and a significant increment in the POA. The circulating levels of FSH (experiments 1 and 2) and LH (experiment 2) were significantly depressed whereas serum LHRH was unaltered following deafferentation. In experiment 3, rats were ovariectomized 25 days following either AHD or sham AHD, and were given estradiol benzoate (EB, 10 mug/rat in oil, SC) or oil alone on day 7 postovariectomy and sacrificed 2 days later. Relative to sham AHD, a reduction in the MBH LHRH and a pronounced elevation in the POA LHRH was observed in AHD rats. Serum LH and FSH concentrations were also significantly decreased. EB treatment significantly lowered serum gonadotropins, whereas LHRH levels in the MBH of both AHD and sham AHD rats increased two-fold. Serum LHRH concentrations were also significantly reduced in AHD rats following EB injection. These studies indicate that 1) since a substantial portion of the LHRH activity normally detected in the MBH of female rats appears to be derived from that synthesized in the rostral regions, it is logical to infer that POA LHRH may be involved in the tonic as well as the cyclic discharge of LH, and 2) an increase in the LHRH content of the MBH after estrogen treatment may be due to a partial inhibition in release and/or an increased rate of synthesis of LHRH in the MBH.


Calcium antagonists and islet function. II. Interaction of theophylline and verapamil.

Verapamil inhibits glucose-induced insulin release by the isolated perfused rat pancreas. The dose-response relationship for the inhibitory action of verapamil is shifted to higher concentrations of the drug when the concentration of calcium in the perfusate is increased. The degree of inhibition of glucose-induced insulin release by a given concentration of verapamil decreases as the length of exposure to glucose is increased prior to introduction of the calcium antagonist. Theophylline augments glucose-stimulated insulin release and protects the beta-cell against the inhibitory action of verapamil, both effects of theophylline being dose-related. Even after pretreatment of the pancreas with a high concentration of verapamil, theophylline is able, in the presence of glucose, to stimulate insulin release and, eventually, to restore a nearly normal secretory response to this sugar. We suggest that theophylline, by mobilizing calcium from an organelle-bound pool within the beta-cell, compensates for the verapamil-induced reduction in calcium inward transport into the beta-cell.


Effect of active and passive immunization with luteinizing hormone-releasing hormone on serum luteinizing hormone and follicle-stimulating hormone levels and the ultrastructure of the pituitary gonadotrophs in castrated male rats.

The effect of active and passive immunization with luteinizing hormone-releasing hormone (LHRH) on serum LH and follicle-stimulating hormone (FSH) levels and the ultrastructure of the pituitary gonadotrophs was investigated in castrated male rats. Two weeks after castration, the animals were immunized with Glu1-LHRH conjugated with human serum albumin (hSA), immunized with hSA only, or left uninjected. Immunogens were administered every 2 weeks. Four weeks after the initiation of immunization with hSA-Glu1-LHRH, 2 out of 4 rats showed parallel decreases in serum LH and FSH levels associated with a rise of serum antibody titer to LHRH. Serum LH and FSH levels remained suppressed throughout the experiment in these rats. On the other hand, both LH and FSH levels in hSA-immunized rats or non-immunized rats remained elevated, and typical castration cells containing large vacuoles were found in the pituitary. Although castration cells existed in the pituitary of rats which produced antibody to LHRH by active immunization, these cells were markedly degranulated, and secretory granules were scarce in the cytoplasm. In another experiment, rats were injected iv with one ml sheep anti-LHRH gamma-globulin (anti-LHRH) or normal sheep gamma-globulin (NSG) every 2 days for 3 weeks, starting one day after castration, when serum LH and FSH levels were already elevated. All the animals which received anti-LHRH showed a decrease in both serum LH and FSH levels, which remained low throughout the study, in a range comparable to those in intact normal male rats. On the other hand, in the animals which received NSG, both LH and FSH levels remained high or increased further throughout the experiment, and the pituitary contained numerous castration cells. Castration cells were completely absent from the pituitaries of rats treated with anti-LHRH, suggesting that castration cells are formed as a result of increased secretion of LHRH. Some FSH gonadotrophs in these castrated rats were atrophic. It was difficult to distinguish the LH gonadotrophs in rats which were either actively or passively immunized with LHRH; however, they seem not to have contributed significantly to the development of castration cells. In any case, antibody to the LHRH decapeptide drastically affected both LH and FSH cells, providing additional evidence for the concept that LHRH represents the physiological LHRH and FSHRH.


Distribution of luteinizing hormone-releasing hormone (LHRH) in the guinea pig brain.

With the use of the unlabeled antibody enzyme technique and antiserum to luteinizing hormone-releasing hormone (LHRH), the distribution of LHRH in the adult male guinea pig was studied. Immunoreactive deposits were found in the cell bodies of hypothalamic neurons in the medial preoptic, anterior hypothalamic, suprachiasmatic, and arcuate nuclei. Ten to thirty LHRH-containing perikarya were seen per brain. Four fiber tracts positive for LHRH were described: Tract I runs on the pre-commissural side of the anterior commissure from the bed nucleus of the stria terminalis and medial preoptic area to the suprachismatic nucleus: Tract II runs on the post-commissural side to the retrochiasmatic portion of the suprachiasmatic nucleus; Tract III originates in the arcuate nucleus and the ventral portion of the ventromedial nucleus and courses medially and caudally to enter the median eminence; Tract IV travels from the mammillary bodies to the mid-brain. Three weeks after surgical isolation of the medial basal hypothalamus there was a slight decrease in the amount of LHRH in the median eminence. These data suggest that LHRH is synthesized in more than one hypothalamic nuclear group but that the majority of axons containing the hormone in the median eminence originate in the medial basal hypothalamus.


The channeling of natural stimuli that evoke the ejection of milk in the rat. Effect of transections in the midbrain and hypothalamus.

The afferent and the efferent pathways of the milk ejection reflex were studied in conscious lactating rats subjected to suckling after experiencing stereotaxically-controlled transections in the midbrain or hypothalamus. Extensive transections in midbrain or hypothalamus. Extensive transections in the midbrain or caudal hypothalamus blocked reflex milk ejection while less extensive cuts, sparing either the dorsal or the ventral fibers, did not. The frontal plane immediately caudal to the neurosecretory nuclei intersects both afferent and efferent fibers. All cuts at this plane, regardless of size, caused blockage whenever the neurosecretory fibers located at the lateral ventral hypothalamus were severed. A multiple cut in the near vicinity of both supraoptic nuclei caused blockage of milk ejection, probably by severing the combined neurosecretory tract originating in both the supraoptic and paraventricular nuclei. If the multiple cut was performed unilaterally, a blockage of milk ejection was not observed, indicating that reflex action can be sustained by preserving one side of the neurosecretory pathway. Simple cuts in the same region revealed that the efferent pathway takes on a caudo-medial direction towards the neurohypophysis. In the near vicinity of the infundibulum, simple cuts showed that the efferent fibers enter the infundibulum from the sides, and also established that the milk ejection reflex persisted even when a small number of fibers in the pituitary stalk remained intact. The results showed that the afferent pathway for the reflex is diffuse, while the efferent pathway is compact. Only complete transection of one of the two pathways caused blockage.


A comparative controlled study between carbamazepine and diphenylhydantoin in psychomotor epilepsy.

A double-blind study of the antiepileptic effect and side effects of carbamazepine (CARB) and diphenylhydantoin (DPH) was undertaken in 38 patients with psychomotor epilepsy and without grand mal epilepsy except for a single previous seizure. The patients were treated with CARB and DPH only, each in periods of 16 weeks and with a crossover of 4 weeks. The initial dosage of 6 mg/kg DPH or 15 mg/kg CARB was corrected according to the serum values aiming at therapeutic intervals of 8-16 mg/1 DPH and 6-10 mg/1 CARB. The trial had to be discontinued in 12 patients. The effect of the two drugs in preventing psychomotor seizures was the same. Some patients, however, had considerably fewer seizures while on CARB; others had fewer seizures on DPH. It seems advisable, therefore, to try both drugs separately before proceeding to combined medication. During CARB treatment the selected therapeutic interval was more easily reached and maintained than during DPH. During the latter treatment, one-third of the monthly serum value determinations were below the level in spite of dosage corrections. Side effects were equally mild and occurred as often during DPH as during CARB treatment.


Dissociation kinetics of complexes between the antibiotic rifamycin and DNA-dependent RNA polymerase from Escherichia coli.

Phosphocellulose chromatography was employed to measure the binding of 3-(2-[14C]acetamidoethyl)-thiorifamycin(abbreviated[14C]AcNHEtS-Rif) to RNA polymerase core enzyme. The technique yielded a correct value for the stoichiometry of interaction. The same method was successfully applied to an investigation of the dissociation kinetics of the [14C]AcNHEtS-Rif - core-polymerase complex. We observed biphasic dissociation kinetics not in agreement with the existence of one single first-order dissociation step. Assuming two independent dissociation reactions, rate constants have been evaluated differing roughly by 10-fold (1.7 X 10(-3) s-1 and 1.5 X 10(-4) s-1 at 25 degrees C). The ratio of the amplitudes of the biphasic dissociation kinetics changed with temperature. The kinetic data are interpreted as indirect evidence for the existence of two enzyme species differing in their dynamic properties with respect to the binding of the antibiotic rifamycin. Our data furthermore lend support to the assumption that the two enzyme forms are in equilibrium. The observed sigmoidal dependence of the dissociation rate on temperature could indicate a conformational transition of RNA core polymerase with a transition midpoint at around 20 degrees C. The dye, rose bengal, was found to be as effective as AcNHEtS-Rif itself as a competing agent. The dissociation kinetics of the [14C]-AcNHEtS-Rif - core-polymerase complex in the presence of an excess of the dye rose bengal were found to be very similar to those measured in the presence of AcNHEtS-Rif. This could mean that rose bengal and AcNHEtS-Rif compete for the same site at RNA core polymerase. The dissociation of the ternary complex [14C]AcNHEtS-Rif - core-polymerase - poly[d(A-T)] was followed by gel filtration. Up to the extent of dissociation measured, the reaction appeared to follow first-order kinetics. The dissociation rate constant was calculated to be 1.7 X 10(-4) s-1. Experiments to determine the effect of the antibiotic streptolydigin on the dissociation kinetics of the [14C]AcNHEtS-Rif - core-polymerase complex have not led to conclusive results.


Significance of folded chromosomes released from amino-acid-starved Escherichia coli cells.

1. Folded chromosomes from amino-acid-starved Escherichia coli DG 75 cells are to a large extent released as envelope-bound complexes which sediment more rapidly than envelope-bound complexes from exponentially growth cells. A minor fraction (about 3%) represents relatively slow sedimenting envelope-free nucleoids. 2. Morphological analysis of the sensitivity of amino-acid-starved cells to the action of lysozyme and/or detergents indicates that these cells are less susceptible to lysis than exponentially grown cells. This results in the production of fast sedimenting envelope-bound complexes from non-dividing cells. We infer that it is not the amount of DNA, as suggested by Ryder and Smith (1974), but the low degree of envelope fragmentation that causes the high sedimentation rate. 3. After prolonged periods of starvation about 3% of cells in the process of division persist in the population. The results indicate that these cells release their (terminated) chromosomes in the envelope-free form. At this stage it is impossible to conclude whether these chromosomes are released because of their detachment from the membrane in situ (cf. Worcel and Burgi, 1974) or because of an enhanced susceptibility of dividing cells to lysis.


Existence, localization and regulation of the biosynthesis of aminoendopeptidase in gram-negative bacteria.

An enzyme capable of hydrolyzing the substrate L-alanine p-nitroanilide has been found in 18 gram-negative Enterobacteriaceae and Pseudomonas that we tested. This enzyme might be located near the cell surface. Contrastingly we have not detected this activity on colonies of the 8 gram-positive Bacillus that we tested, which suggest a taxonomic value for this test. The aminoendopeptidases found in the various gram-negative bacteria showed similar electrophoretic mobilities and immunological cross-reactivity when tested again Escherichia coli anti-aminoendopeptidase antiserum. The regulation of aminoendopeptidase biosynthesis by the endogenous level of inorganic phosphate that we previously demonstrated in E. coli has been found to exist in all gram-negative organisms tested.


Two forms of RNA polymerase B in yeast. Proteolytic conversion in vitro of enzyme BI into BII.

Special care to prevent proteolysis during yeast RNA polymerase B purification leads to the appearance of two forms of enzymes, BI and BII, with different molecular weight (465 000) and 435 000, respectively). The two forms of enzyme can be separated by ion-exchange chromatography or polyacrylamide gel electrophoresis. Their subunit structures were compared by sodium dodecylsulfate gel electrophoresis, the only observed difference between the two enzymes is in the molecular weight of the heaviest subunit which is 220 000 for enzyme BI and 180 000 for enzyme BII. Otherwise, the two enzymes have seven common subunits of molecular weights 150 000, 45 000, 26 000, 22 500, 14 500, 12 500 and 9000. Two additional polypeptide chains of 32 000 and 16 500 Mr are dissociated from the enzyme upon polyacrylamide gel electrophoresis or DEAE Sephadex chromatography. The largest subunit of enzyme BI (Mr 220 000) can be specifically cleaved in vitro by a yeast protease extract, generating a polypeptide chain indistinguishable from the largest subunit of enzyme BII. This proteolytic cleavage of enzyme BI in vitro is inhibited by phenylmethylsulfonyl fluoride and does not significantly change the activity of the enzyme with single-stranded or double-stranded DNA as template. The precursor-product relationship of the different forms of class B RNA polymerases in eukaryotic cells is discussed.


Purification and properties of an N-formylmethionyl-tRNA hydrolase.

The isolation and properties of a novel N-formylmethionyl-tRNA hydrolase (hydrolase II) from Escherichia coli are described. This enzyme is difficult to detect in crude extracts; purification, however, unmasks the activity. Sedimentation and gel filtration parameters of this enzyme differ from those of the previously described peptidyl-tRNA hydrolase (hydrolase I), and preparations can be obtained where the two activities are free of each other. A mutant of hydrolase I has wild-type levels of hydrolase II. These data indicate that hydrolase II is a different enzyme, or an altogether different form of hydrolase I. The bulk of the enzymic activity occurs in the ribosome-free cytoplasm; the remainder is found on intact or dissociated 70-S ribosomes. Purified preparations of hydrolase II analyzed by two-dimensional gel electrophoresis contain 2 protein bands. These 2 proteins do not coincide in electrophoretic mobility with any known ribosomal proteins. Analysis after mixing experiments verifies this conclusion. The purified enzyme (hydrolase II) is inhibited by ribosomes bearing bound N-formylmethionyl-tRNA. The inhibition is potentiated by sparsomycin and other antibiotics that block specifically peptide-bond synthesis. The relationship of this enzyme to other hydrolytic activities, including a newly described ribosome-dependent hydrolase, are discussed.


On the kinetics of the rifampicin-RNA-polymerase complex. Differences between crude and purified enzyme fractions.

The antibiotic rifampicin forms a very tight complex with DNA-dependent RNA polymerase of Escherichia coli. The rate constants of association and dissociation of this complex have been measured and found to be dependent on the purity of the enzyme. Thus a crude RNA polymerase (fraction-3 enzyme) has rate constants different from those of an enzyme further purified by DEAE-cellulose chromatography (fraction-4 enzyme). The complex produced by the antibiotic and the fraction-3 enzyme is about ten times more stable and is formed about ten times more slowly than the complex with fraction-4 enzyme. It has been shown that the RNA present in the crude enzyme and removed by chromatography on DEAE-cellulose is the cause of the change in the kinetics of the complex. tRNA of rat liver and crude rat liver RNA added to purified RNA polymerase have a similar effect. Mg2+, which has no intrinsic influence, augments the effect of the nucleic acids, whereas monovalent cations do not. Since nucleic acids increase the stability of the complex, but at the same time decrease the rat of its formation, the equilibrium constant, Keq, remains almost the same. The possible effects of nucleic acids on the rifampicin binding site are discussed.


Immunochemical studies on lipopolysaccharides from wild-type and mutants of Escherichia coli K-12.

Lipopolysaccharides from a number of mutants of Escherichia coli K-12 were investigated by means of chemical and serological methods. Inhibition of passive hemagglutination and inhibition of precipitation show that L-rhamnose is the immunodominant sugar in the lipopolysaccharide from wild-type E. coli K-12. The disaccharide rhamnosyl-KDO (where KDO is 3-deoxy-D-manno-octulosonic acid) was isolated and characterized after mild acid hydrolysis of the lipopolysaccharide. It is concluded that rhamnose is present in the innermost part of the core as a side-chain substituent on KDO. From crosses between an E. coli K-12 donor and E. coli O8, hybrids were obtained which contained either one or both of the donor rfa and rfb clusters. Serum absorption studies with lipopolysaccharides from these hybrids indicated that the histidine-linked rfb cluster is responsible for the presence of rhamnose in the K-12 core oligosaccharide. Using paper chromatography of 32P-labelled lipopolysaccharides we have found heterogeneous lipopolysaccharide in two strains as well as some differences between two wild-type strains. The latter difference is believed to be due to varying contents of KDO-linked ethanolamine phosphate. The overall results presented together with those described in the companion paper clearly show that the core oligosaccharide in E. coli K-12 has a structure different from the types previously described for other strains of E. coli (designed coli R1 to coli R4).