A study of anaesthesia depth by power spectral analysis of the electroencephalogram (EEG).

The feasibility of using computer-based EEG spectral analysis to monitor the level of anaesthesia during nitrous oxide-alphaprodine anaesthesia has been established by this study. At present, this system is capable of estimating the level of anaesthesia correctly from 55 per cent to 80 per cent of the time. There are several possible clinical applications of such a monitoring system during anaesthesia. It provides a continuous estimation of the depth of anaesthesia, without requiring any special EEG training on the part of the anaesthetist. This system can also be of particular benefit during anaesthesia for critically ill patients, or in specific cases, as in neurosurgery and caesarian section when there may be periods of time when the gross clinical evaluation of depth of anaesthesia may not be precise or reliable and yet it is imperative not to deepen the anaesthesia unnecessarily. In such instances it appears that a monitoring system such as we have developed could provide valuable indication of the depth of anaesthesia. Other potential applications might be in the training of students in the clinical assessment of patients during anaesthesia and in the study of new anaesthetic agents.


Enzymes in colon cancer. General information.

Serum enzymes have not proved useful in evaluation of patients with early colon cancer, but certain enzymes such as transpeptidase, phosphohexone isosomerase, or 5'-nucleotidase have been of assistance in following the course of the disease, particularly in patients with metastatic spread to the liver. Attempts have been made to improve the utility of enzyme analysis in colon cancer by examination of enzyme patterns in colon biopsy specimens, feces, and colon washings. These studies, which will be summarized, are of importance in the possible development of diagnostic tools and as probes in the understanding of the etiology of colon cancer. The technical problems in carrying out these assays in humans, as well as the significance of the activity of aryl sulfatase, beta-glucuronidase, beta-glucosidase, lactic dehydrogenase, glucose-6-p-osphate dehydrogenase, and other enzymes will be considered.


The role of colon anaerobes in the metabolism of bile acids and steroids, and its relation to colon cancer.

The principle enzymes in the metabolism of both the substituent groups and the nucleus of the bile acids and of cholesterol are reviewed, together with their possible relevence to the etiology of large bowel cancer. Since the incidence of the disease appears to be related to the bile acid concentration and the activity of the 7-dehydroxylase and the delta4-dehydrogenase enzymes, the study of bile acids with a 4,6-dien-3-one structure is strongly recommended.


Role of bile metabolites in colon carcinogenesis. Animal models.

Epidemiological data indicate that colon cancer incidence is associated mainly with high dietary fat intake. Studies in metabolic epidemiology have shown a strong association between dietary fat intake, level of fecal bacteria, fecal acid, and neutral sterols, and the risk of colon cancer among different populations. Current concepts visualize that colonic bile acids and cholesterol metabolities play a modifying role in large bowel carcinogenesis, and that these compounds are derived from dietary factors, directly or indirectly, and subsequently are modified by the intestinal bacteria.  In animal models, lithocholic acid and dexycholic acid, which are present in high concentration in the large bowel of man, acted as promoters of colon carcinogenesis. The carcinogenic effect of azoxymethane in rats was enhanced by the increase of bile salts in the colon induced by surgical means. Animals fed a high fat diet were more susceptable to colon tumor induction by dimethylhydrazine compared with rats fed a normal diet. Our data also demonstrate that the intestinal microflora played a modifying role in accelerating colon tumor production by dimethylhydrazine.


Chemotherapy of large intestinal carcinoma. Current results and future prospects.

Chemotherapy of advanced stages of large bowel cancer has until recently made little progress since the introduction of 5-FU 16 years ago. While survival is improved for patients who respond, 5-FU alone has made little impact on life span of the overall population of patients. Mitomycin-C and the chloroethyl nitrosourea antitumor agents, and in particular methyl-CCNU, have also demonstrated marginal activity in large bowel cancer. Two recently reported controlled clinical trials of combination chemotherapy have demonstrated response rates that are substantially better than those obtained with 5-FU alone; a 43% response rate in colorectal carcinoma has been reported using a combination of 5-FU, BCNU, vincristine, and DTIC, compared to a 25% response with 5-FU as a single agent; a 44% objective response rate with a combination of 5-FU, methyl-CCNU, and vincristine has been reported to be significantly better than 5-FU alone. 5-FU as an adjuvant following surgical resection with curative intent has not prevented tumor relapse; however, it is hoped that future studies employing more effective drug combinations will result in increased number of patients achieving disease free survival.


Biochemical approaches to the combination chemotherapy of colon cancer.

The employment of biochemical concepts to select drugs for use in the treatment of colorectal cancer is advocated. It is stressed that new drug mixtures, even those employing agents inactive alone, with unique mechanisms of action may be fashioned through biochemical design. Following delineation of activity in animal model systems, these drug combinations then become candidates for use in man. It is emphasized that 6-thioguanine is a particularly attractive agent for consideration as a component of new combinations of drugs to be used in patients with cancer. The desirability of this agent derives from (a) the known, albeit weak, activity of 6-thioguanine against colorectal neoplasms of man, thereby providing some inherent activity to be joined by additional materials; (b) a knowledge of several major biochemical and pharmacologic determinants of tissue susceptibility to its cytotoxic action, possibly allowing the ultimate selection of patients with a high probability of response; and (c) the availability of four different agents or classes of agents which synergistically interact with 6-thioguanine to inhibit the growth of malignant cells by diverse biochemical mechanisms.


The present status of DEA in diagnosis, prognosis, and evaluation of therapy.

Despite nonspecificity for the diagnosis of colon cancer, the assays for CEA widely studied to date may be useful in the management of patients with colorectal cancer by aiding detection of colonic cancer and especially of widespread metastases to the liver. Use of serial quantitative measurements may also be useful in determining persistence of residual or metastatic tumor after apparently complete surgical resection, in enabling detection of recurrence at an earlier stage than may be otherwise possible, and in helping to evaluate the effects of chemotherapy, provided that the assays are used only in context with complete clinical and laboratory findings, including cancer staging, histopathologic findings, assessment of liver status, and with appreciation of methodologic complexities. Both the further investigation of the clinical use of CEA and the intensified search for more specific markers are encouraged by the findings to date.


Copper and zinc levels in serum from human patients with sarcomas.

Serum copper levels (SCL) and serum zinc levels (SZL) were evaluated in 19 patients with sarcomas, 12 of which were osteosarcomas at various stages. Patients with primary or metastatic osteosarcoma had elevated SCL, whereas amputated osteosarcoma patients who were clinically tumor-free had nearly normal SCL. Patients with primary osteosarcoma had elevated SZL, those with metastases had depressed zinc levels, and amputated patients who were clinically tumor-free and nearly normal SZL. Thus, the ratio of SCL:SZL in metastatic osteosarcoma patients is higher than in patients with primary osteosarcoma. SCL and SZL are compared to clinical histories for selected patients. Patients with the more advanced disease and poorest prognoses had the most elevated SCL and highest SCL:SZL ratios. It appears that the determination of SCL and SZL in osteosarcoma patients may be of value in prognosis and therapy evaluation; furthermore, the ratio of SCL:SZL may be useful in discriminating between patients with primary and metastatic osteosarcoma.


Mutagenicity of azathioprine.

Azathioprine (6-[(1-methyl-4-nitroimidazol-5-yl)thio]purine; lmuran) is mutagenic for Salmonella typhirmuium. Demonstration of this mutagenic effect requires a period of anaerobic incubation of the bacteria with the test agent.


Electron microscopy and immunofluorescence of glomerular immune complex deposits in cancer patients.

Kidneys of 29 patients without clinical renal disease were studied by electron microscopy for the presence of glomerular basement membrane deposits: those from 11 of 20 patients with cancers of various sites, but only 1 of 9 patients without cancer contained electron-dense subendothelial deposits. The majority of these kidneys gave positive immunofluorescent reactions for immunoglobulin and complement. However, among a number of the cases studied, a lack of correlation between electron microscopic and immunofluorescence findings has yet to be investigated. Although the number of patients in this study is small because of the difficulty in obtaining tissue for electron microscopy, it is postulated that the deposition of immune complexes in the kidney occurs with a high frequency among cancer patients. The kidneys may thus be a valuable source for isolating tumor-associated antigens and corresponding antibodies.


Cytochemical and immunofluorescence investigations of insulin-like producing cells in the intestine of Mytilus edulis L. (Bivalvia).

Insulin-like immunoreactivity can be localized to cells of the intestine in the area of the hepatopancreas of Mytilus edulis L. No cross-reactivity can be obtained with anti-glucagon, anti-gastrin, anti-pentagastrin or anti-caerulin. The cells containing the substance immunoreactive to mammalian anti-insulin, can be restrained with paraldehyde-fuchsin.


Gastrointestinal somatostatin cells in the human fetus.

The stomach, duodenum, jejunum and ileum from 6 to 24 week-old human fetuses or deceased premature infants and from one totally anencephalic fetus were stained with antisomatostatin serum. The somatostatin containing cells appear in different segments of the gastrointestinal tract from the tenth week of gestation. The somatostatin-containing cells are lead haematoxylin positive. Somatostatin was also detected in the duodenum of the anencephalic fetus. The study of inhibition of the immunofluorescent reaction by homologous and heterologous antigens confirmed the specificity of antiserum. These data demonstrate that somatostatin can be synthetized elsewhere than in the hypothalamus.


Adaptation of the cells of Escherichia coli to the presence of hydroxyurea increases the level of inorganic pyrophosphatase acttivity.

Hydroxyurea, an inhibitor of ribonucleoside diphosphate reductase, completely arrested the net synthesis of DNA for 3-4 h, when it was added in 30 mM concentration to growing cultures of Escherichia coli K12. Thereafter the net synthesis of DNA started again, although slowly, and simultaneously with it the formation of inorganic pyrophosphatase activity was stimulated leading to a 2-fold increase in the specific activity of the enzyme in 2-3 h. Subsequently cell division began again. In this way a new steady state, stable in the presence of hydroxyurea, was reached. This new state was characterized by the high specific activity of inorganic pyrophosphatase, a small but constant amount of DNA/cell mass (1/4 of the normal value), and large elongated cells. All these changes were slowly reversed during 5-6 h, when the cells were transferred into a drug-free medium. The activity of isoleucyl-tRNA synthetase, assayed as a control, did not change significantly in the presence of hydroxyurea. Hydroxyurea had no effect on the activity of inorganic pyrophosphatase in vitro.


Carcinogenic mechanisms: a critical review and a suggestion that oncogenesis may be adaptive ontogenesis.

The precise mechanism(s) whereby normal cells become malignant are not known with any degree of certainty. However, many mechanisms have been proposed on the basis of available experimental evidence as interpreted by the proposer. These fall into two main groups and are based upon changes in genetic structure (somatic mutation hypotheses) or in genetic expression (epigenetic hypotheses). Yet a third group embodies elements of the first two. The more important of all these proposals are critically reviewed and yet another hypothesis is ventured. In this hypothesis, the induction of neoplasia is envisaged as embodying (a) initiation of preferentially partly-differentiated and resting stem cells and (b) promotion of the initiated cells, through mitosis and further differentiation and by adaptations of normal ontogenic mechanisms, into a variety of novel phenotypes which are malignant or potentially so. Cancer-specifying genes, altered chromosomes, de-differentiations and interrupted re-differentiations are not considered to be causally involved, although the last three of these can be present as epiphenomena. Evidence cited in support of this proposal appears to show a general absence from cancer cells of any single property, including an abnormality in genetic constitution or in cellular expression, which is specific to malignancy. Malignancy is thus envisaged as abnormal expressions of the genetic potential of the zygote. Some practical and theoretical implications of this concept are discussed.


The effect of 5-iodouracil on the growth and biosynthetic processes of bacteriophage T4td8 in the absence of light.

5-Iodouracil (IUra)-substituted progeny bacteriophage T4td8 were grown under conditions such that, upon CsCl equilibrium isopycnic gradient centrifugation, progeny with density distributions about the median similar to that of unsubstituted phage are obtained. In the absence of light a monotonic relationship exists between decreasing progeny viability and increasing percent IUra substitution. IUra is equivalent to thymine as a growth factor on a molar basis, and at concentrations of IUra plus thymine above that required for maximum particle production, the percent IUra substitution in phage DNA is determined by the mole fraction of IUra in the medium. The lethal effects of 5-iodo-2'-deoxyuridine (IdUrd) and IUra are equivalent, and are not produced by a direct effect on the phage particles. At equivalent percent substitution in phage DNA the order of lethality is IUra greater than 5-bromouracil (BrUra) greater than 5-chlorouracil (ClUra). There is no interference with the transfer of thymine from host cell to progeny phage by the presence of IUra in the medium, and IUra affects neither the time of lysis nor the content of phage DNA in the infected cells.


Removal of minor methylation products 7-methyladenine and 3-methylguanine from DNA of Escherichia coli treated with dimethyl sulphate.

Persistence of methylpurines in DNA methylated in vitro and in vivo in Escherichia coli WP2 cells, by dimethyl sulphate (DMS) was studied, with particular reference to the minor products 7-methyladenine and 3-methylguanine, not previously investigated in this respect, but known to be removed from DNA in vitro by spontaneous hydrolysis at neutral pH. The half-life of 7-methyladenine in vivo was relatively short (2.6 +/- 0.2 h) but not significantly shorter than in vitro at pH 7.2, 37 degrees C. The half-life of 3-methylguanine was 3.6 +/- 0.3 h in vivo, markedly shorter than in vitro, where its stability was somewhat greater than that of 7-methylguanine. Enzymatic excision of 3-methylguanine was therefore indicated to occur in E. coli. Previous findings that 7-methylguanine is probably not enzymatically excised from DNA in vivo, whereas 3-methyladenine is rapidly removed, were confirmed, and additional support for the concept of enzymatic removal of 3-methyladenine was obtained by showing extensive inhibition of its removal from cells treated with iodoacetamide prior to methylation. It is suggested that methylations of adenine or guanine in DNA at N-3 constitute blocks to template activity of DNA and stimulate a "repair" response of enzymatic removal of 3-methylpurines. Possible valence bond structures for 3-methylpurine residues in DNA are discussed, leading to the suggestion that ionized forms with positively charged amino groups may be the most effective blocks to template activity.


Receptivity to malaria in Europe.

Experimental work has confirmed the refractoriness of Anopheles atroparvus to tropical strains of Plasmodium falciparum to which A. labranchiae may also be refractory. This indicates a lower receptivity to malaria in Europe than the existing vector densities and increasing number of parasite carriers would suggest.


A strain of Plasmodium vivax characterized by prolonged incubation: morphological and biological characteristics.

Numerous strains of P. vivax, distinguishable chiefly by their biological characteristics, are known to exist. Two main varieties are recognized: the so-called temperate and tropical strains. The most extreme example of the former-designated by Nikolaev as P. vivax hibernans-constantly exhibited an extremely long incubation period. The strain is no longer in existence and no type material has been preserved. In its place, a North Korean strain with a generally long incubation period has been studied and compared with the well-known tropical Madagascar strain, which frequently but not constantly has a short incubation period. The data presented here concern the behaviour of various strains from the USSR and the morphological characteristics of the North Korean and Madagascar strains. Splenectomized chimpanzees were used as the host of these parasites, particularly in regard to exoerythrocytic schizogony. Attempts were also made, by late biopsies of the liver of the apes, to elucidate the prolonged latency of the North Korean strain. Although there was no evidence of specifically dormant forms, it is probable that certain sporozoites fail to develop in the normal time and that they are reactivated by an unknown factor a year or more after inoculation.


Thick-smear Plasmodium falciparum antigen from in vitro cultures for the indirect fluorescent antibody test.

An important prerequisite for serological studies is the availability of specific antigens with which a high, consistently reproducible degree of test sensitivity can be obtained. In the present study, thick films of P. falciparum antigen were made from in vitro cultures in order to evaluate this antigen in terms of the sensitivity and reproducibility of the indirect fluorescent antibody test, as compared with an antigen prepared from washed infected erythrocytes of Aotus trivirgatus monkeys. The test was performed in 132 serum samples from 4 different sources. The results showed that the sensitivity and reproducibility of the two antigens compared well. No binding of donors' antibody to antigen was noticed within the 24-hour period of in vitroculture.


Bacteriological status (point prevalence) of lepromatous outpatients under sulfone treatment.

The study concerns 337 outpatients with lepromatous leprosy who had been receiving dapsone treatment for 1-26 years-69% of them regularly and 31% irregularly. Routine bacterial examination (10 min per slide) by a paramedical technician showed only 50% of these patients to be bacteriologically positive. This rate attained 99% when each slide was examined for 30-60 min by a qualified bacteriologist. Other factors-apart from the limited action of sulfones-might account for these unexpected results: the material was collected by an experienced leprologist; the disease was still clinically active in 75% of the patients; about 25% of them had been treated for only 1-4 years; and the intake of dapsone in long-term treatment gradually decreases.


Controlled field trial on the effectiveness of one and two doses of acetone-inactivated and dried typhoid vaccine.

A controlled field trial was carried out with acetone-dried vaccine on about 35 000 people on the Tongan islands of tongatapu and 'Eua where typhoid fever is endemic. Volunteers were distributed at random into 3 groups, 1 of which received 1 dose of typhoid vaccine and a second 2 doses; the third, a control group, received tetanus toxoid. The population was vaccinated in 1966 and was studied until the end of 1973. Evaluation of the effectiveness of the vaccine was based on cases of typhoid fever that were confirmed by positive blood cultures. Morbidity rates in the 3 groups indicated that the acetone-dried vaccine used was effective and that a single dose of vaccine gave reasonable protection for a short period, but that 2 doses gave greater and longer protection. The results of this trial are compared with those of earlier field and laboratory studies.


Clinical evaluation of a new measles-mumps-rubella combined live virus vaccine in the Dominican Republic.

Over 900 children were enrolled in a double-blind placebo-controlled clinical study of measles (Schwarz strain), mumps (Jeryl Lynn strain), and rubella (Cendehill strain) trivalent vaccine. The trivalent vaccine caused about the same degree of reactivity as is generally associated with the Schwarz strain measles vaccine. Paired sera from triplesusceptible vaccinees had seroconversion rates of 99% for measles, 94% for mumps, and 93% for rubella. The results of this study show that this trivalent vaccine is as well tolerated and as effective as its component vaccines.


Absolute determination of cardiac output in intra-aortic balloon pumped patients using the radial arterial pressure trace.

We describe a new method for the absolute determination of cardiac output in intra-aortic balloon pumped (IABP) patients. The method uses the known pumping volume of the IABP balloon and the radial arterial pressure trace, which is commonly used to monitor IABP patients, to determine the cardiac output. Two pressure excursions denoted by P1-P0 and P2-P0, characterizing IABP balloon deflation, and ventricular ejection, respectively, are extracted from the radial trace. The cardiac output (CO) is then determined by the simple relation: CO = (BV) x (P2-P0)/(P1-P0) x HR where HR is the heart rate, and the value for pumped balloon volume (BV) is corrected for the effect of the pressure in the patient's aorta. Comparison with dye dilution and thermal dilution procedures as carried out on a routine basis in a clinical setting produced a good correlation (r = .928). When fit to a straight line through zero output, the data yielded a constant of proportionality of 0.973 between the above formula and the clinical procedures. The procedure does not disturb the patient in any way, and enables continuous monitoring of cardiac output. This has been implemented using a real-time, miniaturized computer and allows much more information to be obtained than in usual single measurements.


Late dysrhythmias and disturbances of conduction following Mustard operation for complete transposition of the great arteries.

Between 1964 and 1971, 49 patients were discharged from hospital following atrial baffle repair for transposition of the great arteries. Electrocardiograms of 47 of these patients were available for review seven months to eight and a half years (average 31 months) after operation. Of the 46 patients in sinus rhythm prior to operation, 40 (87%) were in sinus rhythm with normal atrioventricular conduction when last seen. Four patients (8.7%) had benign supraventricular dysrhythmias: three were junctional, one was atrial. None was noted to experience rapid dysrhythmias. Two patients showed evidence of abnormal atrioventricular conduction. There were five late deaths but in only one of these patients was a dysrhythmia a possible factor. The effects of variations in caval cannulation, extent of excision of the atrial septum and placement of the baffle suture line on the rhythm present at last review were examined. To preserve sinus rhythm it appears necessary to avoid surgical trauma in the vicinity of both the sinus node and the A-V node. Preservation of the internodal tracts appears less important. It is uncertain whether the 'sinus' rhythm seen after operation originates in the sinoatrial node but the rhythm is functionally similar.


Late postoperative hemodynamic results and cineangiocardiographic findings after Mustard atrial baffle repair for transposition of the great arteries.

Forty-nine patients with transposition of the great arteries who underwent a Mustard atrial baffle repair between 1964 and 1971 were assessed late postoperatively. There have been five late deaths: two related to baffle obstruction, two from noncardiac causes, and one sudden and unexpected. Hemodynamic data were available in 42 patients and autopsy in four. Obstruction of the lower venous channel was not encountered. Three patients had severe obstruction of the upper venous channel and in four there was mild restriction. Two patients had severe pulmonary venous obstruction resulting in late death; mild asymptomatic obstruction could not be excluded with certainty in six patients. Tricuspid incompetence was infrequently encountered in patients with an essentially intact ventricular septum. Left ventricular outflow tract obstruction was found in eight patients. In three it was present after satisfactory but incomplete surgical relief and in five it had not been recognized prior to operation. In only one of the latter patients was the obstruction important. Seventeen patients were operated on prior to one year of age. While baffle obstruction was confined almost entirely to these patients, the five youngest patients, aged one to nine weeks at operation, had adequate pulmonary and caval compartments at restudy two to three years later.


Hemodynamic studies in children four to ten years after the Mustard operation for transposition of the great arteries.

Fourteen patients have been studied hemodynamically 4-10 years (mean 5.5 years) after the Mustard operation for transposition of the great arteries. Investigation was directed principally at 1) the detection of baffle obstruction by catheterization of the pulmonary veins (PV) and venae cavae and recording of simultaneous right ventricular (RV) and pulmonary capillary wedge pressures (PCW); 2) the detection of intra-atrial baffle leaks by dye curves and selective angiography; 3) the assessment of RV and LV function by calculating peak VCE (dp/dt/28p) from high fidelity recordings in 11 patients. Severe baffle obstruction to the PV return was found in only one patient. The others had no or minimal gradients between RV end-diastolic and PCW pressures (mean 1.3 +/- 0.69 mm Hg). Cardiac output was normal at rest (4.1 +/- .22) and increased to 7.1 +/- .62 L/min/m2 (+73%) but the gradient between the RV end-diastolic and PCW pressures remained insignificant (2.2 +/- 1.13 mm Hg). No evidence of caval obstruction was found in any patient. Baffle leaks were found in five patients with mild bidirectional shunting. All arterial oxygen saturations were above 90%. Mild tricuspid regurgitation was demonstrated in two patients by RV angiography and was absent in 12 others. The contractility index peak VCE averaged 1.87 +/- .122 sec-1 for the RV and was significantly lower in the LV (1.53 +/- 1.35 SEC-1, P less than 0.01). Only one patient presented significantly decreased RV contractility with a peak VCE of 1.07 sec-1 and poor contraction on the RV angiogram. These data indicate that the long-term prognosis after the Mustard operation should be good in most patients and that the right ventricle is capable of functioning at the level of contractility of a normal left ventricle.


Paradoxical embolism. A diagnostic challenge and its detection during life.

Two cases of paradoxical embolism, one with recurrent cerebral embolism and one with brachial and coronary embolism and both associated with pulmonary embolism, were diagnosed during life. Although there was neither pulmonary hypertension nor intracardiac shunt present at the time of cardiac catheterization in both cases, the presence of a patent foramen ovale with an interatrial right-to-left shunt was demonstrated by a simple ascorbate dilution technique following a Valsalva maneuver. Each patient was treated by surgical interruption of the inferior vena cava and did well. Paradoxical embolism should be included in the differential diagnosis of arterial embolism for which there is no obvious source, especially when there is also evidence of venous thrombosis or pulmonary embolism.


Histological and immunological studies on eosinophilic granuloma of soft tissue, so-called Kimura's disease.

Increase of serum IgE with frequent localization of IgE in the germinal centres, mast cell hyperplasia in lymph nodes and changes of specific granules in the infiltrated eosinophils, such as roughness of the matrix and appearance of tubular structures together with fusing and disappearance of the core, were demonstrated in eosinophilic granuloma of the soft tissue, so-called Kimura's disease, in association with increase of anti-Candida IgE antibody. It is suggested that this disease may be due to atopic allergy to Candida albicans.


Human pituitary gonadotrophin index. II LHRH test and clomiphene response before and after LHRH stimulation.

To monitor the effect of LHRH treatment on hypothalamo-pituitary-gonadal function, women with functional amenorrhoea were investigated by standardized LHRH and repeated clomiphene tests before and after LHRH therapy. The actual pituitary gonadotrophin reserve was defined by a Human Pituitary Gonadotrophin Index (HPGI). Clomiphene response served as hypothalamic function test, plasma oestradiol and progesterone concentrations were measured for assessment of the gonadal function. LHRH treatment as performed in this study did not change basal gonadotrophin levels or the pituitary responsiveness in our standardized LHRH test. Plasma oestradiol concentrations remained unaltered at the lower limit of the early follicular phase values of a normal menstrual cycle. The inability to respond to clomiphene was changed to clomiphene responsiveness during therapy in eighteen out of twenty-nine women with anovulation. The majority of the responders had HPG-Indices of R2. Patients with hyperprolactinaemic anovulation did not convert. The possibility of an ultrashort feedback action of LHRH on its own production in the human is discussed.


Inhibitory effect of serotonin antagonists on growth hormone release in acromegalic patients.

We evaluated the effect of the serotonin antagonists cyproheptadine (Cypro) and methysergide (Methy) on growth hormone secretion in six patients with acromegaly. Two days administration of Cypro decreased the plasma GH concentration during oral glucose tolerance tests in four of the six patients evaluated; 2 days administration of Methy reduced the plasma GH levels of only one of the four patients evaluated. The one patient whose plasma GH concentration was lowered by Methy, did not have a decrease in plasma GH concentration after Cypro administration. Acromegalic patients have normal serum serotonin concentration and normal 5-hydroxyindoleacetic acid excretion. If Cypro lowers plasma GH by antagonizing serotonin, our data would suggest that serotoninergic neuronal pathways are important in the regulation of pituitary GH secretion in some patients with acromegaly.


A comparative study on the local inflammatory and immunosuppressive activities of anti-mouse anti-lymphocyte sera.

Local inflammatory reaction at the site of injection of anti-human antilymphocyte serum is a troublesome side effect. In this paper, a simple experimental model is presented for studying the local reaction caused by antilymphocyte serum. Anti-mouse antilymphocyte sera were injected intracutaneously and the intensity of the consequent oedema was estimated by the extravasation of Evans Blue dye solution given intravenously. It was found: (a) that rabbit anti-mouse anti-spleen sera produce consistently stronger local reactions than either anti-lymph node or anti-thymus sera; (b) that there is as yet no correlation between the intensity of the local reaction and the immunosuppressive (graft-protective) activity of the anti-lymphocyte serum pools tested. The possible implications of these findings are also discussed.


Humoral and cellular immune reactions 'in vitro' against allogeneic and autologous human melanoma cells.

Based on 51Cr release from an allogeneic human melanoma cell (M1) cell-mediated (CMC) and antibody-dependent cellular cytotoxicity (ADCC) were determined in twenty-eight melanoma patients, thirty-one healthy controls, ten patients with other tumours and eleven chronic lymphocytic leukaemia (CLL) patients. The results were related to simultaneously performed microcytotoxicity (MC) tests, HL-A typing, plasma membrane fluorescence and B:T cell ratios in the peripheral blood. Furthermore, lymphocytes from six melanoma patients were tested in CMC and ADCC assays against autologous tumour cells. The following results were obtained. (1) A large number of healthy controls possessed lymphocytes which readily lysed M1 target cells in CMC and MC assays. (2) CMC activity of lymphocytes from melanoma patients was generally lower than that of control lymphocytes and decreased further with progression of the disease. (3) CLL lymphocytes were virtually non-toxic for M1 cells, even at high aggressor:target cell ratios. (4) ADCC assays with a heterologous rabbit-anti-M1 serum showed generally higher isotope release than CMC assays; this was particularly pronounced in the melanoma group and in the group of patients with other tumours. (5) No tumour-specific blocking factor could be detected in melanoma sera, as judged by the capacity of the sera to block CMC activity. (6) No obvious correlation was found between the results obtained in short-term CMC and long-term MC assays. (7) T lymphocytes, as determined by E-rosette formation, were significantly diminished in melanoma patients. (8) The HL-A type of lymphocytes from normal donors and melanoma patients did not appear to be related to high or low activity in CMC and MC assays. (9) Preliminary results of 51Cr release tests with autologous melanoma cells were encouraging with respect to the correlation of the results to the clinical course of the disease.


Role of the thymus in programming of neuroendocrine functions.

Specific derangements of thyroid and gonadal functions were observed in athymic nude and neonatally thymectomized mice. Such endocrine alterations are already established during the perinatal period and maintained through adult life. Passive transfer of lymphoid cells from normal donors does not prevent such alterations. In nude mice thymus implantation at birth fully reconstitutes oestrogenic function, but thyroid and progestational functions remain defective. Peripheral endocrine glands (thyroid, adrenals and ovaries) respond normally to ACTH, TSH and LH. Thus the thymus may well have a basic role in the organization of the adult hypothalamus-pituitary axis for thyroid and sexual functions.


Mechanisms of protective immunity in experimental cutaneous leishmaniasis of the guinea-pig. II. Selective destruction of different Leishmania species in activated guinea-pig and mouse macrophages.

Macrophages activation as the effector mechanism in destroying L. enriettii in the guinea-pig, and L. tropica in the mouse, was tested in vitro. Activated guinea-pig macrophages, with enhanced anti-Listeria capacity had no effect on the survival of intracellular L. enriettii, irrespective of the antigen used. Activated mouse macrophages, on the other hand, destroyed ingested L. enriettii within 24-48 hr but had no effect on L. tropica during the same time period. It is suggested that the pathogenicity of a Leishmania parasite in a given host depends on the ability of the parasite to survive in the host's activated macrophages. The possible mechanisms by which L. enriettii evades destruction in activated guinea-pig macrophages are discussed.


Studies on the pathogenesis of chronic inflammatory liver diseases. I. Membrane-fixed IgG on isolated hepatocytes from patients.

Membrane-fixed IgG on isolated hepatocytes from biopsy material could be demonstrated by direct immunofluorescence in nine of thirty-four patients with acute virus-B hepatitis and in seventeen of forty-nine cases with chronic active hepatitis (CAH). Patients with acute virus-A hepatitis, chronic persistent hepatitis (CPH) or metabolic liver diseases did not show this phenomenon. Cases with CAH and IgG on the hepatocytes-HBsAg-positive as well as HBsAg-negative-had high inflammatory activity. Antibodies against HBsAg were not present in any serum. Autoimmune phenomena (antibodies against smooth muscle, mitochondria and nuclei) were only rarely demonstrable. The findings suggest that an antibody- or immune complex-mediated lymphocyte cytotoxicity may be involved in the pathogenesis of chronic liver diseases.


The role of polymorphonuclear leucocytes in the autologous phase of nephrotoxic nephritis.

The role of polymorphonuclear leucocytes (PMN) in the autologous phase of nephrotoxic nephritis (NTN) in the rabbit has been investigated. Depletion of circulating PMN by nitrogen mustard protected renal function and immunofluorescent examination showed reduction in glomerular fibrin deposition. Depletion of circulating PMN using a highly specific goat anti-PMN serum (APS) provided similar protection of renal function, highly significant reduction in proteinuria and histological and immunofluorescent examination showed reduced glomerular PMN infiltration, extracapillary cell proliferation and virtual absence of fibrin deposition. Although protection by nitrogen mustard may have been partly due to immunosuppression, no reduction in antibody response was detected in the APS-treated rabbits. The results implicate the polymorph as the principal injurious agent in this model of NTN, responsible directly or indirectly for both proteinuria and glomerular fibrin deposition.


B- and T-cell markers on human lymphoblasts after stimulation with mitogen or antigens.

Receptors for sheep erythrocytes and for the third component of complement were demonstrated on human lymphoblasts after stimulation with various antigens and mitogens. With these markers B- and T-cell stimulation could be differentiated. Phytohaemagglutinin (PHA) and purified protein derivative (PPD) proved to activate predominantly T cells, whereas foetal calf serum (FCS) was shown to be a B-cell stimulator. Candida albicans and allogeneic cells, on the other hand, stimulated both B and T cells.


Immunological studies of human placentae. Binding of complexed immunoglobulin by stromal endothelial cells.

Endothelial cells of foetal stem vessels in cryostat sections of normal, full-term human placentae bind fluorescein-conjugated heat-aggregated human IgG. Soluble immune complexes of sheep anti-human albumin also bind in a pattern that is similar to that of aggregated human IgG, but native human IgG is not bound by placental endothelial cells. Aggregated IgG binding, unlike soluble immune complexes, is blocked by pretreatment of the sections with antiserum to human IgM. Cross-blocking experiments with aggregated IgG and immune complexes suggest that they may be bound by different receptors.


Influence of IgG antibody and glycopeptide allergens on the correlation between the radioallergosorbent test (RAST) and skin testing or bronchial challenge with alternaria.

The radioallergosorbent test (RAST) for alternaria was compared to skin tests and bronchial challenges in children suffering from chronic intractable asthma. In contrast to when such children were tested with a timothy grass pollen extract, the bronchial challenge and skin test results against alternaria did not correlate significantly. When alternaria allergens were coupled to cyanogen bromide-activated microcrystalline cellulose, the RAST correlated with the results of skin testing but not bronchial challenge. It was demonstrated by column immunabsorption that some allergic sera contained sufficient IgG antibody against alternaria to competitively inhibit the RAST. When Sepharose 2B was substituted for cellulose as the insoluble support, the inhibition by IgG antibody was largely overcome and then the RAST correlated with both skin test and bronchial challenge results. Glycopeptides contribute significantly to the allergenicity of alternaria, and when these materials were coupled to a Sepharose 2B conjugate by mild oxidation, the RAST correlated with bronchial challenge, but not skin test, results. It was concluded that in this group of steroid-dependent asthmatic children, the correlation of the RAST with the in vivo challenges was strongly influenced by the presence of IgG antibody in the allergic sera and the chemical nature of the mould allergens investigated.


Electrophoresis of lymphoid cells. Differences in the cell membrane structure of murine thymocytes, T and B cells revealed by enzyme and formalin treatment.

Low concentrations of protease and trypsin reduced the electrophoretic mobility (EPM) of thymocytes; with higher concentrations it was normal or above. Differences in membrane structure of thymocytes, T and B cells was found as B cells showed no reduction while T cells gave intermediate values. Further the reduction was greater with protease than with trypsin. Formalin fixation increased the EPM of all normal cell types to a similar degree. The EPM of proteolytically treated thymocytes and B cells was increased to a similar level and to a greater degree than neuraminidase-treated thymocytes. Small amounts of sialic acid were detected in the supernatant after proteolytic treatment of thymocytes. Protease reduced the binding of anti-lymphocyte serum, while no definite effect was obtained with trypsin. Neither sublytic doses of phospholipase C nor ribonuclease appeared to change the EPM.


Microtechnique for simultaneous determination of immobilizing and cytotoxic sperm antibodies. Methodological and clinical studies.

A microtechnique for simultaneous detection of immobilizing and cyctotoxic sperm antibodies was elaborated according to the principles of Terasaki and McClelland. The technique was found reproducible, easy to perform and thus suitable for large scale examinations. The test includes determination of titres for immobilizing and cytotoxic effects and provides at the same time an opportunity to observe both complement-dependent and independent activities. Furthermore, agglutination patterns can easily be recorded. The requirement of only small volumes of test samples makes the test suitable also in testing secretions from the genital tract. In these cases, inclusion of a control for anticomplementary activity of the sample is advisable. In serum from 288 men from infertile couples simultaneous occurence of immobilizing and cytotoxic antibodies was observed in eight cases; all of them also had sperm-agglutinins in serum. In two of these cases, immobilizing and, in one case, cytotoxic activity was revealed in seminal plasma using undiluted samples. Patients with negative findings in serum also revealed negative findings in seminal plasma. Immobilizing and cytotoxic antibodies were not disclosed in serum from 247 women from infertile couples.


Antigen presentation as a factor in the protective immune response to renal infection.

Host protection against renal infection may be augmented by active immunization against the causative organism. In these experiments we have investigated the effect of varying amounts and methods of presentation of bacterial antigen on the seconday immune response. Primary immunization with varying amounts of both killed and live antigen did not affect the nature of the secondary immune response although active renal infection did have a noticeable effect on the titre of serum antibody during the primary immune response. The experiments confirmed the presence of immunological memory to the somatic antigen of E. coli and showed that memory persisted for at least 6 months after primary immunization. Experiments have also been carried out which have demonstrated that memory to the somatic antigen of E. coli is carried by the B lymphocyte.


Cellular and circulating immunity to diabetic basement membrane, a negative finding.

A linear deposition of IgG was seen by immunofluorescence on the glomerular basement membrane of a diabetic kidney. However, when the remaining kidney was subjected to elution with acidic buffer the eluate had no affinity for glomerular basement membrane. The leucocytes from normal and diabetic subjects were also tested for an in vitro cell-mediated response to diabetic and normal basement membrane. No difference was found between the reaction of leucocytes from diabetics and those from normal age- and sex-matched controls.


Immunosuppression with cyclophosphamide in the dog.

Cyclophosphamide significantly diminished the canine humoral antibody response to sheep red blood cells and tended to prevent arterial lesions in renal homografts. However, cyclophosphamide failed to prolong renal homograft survival when administered to dogs as the sole immunosuppressive agent, and it did not add to the effectiveness of azathioprine when given as a supplement to the azathioprine and administered simultaneously or sequentially.


Dynamics of thymidine incorporation by spleen cells from rats infected with Plasmodium berghei.

The in vitro incorporation of thymidine by spleen cells of rat infected with Plasmodium berghei was higher than that of normal rat spleen cells. The incorporation was proportional to the number of cells in the system and was related to the day of infection, e.g. spleen cells from malarious rats incorporated up to forty times as much thymidine as did normal spleen cells 21 days after inoculation. At the same time, the response of the malarious spleen cells to phytohaemagglutinin (PHA) was only one-twentieth of that observed for normal spleen cells. The thymidine was incorporated by non-adherent spleen cells in a single pulse during the first 8 hr in culture.


Infantile nephrotic syndrome.

The clinical features and renal histology of twelve chinldren who developed nephrotic syndrome in the first year of life were studied. Six suffered from microcystic disease and six from primary mesangial cell proliferation and/or sclerosis. A consistent family history, premature birth, large placenta pressence of other congenital abnormalities, onset in the first two months of life and lower plasma albumin level all suggested microcyste disease, but the most reliable distinction was histological. All microcystic children died within two years, whereas four with primary mesangial disease survived indefinitely. Corticosterid and immunosuppressive herapy failed to help either group and most deaths were due to sepsis, especialy with E. coli.


Hypergastrinemia and gastric acid hypersecretion in uremia.

Twenty-one chronic hemodialysis patients were investigated. While only two had radiologic evidence of peptic ulceration, three had markedly elevated basal acid outputs, thirteen had significantly elevated maximal acid outputs and seven had fasting duodenogastric reflux. Elevated fasting serum gastrin levels and prolonged gastrin circulation following stimulated endogenous release were also demonstrated. The abnormalities in gastric function may be explained by fasting and stimulated hypergastrinemia.


Rapidly progressive glomerulonephritis with antibodies against glomerular basement membranes in serum and kidneys.

Four cases of rapidly progressive glomerulonephritis with similar clinical courses are presented. Examination of kidney biopsies from these patients showed severe glomerulitis with capillary necrosis, fibrin thrombi and interstitial inflammation but no vasculitis. Electron microscopy showed wrinkled capillary basement membranes which were irregularly thickened, homogenous and had an irregular fibrillar structure. No localized deposits were observed. Immunohistological examination demonstrated linear and diffuse deposition of IgG and C3 along glomerular basement membranes. Nephrectomized kidneys from these patients were eluted and shown to contain antibodies against glomerular basement membrane. These antibodies were also present in sera of three of the patients.


Embryonic induction.

Inductive interactions between tissue components in proximity constitute a universal guiding principle for synchronized development during embryogenesis. Such sequential morphogenetic events involve both specific, determinative "instructions" and less specific, supporting or "permissive" influences acting upon predetermined target cells. Transmission of these intercellular messages may be mediated by diffusible signal substances, by morphogenetically active interfacial materials,or via actual cell contacts. Inductive interactions can be upset experimentally by exposure to various exogenous agents known to be potential teratogens, and several mutant strains of animals are known in which a genetic defect is manifested as a malformation through a defective interactive process. Hence, such inductive interactions should be considered likely targets for both genetic and exogenous factors in teratogenesis.


Screening for endometrial cancer.

Since Gusberg's description in 1947 of adenomatous hyperplasia (15), the role of precursors in the development of endometrial carcinoma has been well studied. There is now no doubt that in many patients histologic precursors can be demonstrated in the endometrial cavity prior to the development of invasive cancer. At this point in the continuum, interruption by hysterectomy or other therapy will insure the patient's health. We have discussed a wide variety of techniques designed to provide cytologic or histologic samples of the endometrium that are highly effective in the detection of early neoplasia. As a goal, universal endometrial sampling on a periodic basis is probably impractical and may be unecessary or undesirable. However, surely the patient at high risk for endometrial cancer requires close periodic screening. The high-risk category may be expanded to include others beyond the group of hypertensive, diabetic, obese, anovulatory, nulliparous women. It should include patients with irregular vaginal bleeding, those with a strong family history of genital and breast cancer, those patients receiving hormone therapy, and patients in the menopausal years who experience changes in the menstrual pattern. With intelligent and aggressive application of outpatient screening, uterine cancer can be diagnosed when patients are virtually completely curable, thus resulting in further reduction in mortality from this disease.


Tumor-associated antigens in gynecologic cancer.

If the study of tumor immunology is to have a profound impact on clinical medicine, certain hypotheses must be proven to be valid.  First and foremost, it must be demonstrated that malignant tissue possesses antigenic substances (probably protein moieties) that are unique to that particular malignant process.  In addition, these antigenic substances must be very similar in histologically similar tumors.  Second, the host defense mechanisms must be capable of reacting to these tumor-associated antigens.  The reaction is, of course, necessary in order to develop both diagnostic and therapeutic routes of application.  The reaction of the immunologic system to these tumor-associated antigens could be monitored as an early serodiagnostic tool for subclinical cancer, and the cytotoxic reaction holds great promise as an immunotherapeutic tool.  The essence of tumor immunologic research can thus be stated in the form of the following questions:  1.  Do histologically similar cancers from identical primary sites share common tumor-associated antigens?  2.  Does the immunologic system react to these antigens?  3.  Can this reaction be assayed on one hand for serodiagnosis and augmented on the other for immunotherapy?  Specific antigens have been found in animal tumors and have been divided into two classes: the viral induced tumors, which share common antigens when caused by the same viral agent, and carcinogen-induced tumors, which appear to have unique antigenic determinants for each tumor.  In recent years a great many human tumors have been found to have tumor-associated antigens; these include colonic carcinoma, neuroblastoma, melanoma, soft tissue and osteogenic sarcoma, bladder carcinoma and Burkitt's lymphoma.  This report includes evidence for the existence of such antigens in adenocarcinoma of the ovary and squamous cell carcinoma of the cervix.  The laboratory evidence that has been presented would suggest that there are both a cell-mediated response and humoral response to the antigenic determinants of these two gynecologic cancers.  It would appear that the mediated (lymphocyte) effect is considerably more cytotoxic and definitive than the humoral factors measured.  In addition, the allogenic experiments would suggest strongly that indeed (at least with regard to these two cancers) histologically similar cancers from the same organ share common antigenic determinants.  The identification and isolation of these tumor-associated antigens appears complex.  The complexity is increased when one studies patients afflicted with these cancers for plasma carcinoembryonic antigens.  This antigen, which was thought to be specific for adenocarcinoma of the colon, is found in the blood of a significant number of patients with adenocarcinoma of the ovary and squamous cell carcinoma of the cervix.


Prolonged apnea of prematurity: Treatment with continuous airway distending pressure delivered by nasopharyngeal tube.

Five premature infants experiencing frequent episodes of apnea and bradycardia were treated with continuous positive airway pressure delivered by nasopharyngeal tube. A significant decrease in the frequency and severity of apneic spells was observed. Premature withdrawal from end expiratory pressure resulted in an increase in both the incidence and the duration of the apneic episodes. We suggest that hypoventilation and a reduced functional residual capacity (FRC) are related to the development of prolonged apnea. Expansion and stablization of FRC with small amounts of end expiratory pressure appears to be beneficial.


Free skin flap transfer.

In this article we have described general considerations relative to free flap transfers, introduced our operative technique of free flap transfers and outlined some of our representative cases. We also set forth the advantages and disadvantages of free flap transfers as we have experienced them.


Resurfacing problems in the hand.

Some of the many acceptable methods of achieving primary skin cover of optimal quality under varying conditions in hand injuries have been briefly described. The overriding principles of hand coverage following injury remain: to achieve, by the simplest methods appropriate to the circumstances, the replacement of lost tissue similar or nearly similar in quality to that lost and to accomplish this with as little morbidity and as little donor area scar as possible, and as expeditiously as is consonant with the best results.


Dupuytren's disease: controversial aspects of management.

Surgical literature is replete with descriptions of Dupuytren's contracture and the various operations which surgeons have utilized to correct contractures of the palmar fascia. All that is worthy of presentation now are the unknown factors or frontiers of our knowledge. Etiology and control of major complications such as pain, joint stiffness, and recurrence are the frontiers which seem most intriguing to the author. The first step in scientific exploration of these areas is to form a hypothesis which takes into account all of the known factors. In this treatise, the author has stated a hypothesis for each of the frontiers. One hypothesis is that genetic predisposition for selective hyperkinetic collagen metabolism in the palm may be a biological counterpart to the condition found in transversalis fascia in patients with direct inguinal hernia. A hypothesis for pain syndromes is based upon general visceral afferent impulses striking a preconditioned central tract or sensitized central receptor. Joint stiffness has been attributed to the protracted release of polypeptides which change the electrical charge on crystalline protein and result in binding of water which then leads to secondary remodeling of joint structures. Recurrence or persistence of Dupuytren's contracture has been considered to be the result of a persistent inductive phenomenon by cells in the deepest layer of the dermis. Brief arguments supporting these hypotheses as being more tenable now than most others have been presented. For the most part such deductions have been based primarily upon the argument that no other hypothesis presently before us takes into account all of the available data or clinical observations, meager as they may be. Prejudice for surgical biology as a means of enlightenment, intuition, and, at times, empirical reasoning has been admitted in an attempt to stimulate imagination. The rest is left to the reader.


Practical microsurgery.

The reconstructive surgeon who wishes to learn microsurgery must realize that its acquisition demands extensive practice in the research laboratory with clinical application occurring after perfection of the fundamental techniques. Their initial usage should be in traumatic extremity injuries followed by replantation of complete and incomplete amputations. Elective reconstructive microsurgery demands consummate clinical skills and should not be attempted except by those who have convincingly demonstrated their microsurgical skills either in replantation surgery or in the research laboratory.


Problems in the treatment of burnt hands.

The treatment of burnt hands is not simple. By emphasizing problems that are frequently encountered, I have attempted to stress certain methods of treatment based on sound principles of burn wound care and skin grafting. Great responsibility rests on the person who does the initial skin grafting in the full-thickness loss burn of the hand, just as there is on the person who is treating the burnt hand prior to grafting. Such responsibility demands the maintenance of adequate range of motion during the preparatory wound care, after the important initial grafting, and during the rehabilitation period, so that maximum final function can be attained. If one does not recognize the importance of these principles of treatment, a stiff, malpositioned, contracted hand will result that is impossible to adequately correct, leading to significant permanent disability and loss of earning power. All who treat burned patients should realize that the major permanent disability of burns is in the hands. Proper treatment based on sound principles can greatly reduce or eliminate that disability.


Management of mutilating injuries of the hand.

In the devastating destruction of parts associated with mutilating injuries of the hand, it is often not possible to salvage the elements essential to normal function of the hand. The objective of primary treatment is re-establishment of circulation to the devitalized part, realignment of the remaining skeletal structures, and skin cover of the denuded portions. Definitive reconstruction has to be delayed until survival of the salvaged parts is assured. Occasionally, complex procedures have to be carried out to convert a marginal remnant of the hand into a useful functional unit. These may comprise rearrangement of bony elements to provide a radial digit with intervening space to permit pinch and grasp. Lack of sensibility can be corrected by shifting neurovascular pedicle or by immediate transfer of free neurovascular flap from a distance. Challenge met by skill, tempered by knowledge and sound judgment, comprise the elements of reconstructive hand surgery in the face of mutilating trauma. It is a field in which the surgeon is continually reminded of humility and yet it is filled with rewards for both patient and plastic surgeon.


Children's drawings about dentistry.

Drawings about the dentist at work were solicited from 1,101 children in grades 2, 4, 6 and 8 in an urban school district. A system to classify the contents of these drawings was developed. The frequency of various items occurring in the children's drawings was determined. The "typical" or most frequent child's drawing of the dentist at work was described. This drawing contained a normal dental chair, dentist, a patient in the chair and dental cabinetry or furniture. The picture was a very matter-of-fact representation. Abnormal or bizarre pictures occurred infrequently. A few children drew pictures that did not relate to dentistry.


A study of multiracial malocclusions.

The prevalance of a number of malocclusion traits was investigated for 1,000 modern British caucasoid, 70 medieval British, 60 Anglo-Saxon, 100 negroid and 100 mongoloid dentitions. Marked contrasts were evident in the sagittal, vertical and transverse occlusal and spacing anomalies between the various samples, with dental crowding being particularly prevalent in the modern British caucasoid sample and spacing between the teeth in the Anglo-Saxon sample. The method of quantification of malocclusions was shown to be applicable for other epidemiologic studies.


Thermodilution and Fick cardiac index determinations following cardiac surgery.

With the thermodilution technique, repeated determination of cardiac index (CI) has become a rapid, easily accomplished, safe procedure. We paired 77 CI determinations measured by direct Fick and thermodilution techniques in 21 patients who underwent myocardial revascularization. Commercially available thermistor-tipped catheters and a cardiac output computer were used to determine CI according to the manufacturer's instructions. Oxygen consumption and arterial-venous oxygen content differences were measured directly to determine CI by the Fick method. Comparisons were made during mechanical ventilation with and without positive end-expiratory pressure (PEEP) and during spontaneous ventilation with and without PEEP. Cardiac indices measured by the two techniques were within +/- 0.5 L/min/m2 of each other only 76% of the time and within +/- 1.0 L/min/m2 96% of the time, if CI greater than or equal to 4.0 L/min/m2 were omitted. Ventilatory pattern had no apparent effect on results.


A tongue stent for prevention of oral trauma in the comatose patient.

This paper presents the need for and offers a solution to the problem of factitial tongue and other intra-oral injuries in comatose and decerebrate patients. The neurophysiology of jaw movement in the comatose patient is the basis for the design of an intraoral prosthesis which in two patients has prevented discoordinate mandibular chewing movements and facilitated healing of preexisting factitial lesions. The authors delineate in detail the fabrication, insertion, and maintenance of this protective prosthesis and emphasize the need for joint effort between the intensive care, neurosurgical, and oral surgical teams.


The pulmonary response to fiberglass dust. Report of the Committee on Environmental Health. American College of Chest Physicians.

Fiberglass inhalation seems to produce a minimal tissue response in the lungs, and the reaction is one of macrophagic mobilization and is characteristic of the pulmonary response to those nonfibrogenic dusts classified as nuisance dusts. In order to merit the designation of a nuisance dust, the pulmonary response must fulfill the following three requisites:31(p5) (1) The alveolar architecture must remain intact. (2) The stromal proliferation is minimal and consists mainly of reticulin. (3) The tissue reaction is potentially reversible. Inasmuch as the pulmonary reaction to the dusts of fiber glass fulfills all of these requirements, it should be classified as a nuisance dust. 31(p5) There is no evidence to indicate that inhaling fiber glass is associated with either  permanent respiratory impairment or carcinogenesis; however, the final verdict as far as the latter is concerned must await the findings of long-term mortality studies.


Surgical management of radiation injury of the small and large intestine.

The following principles should be observed during operations for radiation injuries of the small and large intestine: 1) The objective of operation is modest: to relieve symptoms. 2) Only healthy bowel, which was outside the radiation field, should be anastomosed. 3) Isolated small intestinal injuries should be resected or bypassed, and extensive dissection should be avoided. 4) Colorectal injuries should be treated by diverting descending colostomy, with or without resection of the diseased bowel.


A controlled study comparing the conventional treatment of idiopathic anorectal abcess with that of incision, curettage and primary suture under systemic antibiotic cover.

The treatment of anorectal abscess by deroofing and packing on an initial inpatient basis has been compared in a controlled trial with that of incision, curettage and primary suture under systemic antibiotic cover in the Accident and Emergency Department. Over a three-year period 219 patients with anorectal abscess were randomly allocated to one or other treatment and subsequently followed up in a rectal clinic. In terms of the time taken for complete healing and the periods lost from work postoperatively, the method of incision, curettage and primary suture under systemic antibiotic cover was found to be significantly superior, without any increased risk of recurrence of the abscess or of subsequent fistula formation.


Fenfluramine: a review of its pharmacological properties and therapeutic efficacy in obesity.

Fenfluramine has been used for a number of years as a short-term adjunct to diet in the management of obesity. Controlled studies and clinical experience have shown that it possesses anorectic activity at least as good as that of other therapeutically useful drugs of its type, but like these drugs it has only a limited role in the overall management of obesity. Tolerance to the anorectic effects of fenfluramine may possibly develop more slowly than to other chemically related drugs in patients with refractory obesity. The mechanism of its anorectic action is probably by an effect on the appetite control centres in the hypothalamus, rather than by an effect on glucose and lipid metabolism. However, its effect in enhancing glucose uptake into skeletal muscle may be of advantage in diabetes mellitus, preliminary studies suggesting that it is of potential use in maturity-onset obese diabetics who cannot be adequately controlled by dietary measures alone. The starting dosage in obesity of 40mg daily should be increased gradually over 2 to 4 weeks to 60 to 120mg. In general, little extra benefit is gained by higher dosage. When a course of therapy is to be discontinued, fenfluramine dosage should be reduced gradually over a period of 2 to 4 weeks in order to avoid mood depression which has occurred in some patients on abrupt withdrawal of the drug. With these recommendations, the majority of patients tolerate fenfluramine satisfactorily, although some patients may have to discontinue the drug because of troublesome gastro-intestinal problems, diarrhoea, drowsiness or dizziness. Unlike other amphetamine-derived anorectics, fenfluramine is not a central stimulant in therapeutic doses, and it probably has little abuse potential.


Effects of synthetic gonadotropin-releasing hormone on incorporation of radioactive glucosamine and amino acids into luteinizing hormone and total protein by rat pituitaries in vitro.

The influence of synthetic gonadotropin-releasing hormone (GnRH) on incorporation of glucosamine and amino acids into LH and total protein was investigated. Rat pituitaries were incubated in vitro with radioactive precursors for 4 h at 37 C. Labeled LH was isolated by immunoprecipitation with specific anti-LH-beta serum. Total LH in the medium and pituitary glands was measured by radioimmunoassay. GnRH significantly stimulated incorporation of [3H]glucosamine into LH in pituitaries from immature male, intact female, and ovariectomized rats. Pituitaries from ovariectomized rats synthesized more [3H]glucosamine-labeled LH than those from intact adult rats. GnRH enhanced release of [3H]glucosamine-LH into medium in pituitaries of both adult intact and ovariectomized rats. The response to GnRH was greatly reduced when pituitaries were exposed to cold shock before the 4 h incorporation period. In contrast to its effect on incorporation of [3H]glucosamine into LH, GnRH had either no or little effect, depending on experimental conditions, on uptake of [3H]glucosamine by pituitaries. Incorporation of [3H]glucosamine into total protein was not affected by GnRH treatment. GnRH increased release of either [3H]leucine- or [3H]alanine-labeled LH into medium, but had no significant effect on incorporation of labeled amino acids into total LH in the system. GnRH modified neither uptake nor incorporation of amino acids into total protein. GnRH significantly stimulated the release of cold LH into medium under all conditions, but the total amount of immunoassayable LH in the system was not detectably modified by GnRH treatment.


Uptake of (3H)progesterone and (3H)5alpha-dihydroprogesterone by rat tissues in vivo and analysis of accumulated radioactivity: accumulation of 5alpha-dihydroprogesterone by pituitary and hypothalamic tissues.

These in vivo studies explored the possibility that the metabolism of progesterone to 5alpha-dihydroprogesterone (5alpha-DHP) and 3alpha-hydroxy-5alpha-pregnan-20-one in hypothalamus and pituitary may influence gonadotropin release. [3H]progesterone or [3H]5alpha-DHP was injected iv into ovariectomized or ovariectomized-adrenalectomized rats for 10 0r 30 min. 3H content was determined for plasma, anterior pituitary, medial basal hypothalamus (MBH), cerebral cortex, muscle and uterus. Isotopic dilution analyses of the accumulated 3H were made for progesterone, 5alpha-DHP, 3alpha-hydroxy-5alpha-pregnan-20-one, 20alpha-dihydroprogesterone, 20alpha-hydroxy-5alpha-pregnan-3-one, and 5alpha-pregnane-3alpha, 20alpha-diol on samples from the 10 min groups. With progesterone injections, most of the tissue 3H was distributed among progesterone, 5alpha-DHP, and 3alpha-hydroxy-5alpha-pregnan-20-one. Progesterone was the predominant 3H-steroid in uterus, MBH, cerebral cortex and muscle. [3H]5alpha-DHP was the other major 3H-steroid in MBH and the predominant one in pituitary. In terms of tissue/plasma concentration comparisons, no tissue concentration of [3H]progesterone was greater than that in plasma except for MBH in the ovariectomized-adrenalectomized group. In contrast, [3H]5alpha-DHP levels in pituitary, MBH and cerebral cortex were many fold greater than those in plasma and muscle. MBH and pituitary levels were significantly greater than that in cerebral cortex. With 5alpha-DHP injections, most tissue 3H was associated with 5alpha-DHP and/or 3alpha-hydroxy-5alpha-pregnan-20-one. No [3H]progesterone was detected. [3H]5alpha-DHP predominated in pituitary and MBH, while 3alpha-hydroxy-5alpha-pregnan-20-one predominated in the others. In terms of tissue and plasma concentration comparisons, MBH, pituitary and cerebral cortical concentrations of [3H]5alpha-DHP were markedly higher than plasma, muscle, and uterine levels. Pituitary and MBH concentrations were also greater than that in cerebral cortex. Tissue levels of [3H]3alpha-hydroxy-5alpha-pregnan-20-one were not significantly greater than that in plasma. Thus, 10 min after injection of either [3H]progesterone or [3H]5alpha-DHP, high and significant amounts of 5alpha-DHP are accumulated in pituitary and hypothalamus, but not in uterus, which suggests that its presence may be functionally important in governing progesterone-sensitive processes in these feedback tissues.


Effect of luteinizing hormone releasing hormone (LHRH) and an LHRH antagonist of hypothalamic and plasma LHRH of hypophysectomized rats.

Stalk-medium eminence (SME) and plasma LHRH activities of chronically hypophysectomized immature female rats were evaluated by bioassay following a single subcutaneous injection of varying doses of either LHRH or the LHRH antagonist, [D-Phe2, D-Ala6]-LHRH (Wy-18,185). Administration of LHRH to hypophysectomized rats produced parallel dose-related increases in SME and plasma LHRH activities. Wy-18,185 produced a similar, but attenuated dose-related increase in SME-LHRH activity, while a dose-related decrease in plasma LHRH activity was observed. Collectively, the data suggest that (1) exogenous LHRH may be sequestered by the hypothalamus leading to significant increases in hypothalamic LHRH content, and (2) peptide antagonists of LHRH inhibit the release of endogenous LHRH at the hypothalamic level.


Somatostatinergic neurons in anterior hypothalamus: immunohistochemical localization.

The distribution of somatostatin was studied in the rat with an immunoperoxidase technique and rabbit anti-somatostatin. Somatostatinergic neurons were identified in the preoptic and anterior periventricular hypothalamus between the anterior commissure, optic chiasm, and the anterior portion of the ventromedial nucleus.


Somatostatin inhibition of insulin and glucagon secretion in rat islet culture: reversal by ionophore A23187.

Both insulin and glucagon release by monolayer cell cultures of newborn rat pancreas were increased when calcium concentration was raised from 1.8 mEq/1 to 7.2 mEq/1. In low calcium medium, the calcium ionophore A23187 (10 mug/ml) enhanced insulin and glucagon secretion. Incubation with somatostatin (1.0 mug/ml), which inhibited hormonal release in a low calcium environment, paradoxically caused augmented insulin and glucagon secretion when A23187 was also present.


Effects of intravenous infusion of catecholamines on rat plasma luteinizing hormone and prolactin concentrations.

Catecholamines were infused through an atrial cannula in unanesthetized rats on the afternoon of proestrus and blood was withdrawn through a second cannula for radioimmunoassay of LH and prolactin. Infusion of epinephrine, but not of norepinephrine or dopamine, blocked spontaneous pituitary LH release and ovulation. Ultimately, this effect appears to be exerted on the brain and not on the pituitary or through changes in pituitary blood flow. Pituitary LH release in response to exogenous LHRH, when administered in an amount that simulated the proestrous LH surge in phenobarital-treated rats, was unaltered by epinephrine infusion. In addition, epinephrine infusion did not alter the timing of the rise in plasma prolactin. Infusion of dopamine blocked the spontaneous rise in plasma prolactin and depressed basal prolactin levels. After the end of infusion, plasma prolactin rose rapidly. Infusion of norepinephrine or epinephrine partially suppressed the prolactin rise but only after 2 h of infusion. 1) point out the possibility that chronic release of epinephrine from the adrenal medulla may be involved in phenomena in which "stress" inhibits reproductive function; and 2) are consistent with the view that dopamine, but not norepinephrine, may be PIF.


Inhibition of luteinizing hormone release by analogs of luteinizing hormone-releasing hormone (LHRH) in vitro.

Sixteen synthetic analogs of LH-releasing hormone (LHRH) were tested for their ability to inhibit the stimulation of LH release induced by 3 X 10(-9)M LHRH in anterior pituitary cells in monolayer culture. Half-maximal inhibition of LHRH-induced LH release was obtained with 7 analogs at concentrations which ranged from 3 X 10(-6)M to 3 X 10(-5)M. None of these seven analogs had significant LH-releasing activity at concentrations up to 10-5M. Nine analogs had no detectable antagonistic activity when tested in up to a 3000-fold molar ratio of analog to LHRH.


Re-examination of porcine and bovine hypothalamic fractions for additional luteinizing hormone and follicle stimulating hormone-releasing activities.

More than 150 hypothalamic fractions were reassayed for luteinizing hormone-releasing hormone (LHRH) and follicle stimulating hormone-releasing hormone (FSHRH) activities in search for LHRH and FSHRH which differ from the decapeptide (pyro)Glu-His-Trp-Ser-Try-Gly-Leu-Arg-Pro-Gly-NH2 (I). Among the porcine fractions tested were those obtained: 1) from the isolation of thyrotropin-releasing hormone; 2) from two isolation procedures for LHRH; and 3) from methanolic and aqueous 2N acetic acid extracts which were subjected to Biogel P-2 filtration and partition chromatography. Some bovine hypothalamic fractions were also tested. Both in vivo and in vitro assays were used for measuring LHRH and FSHRH activities. The values obtained were in each case compared with those resulting from the administration of pure natural or synthetic LHRH decapeptide I. A radioimmunoassay for LHRH (I) was also utilized for some fractions. In all the purification steps the location of LHRH and FSHRH activity, as determined by in vivo assays, corresponded to that of the decapeptide I. Purification of hypothalamic extracts on Biogel P-2 and by partition chromatography separated a fraction from the decapeptide I, which released more FSH than LH in vitro from the pituitaries of immature female rats. However, this material was inactive in vivo and in other in vitro systems, so that its significance is obscure. The results suggest that if material with LHRH and FSHRH activity other than the decapeptide I is present in acid extracts of porcine hypothalami, then its FSHRH and LHRH activity would be a minor part of the total LHRH/FSHRH activity in the extracts. (Pyro)-Glu-His-Trp-Ser-Tyr-Gly-Leu-Arg-Pro-Gly-NH2 appears to account for most of all of the LHRH and FSHRH activity found.


Cytochalasin B-induced impariment of glucose metabolism in islets of Langerhans.

Cytochalasin B (10 mug/ml) facilitated glucose-, glyceraldehyde-, and leucine-induced insulin release. It inhibited glucose uptake, utilization, and oxidation, as well as lactate output in islets exposed to glucose (16.7 mM). However, it failed to affect lactate output in the presence of glyceraldehyde, and leucine oxidation. Cytochalasin B also caused a partial inhibition of 45calcium uptake and proinsulin synthesis evoked by glucose in low concentration (5.6 mM), these findings being compatible with a modest impairment of the process of glucose recognition by the beta-cell. At a higher glucose level (16.7 mM), cytochalasin B failed to affect proinsulin synthesis, the immediate inhibitory effect of glucose upon 45calcium efflux, and the subsequent accumulation of 45calcium in the islets. In the presence of cytochalasin B, mannoheptulose further reduced glucose utilization and lactate production and suppressed glucose-induced insulin release. These data suggest that, although insulin release in the presence of cytochalasin B apparently remains dependent on a sufficient glycolytic flux, the facilitating effect of the drug upon insulin secretion cannot be ascribed to any favorable influence on glucose handling by islet tissue. It is suggested that cytochalasin B, possibly through its effect on the microfilamentous web which is part of the cell boundary, may both facilitate insulin release  and inhibit glucose transport across the cell membrane, although no direct cause and effect relationship would exist between the two phenomena.


Simulation of the proestrous luteinizing hormone (LH) surge after infusion of LH-releasing hormone in phenobarbital-blocked rats.

Four-day cycling rats were kept in a room with the lights on from 0500-1900 h. Injection of an ovulation-blocking dose of phenobarbital at 1230 h on proestrus did not alter the rise in plasma LH concentration in response to rapid injection of 12.4, 124, or 1240 ng of LHRH at 1300 h. In additional blocked rats, blood was rapidly withdrawen through one of two indwelling atrial cannulas while LHRH was infused at a constant rate through the other. Administration of a given amount of LHRH by slow infusion was much more effective in elevating plasma LH than was rapid injection of the same amount of releasing hormone. The pattern of plasma LH concentration after infusion of approximately 50 ng of LHRH per hour from 1500-1810 h was remarkably similar to that of the spontaneous LH surge, i.e., a gradual rise in plasma LH concentration followed by a steep linear increase to high levels which remained elevated for a period of approximately 2 h before declining rapidly soon after the end of infusion. In rats given a second 3 h infusion of LHRH at the same rate, from 2200 to 0100 h, a different response pattern was seen: the initial increase in plasma LH was greater, but the linear rise, which ensued after a lag period of similar duration (about 45 min), was less marked. Prolongation of the first infusion beyond 1800 h did not prolong the plateau: plasma LH levels declined before the infusion was terminated. This decline was less rapid than that seen at the end of a spontaneous LH surge, which in turn was less rapid than that seen after termination of a 3 h and 10 min infusion starting at the same time (1500 h), suggesting that both LHRH release and pituitary responsiveness are diminished (but not abolished) at this time. These findings clearly indicate that, in phenobarbital-blocked proestrous rats, the major part of the proestrous LH surge (including rising and plateau phases) can be simulated by a constant-rate infusion of about 150 ng of LHRH over the 3 h and 10 min period beginning at 1500 h. Since the data also suggest that LHRH release is reduced and/or occurs sporadically during the terminal phase of the surge (when plasma LH levels are declining), these experiments imply that the LH surge is caused by a properly timed, nearly constant-rate release of LHRH for about 3 h (beginning about 1500 h of proestrus) followed by a period of diminished LHRH release.


Simulation of the early phase of the proestrous follicle-stimulating hormone rise after infusion of luteinizing hormone-releasing hormone in phenobarbital-blocked rats.

Four-day cycling rats were kept in a room with the lights on from 0500-1900 h. Plasma FSH concentrations in blood withdrawn through atrial cannulas at hourly intervals from 1400-2000 h on proestrus were very similar to serum FSH concentrations in blood collected by decapitation. Additional cannulated rats were bled at 20 min intervals from 1400-1600, 1600-1800, or 1800-2000 h. In most rats, plasma FSH concentration rose gradually to approximately three times pre-rise levels by 1900 h. It then decreased slightly by 2000 h. Injection of an ovulation-blocking dosage of phenobarbital at 1345 h blocked the FSH rise. Rapid injection of 124 or 1240 ng of LHRH at 1300 h did not elevate plasma FSH by 1315 h but the 1240 ng dose did by 1400 h. Phenobarbital injection at 1230 h did not alter this response. In additional blocked rats, blood was rapidly withdrawen through one of two indwelling atrial cannulas while LHRH was infused at a constant rate through the other. Administration of LHRH by infusion was much more effective in elevating plasma FSH than was rapid injection of the releasing hormone. The pattern of plasma FSH concentration after infusion of about 50 ng of LHRH per hour from 1500-1810 h and then about 12 ng of LHRH per hour from 1810-1920 h was remarkably similar to that of the spontaneous FSH rise. These experiments imply that the early phase of the FSH surge (the one associated with the proestrous LH surge) is caused by a properly timed, nearly constant-rate release of LHRH for about 3 h (beginning about 1500 h of proestrus) followed by a period of diminished LHRH release.


Effect of administration of anti-serum to luteinizing hormone-releasing hormone on gonadal function during the estrous cycle in the hamster.

One-half ml of sheep-anti-LHRH-serum (No. 772) completely blocked ovulation when administered iv or sc at any stage of the estrous cycle in cycling hamsters. This anti-ovulatory activity lasted 12-13 days. The minimal effective iv dose (MED) of the anti-LHRH serum for completely blocking the preovulatory LH surge and ovulation when administered at 1200 h on proestrus was 0.2 ml. Injection of LHRH on the afternoon of P (proestrus) induced ovulation in the antiserum-treated hamsters when the antiserum was injected on P, but not when injected on D1 (diestrus 1) or D2 (diestrus 2). This suggests that the anti-LHRH serum acts differently in blocking ovulation during D and P, by suppressing follicular development and inhibiting preovulatory surge of gonadotropins, respectively. Serum estradiol levels, measured by radioimmunoassay, were significantly reduced but not completely suppressed after injection of 0.5 ml of anti-LHRH-serum. Histological examinations of the ovaries revealed that an arrest of follicular maturation resulted 3 days after antiserum injection. 17-beta-Estradiol administered 22 h before the presumptive preovulatory LH surge improved significantly (P less than 0.05) the LH response to LHRH in the antiserum-blocked hamsters. This suggests a direct modulation of pituitary LH responsiveness by estradiol in the absence of endogenous LHRH activity. When the integrated levels of serum LH following an injection of a minimum effective dose of exogenous LHRH to induce full ovulation in anti-serum-blocked hamsters were compared with those during the physiological preovulatory LH surge, it was found that only 11% of the amount of LH released on the afternoon of proestrus was sufficient for inducing full ovulation.


[Decomposition of steroids during incubation with beta-glucuronidase and during storage of urine].

Androsterone, etiocholanolone, pregnanetriol, dehydroepiandrosterone, pregnanediol, tetrahydrocortisol, 5-pregnenolone and 11-beta-OH-androsterone were incubated with beta-glucuronidase preparations (Helix pomatia, bovine liver and E. coli) for 96 hrs at 37 degrees C. After extraction and silylation they were gas-chromatographed. The first 3 steroids were left practically intact. The least decomposition of the last 5 steroids occurred with the liver enzyme. Testosterone and 11-ketoandrosterone without the enzymes showed 74 and 35% recoveries. Cortisol and tetrahydrocortisol, incubated with the first two enzymes for 18 hrs at 37 degrees and 48 degrees C, showed nearly 100% recoveries. The recoveries of 17-OHCS in urines (pH 7.8-8.8), stored for 7 days, was 80% at 20 degrees-25 degrees C and 55% at 25 degrees-30 degrees C. The same samples, brought to pH 1.8-2.8 WITH NaHSO4 before the storage, showed a 100% recovery.


Insulin secretion of isolated islets of sand rats (Psammomys obesus) during adaptation on captivity.

In normoglycemic sand rats the insulin secretion of isolated islets was investigated dependent on the time of artificial nutrition in captivity. Whereas the islets of short-term adapted animals did not respond within 15 min with an enhanced insulin secretion after stimulation with 16.5 mM glucose or 10 mM arginine, prolongation of incubation time resulted in a significantly enhanced hormone release. An intraveneous glucose injection (1 g/kg body weight) 45 min prior to the excision of the pancreas caused an immediate insulin secretion of the isolated islets in response to glucose or arginine. Islets of sand rats adapted for more than 10 weeks to artificial nutrition responded immediately with an enhanced insulin release in contrast to the islets of short-term adapted animals. These differences could not be correlated to the insulin content, the A/B cell ratio, and ultrastructural alterations of the islets.


Processing of the 17-S Escherichia coli precursor RNA in the 27-S pre-ribosomal particle.

An RNase activity probably involved in the maturation of 16-S pre-ribosomal RNA in Escherichia coli has been partially purified from crude cell extracts. When 27-S ribosome precursor particles are incubated with this enzyme preparation in vitro, their 17-S RNA is converted to a product with the same electrophoretic mobility as mature 16-S rRNA. Fingerprint analysis of this product shows that it contains the 3'-OH but not the 5'-P terminus of mature 16-S rRNA. Generation of the normal 5'-P terminus seems to require a factor present in cell extracts since incubation of the 27-S precursor particle in an extract obtained after centrifugation at 30 000 x g causes conversion of the 17-S RNA to a 16-S species containing both termini of mature 16-S rRNA. Preliminary experiments suggest that correct maturation of the 5' end of the 17-S precursor RNA requires a system in which protein synthesis can take place.


Carcinogen-induced DNA repair in nucleotide-permeable Escherichia coli cells. Analysis of DNA repair induced by the carcinogens N-acetoxy-N-2-acetylaminofluorene and 7-bromomethyl-benz(a)anthracene.

Upon exposure to the carcinogens N-acetoxy-N-2-acetylaminofluorene and 7-bromomethyl-benz[a]anthracene, which bind covalently to DNA, ether-permeabilized (nucleotide-permeable) Escherichia coli wild-type cells responded with DNA excision repair. This repair was missing in mutants carrying defects in genes uvrA, uvrB and uvrC, whereas it was present in uvrD and several rec mutants. Enzymic activities involved were identified by measuring repair polymerization and size reduction of denatured DNA. 1. An easily measurable effect in E. coli wild-type cells was carcinogen-induced repair polymerization. When initiated by N-acetoxy-N-2-acetylaminofluorene or 7-bromomethyl-benz[a]anthracene, it depended upon an ATP-requiring step; CTP, GTP or UTP did not substitute for ATP. DNA repair synthesis was inhibited by p-chloromercuribenzoate and quinacrine. In uvrA, uvrB and uvrC mutants no carcinogen-stimulated DNA synthesis could be detected, indicating that steps involved in pyrimidine dimer excision are also involved in chemorepair. In recA, recB and recC mutant cells, repair synthesis was stimulated by the carcinogens to a normal extent. This evidence excludes the ATP-dependent recB,C deoxyribonuclease and recA gene products as playing an important role in carcinogen-induced excision repair. polA1 cells showed drastically reduced levels of rapair polymerization, indicating that DNA polymerase I is the main polymerizing enzyme. 2. As determined by DNA size reduction in alkaline sucrose gradients, the arylalkylating carcinogens caused endonucleolytic cleavage of endogenous DNA in wild-type cells. This incision step was most effectively performed in the presence of ATP; UTP, CTP and GTP were only slightly effective. Incision was inhibited by p-chloromercuribenzoate and quinacrine. When exposed to the arylalkylating carcinogens, uvrA, uvrB and uvrC mutant cells did not perform the incision step in the presence of ATP, suggesting the involvement of the respective gene products in the initiation of chemorepair.


The involvement of protein L11 in the joining of the 30-S initiation complex to the 50-S subunit.

Ribosomal protein L11 participates in the coupling of the 30-S initiation complex with the 50-S subunit. P37 cores, lacking L7, L8, L12, L33, L10 and L11 were reconstituted with L7 and L10. These particles are unable to join successfully to the 30-S initiation complex, whereas reconstitution of the same cores in the presence of L7, L10 and L11 restores 60-80% of the original coupling activity. P0 cores lacking only L7, L8, L12 and L33 are able to carry out one round of initiation, addition of L7 resulting in complete restoration of full activity. The data obtained with these P37 core particles resemble those obtained with untreated 50-S particles carrying thiostrepton, which prevents the binding of initiation factor IF-2 into the 70-S initiation complex.  It is postulated that L11 induces a niche on the ribosomal surface to facilitate the proper binding of the IF-2 X GTP X fMet-tRNA complex. This binding of IF-2 enables the 30-S initiation complex to join to the 50-S subunit, because of the associative ability of IF-2. If joining is impaired than both the level of fMet-tRNA binding and of the IF-2-mediated GTP hydrolysis is lowered.


[Acute intoxication by cosmetics].

Intoxications due to cosmetics are of various types, but certain substances may be particularly harmful, especially when the constituants include acetone, boric acid and borates, ethyl alcohol, bromates, formol, methyl alcohol, propylene glycol, thallium, thioglycolate.. Every cosmetic substance may induce accidental intoxications. Most often, fluid cosmetics are absorbed either by children or by feeble-minded subjects. In all intoxication, one must take account of the age and weight of the patient, of the quantity absorbed, of the toxicity and of the constituants of the substance.


[Effects in the rat of a weak dose of acrolein inhaled continuously].

The results of an experiment on 173 S. P. F. rats inhaling 0.55 ppm of acrolein, compared to 173 control rats, are reported. In what concerns the respiratory apparatus, this dose of acrolein affects its defense mechanisms, leading to a greater susceptibility to the airborne Salmonella enteritidis infection, compared to the control group. These phenomena disappear spontaneously when intoxication is prolonged more than three weeks. On the contrary, the general toxic action, manifesting itself through diminished weight growth and under-nourishment, compared to control group, lasts as long as intoxication and disappears only after acrolein inhalation has stopped. These results are discussed.


A rapid method for the verification of drug injection into the cerebral ventricular system of the rat.

A precise method for the injection of drugs into the cerebroventricular system of small animals used for experimentation is described. This method, based on the intraventricular pressue record, gives absolute certainty for the injection of a drug into a previously selected site and thus avoids the subsequent histological studies.


Inflammatory factors produced by sensitized guinea-pig peripheral blood lymphocytes.

The supernatants obtained from stimulated tuberculin-sensitive guinea-pig peripheral blood lymphocytes contain factors that induce a cutaneous inflammatory response in normal guinea-pigs similar to the tuberculin reaction and inhibit the migration of normal guinea-pigs peritoneal exudate cells. There appears to be a correlation between the presence of in vitro migration inhibitory activity and inflammatory activity in vivo.


The functioning and interrelationships of blood capillaries and lymphatics.

The structure and function of blood capillaries, as related to permeability, depends on tight, close and (in injured vessels) open junctional regions, small vesicles, vacuoles (in injured vessels) and fenestrae. The basement membrane presents a hindrance to the larger macromolecules, at high flow rates, but not to small molecules. The connective tissue channels are probably the paths by which macromolecules, and most of the small ones, pass from the arterial-limbs to the venous ones, and to the lymphatics. In some regions these channels are grouped in special systems: the prelymphatics. The initial lymphatics take up material via open junctions, which close during tissue-compression. The collecting lymphatics retain the lymph because they do not have open junctions. In the close junctional regions the motive force for water flow is the result of Starling's forces; diffusion is very important for other small molecules. The small vesicles transport macromolecules slowly by Brownian motion, as may the vacuoles, but possibly these latter are moved actively. There is much evidence that colloids can develop high effective osmotic pressures even across pores much larger than their molecules, and that proteins can be dragged up a concentration gradient by the resultant fluid flow. On the basis of this, hypotheses have been developed about the functioning of venous-limb fenestrae and the initial lymphatics, for which there is much theoretical, in vitro, and in vivo evidence. Thus, in fenestrated regions there is held to be a large local circulation through the tissues, of which a quantitatively small, but qualitatively vital, part goes to the lymphatics. Material is considered usually to enter these latter because of the relative concentration of the lymph. It is becoming increasingly evident that in the study of the microvasculature, as with other systems, there is much to be gained by quantifying fine structural observations and by combining and contrasting this data, via physical laws, with that obtained by other methods where the characteristics of whole organs and regions are studied. Thus one can obtain interrelated information, which is not possible by either method alone, and which gives us a vital, comprehensive, perspective of the ways in which whole systems function, and how different systems interact. In this paper I shall show how this approach has yielded much that is new about the functioning of different kinds of blood capillaries, of the tissue channels, of the whole lymphatic system, and of the ways they affect each other.


[Toxicity and tolerance of toxogonin].

A comparative characteristic of acute toxicity of toxogonine and dipiroxime is given for different animal species with various routes of introduction of the compounds from which it follows that, as concerns the toxicity parameters and the area of toxic action, toxogonine is in the lead. It is also shown that with its multiple administration in a therapeutic dose toxogonine does not affect the peripheral blood, the hepatic and renal functions, the cardio-vascular system, this being also supported by the anatomo-pathological findings. With its intramuscular introduction toxogonine does not produce any local irritation.