Vertical transmission of hepatitis-B surface antigen. Transmission of Hepatitis B virus from mother to infant can cause a severe type of neonatal hepatitis. Comparing chronic carrier mothers with mothers who have acute hepatitis in pregnancy we find that the latter group present the greater risk to their infants. Differences in the presence of Hepatitis B core and Hepatitis B e antigen and antibody in the acute case and in the carrier state may expoain the differences observed in the transmission rates of two groups. In countries where the prevalence of the carrier state is high it appears that vertical transmission of the carrier state is also common. This pattern may be explained by differences in the geographical distribution of carriers of Hep B e antigen, which has been recently described as a virulance factor.


HLA and other immunogenetic approaches to the study of diseases in man. We have attempted to focus on several areas that can be practically explored to elucidate the mechanisms accounting for the polymorphism of the human major histocompatibility complex and attendent disease predispositions. In addition to widespread serologic HLA typing of specific populations, diseases, and families, it is important to improve discriminating methods for expoloration of other areas of the HLA supergene, especially those involved in specific immune responsiveness. It may also be necessary to take into account possible modulating effects of the MHC on other recognized human genes. Application of these improved methods to the study of infertile couples, recognized genetic syndromes, and human malignancies may assist in unraveling the immunogenetic enigma of these diseases.


Pulmonary surfactant and dog lung transplant. The pulmonary sufactant was studied in the dog after crossed lobe autotransplantation and the influence of graft preservation time before reimplantation was considered. 1) The phospholipid composition of the grafted lobe is unchanged. 2) The incorporation of 32P orthophosphate in phosphatidylcholines is increased in the entire grafted lung (transplanted and ungrafted lobes). 3) Conservation of the graft for 48 hrs before the autograft changes neither surfactant composition nor 32P incorporation.


Study of the correlation between glomerular and urinary sediment deposits using immunofluorescent technique. Correlations between immunofluorescent protein deposits in the glomeruli, urinary sediment and proteinuria selectivity pattern have been attempted in different glomerulonephritis. The overall study showed following results: a) Glomerular and urinary casts deposits of immunoglobulins, C3 and fibrin/fibrinogen are related to moderately selective proteinuria; b) IgG and IgA are most often found in urinary sediment and c) Glomerular deposits of IgG and IgA are well correlated with the presence of these immunoglobulins in urinary casts. Analysis according to different histological types of nephritis: a) In "minimal changes" nephropathy, deposits are infrequent and well correlated with urinary sediment, when they are present; b) In lupus nephritis, constant and intense glomerular deposits of immunoglobulins, fibrin/fibrinogen are correlated with the same proteins found in urinary casts; c) Inconstant correlations are found in membranous nephritis and in IgA-IgG nephropathy.


Reticulocyte motility and form: studies on maturation and classification. A new two-stage living cell cytological classification is presented for reticulocytes in the rat and shown on an overall population basis to be the equivalent of the classical new methylene blue staining characterization. Class 1 reticulocytes (R1) are motile and multilobular. They comprise about 25% of normal bone marrow reticulocytes, but none of the reticulocytes in normal blood. Class 2 reticulocytes (R2) are asymmetrically "deep dished" in appearance and contain visible refractile granules, viewed in phase-contrast microscopy. In animals "stimulated" by bleeding, the percentage of motile marrow reticulocytes is found to be a linear function of hematocrit over the range of about 25%-70% total reticulocytes. In the blood, the associated maximum rise of class R1 is only to about 8%. These and related cellular properties are discussed with respect to the maturation and release of normal reticulocytes. Applicability of this work to studies on humans and to pathology is also indicated.


Factors controlling stem cell recirculation. III. Effect of the thymus on the migration and differentiation of hemopoietic stem cells. Experiments were carried out to investigate the effect of thymectomy on the migration and differentiation of hemopoietic stem cells released from shielded parts of bone marrow after irradiation of mice with lethal doses of x-rays. In 2-3 wk after thymectomy, the rate of migration declined and the differentiation of stem cells into granulocytic colonies was inhibited. Transplantation of syngeneic thymus or lymph node cells into thymectomized mice enhanced the migration of stem cells from the bone marrow and restored the usual pathways of their differentiation.


Effect of corticosteroids on lymphocyte activation. Human peripheral blood lymphocytes were stimulated by concanavalin A, sodium periodate, and neuraminidase plus galactose oxidase. Response to mitogens was measured by the amount of tritiated thymidine incorporated as well as the percent of "giant sheep red blood cell rosettes" generated. The thymidine incorporation was diminished by the absence of monocytes or the presence of corticosteroids. The percent of giant rosettes generated was not influenced by either change. This finding suggested that considerable lymphocyte activation could still take place in the presence of corticosteroids. When subjects received 60 mg of prednisone, they developed lymphopenia 5 hr later. The circulating lymphocytes at that time responded less well to mitogen stimulation when measured by both thymidine incorporation and percent giant rosettes, suggesting a selective sequestration of mitogen-responsive lymphocytes outside the circulatory compartment.


Cell marker analysis in acute monocytic leukemias. Leukemic cells from nine cases of acute monocytic leukemia (AMoL) were characterized by multiple differentiation markers. Cells in most cases were phagocytic, carried an Fc receptor, and stained positively for alpha-naphthyl acetate esterase but negatively for naphthol AS-D chloroacetate esterase. However, subtle differences in marker expression were observed which suggested different degrees of leukemic cellular maturation or activation. Cell marker analysis proved to be a useful adjunct to conventional morphology in confirming the diagnosis and the recognition of the neoplastic cells in AMoL, and may ultimately provide insight into the functional state of these cells.


Lipid A as the biologically active moiety in bacterial endotoxin (LPS)-initiated generation of procoagulant activity by peripheral blood leukocytes. Preparations of rabbit or human leukocytes, when incubated with bacterial endotoxins (lipopolysaccharides, LPS) are stimulated to generate a procoagulant-tissue factor activity (TFa). As LPS has been shown to consist of specific repeating oligosaccharide side chains (O-antigen) linked to a central polysaccharide core region that is, in turn, linked to the lipid region of the molecule (lipid A), we have examined the biochemical requirement of the LPS necessary for generation of TFa. Using preparations of LPS from mutant strains of bacteria, which contain varying amounts of polysaccharide in relation to lipid A, we have demonstrated that activity is associated with the lipid A region of the LPS molecule. These observations have been confirmed using isolated lipid A, which is a potent stimulator of TFa, as well as a native protoplasmic polysaccharide that is both devoid of lipid A and without detectable TFa stimulatory activity. Modification of LPS by treatment with mild alkali abrogated its capacity to stimulate TFa generation. In addition, such altered preparations of LPS partially inhibit the stimulatory effect of native LPS. Similarly, treatment of LPS (or lipid A) with the antibiotic polymyxin B substantially inhibited the stimulatory effect of LPS.


Photon absorptiometry of bone after successful renal transplantation. Photon absorptiometric measurements of the right lower femur were carried out at regular intervals of one to three months in 58 recipients of renal transplant. (1) During the first six months after transplant 57% showed a significant and abnormal rate of loss of bone mineral (mean 11.7% per year. +/- 1.1% S.E.M.) while 30 months' after transplantation only 17% showed such a significant loss (p=0.025). (2) Eighteen months after transplantation both male and female recipients of transplants had a significantly lower mean bone mineral index than controls (p less than 0.001). (3) Male patients who developed new post-transplant fractures had a lower mean bone mineral content compared with age and sex-matched controls taken from transplant recipients without such fractures (p less than 0.01). Similarly male patients with post-transplant fractures had a significantly longer mean period on regular haemodialysis (p less than 0.05) compared with patients without such fractures. Regular photon absorptiometric measurements provide an accurate, informative and non-invasive technique for following changes of bone mineral content after successful renal transplantation.


Single dose intra-incisional antibiotic prophylaxis of surgical wound sepsis: a controlled trial of cephaloridine and ampicillin. In a series of 410 consecutive potentially contaminated operations, we have compared the relative efficacy of intra-incisional cephaloridine and ampicillin in single doses of 1 g in 2 ml of water. In high risk operations (ileocolorectal surgery, perforated appendicitis, or when the patient has 2-5 cm or more of subcutaneous fat at the site of the incision) cephaloridine prophylaxis resulted in a primary sepsis rate of 14 per cent compared with 36 per cent for ampicillin. In all other patients the two antibiotics were equally effective. Secondary sepsis, following discharge from the wound of a substance other than pus, was equally common in the two groups.


Diagnosis of invasive candidosis by enzyme immunoassay of serum antigen. Enzyme immunoassay was used to measure Candida albicans-related antigen in sera of rabbits and mice infected with C albicans. A range of heterologous antigens tested gave no cross reactions. Of the three patients who were investigated and gave positive reactions, two were confirmed as having deep candida infections. Enzyme immunoassay is efficient, simple, and sensitive, and may prove valuable in the early diagnosis of invasive candida infections.


Intravenous tyramine response in migraine before and during treatment with indoramin. We studied the response of 31 migraine sufferers (20 women, 11 men) to intravenous tyramine (the tyraminedose)pressor response test). Patients were treated either with pacebo tablets or indoramin, and alpha-adrenergic blocking agent, in a double-blind crrossover trial. We found that patients with migraine required significantly less tyramine to increase their cystolic blod pressure by 30 mm Hg when compared with matched controls. Indoramin significantly increased the amount of tyramine needed to raise the systolic blood pressure among migraine suffers and reduced the incidence of posttyramine migraine for m 46% while patients were on placebo tablets to 8% when they were receiveing indoramin. There was no association between tyramine sensitivity and a history of premenstrual or dietary migraine, nor was there a significant difference in the indierenence in the incidence of post-tyramine migrain between men women. We conclude that the intravenous tyramine test may be valuable in assessing migraine suffers who will respond to an alpha-advenergic blocking agent such as indoramin.


Clinical aspects of polycystic disease of the kidneys. Seventy-eight patients were treated for polycystic disease of the kidneys. An analysis of the interval between the onset of symptoms and end-stage renal failure made it possible to give and accurate prognosis in individual cases. Pregnancy and urinary infection did not appear to accelerate deterioration of renal function, but Rovsing' operation precipitated renal failure in some cases. Forty-two patients needed replacement treatment for end-stage renal failure, and 24 patients received 29 renal allografts. Transplant function at all times was better than a matched group of 70 patients indications for removal of polycystic kidneys in graft recipients were persistnet or recurrent infection, erythraemia that failed to respond to conservative treatment, and to make room for the transplant.


Arthritis in Flemish paintings (1400-1700). A close examination of the hands of people depicted in paintings of the Flemish school showed that in five paintings there were figures with hand lesions resembling those of rhematoid arthritis. Although none of the deformities or swellings are indisputable examples of rheumatoid arthritis, they do at least suggest that the painters must have been confronted with rheumatoid-like lesions in their models. In two other paintings there were signs of rheumatic fever and of temporal arteritis. No arthritic lesions were found in the works of painters of the Italian Renaissance, probably because they are less detailed. The finding of rheumatoid deformities in the Flemish paintings does, however, question the general belief that rheumatoid arthritis is a condition that has arisen relatively recently.


Comparative trial of endocrine versus cytotoxic treatment in advanced breast cancer. Ninety-two women with advanced breast cancer were allocated at random to receive either cytotoxic or endocrine treatment. Out of 45 women included in the cytotoxic treatment group, 22 (49%) achieved complete or partial remission of their disease, whereas of the 47 included in the endocrine treatment group, only 10 (21%) achieved such remission. Significantly longer survival times in the cytotoxic treatment group were most apparent among premenopausal women, 75% of such patients responding to cytotoxic drugs (median survival 46 weeks) compared with only 11% benefiting from ovarian ablation (median survival 12 weeks). In postmenopausal women with predominantly soft-tissue disease, however, additive hormonal treatment with tamoxifen produced remission rates and survival times equivalent to those produced by cytotoxic drugs.


Prophylactic use of cephazolin against wound sepsis after cholecystectomy. A trial of antibiotic prophylaxis with cephazolin against postoperative wound sepsis was carried out on 201 patients undergoing routine cholecystectomy. Wound sepsis occurred in 11 out of 65 controls (16.9%), who were not given the drug; two out of 63 patients (3.2%) given a single dose preoperatively; and four out of 73 patients (5.5%) given the single preoperative dose plus a five-day course postoperatively. The difference between the controls and patients given the single preoperative dose was significant.


Immune complexes in Behçet's syndrome and recurrent oral ulceration. Seventeen patients with Behçet's syndrome, 11 with recurrent oral ulceration, and eight controls were studied in an investigation of the part possibly played by immune complexes in the transition from focal oral ulceration to the multifocal syndrome. Changes in the distribution of C3 within the first peak of Sephadex G200 fractionated plasma were found in nine of the 17 patients with Behçet's syndrome (55%), three of the 11 patients with recurrent oral ulcers, and none of eight controls. These findings provide indirect evidence that immune complexes are found in the plasma of these patients. Immune complexes were more common in patients with the neuro-ocular type of Behçet's syndrome than in those with the mucocutaneous type, and in those with herpetiform ulcers than in those with major or minor aphthous ulcers. Immune complexes were also associated with active disease. These findings support the hypothesis that the formation of immune complexes is an important step in the pathogenesis of Behçet's syndrome.


Randomised controlled trial of treatment for mild hypertension: design and pilot trial. Report of Medical Research Council Working Party on Mild to Moderate Hypertension. A multicentre pilot trial to assess the feasibility of undertaking a full-scale national trial of treatment for mild to moderate hypertension has been performed and is being continued. By February 1977 over 1800 patients had entered the trial and some have been under observation for three years. The results so far show that the definitive trial is administratively and scientifically feasible and ethically justified.


Amino acid uptake and protein synthesis in germinating spores of Saccharomyces cerevisiae. Spores transferred to germination medium incorporated exogenous lysine into protein within 20 min but required 2-3 to begin incorporation of exogenous proline or alanine. During this time considerable uptake of amino acids into the intracellular pool occurred. Cycloheximide added to the germination medium inhibited incorporation of lysine into protein but did not lessen in accumulation in the pool. Spore germination was inhibited by cycloheximide.


The identification, characterization, and mapping of a gene for flocculation in Saccharomyces sp. Genetic studies of a flocculent haploid strain of Saccharomyces have revealed the flocculation to be dominant and controlled at a single gene locus. The flocculation character of both hybrids and haploids derived from such hybrids appears to be influenced by the repression or derepression status of the culture. Mapping studies of this flocculation gene have revealed that it is linked to ade 1 and therefore located on Chromosome I. Consequently, this is a different gene to the three flocculation genes studied by other laboratories because they have found such genes to be unlinked to ade 1. The flocculation gene being discussed in this paper has been designated FLO4. FLO4 has been located 32-33 cM from the Chromosome I centromere and 37 cM from ade 1 (i.e., FLO4 is on the opposite side of the centromere to ade 1).


Relation of colonial morphologies in soft agar to morphological and biological properties of the K-9 strain of Klebsiella pneumoniae and its variants. During repeated subcultures of strain K-9 of Klebsiella pneumoniae, three variants, A, B, and C, were obtained showing different colonial morphologies in soft agar. The parent strain K-9 produced colonies that were large, smooth, and globular; variant A, wedged balloon forms somewhat elongate; variant B, rain-drop-like with some streaming; and variant C, small compact rough globules. These colonial forms in soft agar medium correlated well with the size of capsule determined by cell volume index and light microscopy. Organisms exhibiting large globular colonies did possess extra large capsules while strains producing compact-type colonies in soft agar were lacking capsules. Capsular size of the strains correlated well with mouse virulence, but most biochemical properties, including the amount of endotoxic substance, were the same in all strains.


Pollution indicator bacteria associated with municipal raw and drinking water supplies. A total of 3819 bacterial cultures isolated from municipal water samples were identified using a combination of Enterotubules and confirmatory media. Frequency distributions for the different genera or groups of bacteria were similar for raw water and drinking water isolations, except for Escherichia organisms which doubled their frequency in raw water. Differences between the membrane filter (MF) and presence-absence (P-A) test with regard to types of organisms isolated were limited to Klebsiella organisms which were preferentially cultured from MF plates. Members of the genus Enterobacter were isolated more than twice as frequently as any of the other coliform genera dealt with in this study. Aeromonas organisms were detected almost as often as such individual genera as Escherichia, Citrobacter, or Klebsiella. Although non-lactose fermenting colonies (false-negatives) of the coliform genera would not be detected by the MF technique, their lack of detection would likely be offset by the Aeromonas colonies (false-positives). At least 25% of the coliform isolates were either anaerogenic or non-lactose fermenters and would therefore go undetected by the most probably number (MPN) technique.


Historical outline of attempts to classify skin diseases. Over the years physicians have attempted to classify skin diseases. Plenck and Willan were the first to outline clearly the basic components of skin diseases and to devise classifications based on living gross pathologic features. With the development of molecular biology, etiologic classification--a system unrelated to that of clinical appearance--was begun. Most current textbooks present combinations of these two systems and those based on location or on other concepts.


Allergy testing: comparison of skin and in vitro tests of allergic reagin. Skin tests have been used for many years to detect reaginic antibodies in the investigation of allergic patients. Recently in vitro assays of allergic reagins, including the radioallergosorbent test (RAST) and the rat mast cell test (RMCT) have become available. A comparison of the clinical usefulness of these tests suggested that skin tests and the RAST are of comparable diagnostic accuracy and reliability. The RMCT was found to be poorly reproducible and unreliable. For routine cases skin tests should continue to be the procedure of choice. The RAST may reasonably be used when skin tests are unreliable, impractical or contraindicated. The RAST may also be helpful in some cases in resolving discrepancies between skin test results and the clinical history.


[The Baie disease: was it syphilis?].

[The Baie disease: was it syphilis?]. In 1773 an epidemic disease with cutaneous manifestations appeared in Baie Saint-Paul, Québec and spread rapidly from nearby les Eboulements to the entire island of Montreal. The epidemic was in many ways reminiscent of a typical outbreak of syphilis, a condition then well known in Europe. Dr. Charles Blake of Montreal, as well as Drs. James Bowman and Philippe Badelart of Quebec, would not acknowledge any other diagnosis. The latter two physicians were commissioned by General Haldimand, governor of Canada, to investigate and treat this new disease. Patients were often cured by potions or ointments containing mercury if used from the onset of symptoms. However, Dr. Robert Jones, another physician from Montreal, submitted a different opinion: the clinical course of the disease, the anomalies of its transmission, its sometimes intriguing sequelae and its unpredictable response to mercurial therapy led him to believe that it might be an entity entirely different from syphilis as it was then known in Europe. Half a century earlier, in Scotland, a similar outbreak had occurred for which the same reservation had been made with regard to a possible diagnosis of syphilis.


The mutagenicity of methylbenzylnitrosamine and its alpha-acetoxy derivatives. Biological activity of the alpha-acetoxy derivatives of methylbenzylnitrosamine was evaluated using tester strains of Salmonella typhimurium. Compound III, oxidized on the benzyl moiety, was more toxic and more mutagenic than Compound IV, oxidized on the methyl side chain. Compound IV was weakly toxic and was non-mutagenic at the concentrations tested. The presence or absence of the uvrB repair system had no effect on the toxicity of either Compound II or IV. Neither the alpha-oxidized compounds nor the parent nitrosamine reverted the frameshift mutants. As a mutagen, Compound III was approximately as active as N-nitroso compounds not requiring metabolic activation, more active than alpha-acetoxy dialkylnitrosamines and less active than the cyclic alpha-acetoxynitrosopyrrolidine.


Inhibitory effects of selenium of the mutagenicity of 2-acetylaminofluorene (AAF) and AAF derivatives. Selenium (Se) decreased the mutagenicity of 2-acetylaminofluorene (AAF), N-hydroxy-2-acetylaminofluorene (N-OH-AAF) and N-hydroxyaminofluorene (N-OH-AF) in the Salmonella typhimurium TA 1538 bacterial tester system. Metabolism of AAF and N-OH-AFF to the active mutagen, N-OH-AF, was accomplished by rat liver extracts. Graded decreases in mutagenicity with increasing Se concentrations were observed for each of the three mutagens. Se decreased the mutagenicity of AAF, N-OH-AAF and N-OH-AF to 65, 68 and 61% of their respective controls with mutagen alone. The effective molar ratios of Se to mutagen yielding these decreases were approximately 10:1 (Se:AAF), 10:1 (Se:N-OH-AAF) and 300:1 (Se:N-OH-AF). The largest Se effect observed was accomplished by a molar ratio of 100:1 (Se:N-OH-AAF) yielding 28% of the mutagenicity elicited by N-OH-AAF alone.


Mutagenicities of protein pyrolysates.

Mutagenicities of protein pyrolysates. Smoke condensate obtained by pyrolysis of proteins, such as lysozyme and histone, was shown to be mutagenic to Salmonella typhimurium TA100 and TA98. In vitro metabolic activation by a mammaliam postmitochondrial enzyme preparation (S-9 Mix) was required. Smoke condensates obtained by pyrolysis of DNA, RNA, starch and vegetable oil were slightly mutagenic, whereas those from pyrolysis of L- and D-tryptophan and 5-hydroxy-D,L-tryptophan were very strongly mutagenic with metabolic activation by S-9 Mix. Because of the high correlation between mutagenicity and carcinogenicity, it is theorized that the cooking of proteinaceous foods might be an important cause of human cancers.


Monitoring immunotherapy with Bacillus Calmette-Guérin by antibody titer. Antibody titer to Bacillus Calmette-Guérin (BCG) was determined by complement fixation in 111 normal volunteers and 83 melanoma patients. In 43 of these melanoma patients, sequential determination of antibody titer was made and correlated with clinical course. Low titers of antibody to BCG were found frequently in normal volunteers and in melanoma patients prior to BCG immunotherapy. The typical response to BCG immunotherapy was a rapid rise of antibody titer to high levels. Six of 19 patients with recurrence had disappearance of antibody preceding clinical recurrence by up to 5 months. In 13 of 40 patients receiving BCG, serum antibody was a better indicator of the patient's response than measurement of delayed cutaneous hypersensitivity to purified protein derivative. These results suggest that measurement of the antibody response to BCG may be useful in developing an optimum mode of BCG immunotherapy as well as predicting clinical recurrence in patients with melanoma.


Effects on nutrition of surgery of the liver, pancreas, and genitourinary tract. Carcinoma of the pancreas is increasing in the United States and has a grave progonosis. Surgical treatment has moved from subtotal pancreatectomy to total pancreatectomy and now to en bloc resection and vascular replacement. Pancreatic exocrine and endocrine insufficiency following resection add to the nutritional problems presented by this major surgery and its high complication rate. Recognition of these problems and adequate treatment decrease morbidity and mortality. Major hepatic resection imposes metabolic problems in the immediate postoperative period that are minimized by improving preoperative nutritional status and by providing adequate postoperative support with albumin and carbohydrate. Urinary tract diversion for pelvic cancer involving the ureters and/or bladder has progressed from ureterosigmoidostomy with its high incidence of disturbances of electrolyte and acid-base balance to ureteroileostomy with its appreciably lower rate of complications.


Enhancement of antileukemic effect in combination of 5-fluorouracil and OK-432. OK-432, a streptococcal preparation with potent antitumor activity, has been evaluated for its efficacy in experimental and clincal trials. This preparation, however, was ineffective against mouse L1210 leukemia in all treatment schedules. The results of this study indicate that treatments with OK-432 and nucleic acid antimetabolites, such as 5-fluorouracil (5-FU), exert a synergistic effect against L1210 leukemia probably in conjunction with the immunologic defenses of the host. This therapeutic synergism was to some extent dependent on the dose level of 5-FU and was not produced against the 5-FU-resistant L1210 subline. In mice pre-treated with OK-432 prior to the leukemia implantation, there was no synergistic effect as a result of post-treatment with 5-FU. When BDF mice had previously received X-ray irradiation or administration of corticosteroids, the synergism could not be expected either. Comparative combination therapy with BCG or group C streptococcus resulted in failure to produce therapeutic synergism in this system.


Evaluation of single-drug versus multiple-drug chemotherapy in the treatment of advanced breast cancer. Fifty-one postmenopausal patients with advanced breast cancer were randomized to receive either cyclophosphamide given continuously or cyclophosphamide given continuously with methotrexate, 5-fluorouracil, vincristine, and prednisone given intermittently. The results with the multiple-drug therapy were significantly better than with the single-drug therapy, both with regard to percentage (63% versus 25%) and median duration (400 versus 210 days) of objective response. Toxicity was moderately increased with the combination as compared to the single-drug treatment.


Localization of neurophysin in the rat supraoptic nucleus. I. Ultrastructural immunocytochemistry using the post-embedding technique. Localization of neurophysin in neurons of the supraoptic nucleus was accomplished using an unlabeled-antibody, post-embedding, immunoperoxidase technique. Neurophysin was exclusively associated with neurosecretory granules within cell bodies of supraoptic neurons and their processes.


Use of calcium ionophores to determine the effects of intracellular calcium on the action potential of canine cardiac Purkinje fibers. The effects of calcium ionophores X-537A, A23187, and PR-47 on the action potential of canine cardiac Purkinje fibers were studied using standard microelectrode techniques. The ionophores hyperpolarize the membrane potential, eliminate the notch on the action potential plateau, decrease action potential duration, decrease plateau amplitude and duration, decrease spontaneous diastolic depolarization and excitability, and decrease the rate effect on action potential duration. These effects were shown to be independent of catecholamines, membrane-bound calcium, and the patency of the slow inward current channel. The effects of the ionophores depended on the presence of calcium in the external solution. A plausible interpretation of the data is that an ionophore-mediated increase in intracellular calcium shifts the voltage dependence of transmembrane potassium currents to more negative levels.


Gonadal function in Bloom's syndrome.

Gonadal function in Bloom's syndrome. Five patients with Bloom's syndrome aged from 2 8/12 to 27 years, all of whom had hypogonadism, were subjected to an i.v. LHRH test and two of them to an i.m. HCG test. There was increased responsiveness of plasma LH and FSH, indicating that the hypogonadism is primary in nature and of early development. The tubular element of the testis seems to be mainly affected, as indicated by the particularly high FSH response to LHRH stimulation, a history of sterility in the two adult patients and documented azoospermia in one of them. The Leydig cells seem to be less affected and secrete sufficient androgens to enable puberty within acceptable normal limits. Hypogonadism seems to be a major characteristic of Bloom's syndrome.


Hormonal changes associated with testicular atrophy and gynaecomastia in patients with leprosy. Basal LH, FSH, 17 beta-oestradiol and testosterone and the gonadotrophin responses to luteinizing hormone releasing hormone (LHRH) were studied in male patients with leprosy (twenty-four with lepromatous and six with tuberculoid leprosy). The mean basal LH and FSH was significantly elevated in the lepromatous group and was associated with an excessive response of both gonadotrophins following LHRH administration. The mean basal testosterone and 17 beta-oestradiol values in the lepromatous group were significantly lower than those of the tuberculoid and control groups. The abnormal gonadotrophin and sex steroid values in the lepromatous group are in keeping with the testicular atrophy and gynaecomastia accompanying this form of leprosy. However, the lack of a significant correlation between basal FSH and testicular atrophy should be noted. In addition, no correlation between any of these hormonal values and gynaecomastia could be demonstrated. The patients with tuberculoid leprosy had essentially normal hormonal profiles (except for two who had raised 17 beta-oestradiol values). This is compatible with the lack of gonadal involvement in these patients.


Immune complex detection by immunofluorescence on polymorphonuclear leucocytes. Polymorphonuclear leucocytes (PMN) from patients with systemic lupus erythematosus (SLE) were isolated from defibrinated and heparinized blood. In addition, PMN from a healthy donor were incubated with sera from SLE patients and with sera containing artificially prepared immune complexes of hepatitis B surface antigen (HBsAg) and human anti-HBsAg immunoglobulin (anti-HBs) with well defined variations of the antigen/antibody ratio. To one group of blood samples, 5 mM monoiodine acetic acid (MIAA) was added to block in vitro phagocytosis. The Pmn were examined for the presence of IgG, IgM, and HBsAg by the immunofluorescence technique. PMN from defibrinated blood of SLE patients showed in up to 80% immunoglobulin (Ig)-inclusions. However, addition of 5 mM MIAA reduced the number of Ig-containing PMN to at most 40%, which levels were equal to numbers found in specimens from heparinized blood. Addition of 5 mM MIAA to heparinized blood did not reduce the number of PMN with Ig inclusions. Normal donor PMN isolated from defibrinated, heparinized, and EDT blood showed equal amounts of Ig inclusions after incubation with SLE sera, but none when MIAA had been added. In PMN incubated with HBsAg-anti HBs immune complexes with an antigen antibody ratio between 5 and 0-2, both HBsAg and IgG could be detected. It is concluded that Ig inclusions in PMN from heparinized blood from SLE patients are due to in vivo phagocytosis, presumably of circulating immune complexes. In vitro phagocytosis of Ig from SLE sera by normal donor PMN also suggests the presence of immune complexes. Dependent on the antigen-antibody ratio, artificial HBsAg/anti-HBs immune complexes can be detected by in vitro phagocytosis by PM.


In vitro effect of transfer factor on active rosettes and leucocyte migration of patients with cancer. The in vitro effect of transfer factor (TF) and its obtained by gel filtration was studied on the active rosettes and leucocyte migration inhibition. TF and one fraction (IV) restored the reactivity of lymphocytes from tumour-bearing patients to tuberculin and Candida antigens in the leucocyte migration assay. TF and fraction IV was also found to enhance the number of active rosettes of tumour-bearing patients, whereas no such effect was observed on lymphocytes of patients with active SLE or controls.


E-rosette forming cell numbers in the blood of human renal allograft recipients. The incidence of circulating T lymphocytes (ET-RFC) and a sub-population of T lymphocytes (EE-RFC) were monitored in the blood of seventy-one cadaver renal allograft recipients for the first 2 months after transplantation. In patients with uneventful post-operative courses, the incidence of both ET-RFC and EE-RFC fell promptly upon initiation of immunosuppression returning approximately to pre-operative levels 3-5 weeks after operation; the fall in cell numbers was greatest in those patients receiving adjunct ALG therapy. With the onset of an acute rejection episode, the EE-RFC level rose quickly eventually exceeding the pre-operative level; in 88% (thirty episodes) of cases this rise occurred 1-6 days before clinical diagnosis of rejection and in 12% of cases on the same day as clinical diagnosis. The incidence of ET-RFC rose in conjunction with some cases of acute rejection but remained unchanged in other cases. It is suggested that measurement of the incidence of EE-RFC in blood is valuable in predicting the onset of acute rejection and for the differential diagnosis of acute rejection and ischaemic renal damage.


Immunoglobulin-containing cells in human tonsils as demonstrated by immunohistochemistry. Intracellular immunoglobulin has been demonstrated in human palatine tonsils by the unlabelled antibody peroxidase-antiperoxidase complex (PAP) method in which rabbit antiserum to a range of human immunoglobulins (Igs) was linked to the PAP complex by an intermediate stage of swine antiserum to rabbit Ig. The effects of different methods of fixation and processing have been compared, formol-saline fixation giving the best results. The PAP technique proved greatly superior to the fluorescein isothiocyanate (FITC)-based technique, not only in sensitivity but in permitting study of the finer histological and cytological features. The lymphoid follicles are shown to have three distinct zones, two forming the follicle centre (zones (a) and (b)), and the third (zone (c)) the lymphocyte cap. Ig synthesis appeared to begin in the cells in zone (b). IgG, IgA, IgM, IgE and IgD were present in all tonsils, with IgG predominating, confirming that the tonsil resembles lymph nodes more closely than it does alimentary lymphoid tissue. Some follicles contained more than one type of Ig. The tonsil appears to have a well-developed T-dependent area, the lymphoid follicles forming a B-cell area. The structure of the tonsil would seem to facilitate contact between its lymphoid tissue and antigens in the crypts, and it is postulated that some T cells within the crypt epithelium, after contact with antigen, may leave the tonsil by the efferent lymphatics and enter the peripheral circulation by the thoracic duct, whilst other primed T cells interact with B cells in the follicle centres. Some B cells may then start to synthesize immunoglobulin, whilst others become memory cells in the lymphocyte 'cap' of the follicle.


Antibody formation by human tonsil cells in vitro. The ability of human tonsil lymphocytes to give an anti-SRBC response in conventional cultures and in microcultures was studied. It was found that about two-thirds of tonsils responded with a significant number of plaque-forming cells (PFC), and that in some instances the response could be augmented if allogeneic tonsil cell (irradiated or intact) were added. Moreover, tonsil lymphocytes which failed to give a response on their own often responded upon addition of an appropriate number of allogeneic tonsil cells. The response was remarkably improved if allogeneic tonsil supernatant or conditioned medium were added. An anti-SRBC response was also obtained if SRBC was omitted from the cultures. The frequency of anti-SRBC specific B cells was estimated as 1/60000 (f = 1-7 X 10(-5)).


Human and guinea-pig cross-reacting spermatozoa autoantigens and autoantibodies. Cross-reactivity between human and guinea-pig spermatozoa autoanigens has been studied in two systems: (1) guinea-pig anti-autoantigens S, P and T immune sera reacting on human spermatozoa and (2) activity of human anti-sperm sera on guinea-pig spermatozoa. These assays, as well as the results of cross-absorptions in the two systems, revealed a close antigenic relationship between the two species of spermatozoa concerning the guinea-pig autoantigen S. However, there were some differences in its localization and serological manifestations in both species. The guinea-pig autoantigen T bore a more distant, though definite, relationship with human spermatozoa. No clear evidence of cross-reactivity between the two species was found for autoantigen P. At variance with autoimmune (or isoimmune) human antibodies, 'natural' human antibodies active on guinea-pig spermatozoa were absorbed by guinea-pig spleen cells.


Induction of anti-glomerular basement membrane antibodies in the Brown-Norway rat by mercuric chloride. Anti-glomerular basement membrane (GBM) antibodies were induced in the Brown-Norway rat by mercuric chloride. The existence of anti-GBM antibodies was suspected because of the immunofluorescent linear pattern. It was proved because eluted antibodies from kidneys and circulating IgG had an anti-glomerular basement membrane activity. A glomerular basement membrane antigen modified by HgCl2 is probably responsible for the appearance of such antibodies. The previous demonstration of the occurrence of an immun complex type glomerulonephitis, in outbred Wistar rats, under the same experimental conditions, suggests the existence of a genetic control for this type of immune response.


Immunological studies in the neonate of a mother with Addison's disease and diabetes mellitus. In a baby born to a mother who had idiopathic (autoimmune) Addison's disease and gestational insulin-dependent diabetes, antibodies to adrenal cortex and to pancreatic islet cells were demonstrated in the cord blood and serum for at least 41 days. There was no clinical or objective evidence of adrenocortical failure or of disturbed carbohydrate tolerance in the baby.


Myosin autoantibodies detected by immunofluorescence. Autoantibodies to striated and smooth muscles myosins were detected by indirect immunofluorescence and confirmed by absorption with purified contractile proteins extracted from human, rabbit and chicken muscle. Myosin antibodies were rare: of fifty-five sera examined from patients with various skeletal and cardiac muscle disorders, only one serum, from a case of Coxsackie viral pericarditis, had anti-myosin activity. It reacted with cardiac muscle and type 1 fibres of skeletal muscle, staining the 'A' band of the sarcomere only. The antibody was absorbed by skeletal myosin and by skeletal heavy meromyosin fragments, but not by smooth muscle myosin. Two types of smooth muscle myosin autoantibodies are described. One is restricted to smooth muscle myosin and examples were found in polyclonal and monoclonal SMA sera. The second type of smooth muscle myosin antibody cross-reacted with skeletal and cardiac muscle and with cytoplasmic myosin in liver, kidney and thyroid cells. It was completely absorbed using either smooth or skeletal myosin and by heavy meromyosin fragments. The different types of myosin autoantibodies reflect the variety of myosins found in mammalian tissues. Cross-reacting myosin antibodies indicate epitopes on the heavy meromyosin fragment which are common to several different tissue myosins.


C1q binding substances in pemphigus and bullous pemphigoid. Detection with a [131I] C1q binding assay. A modification of the [125I]C1q binding assay was developed to allow the estimation of C1q binding activity (C1q BA) in pemphigus and bullous pemphigoid sera. The modifications include lower final concentration of PEG 6000 (1-5%) which permitted the use of sera that had been stored at -20 degrees C for extended periods of time; use of 131I instead of 125I and an [131I] C1q concentration of 5 microng/ml rather than 1 microng/ml. EDTA was used at a final concentration of 0-13 M to obviate the need for heat inactivation of sera. Sera from seventy-one patients with pemphigus and from 142 patients with bullous pemphigoid were tested for C1q BA. Of these 40% of the pemphigus and 20% of the bullous pemphigoid patients showed elevated C1q BA. A relationship between elevated C1q BA in serum and active disease was noted. Sequential samples from forty patients with pemphigus and thirty-seven patients with bullous pemphigoid demonstrated two different types of relationship between serum antibody titres to cutaneous antigens and C1a BA. In some patients serum antibody titres and C1q BA increased and decreased simultaneously; in others, increase of C1q BA followed increase of antibody titre and coincided with its decrease. The latter relationship supports the hypothesis that C1q BA may represent at least in part antigen-antibody complexes containing cutaneous antigens.


Cephalexin: clinical and laboratory evaluation in infants and children. Cephalexin appears to be a highly effective antibiotic. It possesses the qualities of rapid oral absorption, production of high drug levels in the blood and urine, and near absence of side effects. It is effective against infections due to gram-positive cocci infections, with the exception of Enterococcus, and for most infections caused by E. coli and Klebsiella. It is useful in the treatment of a wide variety of infections in infants and children, and particularly valuable with susceptible infections in patients who do not require parenteral antimicrobial therapy.


Studies on digitalis. XII. Kinetic pattern of digitoxin metabolism in patients with biliary fistulas. The metabolic pattern of cardioactive and inactive, conjugated metabolites (a maximum of 24 substances) was studied after a single intravenous dose of 0.6 mg digitoxin in two female patients (aged 72 and 62 yr) with biliary fistulas. Bile and urine were collected every twenty-fourth hour and the 1-, 2-, 4-, 6-, and 8-day samples were analyzed. With the methods used, enzymatic cleavage of conjugation bonds, TLC (thin-layer chromatography), and a modified 86Rb method, the products of hydroxylation, hydrolysis, and conjugation could be separated. All cardioactive metabolites were present in bile and all were conjugated. Unchanged digitoxin was the main substance excreted. Hydrolyzed and conjugated metabolites formed a greater part of the substances excreted in bile than hydroxylated metabolites. The metabolic pattern in bile did not change much with time. The metabolic pattern in urine showed no close resemblance to that in bile. Hydroxylated, hydrolyzed, and conjugated metabolites were equally predominant in urine. Interruption of the enterohepatic circulation by T tube drainage not only changed the elimination kinetics of digitoxin but also changed the pattern of digitoxin metabolites in urine.


Influence of alprenolol on hemodynamic and metabolic responses to prolonged exercise in subjects with hypertension. In 7 young men with essential hypertension, central and regional hemodynamics and leg metabolism were studied at rest, during and after a prolonged exercise, and with and without long-term alprenolol treatment. Alprenolol (200 mg twice daily) lowered arterial blood pressure. Heart rate decreased in relation to plasma levels during and after exercise. Cardiac output was not significantly influenced, but leg blood flow was reduced at rest. Lipolysis was also attenuated by treatment both at rest and during exercise, and the increment in plasma insulin after exercise was decreased. A reduction in the release of leg muscle lactate was noted during exercise.


Plasma protein binding of phenytoin and warfarin in patients undergoing renal transplantation. The plasma protein binding of phenytoin and warfarin was studied in vitro by equilibrium dialysis at 37 degrees C in plasma from patients with chronic renal disease before and after renal transplantation. The plasma protein binding of these two drugs (which is decreased in the uraemic state), increased dramatically during the first 2 to 4 postoperative days and reached values slightly below normal on the 10th to the 15th postoperative day. This increase in binding is suggested to be due to the elimination of inhibiotrs of drug albumin binding, earlier shown to be present in uraemic serum.


Relationship between blood level of atenolol and pharmacologic effect. Thirty-five hypertensive patients were treated with atenolol in weekly increasing doses (25, 50, 100, and 200 mg thrice daily). Factors determining the blood level of the drug were studied along with the relationship between blood level, the degree of cardiac beta blockade, and the antihypertensive effect of the drug. The blood level obtained varied with the daily dose, the time of blood sampling during the day, the body weight, and the creatinine clearance. The degree of beta blockade was assessed by measuring maximum-exercise tachycardia and was correlated with the blood level of atenolol. The reduction of the maximum exercise heart rate was independent of age. The hypotensive effect was not closely correlated with the blood level. Three days after the termination of long-term atenolol treatment, blood levels and beta blockage were still detectable.


Computer-aided tumour classification and treatment selection in breast cancer. In order to provide a common basis for treatment decisions and the future evaluation of breast cancer therapy, the breast cancer protocol used in our clinic was formulated for the computer. A system for the simulation of clinical reasoning was used which allows the physician to express the medical logic as a series of inferences to be confirmed or rejected on the basis of Boolean combinations of medical criteria. The system enables the physician to rearrange these criteria into a questionnaire for complete and accurate recording of patient data. These data are then fed into the computer to produce a patient status report and treatment recommendations. The data from 26 patients in various stages of breast cancer have been processed by the computer and the computer's conclusions compared to the assessment made by a junior physician in our department. In three cases the staging was not identical, in 15 cases the treatment decisions were not identical and in all cases investigations were left out by the physician. The system has been of considerable value in standardising patient examination and treatment and in training inexperienced physicians.


Serum level monitoring and clinical pharmacokinetics of lithium. Short-term antimanic therapy with lithium and relapse-repressive, so-called "prophylactic" long-term therapy with lithium, may present clinical problems which demand an understanding of two cardinal properties of this form of therapy--the need to individualise the dose and the recognition that successful therapy involves the use of near-toxic dosage. Therefore, treatment must be constantly supervised, not only by the physician but also primarily by the patient himself, especially to avoid the ever-present risk of intoxication. Results of 25 years' clinical experience and more recent knowledge of the clinical pharmacokinetics of the lithium ion have shown that a serum level standardised with regard to dosage schedule, a fixed interval between last intake and blood sampling, blood sampling at the same hour, and choice of tablet brand, must all be considered essential to adjust dosage and to correctly monitor treatment. Optimum use of the lithium ion as a psychotherapeutic drug and of the standardised 12 hour lithium serum concentration, presupposes that the pharmacokinetics of the lithium ion are well understood by the clinician.


Automatic data processing in the cardiac catheterization laboratory. A review of automatic data processing in the cardiac catherization lab is presented. The emphasis placed on on-line manometry, indicator dilution and off-line quantitative ventriculography. The system organization is described and several specific examples given to illustrate the level of detail necessary to specify such a system. The clinical use of the system is described together with an evaluation of the original design goals in terms of the actual performance of the system. A few unexpected benefits have emerged with respect to quality control and reliability, but one of the original design goals, speeding up the catheterization procedure, has proven to be unrealistic. The next logical steps in the software and hardware evolution are described with the emphasis placed on making the system a more effective tool for the clinician.


Chemotherapy used in dermatology.

Chemotherapy used in dermatology. Although systemic corticosteroids have been helpful in certain dermatologic conditions, their prolonged use may be cursed with serious side effects. Currently several dermatologic, immunologic, and proliferative disorders have been helped or controlled with cytotoxic and immunosuppressive drugs. A guideline for their use is advocated and described. The short- and long-term toxicity of these drugs is presented. The most frequently prescribed therapeutic programs for psoriasis, pemphigus and bullous pemphigoid lymphoma cutis, and metastatic melanoma are outlined and discussed. Lists of the most commonly used chemotherapeutic agents and of the diseases or conditions for which they have been or are used and of dosage and toxicities are given.


Alternatives in  hair replacement.

Alternatives in  hair replacement. Many methods of hair replacement have evolved over the past two decades. This article describes these alternatives and lists the advantages and disadvantages of newer hairpieces, hair weaving, hair implants, strip grafting, and hair transplantation. Hairpieces and hair transplantation are my preferred methods for most patients. Hair implanting is by far the worst alternative.


Two new bioassay techniques for nitrofurans: Bacteroides fragilis and rec-Escherichia coli as indicator strains. Techniques for the microbiological assay of nitrofurans are described. In one the indicator strain is Bacteroides fragilis; use of this system enables concentrations of nifuratel and furazolidone of down to 0.7 micrograms/ml to be estimated. The other system uses a recombination-deficient (recA-uvrA-) mutant of Escherichia coli; with this indicator, concentrations of 0.2 micrograms/ml, or less, of five nitrofurans can be assayed.


The influence of 5-fluorocytosine on nucleic acid synthesis in Candida albicans, Cryptococcus neoformans, and Aspergillus fumigatus. 5-Fluorocytosine (5-FC) has a rapid inhibitory effect on the synthesis of RNA and DNA in the yeast and hyphal form of Candida albicans. 5-FC has a less marked effect on the RNA and DNA content of sensitive strains of Cryptococcus neoformans and has no effect on the nucleic acid content of Aspergillus fumigatus nor of resistant strains of C. albicans and C. neoformans. 5-FC has a slower inhibitory effect on yeast cell number increase and no effect on hyphal length of hyphal phase C. albicans over a 7-h incubation period. Rapidly growing yeasts of C. albicans and C. neoformans decrease in volume and in dry weight per cell. 5-FC prevents this decrease in sensitive strains. These results have been discussed with respect to the known metabolic pathway of 5-FC, the fungistatic and fungicidal action of 5-FC and the development of resistance to 5-FC.


Long-term treatment with sulphamethoxazole/trimethoprim (Bactrim) and nitrofurantoin in chronic urinary tract infections. A controlled clinical trial. In a controlled clinical trial based on 30 geriatric patients with recurrent urinary tract infection, 12 out of 17 patients fulfilled a 12-month treatment with sulphamethoxazole/trimethoprim (Bactrim) with continuous sterile urine compared to 1 out of 13 patients treated with nitrofurantoin (p less than 0.05). There was a slight but statistically significant increase in serum creatinine during treatment for 12 months in the sulphamethoxazole/trimethoprim group, but this probably does not reflect any deterioration in kidney function. The remaining laboratory values showed no significant changes whatsoever.


[Possibilities of controlling blood less in liver resection]. The methods are described by which blood loss can be reduced during hepatic surgery. This requires the proper surgical techniques (control method of hepatic lobectomy and occasionally the atypical resection with the use of a clamp- "crush" method). In additions clamping of the liver hilus and resection under hypothermia, the resection of the isolated bloodless organ under hypothermia, the application of an internal caval shunt, intraoperative autotransfusion, and acute preoperative hemodilution should be performed. The internal caval shunt can be successfully used in the case of emergency as well as during excision of large tumors which have involved the liver tissue adjacent to the vena cava. In these cases the method of complete vascular isolation and hypothermic perfusion should be performed additionally. Acute preoperative hemodilution should be widely applied with hepatic surgery; blood clotting is not impaired by this method.


[Indications for machine suture technics involving the gastrointestinal tract. Surgical results of 300 cases]. Among 300 gastrointestinal operations performed with mechanical suture techniques 2% deadly complications due to the sutures occurred. Mechanical sutures seen to be a preferable method in the gastrointestinal region. They are limited by specific local and at the colon general contraindications.


[Chemotherapy of malignant bone tumors]. In several primary malignant tumors significant improvement of formely bad prognosis has been achieved by the introduction of new cytostatic compounds and the study of new cytostatic combination regimens. Adjuvant chemotherapy in osteosarcoma and Ewing's sarcoma led to remarkable increase in survival rates. Leaning on natural history and on remission rates reached by cytostatic treatment in metastasizing stages of disease, proposals for adjuvant chemotherapy are made and chemotherapy regimen appliable on out-patient basis is described.


[Indications and experiences in saving of the lower leg following injuries and tumors]. In the primary treatment of skin and soft tissue defects of the lower leg, after injuries or tumor excision, split skin grafting is the method of choice. But in respect to the late results, frequently additional plastic reconstructive measures, preferrably skin flap procedures, must be considered. Follow-up over decades and if necessary, skin transplantation, are mandatory to prevent interference of growth and function of the leg, as well as malignant degeneration of the scars.


[Gastrointestinal sarcomas].

[Gastrointestinal sarcomas]. In 45 primary sarcomas of the gastrointestinal tract the authors attempt to derive criteria for prognosis from histology and localization of the tumors and from clinical parameters. Their observations lead to the conclusion that 1) proximal sarcomas of the gastrointestinal tract have a better prognosis than distal sarcomas, 2) lymphocytic malignant lymphomas has a better prognosis than other histologic types, and 3) there is a correlation between blood sedimentation rate and prognosis.


[Utilization of the small intestine fistula technique in paralytic ileus. Report on clinical experience]. Seventy-three patients with paralytic ileus hospitalized at the Surgical Clinic of the Hospital in Herford during the years 1971-1975 are reviewed. All the patients were treated with a small bowel fistula according to a modified technique of Witzel-Heidenhain. The special indication, the technical details, and the results are discussed. The overall mortality of a total of 73 patients with paralytic ileus undergoing a small bowel fistula operation was 19%. The temporary small bowel fistula according to the modified technique of Witzel-Heidenhain is proposed as a simple, safe, and with accurate indication an effective method for accomplishing total decompression of distended bowel.


The management of acute coronary insufficiency. 1. Coronary insufficiency is a pathophysiologic state that can initiate lethal cardiac arrhythmias in the absence of myocardial necrosis. Patients with suspected coronary insufficiency should be monitored until they are stabilized and a diagnosis is confirmed. 2. Early and adequate intravenous antiarrhythmic prophylaxis with lidocaine to raise the fibrillation threshold in the setting of coronary insufficiency can prevent primary ventricular fibrillation. Classic "warning arrhythmias" are not predictive of ventricular fibrillation. Their persistence during adequate antifibrillatory prophylaxis does not indicate therapeutic failure. 3. The isoenzyme of creatine phosphokinase, CPK-MB, is an extremely sensitive and specific indicator of myocardial necrosis if measured serially during the 24 hours following the onset of symptoms suggesting coronary insufficiency. It may prove most useful in eliminating the false positive diagnosis of myocardial infarction in  difficult clinical cases. 4. The management of heart failure in myocardial infarction requires an understanding of the relationship between ventricular preload and the cardiac output. The treatment of clinical manifestations of an elevated ventricular preload in asymptomatic patients is not justified and may be detrimental. In symptomatic patients, however, judicious manipulation of ventricular preload should be the first therapeutic consideration, and an optimal filling pressure should be achieved and maintained when other determinants of the cardiac output are manipulated. 5. Indications for the prophylactic insertion of a temporary transvenous pacing electrode for heart block associated with myocardial infarction must be individualized. Most authorities agree that prophylactic pacing may be justified in patients with evidence of new infranodal block involving two of the three fascicles. Patients with bifascicular block who progress to complete heart block transiently may benefit from permanent transvenous pacemaker insertion before discharge. 6. Hospitalized patients with persistent pain of suspected cardiac origin but without evidence of myocardial infarction can be studied safely with coronary angiography. A small percentage will be normal or have diffuse disease that is inoperable. Of those with operable disease, short-term mortality appears to be similar for medical and surgical therapy. 7. Patients with an uncomplicated myocardial infarction may be safely discharged from thehospital by day 7-10. 8. Experimental evidence indicates that modification of infarct size is possible. Application of these concepts to human subjects presently is limited by the absence of a proved method of measuring infarct size in vivo in humans.


Fenoprofen: a review of its pharmacological properties and therapeutic efficacy in rheumatic diseases. Fenoprofen1 (dl-2-[3-phenoxyphenyl]propionic acid) is a new non-steroidal anti-inflammatory, antipyretic, analgesic agent advocated for use in rheumatoid arthritis, degenerative joint disease, ankylosing spondylitis and gout. Published data suggest that in rheumatoid arthritis, fenoprofen 2.4 g daily is comparable in effectiveness with moderate doses of aspirin (3.6 to 4 g daily), but generally causes fewer and milder side-effects at the dosages used. In published comparisons with other non-steroidal anti-inflammatory agents of the same chemical group, it is closely comparable with naproxen in effectiveness but tends to cause more minor side-effects than naproxen. However, as no one of the non-steroidal anti-inflammatory agents is the most suitable drug for all patients requiring such therapy, fenoprofen should be considered along with the other drugs of its type in the initial treatment of the arthritic patient. Fenoprofen has compared favourably with phenylbutazone in osteoarthrosis of the hips and with aspirin in osteoarthrosis of the shoulders, hips, knees and spine. Its exact place in the management of gout and ankylosing spondylitis remains to be determined.


Psoriasis: current concepts in management. Psoriasis is a chronic, relapsing dermatosis characterised by scaling, erythema, and less commonly pustulation. Although the clinical spectrum is broad and the nature of the underlying defect responsible for the production of psoriasis uncertain, all currently available effective remedies are capable of inhibiting epidermal mitosis and this remains the most widely accepted concept in the management of psoriasis.


[Critical considerations on the development of composite filling materials]. Following the report given at the FDI congress in Chicago in 1975, the question is raised about the present state of acrylic filling materials, i.e. whether further developments are necessary or even possible. The importance of clinical testing is emphasized and the problems involved in chemical binding to the dental hard substances discussed. The influence of the thermal coefficient of expansion on the marginal seal is discussed in connection with marginal discoloration, and acid cauterization as well as remineralization are critically evaluated. The significance of wear and tear for maintaining the contours is emphasized, especially in connection with occlusal fillings of lateral teeth, as well as the problem of shaping a contact point and tensile strength after repair of an old filling. Improvements in UV light polymerisation are described. The different opinions on the importance of histological findings regarding pulp tolerance are critically discussed and finally the significance of water uptake and radiological opacity is delt with. In conclusion, the indication for acrylic filling materials at the present time is defined.


Effects of hypothalamic factors on insulin and glucagon release from the islets of Langerhans. Isolated pancreatic islets were used to determine whether substances of hypothalamic origin could directly influence the release of insulin and glucagon. Media in which various regions of the brain had been incubated were tested in the islet system, as were the synthetic peptides neurotensin and substance P, and the catecholamines, dopamine and norepinephrine. Substance(s) released from the ventromedial hypothalamic (VMH) segments in vitro inhibited insulin release and stimulated glucagon release from the islets. Incubates of ventrolateral hypothalamic (VLH) or cortex tissue failed to alter insulin or glucagon levels. The VMH medium retained these activities even after oxidation with K3Fe (CN)6, whereas the ability of the catecholamines to inhibit insulin release and stimulate glucagon release was eliminated by this treatment. Neurotensin and substance P (0.1 and 1.0 nmol/ml) inhibited insulin release while glucagon release was increased; however, radioimmunoassay indicated that these peptides were virtually absent from the VMH incubate. These results show that incubates of VMH contain substances which can inhibit insulin and stimulate glucagon release in vitro. They may influence the endocrine pancreas by way of the peripheral circulation although the possibility of their occurrence in or near the pancreas itself has not been excluded.


Magnesium modulation of glucose-induced insulin secretion by the perfused rat pancreas. Increasing levels of magnesium were found to cause a marked depression of glucosestimulated insulin secretion at fixed calcium levels, particularly at levels which bracketed the concentration of ultrafiltrable magnesium found in normal rat plasma (1.3 meq/l), i.e., increasing magnesium from 0.6 to 1.2 meq/l depressed secretion, and increasing magnesium from 1.2 to 2.4 meq/l resulted in a further depression. Paradoxically, when magnesium was omitted from the perfusing medium, insulin secretion was also depressed. The data strongly suggest that the calcium/magnesium ratio is a primary regulator of the insulin secretory process, since a relatively slight alteration of the physiologic ratio of calcium to magnesium (approximately 2.5) results in a marked alteration of total insulin secretion. In addition, small amounts of magnesium are necessary for optimum secretion, possibly reflecting the requirement for magnesium in several enzymatic processes. Thus, magnesium may play an important role in the regulation of insulin secretion by altering the sensitivity of the beta cells of the Islets of Langerhans to glucose.


Effect of a bovine hypothalamic factor on the release and biosynthesis of growth hormone. Partial purification of growth hormone (GH)-releasing factor (GRF) by acid extraction followed by gel filtration on Sephadex G-25 has been attained from bovine hypothalami. When rat pituitaries were incubated in 2 ml Krebs Ringer-bicarbonate-glucose (KRBG) medium, a stimulatory effect of the GRF fraction on immunoreactive GH (IR-GH) release was observed, while that of the factor neither on GH synthesis nor release of the synthesized GH was demonstrated. Stimulation of the GH release was exerted maximally within 30 min of incubation. Cycloheximide and actinomycin D, at a concentration which inhibited protein and RNA synthesis to less than 5 and 20% of the control, respectively, were without effect on the stimulatory action of the factor on GH release. On the other hand, stimulation of GH synthesis was observed under incubation in 0.3 ml medium with the factor and enhancing effect of the factor on the IR-GH release was undetectable. These results suggest that stimulation of the release and synthesis of GH mediated by the hypothalamic GRF fraction is under influence of the pool size of incubation media.


Therapeutic colonoscopy.

Therapeutic colonoscopy. The authors report their experience with regard to operative fibrecolonoscopy both in routine and emergency cases. After taking into consideration the use of this technique for the study and treatment of rectal and colonic polyps, they also recommend the use in emergency conditions of colonic haemorrhage and in the removal of foreign bodies. They conlcude that therapeutic colonoscopy must be recognised as one of the most useful methods of diagnosis and treatment of some lesions of the rectum and colon.


A review of drug "clearance times" in racehorses. A review is presented of published and some unpublished work dealing with aspects of drug clearance from horses. This work includes plasma half-lives and urinary clearance times for specified drugs, as well as a consideration of more general factors likely to influence these values. The review is presented primarily as a guide to the veterinary surgeon in practice, to assist in the drug therapy of horses without contravening the Rules of Racing relating to doping.


Isolation, purification and properties of an intermediate in 3-deoxy-D-manno-octulosonic acid--lipid A biosynthesis. Incomplete lipid A has been purified from a mutant of Salmonella typhimurium which is temperature-sensitive both in synthesis of 3-deoxy-D-manno-octulosonic acid 8-phosphate (dOclA-8-P) and in growth. Pulse-chase experiments have shown that the incomplete lipid A molecule is the intermediate in the biosynthesis of the dOclA-lipid A portion of lipopolysaccharides. The purification procedure included DEAE-cellulose chromatography and electrodialysis. A highly water-soluble precursor material was obtained, consisting of glucosamine, phosphate and 3-hydroxymyristic acid in a molar ratio of 1:1.2:2.1. Labeling experiments as well as chemical degradation procedures revealed the precursor molecule to be composed of a diphosphorylated glucosamine-disaccharide carrying two amide-linked and two ester-linked 3-hydroxymyristic acids. In contrast to the complete dOclA-lipid A part, the intermediate lacks 3-deoxy-D-manno-octulosonic acid as well as nonhydroxylated fatty acids. On the basis of these findings a pathway for the final steps in dOclA-lipid A biosynthesis is proposed.


On the conformation of serine-specific transfer RNA. Studies by small-angle X-ray scattering and ultraviolet absorption of the molecule in solution. The scattered X-ray intensities from dilute solutions of tRNASer (yeast) in 0.1 M Soerensen buffer at pH 7.0 were measured at 25 degrees C. The radius of gyration, molecular weight and volume were determined. A model equivalent in scattering is given. The change of the conformation of tRNASer by heating was followed by small-angle X-ray measurements and ultraviolet absorption in a temperature range 20-70 degrees C. The molecule begins to unfold at about 40 degrees C and 70 degrees C has a random coil conformation. Addition of magnesium stabilizes the tRNASer molecule. The reversibility of the melting process was also studied by both methods. An interesting effect was found by ultraviolet absorption: by heating the tRNASer solutions to 55 degrees C and 60 degrees C and subsequently slowly cooling, the melting curves lie at higher absorption values than the corresponding cooling curves. The small-angle data and optical properties of tRNASer are compared with those of tRNAPhe which has already been thoroughly investigated.


Cardiovascular and metabolic changes in shock and sepsis. Review fo changing concepts. The commonly accepted sequence of low blood flow, tissue hypoxia, lacticacidosis and death does not apply to all patients dying from shock. The hyperdynamic circulation characteristic of severe sepsis is not likely due to peripheral arteriovenous shunts, since in skeletal muscle at least, capillary blood flow is increased and varies directly with cardiac index. A hyperdynamic circulatory state is seen in many patients with sepsis and may be related to metabolic changes rather than changes in oxygen transport. Skeletal muscle capillary blood flow is increased in fasting normal subjects and septic postoperative patients, both of whom are catabolic. Therefore, elevated blood flow, which is characteristic of severe sepsis, may be a response to or necessary for the catabolism of body protein required for energy production. Profound metabolic abnormalities resulting in rapid catabolism may be responsible for the demise of the septic patient. If this concept of sepsis is accepted, it follows that treatment which heretofore has been aimed at increasing blood flow and blood pressure should be redirected to therapy which provides energy substrates and alters hormonal patterns to favor anabolism.


Hypertension--proximal stenosis of double renal artery--autotransplantation. In a case of renovascular hypertension, autotransplantation has enabled the patient to recover a normal blood pressure. For the revascularization of the kidney this procedure was a treatment of choice.


A new method of haemostasis following transvesical prostatectomy. Description of an efficient modification of haemostasis following transvesical prostatectomy with the help of semicircular tightening sutures of the bed. 25 patients have been operated as described here and none of them experienced postoperative complications.


Treatment of ankylosing spondylitis with flurbiprofen or phenylbutazone. Flurbiprofen (150-200 mg daily) and phenylbutazone (300-400 mg daily) were compared in the management of 27 patients with active ankylosing spondylitis. This was a parallel, double-blind, and randomized trial of 6 weeks duration. Both drugs were equally effective in the relief of pain and tenderness of the affected joints. Overall subjective improvement, assessed by the patient and the investigator at the end of the trial, favored phenylbutazone, but it did not reach a statistically significant level. The mean values of the endpoint parameters of spinal motion showed statistically significant improvement in both groups, except in the Schober test in the flurbiprofen group and chest expansion in the phenylbutazone group. Untoward effects characteristic of these drugs were found in a few patients.


Separation and properties of EA-rosette-forming lymphocytes in humans. Human peripheral blood lymphocytes were separated into subpopulations enriched or depleted with respect to B lymphocytes (Ig-bearing cells), T lymphocytes, (cell forming rosettes with sheep erythrocytes: E-RFC) and Fc receptor-bearing lymphocytes (EA-RFC). From the distributions and recoveries of the various cell types it could be concluded that there was very little overlap  between Ig-bearing lymphocytes and EA-RFC. The latter cells partly belonged to "null" (non-T, non-B) cells; it was however demonstrated that 30 % of the EA-RFC were T cells (E-RFC). The lytic capacity in antibody-dependent lymphocytotoxicity (ADL) was shown to correspond with the proportions of EA-RFC in the various fractions. Non-T cells showed enhanced ADL activity when compared to the unseparated cells. Purified T cells populations also displayed ADL activity. Since the latter could not be due to contaminating non-T cells, this activity was ascribed to Fc receptor-bearing T lymphocytes.


Separation of cells with different histocompatibility (H-2) antigens by passage through cellular immunoadsorbent columns. The anti-Ig column technique of Wigzell et al. (Scand. J. Immunol. 1972. 1:75) was adapted to the separation of mouse cells with different H-2 antigens. Fractionation was achieved by a two-step procedure: first the cells were treated with anti-H-2 sera, and thereafter passed over anti-mouse Ig columns. Antibody-coated cells were selectively retained in the anti-Ig column. The method could be applied to the separation of normal mouse lymphocytes or lymphoma cells with different H-2 antigen complexes and for the selective isolation of H-2 loss variants from a mouse carcinoma/fibroblast hybrid.


IgA antibody response to intragastric immunization in high and low immune responder lines of mice. Two lines of mice selected for genes controlling the character "quantitative agglutinin production" to heterologous erythrocytes were immunized orally by the intragastric administration of sheep red blood cells (SRBC). The quantity of circulating IgA anti-SRBC and the numbers of splenic plaque-forming cells of IgA and IgM classes were related to the genetic status of the animal lines.


Effects and duration of resistance acquired by rabbits on feeding and egg laying in Ixodes ricinus L. Rabbits gradually developed a resistance against Ixodes ricinus ticks as a result of sequential experimental infestations. The resistance was characterized by an increase duration of feeding, by ticks engorging to a smaller extent and by reduced egg production. Once established, the immunity persisted for at least 9 months. Changes in the titre of circulating anti-I. ricinus antibodies was measured by indirect immunofluorescence.


Suppression of the secondary immune response by specific antibody, when given together with the secondary antigenic stimulus. It is generally believed that antibody-mediated immunosuppression can be only produced in non-primed individuals, and that this applies both to experimental animals and Rh-negative women at risk. However, in this paper it is reported that the additional injection of 0.2 ml of an antiserum to sheep erythrocytes (SE) together with a secondary antigenic stimulus of 10(8) SE into mice, primarily immunized by a tiny dose of 5 x 10(5) SE 28 days before, was capable of producing effective suppression of the secondary immune response.


Localization of hormone secreting pathways in the brain by immunohistochemistry and light microscopy: a review. Immunocytochemical techniques are now being used to localize hypothalamic neurosecretory hormones and related peptides in the mammalian brain. The data are probably incomplete, due primarily to false negative results. A number of previous assumptions concerning these pathways have been confirmed while other unexpected results were obtained. As expected, vasopressin and oxytocin and their associated proteins, neurophysins, were found in the magnocellular cell bodies of the hypothalamus and in their axonal projections to the neural lobe of the pituitary. Gonadotropin-releasing hormone (Gn-RH), somatostatin, and thyrotropin-releasing hormone (TRH) were located in what appears to be parvicellular nerve terminals on portal capillaries. Gn-RH has been found in perikarya in the arcuate nucleus, which is considered a source of fibers to the portal capillary bed. An extensive network of cell bodies and fibers in the preoptic area was also found to contain Gn-RH, and others in the periventricular nucleus in the anterior hypothalamus reacted with antiserum to somatostatin. Unexpected was considerable evidence that vasopressin is secreted directly into hypophyseal portal blood. This hormone and its neurophysin were also found in parvicellular neurons in the suprachiasmatic nucleus of rodents. All the hormones were found in fibers in the organum vasculosum of the lamina terminalis and in the posterior pituitary gland.


Steroid hormone target cells in the periventricular brain: relationship to peptide hormone producing cells. Steroid hormone concentrating cells in hypothalamic and extrahypothalamic regions are reviewed and the topographic relationship to the periventricular brain and the ventricular recess organs is discussed. Steroid hormone target cells in the brain are considered feedback sites and production sites of polypeptide hormones. The anatomical distribution of estrogen, androgen and progestin target neurons, as defined by autoradiography, is compared with the localization of antibodies to luteinizing hormone-releasing hormone and somatostatin in perikarya of neurons, as characterized by immunocytochemistry. Around the optic recess of the third ventricle in the lamina terminalis and the preoptic nucleus as well as in the periventricular nucleus of the hypothalamus, the steroid hormone target neurons and the assumed polypeptide hormone producing neurons occupy corresponding sites.


Application of the mathematics of coupled oscillator systems to the analysis of the neural control of locomotion. In many animals, the activities of limb motor neurons are rhythmic during locomotion. In some animals it is known that each limb is innervated by a local control center that resides in a discrete portion of the central nervous system. Each local control center is a biological oscillator. Since each limb moves with the same frequency as each other limb and with regulated phase delay with respect to each other limb, then it follows that the local control centers are coupled to one another. The locomotory pattern generator within the central nervous system is therefore a coupled oscillator system. The mathematics of coupled oscillator systems can assist in the construction of a model of the neural pattern generator. This model can be utilized to formulate testable predictions concerning the neural control of locomotion. Experimental data gathered from organisms in several phylums are consistent with the predictions of the model.


Germinal cell aplasia: response of luteinizing hormone (LH), follicle-stimulating hormone (FSH), and testosterone to LH/FSH-releasing hormone with histopathologic correlation. Five male patients with infertility due to biopsy-proven germinal cell aplasia were given a 100-microng bolus of luteinizing hormone (LH)/follicle-stimulating hormone (FSH)-releasing hormone (LRH), and the resultant LH, FSH, and testosterone responses were correlated with their histologic patterns on testicular biopsy. The basal and stimulated FSH values were elevated in four of five patients. Basal LH values were elevated in three patients, while two clearly had exaggerated LH and testosterone responses to LRH. Although there was little correlation between various parameters, elevated basal LH values were associated with  Leydig cell hyperplasia. Higher basal FSH levels were present when fibrosis and complete aplasia of germinal elements were found in the same biopsy specimen, and the magnitude of the FSH response to LRH correlated positively with the basal concentration. The findings of elevated basal LH values, an exaggerated LH response to LRH, lack of testosterone response, and Leydig cell hyperplasia indicate a definite disturbance of the LH-testosterone axis in many patients with germinal cell aplasia. Therefore, the regulation of secretion of both gonadotropins appears to be abnormal in this disorder.


Assessment of pituitary response to nasal application of synthetic gonadotropin-releasing hormone in men. An attempt has been made to assess the pituitary response to the nasal application of synthetic gonadotropin-releasing hormone (GnRH) in three oligospermic and two azoospermic men. Intranasal administration of 3 mg of GnRH in aqueous or natural plant gum solution produced a pituitary response pattern similar to that produced by the intramuscular injection of 100 microng, with respect to plasma concentrations of luteinizing hormone (LH) and follicle-stimulating hormone (FSH). No technical difficulties or side effects were observed. GnRH in a nasal drop preparation seems to be effective in releasing LH and FSH in men. These findings may have a practical application in those cases where long-term therapy with the hormone is indicated.


Effect of mercurascan and tetracycline on ischaemia-altered immunogenicity of liver extract alloantigens in mice. The action of Mercurascan and Tetracycline on ischaemic liver in mice was investigated. The effect was reflected in different immunogenicity (in allotrasplantation reaction) of liver extracts 1 mg. membrane fraction) derived from treated and normal organs in the donor--recipient strain combination B10--B10.LP. In the recipients treated with a single administration of extract from ischaemic liver the survival time of skin grafts was shortened as compared to the untreated control group and the control group given normal liver extract. Immunogenicity of the liver extracts from Mercurascan- or Tetracycline-treated mice was diminished.


A comparative trial of Anafranil, Pertofran and an Anafranil/Pertofran combination. On the grounds of different pharmacological properties and possibly different clinical effects, two antidepressants, Anafranil (clomipramine) and Pertofran (desipramine) were compared in the management of depression in general practice. A further comparison was made to ascertain whether a combination of the two antidepressants was more effective than the drugs given alone. One hundred and seventy-three patients were admitted to a double-blind clinical trial, conducted on a multicentre basis in general practice, in which a double-dummy technique was employed. One hundred and forty-one patients completed the study. Of these, 49 received Anafranil, 49 received Pertofran and 43 the combination. Although there were no statistically significant differences between the three treatment regimes, there was a consistent trend in favour of the combination regime. Ninety-one per cent of the patients who completed treatment on the combination showed satisfactory improvement compared with 81% on the Anafranil regime and 78% on Pertofran. An attempt was made to identify three symptom clusters--anxiety, 'anergia' and biological depression. There was no significant difference in the response of these three clusters to the three treatment regimes, nor was there any difference in the incidence and severity of side-effects.


The management of phobic disorders using clomipramine (Anafranil). The problem of phobic anxiety is viewed in the context of the entire area of mental illness and of its epidemiology in the general population. The importance of the diagnosis of depression in phobic patients and its simultaneous treatment is emphasized. Psychotherapeutic and psychopharmacological methods are discussed and some results of recent trials of clomipramine (Anafranil) are reported. The author concludes that for the successful outcome of treatment an eclectic approach must be considered. The combination of behavioural techniques of desensitization along a hierarchy of anxiety-provoking situations, together with psychotherapeutic support and the simultaneous exhibition of the more specific antidepressant and antiphobic preparation clomipramine would offer the best hope of symptom relief.


Practical considerations on the use of clomipramine (Anafranil) in general practice: an updated review. The subject of dosage of clomipramine (Anafranil) in depression and in obsessional and phobic disorders is discussed. The expectation of success is reported and a recommendation made to adopt flexible dosage. Some side-effects are considered and stress is laid on distinguishing between unwanted pharmacological effects and serious toxic effects. Serious adverse reactions are rare. Contra-indications, both relative and absolute, are discussed. The importance of possible drug interactions is emphasized.


Hypersecretion of gastric inhibitory polypeptide following oral glucose in diabetes mellitus. Gastric inhibitory polypeptide (GIP) is insulinotropic and is released after ingestion of glucose in normal man. Changes in plasma immunoreactive gastric inhibitory polypeptide (IRGIP) were therefore studied during a 50-gm. oral glucose tolerance test in 10 normal subjects and 20 subjects with maturity-onset diabetes mellitus. The diabetics were nonobese and treated by diet alone; they exhibited exaggerated increments of plasma IRGIP in association with delayed and diminished peak increases in plasma immunoreactive insulin, suggesting relative failure of the beta-cell response to GIP. The diabetic subjects also showed a paradoxic rise in mean plasma immunoreactive glucagon, with a peak coinciding with that of plasma IRGIP. It is suggested that the defective beta-cell response may lead to diminished feedback inhibition of GIP secretion by insulin in diabetes mellitus and that the glucagonotropic action of GIP may be expressed under these conditions.


The effects of long-term therapy with oral hypoglycemic agents on the oral glucose tolerance test dynamics in male chemical diabetics. The effect of fixed doses of oral hypoglycemic agents and placebo (diet alone) on the blood glucose, serum insulin, triglyceride, and cholesterol responses during oral glucose tolerance tests done annually for up to four years' follow-up was studied, in a double-blind manner, in five groups of mild male chemical diabetics. The drugs used were chlorpropamide (100 mg. O.D.), tolbutamide (500 mg. b.i.d.), phenformin (50 mg. O.D.), acetohexamide (250 mg. O.D.), and placebo. Each subject was given an individualized diet aimed at attaining and maintaining ideal weight. Comparison by chi-square analysis between the placebo group and each of the drug groups showed (a) no significant differences with regard to the number of subjects with normal glucose tolerance in each of the tests and (b) no change in the insulin secretion dynamics. Comparison between the initial test and each of the subsequent tests within each group showed (a) a greater number of subjects with normal glucose tolerance in the first follow-up test in the chlorpropamide group only, (b) no change in the insulin secretion dynamics except in the chlorpropamide group, where there was an increased insulin/glucose ratio in the first follow-up test, and (c) no change in the fasting serum triglyceride and cholesterol levels.


Effect of anti-thymocyte serum, anti-macrophage serum, and latex particles on the therapeutic efficacy of BCG or Corynebacterium liquefaciens (Propionibacterium acnes C7) in syngeneic mice. In a syngeneic mouse-tumor system, anti-thymocyte serum, anti-macrophage serum, and latex particles were used for a comparative study of the immunotherapeutic efficacy of intradermal inoculation of tumor cell-BCG and tumor cell-Corynebacterium liquefaciens (=Propionibacterium acnes C7) vaccines. Anti-thymocyte serum treatment nullified suppression of tumor mediated by BCG (living and nonliving) and living C. liquefaciens. However, the effect of nonliving C. liquefaciens was not affected so much by treatment with anti-thymocyte serum. Treatment with anti-macrophage serum or latex particles also imparied the therapeutic efficacy of living BCG, but had no influence on the efficacy of living and nonliving C. liquefaciens.


Improved infusion system for intraluminal esophageal manometry. An improved catheter infusion system is needed for esophageal intraluminal manometry. Using conventional syringe-pump infusion systems undesirably rapid infusion rates of 6 ml per min or more are often needed to achieve accurate recording of esophageal peristaltic pressure. These rapid base line infusion rates are necessitated by the high compliance of syringe-pump systems which causes substantial reduction in the infusion rate during dynamic pressure transients. In this study we tested a hydraulic-capillary infusion system designed to have low compliance. This minimally compliant system yields accurate recording of esophageal peristaltic pressure at infusion rates of 0.6 ml per min or less. We believe that the hydraulic-capillary infusion system is a useful tool for performing both clinical and investigative studies of esophageal motor function.


Controlled trials of aluminum hydroxide gels for peptic ulcer. Relief of duodenal ulcer pain by aluminum hydroxide gel (AG) was compared with that obtained by a dummy gel (DG) in randomized trials. In 44 individual pain episodes, complete relief was obtained by 15-ml doses of AG in 79% and by DG in 45% (P less than 0.05). In 48 identical blind trials replicated at another hospital the difference was not significant. The gels were also tested against ulcer pain induced by intragastric acid instillation (Palmer test) in 35 patients; pain was relieved by AG in 63% and by DG in 62%. Presumed effectiveness in terminating ulcer episodes was studied in 65 patients admitted for pain; 37 received milk and cream hourly and 28 did not. All were treated with 15 ml of AG or DG during waking hours. Median time for complete disappearance of spontaneous pain was 3 days for AG and 7 days for DG, the same in both groups. In all patients the acid instillation test was repeated every few days. For the milk and cream group it became negative after 4 days with AG and after 6 days with DG. In 18 patients with gastric ulcer treated for 4 weeks AG led to greater reductions in size than did DG. A number of these trials indicate AG to be more effective than DG, but sampling and other methodological problems limit the certainty of any conclusions.


Regulation of newly evolved enzymes. III Evolution of the ebg repressor during selection for enhanced lactase activity. The evolution of lactose utilization by lacZ deletion strains of E. coli occurs via mutations in the ebg genes. We show that one kind of mutation in the regulatory gene ebgR results in a repressor which retains the ability to repress synthesis of ebg enzymes, but which permits 4.5-fold more ebg enzyme synthesis during lactose induction than does the wild-type repressor. A comparison between the growth rate of various ebg+ strains on lactose and the amount of ebg enzyme synthesized by these strains shows that the rate of enzyme synthesis permitted by the wild-type repressor is insufficient for growth on lactose as a sole carbon source by a cell with the most active ebg lactase yet isolated. We conclude, therefore, that the evolution of lactose utilization requires both a structural and a regulatory mutation.


Complementation test between alkaline phosphatase regulatory mutations phoB and phoRc in Escherichia coli. A phoRc and a phoB mutation belong to the same complementation group suggesting that there is a single positive control gene for alkaline phosphatase synthesis.


Bipartite structure of the ade3 locus of Saccharomyces cerevisiae. Forty ade3 mutants were examined with respect to their growth requirements, levels of the tetrahydrofolate interconversion enzymes, and/or map positions. Four deletions were detected. Mutations that result in a requirement for adenine and histidine map in one region of the locus; those which result in a requirement for adenine only map in a quite separate region of the locus, a region not disclosed in previous studies. No correlation was observed between growth properties of the strains and enzyme levels.


Kinetics of mutation induction by ultraviolet light in excision-deficient yeast. We have measured the frequency of UV-induced reversions (locus plus suppressor) for the ochre alleles ade2-1 and lys2-1 and forward mutations (ade2 adex double auxotrophs) in an excision-deficient strain of Saccharomyces cerevisiae (rad2-20). For very low UV doses, both mutational systems exhibit linear induction kinetics. However, as the dose increases, a strikingly different response is observed: in the selective reversion system a transition to higher order induction kinetics occurs near 9 ergs/mm2 (25% survival), whereas in the nonselective forward system the mutation frequency passes through a maximum near 14 ergs/mm2 (4.4% survival) and then declines. This contrast in kinetics cannot be explained in any straightforward way by current models of induced mutagenesis, which have been developed primarily on the basis of bacterial data. The bacterial models are designed to accommodate the quadratic induction kinetics that are frequently observed in these systems. We have derived a mathematical expression for mutation frequency that enables us to fit both the forward and reversion data on the assumptions that mutagenesis is basically a "single event" Poisson process, and that mutation and killing are not necessarily independent of one another. In particular, the dose-response relations are consistent with the idea that the sensitivity of the revertants is about 25% less than that of the original cell population, whereas the sensitivity of the forward mutants is about 29% greater than the population average. We argue that this relatively small differential sensitivity of mutant and nonmutant cells is associated with events that take place during mutation expression and clonal growth.


Association of chromosome loss with centromere-adjacent mitotic recombination in a yeast disomic haploid. Experiments designed to characterize the association between disomic chromosome loss and centromere-adjacent mitotic recombination were performed. Mitotic gene convertants were selected at two heteroallelic sites on the left arm of disomic chromosome III and tested for coincident chromosome loss. The principal results are: (1) Disomic chromosome loss is markedly enhanced (nearly 40-fold) over basal levels among mitotic gene convertants selected to arise close to the centromere; no such enhancement is observed among convertants selected to arise relatively far from the centromere. (2) Chromosome loss is primarily associated with proximal allele conversion at the centromere-adjacent site, and many of these convertants are reciprocally recombined in the adjacent proximal interval. (3) Partial aneuploid exceptions provisionally identified as carrying left arm telocentrics have been found. A testable model is proposed suggesting that centromere involvement in genetic recombination may precipitate segregational disfunction leading to mitotic chromosome loss.