Tritium exchange reactions catalyzed by 2-oxo-4-hydroxyglutarate aldolase from Escherichia coli K-12. Tritiated water and tritiated substrates have been used to study exchange reactions catalyzed by Escherichia coli 2-oxo-4-hydroxyglutarate aldolase (4-hydroxy-2-oxoglutarate glyoxylate-lyase, EC 4.1.3.16, 2-oxo-4-hydroxyglutarate in equilibrium pyruvate + glyoxylate). With pyruvate, the enzyme catalyzes a rapid first-order exchange of all three methyl hydrogens in the absence of added acceptor aldehyde (i.e. glyoxylate). This reaction is not rate limiting for aldol condensation or cleavage; quite different pH-activity profiles for the exchange reaction versus aldol cleavage and also comparative effects that pH changes have on Km and V values for the two processes favor this conclusion. The exchange reaction with 2-oxobutyrate, a substrate analog, is stereoselective; one methylene hydrogen is removed at a 6-fold faster rate than the other but eventually both are exchanged. No tritium exchange occurs with glyoxylate.


9,11-Iminoepoxyprosta-5,13-dienoic acid is a selective thromboxane A2 synthetase inhibitor. 9,11-Iminoepoxyprosta-5,13-dienoic acid inhibits the thromboxane A2 synthetase in platelet and lung microsomal enzyme preparations and in intact platelets. It does not inhibit the protaglandin I2 synthetase in aorta or lung microsomes and intact Balb 3T3 fibroblasts. In lung microsomes, which contain both enzymes, 9,11-iminoepoxyprosta-5,13-dienoic acid inhibits only thromboxane A2 formation and augments prostaglandin I2 formation. This inhibitor is more selective than other reported prostaglandin endoperoxide analogs which inhibit the platelet thromboxane synthetase.


Stimulation of phosphatidic acid production in platelets precedes the formation of arachidonate and parallels the release of serotonin. Thrombin rapidly induces the formation of labeled phosphatidic acid from platelets prelabeled with [17C]arachidonate or 32PO34- and specifically decreases by 50--75% the content of phosphatidylinositol. Ionophore A23187 also stimulates phosphatidate labeling, but less effectively than thrombin. This effect on phosphatidic acid is blocked by increasing the levels of cyclic AMP by preincubation with dibutyryl cyclic AMP, cyclic AMP-phosphodiesterase inhibitors or prostacyclin. Indomethacin and eicosatetraynoic acid do not alter the production of phosphatidate, indicating independence from cyclooxygenase or lipoxygenase products. Increased turnover of [14C]- or [32P]phosphatidate occurs within 2--5 s after platelet activation by thrombin and is observed before endogenous, 14C-labeled arachidonate can be detected. The rate of phosphatidate formation parallels the induced rate of serotonin release. Release of [3H]serotonin is not affected by eicosatetraynoic acid. Phosphatidate production reflects the generation of diacylglycerol by C-type phospholipase degradation of phosphatidylinositol. Diacylglycerol and phosphatidic acid may participate in the membrane modification related to the early changes in platelet shape, release reactions or aggregation which occur on stimulation.


Inhibition of 6-phosphogluconate dehydrogenase (decarboxylating) by glucose 1,6-bisphosphate. Glucose 1,6-bisphosphate, the powerful common regulator of several key enzymes in carbohydrate metabolism, was found to exert a potent inhibitory effect on the activity of 6-phosphogluconate dehydrogenase (decarboxylating) from yeast and several rat tissues. These findings suggest that glucose 1,6-bisphosphate may have a regulatory influence on the pentose phosphate pathway.


Alterations in pancreatic islet phosphate content during secretory stimulation with glucose. Isolated rat pancreatic islets were perifused and analyzed for phosphate content immediately following the transient increase in the efflux of orthophosphate which occurs when insulin secretion is stimulated by glucose. In some instances, islets were perifused directly following isolation to minimize preparative delay; in others, islets were prelabeled during incubation with [32P]orthophosphate for 90 min prior to perifusion. In both experimental situations, total islet phosphate content declined 40--50% following exposure to stimulating concentrations of glucose and initiation of enhanced insulin release. In the experiments with prelabeled islets, tissue content of [32P]orthophosphate fell to a similar extent so that the specific radioactivity of islet orthophosphate was unaffected. Inhibited of heightened insulin release with Ni2+ did not modify the decrements in total or radioactive tissue orthophosphate, thus indicating that these responses to islet stimulation reflect events which are proximal to activated exocytosis. Simultaneous analyses for tissue ATP and ADP demonstrated that the efflux in orthophosphate and reduction in tissue orthophosphate content were not mediated via net changes in islet adenine nucleotides. The observations represent the first documentation that a net reduction of tissue inorganic phosphate is one of the early components of stimulus-secretion coupling in isolated pancreatic islets.


Some problems of the ecology and taxonomy of marine microvibrios. The bactericidal effect of water from the Indian and Pacific oceans and Caspian and White seas on Escherichia coli was studied. It is shown that a decrease in the viability of E. coli cells is accompanied by the appearance and active multiplication of small bacteria of a vibrioid form. Two strains of such bacteria were isolated from a suspension of E. coli in seawater and purified from membranes of the substrate organism by the method of centrifugation in a Ficoll gradient. The marine bacteria of vibrioid form are very similar to the bacterial parasite Bdellovibrio bacteriovorus in fatty acid composition and characteristic cycle of development.


T-cell-subset characterization of human T-CLL. Circulating peripheral blood tumor cells in four cases of chronic lymphoproliferative disease were immunologically characterized. By the use of T-cell-specific heteroantisera and indirect immunofluorescence, all were shown to involve proliferation of malignant T cells. Three cases demonstrated morphologic and clinical features consistent with chronic lymphocytic leukemia (CLL), and one case presented as a lymphosarcoma cell leukemia. Antisera specific for normal human T-cell subsets defined the malignant T cells in each case as arising from the TH2--subset. This subset normally constitutes approximately 80% of human peripheral blood T cells. Terminal deoxynucleotidyl transferase (TdT) was not detected in any of the T-cell CLL cases, thus supporting the notion that T-cell CLL represents a malignancy of a mature phenotype. The one patient with lymphosarcoma whose tumor cells were TdT-positive subsequently developed T-cell acute lymphoblastic leukemia (ALL). Moreover, la-like antigen (p23,30) was detected on two of these tumor cell populations. In addition, it was shown that not all tumor cells were E-rosette-positive, since only cells from 3 of 4 patients were capable of forming spontaneous rosettes. These findings demonstrate that heteroantisera can provide an additional important tool for dissecting the heterogeneity of T-cell leukemias and for relating them to more differentiated normal T cells.


A mechanism for the hydroperoxide-mediated inactivation of prostacyclin synthetase. Hydroxyl radical generation was demonstrated during heme-catalyzed decomposition of 15-hydroperoxy arachidonic acid. The hydroperoxide-mediated inactivation of prostacyclin synthetase seems to be related to the generation of this highly reactive species. A relationship between hydroperoxides and the hydroxyl radical may be important in the modulation of prostacyclin synthesis in diseased states.


Comparison of techniques for detecting T-cell acute lymphocytic leukemia. Three versions of the E-rosette test, one using untreated sheep erythrocytes at 37 degrees C, another using such cells at 4 degrees C, and a third using sheep erythrocytes treated with S-(2-aminoethyl)isothiouronium bromide hydrobromide (AET), were applied to each of 72 bone marrow specimens from as many unselected patients with untreated acute lymphocytic leukemia (ALL). The same specimens were also examined for T-cell antigens, based on reactivity with an antithymocyte serum. Lymphoblasts in eight ALL specimens formed E rosettes at 37 degrees C; no other E-positive specimens were identified when the assay was done at 4 degrees C. With AET-treated erythrocytes, lymphoblasts from these eight specimens and six additional specimens readily formed rosettes. T-cell antigens were detectable in all specimens positive for rosette formation withe untreated erythrocytes, in four of the six specimens positive for rosette formation with AET-treated erythrocytes, and in four specimens that showed no rosette formation under any of the experimental conditions used. Altogether, 18 specimens contained lymphoblasts with one or more surface markers characteristic of T-cell leukemia. These findings indicate that more specimens are likely to be identified at T-cell luekemias when E-rosette tests of increasing sensitivity and assayss for T-cell antigens are used. Some leukemic blasts do not possess the full array of membrane receptors and antigens usually associated with T cells. A combination of E-rosette tests and serologic tests is necessary to determine reliably the relationship of the test specimen to either T-cell ALL or common ALL and to establish the clinical significance of blasts that express membrane properties intermediate between those of T-cell ALL and common ALL.


Surface immunoglobulin density on human peripheral blood mononuclear cells. The densities of surface immunoglobulin (slg) on peripheral blood mononuclear cells (PBM) of normals and patients with chronic lymphocytic leukemia (CLL), chronic lymphosarcoma cell leukemia (LCL), and hairy cell leukemia (HCL) were analyzed using the fluorescence-activated cell sorter (FACS). PBM were labeled with fluorescein conjugates of F(ab')2 fragments of affinity chromatography-purified anti-Fab or class-specific anti-mu, anti-delta, anti-gamma, or anti-alpha. Histograms of relative cell fluorescence, rems of relative cell fluorescence, reflecting slg density, were prepared with the FACS. Anti-Fab-labeled normal PBM demonstrated a homogeneous low-density peak that when separated by the FACS and analyzed cytochemically consisted predominantly of monocytes, whereas brighter-staining cells were predominantly lymphocytes. Anti-mu and anti-delta labeled 9.0% and 8.5% of normal PBM, respectively, the slg+ cells being virtually all lymphocytes. Cells labeled by anti-gamma exhibited low homogeneous slg density and consisted of more than 80% monocytes. No normal or leukemic PBM were labeled by anti-alpha. All slg-positive cells (less than 5% monocytes) from 12 of 13 patients with CLL had very low homogeneous densities of slg and bore slgM, Whereas cells from 9 of 13 and 2 of 13 patients bore slgD and slgG, respectively. Similarly, PBM from 2 patients with HCL exhibited low and homogeneous densities of algM, slgD, and slgG, whereas those from a third patient bore only slgG. By contrast, the density of slgM and PBM derived from 3 patients with LCL was very high; slgD and slgG densities varied from very high to undetectable in these patients. The different homogeneous densities of slg on peripheral blood lymphocytes from patients with CLL, HCL, and LCL suggest that these diseases represent malignant transformation of different B-lymphocyte subpopulations.


The accumulation and elimination of diflubenzuron by fish. In summary, diflubenzuron is accumulated from water into fish tissues at levels up to 80 fold within 24 hr when fish are exposed to concentrations of 10 ppb. Within the concentration range of 1-10 ppb, the amount accumulated in a 24 hr exposure is proportional to concentration. After 24 to 48 hr exposure fish degrade and eliminate diflubenzuron and the excretory products are neither the parent compound nor p-chlorophenylurea. The amount of diflubenzuron remaining in fish tissues with time is dependent on the reduction of residue concentration in water; however, the potential for degradation and elimination is very great.


Sternocleidomastoid regional flaps: a new look at an old concept. The main blood supply of the sternocleidomastoid muscle enters it above from branches of the superior thyroid, posterior auricular and occipital arteries. The lower third is supplied by a branch from the transverse cervical artery and at this level there are few if any musculocutaneous branches. Long skin flaps with or without the underlying muscle should be checked with fluorescein before transfer.


Aluminium foil as a wound dressing.

Aluminium foil as a wound dressing. Aluminium foil has been found to be an extremely useful and painless way of dressing wounds prior to delayed skin grafting. However, it is not recommended for use on skin-graft donor sites as it delays epithelial healing.


Reconstruction of full-thickness loss skin wounds using skin collagen allografts. Sheets of allogeneic dermal collagen measuring 20 X 15 mm and prepared by trypsin treatment of full-thickness skin were grafted under skin flaps in rats. After 2 to 5 weeks the protective recipient skin was excised and replaced by split-thickness skin isografts which remained viable on their supportive collagen beds. On average such composite grafts maintained 84 per cent of their original size over 3 to 28 weeks and in contrast with split-thickness skin grafts achieved full-thickness reconstruction of the excised skin.


An alternative method of bowel preparation for barium enemas. A double blind trial is described comparing two methods of bowel preparation prior to barium enema. In 40 randomly selected patients a significant improvement was obtained by the use of an intestinal perfusion method.


Wound drainage following radical mastectomy: the effect of restriction of shoulder movement. A randomized prospective clinical trial has been performed to determine the effect of temporary immobilization of the shoulder on wound drainage following radical mastectomy. In 64 patients admitted to the trial the mean volume of drainage was reduced by 40 per cent in those who had shoulder movement restricted for the first 7 days after operation when compared with the group in whom early arm exercises were encouraged. The mean drainage time was reduced by 29 per cent. Shoulder immobilization did not result in increased shoulder stiffness, although there was an increased incidence of mild lymphoedema of the arm.


The effect of aspirin on the fibrinolytic activity of gastric juice. Fibrinolytic activity in the gastric juice of normal subjects has been studied by a double-blind cross-over technique comparing the effect of placebo and pentagastrin against aspirin and pentagastrin. Aspirin effectively produced a gastritis and pure fibrinolytic activity was detected in the gastric juice, but the number of samples showing pure fibrinolytic activity did not differ between the two groups. In both the placebo and the aspirin groups the presence of a protease active at neutral pH and capable of dissolving fibrin is confirmed. Aspirin is unlikely to cause gastric bleeding by increasing local fibrinolytic activity within the stomach. The model, so constructed, is not sensitive enough to be of value in investigating further the role of gastric fibrinolytic activity in gastric haemorrhage.


Prediction of gall-stone pancreatitis by computer. The clinical features at presentation of 53 patients admitted with primary acute pancreatitis due to gall stones were compared with those of 31 patients in whom the disease was due to other causes. Between these two groups 10 significant differences existed. By listing the frequency of symptoms and signs for each group a computer data base was prepared and incorporated into a program used in the differential diagnosis of acute abdominal pain. A program written to predict the presence of gall stones in patients with acute pancreatitis was accurate in 92% of the patients studied. A predictive index devised from the presence of three of the significantly differing clinical features correctly identified 82% of patients with gall-stone pancreatitis. Predicting the presence of gall stones on admission by analysing the presenting symptoms and signs with a computer had an accuracy comparable to that of ultrasonography or radiology and may be of value in the management of patients with acute pancreatitis.


Value of bromocriptine in unexplained primary infertility: a double-blind controlled trial. In a double-blind controlled study, 47 women with unexplained primary infertility were allocated at random to treatment with either bromocriptine 2.5 mg twice daily (24 patients) or placebo (23). Both groups showed a fall in serum prolactin concentrations but the reduction was much greater in the bromocriptine-treated group. Neither group showed a change in serum oestrogen or progesterone concentrations. Bromocriptine significantly reduced the duration of the follicular phase of the menstrual cycle but had no effect on the luteal phase. Five women conceived during treatment with placebo and seven during treatment with bromocriptine, but analysis of the cumulative conception rates showed no significant difference between the groups. The women who conceived were significantly younger and had a significantly shorter history of infertility than the women who did not conceive, but subtracting the number of years of infertility from age eliminated this difference. The results show that bromocriptine in the dose and duration of administration used in the trial is of no value in unexplained primary infertility.


Controlled trial of plasma exchange in treatment of Raynaud's syndrome. Twenty-seven patients with Raynaud's syndrome had their digital vessel patency assessed by Doppler ultrasound after different thermal stresses. Digital vessel patency rates differed significantly after stresses at 15 degrees C and 45 degrees C. In a randomised controlled trial placebo and heparin had no effect either on patients' symptoms or on the patency of their digital vessels. Plasma exchange improved both symptoms and vessel patency rates at 15 degrees C and 21 degrees C. Improvement in seven out of eight of these patients has been maintained for six months. Assessing digital vessel patency by Doppler techniques allow continuous, atraumatic, and safe evaluation of the effects of different methods of treatment on the patency of the digital vessels and has helped to indicate that plasma exchange is a useful adjunct in the management of patients with severe Raynaud's syndrome.


Mammary cancers and pregnancy.

Mammary cancers and pregnancy. Uncertainties persist about management and prognosis of mammary cancers that occur during and after pregnancy and during lactation. Pathological features of mammary cancers occurring during pregnancy are the same as those in non-pregnant women and survival rates are comparable. Management should be the same as in non-pregnant patients. Termination of pregnancy does not improve survival but it should be advised if the prognosis is poor. Mastectomy apparently presents little danger to the fetus, though treatment such as chemotherapy and irradiation should be avoided. Women who have received treatment for mammary cancer need not be advised against subsequent pregnancy. Routine ovarian radiation in non-pregnant premenopausal women is not generally to be recommended, since it does not prolong survival and would deprive some of the chance of further pregnancy. In lactating women who develop mammary cancers survival is apparently not adversely affected. Lactation should be suppressed initially and followed by mastectomy. Regimens of immunotherapy, chemotherapy, or radiotherapy may then be begun. Until results of current trials of combined treatments of mammary cancers associated with pregnancy are available, management should be neither aggressive nor tentative. It should be based on a well-balanced concept of applying all available treatments, as in non-pregnant patients.


Controlled comparison of cimetidine and carbenoxolone sodium in gastric ulcer. Fifty-four outpatients with endoscopically diagnosed benign gastric ulcer were allocated at random to treatment with either cimetidine 800 mg daily for six weeks or carbenoxolone sodium 300 mg daily for one week then 150 mg daily for five weeks. Ulcers were reassessed by endoscopy at the end of the trial. The endoscopist was unaware of the treatment and did not take part in the clinical care of the patients. Twenty-one of the 27 patients (78%) given cimetidine and 14 of the 27 (52%) given carbenoxolone had healed ulcers. Symptomatic response occurred earlier with cimetidine but was not significantly better. Unwanted effects were more common in the carbenoxolone group: 12 patients developed hypokalaemia, four of whom needed oral potassium supplements. The results suggest that histamine H2-receptor blockade is at least as effective as carbenoxolone sodium for benign gastric ulcer and produces fewer side effects.


Brain-dead kidney donor: selection, care, and administration. Over four and a half years a district general hospital provided 34 cadaveric kidneys for transplantation. All brain-dead patients were regarded as potential donors, flow charts being used to maintain circulation and urine formation and facilitate administration. With this system the time lapse between diagnosis of brain death and removal of kidneys ranged from three to six hours and ischaemia was minimised. It is concluded that adoption of the system by other hospitals of comparable size would result in enough good-quality kidneys to satisfy present needs, thus reducing the initial high failure rate and enabling more patients to be accepted for dialysis.


Comparison of cardiolipin and treponemal tests in the serodiagnosis of yaws. Results of the Veneral Disease Research Laboratory (VDRL), rapid plasma reagin (RPR), Treponema pallidum haemagglutination (TPHA), T. pallidum immobilisation (TPI), and fluorescent treponemal antibody absorption (FTA-ABS) tests on sera of 661 children from a region where yaws is hypoendemic are compared. For 107 (16.2%) out of 661 sera the FTA-ABS test was the only one showing reactivity; in these instances the test was weakly reactive (intensity of fluorescence scored as +) and the children had no history and no signs or symptoms of treponemal disease. A solitary, weakly reactive FTA-ABS test result seems to have no clinical significance in these cases. The FTA-ABS test can be used as a confirmatory test for yaws instead of the TPI test, if only the results of sera showing an intensity of fluorescence scored as ++ or more are considered to be positive. There appeared to be no significant differences in the results of the VDRL, RPR, and TPHA tests as screening tests for yaws when the TPI or FTA-ABS tests were used as reference tests.


Group B streptococcal infection: a review and update. The problems posed by the sudden increase in serious group B streptococcal disease among infants since the early 1970s are described and discussed. Virtually all offspring of colonised mothers harbour the organism and infection develops in about 1% of these infants. The mortality rate, even with immediate antibiotic treatment of early onset disease, is 30%; delay in treatment leads to much higher mortality. Late onset disease starting around the seventh to ninth day of life, but sometimes as late as the second month, is less frequently fatal. Preventive measures include active and passive immunisation or intravenous ampicillin during labour. Experimental evidence indicates that each of these methods gives protection.


Role of humoral versus cellular mechanisms of resistance in the pathogenesis of syphilis. From experimental work to determine the role of humoral and cell-mediated responses in the pathogenesis of syphilis evidence has been collected to indicate that both humoral and cell-mediated immunity have a protective function in syphilis.


Immunohistochemical demonstration of catechol-o-methyltransferase in mammalian brain. Catechol-O-methyltransferase (COMT)(EC 2.1.1.6) was localized using fluorescence immunohistochemistry in rat liver and kidney and in rat, chinchilla, and bovine brains. In the brain, specific fluorescence was visable only in  non-neuronal cellular elements in all three species. Ventricular ependymal cells and cells of the choroid plexuses exhibited the greatest intensity of immunofluorescence. Glial immunofluorescence appeared prominently in large myelinated fiber tracts. Interfascicular and perineuronal satellite oligodendrocytes as well as fibrous astrocytes were immunoreactive, though myelin itself did not exhibit a positive reaction. Bergmann glial cells in the cerebellum also stained brightly for COMT. Although this study indicates that the predominant localization of COMT is non-neuronal, it is important to note that the presence of small quantities of this enzyme in neurons cannot be excluded. The patterns of localization observed in the non-neuronal elements suggest that this enzyme may function as a barrier to free diffusion of catechol compounds within the central nervous system.


Partial characterization of the mode of inhibition of Escherichia coli RNA polymerase by the mixed disulfide, CoASSG. The coenzyme A-glutathione mixed disulfide (CoASSG), when complexed with iron, is capable of inhibiting the RNA polymerase of Escherichia coli. A modified procedure involving a short time of exposure to high salt allowed the reliable preparation of CoASSG-Fe which was active in inhibiting RNA polymerase. The CoASSG-Fe complex acted as a noncompetitive inhibitor for the incorporation of all four nucleoside triphosphates but had a greater effect on GMP and CMP incorporation than AMP and UMP incorporation. Neither temperature nor ionic-strength changes affected CoASSG-Fe inhibition, and the use of rifampicin showed that CoASSG-Fe did not inhibit either the initiation or elongation processes of the polymerase. CoASSG-Fe was a more effective inhibitor at low DNA-template concentrations and it was more effective in inhibiting the incorporation of CMP and GMP on simple dG-dC containing templates and the asymmetric polymer poly d(T-C) . poly d(G-A). The inhibition of transcription of poly d(I-C) was less effective than the inhibition of transcription of poly d(G-C). Equilibrium dialysis in microdialysis cells showed that CoASSG-Fe could associate with DNA in the absence of RNA polymerase.


Torsion of the greater omentum or appendices epiploicae. The authors conducted a 20-year review of the records of patients with torsion of greater omentum or appendices epiploicae admitted to the Vancouver General Hospital. Presenting signs and symptoms, operative findings and some recent reports are examined and conclusions are given. Diagnosis of the condition is rarely made preoperatively owing to the lack of specific symptoms. When a straightforward diagnosis of appendicitis has been made, yet a normal appendix is found, torsion of omentum should be considered and excluded.


Highly selective vagotomy and truncal vagotomy and pyloroplasty for duodenal ulcer: a clinical review. A review was conducted of the operations of highly selective vagotomy (HSV) and truncal vagotomy and pyloroplasty (TVP) performed for peptic ulcer disease. Gastric acid output was reduced equally after both procedures: basal acid output was reduced by 80% and maximal acid output by 50% to 60%. Not surprisingly, therefore, the recurrence rates were similar (6.6% after HSV compared to 5.6% after TVP). However, the mortality following HSV was 0% compared with 0.7% after TVP. The incidence of all side effects was lower following HSV, so that the results in 86% of patients who underwent this operation were considered excellent or very good (Visick grades I and II). The authors conclude that HSV should be considered the primary conservative procedure in the surgical management of peptic ulcer disease.


Early medicine and surgery in New Brunswick. The author discusses some of the major events in medicine and surgery in New Brunswick prior to 1900. The influences of Indian medicine, of early French and Acadian surgeons, of the British colonial surgeons at the siege of Fort Beausejour, of the pre-Loyalist and Loyalist surgeons all led up to the building of marine hospitals and quarantine stations. The introduction of anesthesia with ether and chloroform hastened progress towards"modern surgery" which was carried out in the many general hospitals that were built following the opening, in 1865, of New Brunswick's first general hospital, the General Public Hospital (now the saint John General Hospital).


Ovarian irradiation and prednisone therapy following surgery and radiotherapy for carcinoma of the breast. Following mastectomy, patients with operable breast cancer underwent postoperative irradiation of the chest wall and regional lymph nodes. They were then assigned at random to receive no further therapy, ovarian irradiation (2000 rads in 5 days) or ovarian irradiation in the same dosage plus prednisone, 7.5 mg daily. A total of 705 patients received the randomly assigned treatment and were followed for up to 10 years. In premenopausal patients who received ovarian irradiation the recurrence of breast cancer was delayed and survival prolonged, but not significantly. In premenopausal women aged 45 years or more ovarian irradiation plus prednisone therapy significantly delayed the recurrence of breast cancer (P = 0.02) and prolonged survival (P = 0.02); the survival expectancy of these patients was similar to that of the general population of the same age from the third year after the cancer operation. No value was demonstrated for ovarian irradiation with or without prednisone therapy in postmenopausal patients.


The Brompton mixture versus morphine solution given orally: effects on pain. The Brompton mixture is widely used as an effective method for controlling pain in cancer patients. In a double-blind crossover trial a standard Brompton mixture containing morphine, cocaine, ethyl alcohol, syrup BP and chloroform water was compared with morphine alone in a flavoured aqueous solution; both were administered orally. Pain was measured by means of the pain intensity index of the McGill Pain Questionnaire. Ratings of confusion, nausea and drowsiness were obtained from both the patients and their nurses and relatives. The data showed that there was no significant difference between the Brompton mixture and morphine administered orally for any of the variables. Both relieved pain effectively in about 85% of the patients.


Restrictive antibiotherapy after renal transplantation. Forty-two patients were followed up after 44 renal transplantations in an effort to evaluate possible benefits from the following protocol: systematic microbiologic and clinical surveillance, early and aggressive research for the cause of suspected infections, refusal to use prophylactic antibiotherapy, and selection of treatment according to the established cause of the infection. During 18,030 days of follow-up 124 infections were recorded, of which 110 were bacterial, 11 viral and 3 protozoal. Eighty originated in the urinary tract, 17 in skin wounds and 10 in the lower respiratory tract. Septicemia occurred three times, and one death due to infection was recorded. In the treatment of bacterial infections patients received antibiotics for 2486 days. Ampicillin (given for 816 days) and "minor" drugs such as sulfonamides and urinary antiseptics (given for 1036 days) were used 74.5% of the time, whereas gentamicin was used only 2.6% of the time (64 days). Combined antibacterial therapy was needed 1.2% of the time (29 days). A restrictive policy regarding anti-biotherapy seems to be beneficial to renal transplant recipients.


Pathogenesis of pulmonary edema associated with the adult respiratory distress syndrome. Pulmonary edema is common cause of acute respiratory failure and can be seen in not only cardiac but also noncardiac diseases. The pathophysiologic mechanism for the development of acute pulmonary edema in any clinical situation can usually be explained alterations in the forces governing the transvascular flux of fluid in the pulmonary microvasculature, according to the Starling equation. "Cardiac" pulmonary edema is primarily due to an increase in the capillary hydrostatic pressure of sufficient magnitude to overcome the forces maintaining fluid within the vessel and the ability of the lymphatics to drain the transudated fluid. On the other hand, pulmonary edema occurring in association with noncardiac disease (e.g., sepsis, aspiration or shock) is secondary to an increase in the permeability of the pulmonary microvasculature and is referred to as noncardiogenic pulmonary edema or the adult respiratory distress syndrome. This article examines the mechanisms for the development of pulmonary edema and discusses the differences between the cardiac and noncardiac types.


Differentiation between benign and malignant human lymph nodes by means of immunologic markers. A surface-marker assay combining immunofluorescence with anti-human immunoglobulin or anti-human brain serum (AHBS) and the formation of rosettes with untreated (E), antibody-sensitized (EA) and complement-coated (EAC) sheep erythrocytes was used to study mononuclear cell suspensions of human lymph nodes. The frequency of cells expressing more than one marker was increased in lymphoma nodes as compared to normal and hyperplastic nodes. The cells which simultaneously expressed complement receptors, surface immunoglobulin and the marker identified by AHBS represented the most prominent and characteristic subpopulation identified in neoplastic nodes. Distributions of cells with double and triple markers were studied by combining immunofluorescence with rosetting on frozen tissue sections. The multiple-marker cells had distributions that were characteristic in different human lymphomas. Benign and malignant human nodes could be distinguished on the basis of frequency and distribution of mononuclear cell populations carrying distinctive combinations of T- and B-cell surface markers.


Predictability of immunologic phenotype of malignant lymphomas by conventional morphology: a study of 60 cases. In order to test the immunologic validity of the Lukes-Collins (L-C) classification of the non-Hodgkin's lymphomas (ML), 60 ML in adult patients were studied and their B- or T-cell nature was predicted on a morphologic basis, without knowledge of the clinical history or the results of surface marker (SM) studies (SIg, C', Fc and E-rosettes), which were performed on cell suspensions and cryostat sections from the same specimens used for histology. There was a good correlation between morphologic types and SM (97% for the nodular ML, 81% for the diffuse). The predictions were not confirmed in 6 instances: one nodular ML typed as T; one convoluted lymphocytic ML typed as histiocytic; and four diffuse ML, predicted to be of B-type, bore no detectable SM ("Null" ML). It is concluded that the L-C morphologic criteria do allow in most cases the recognition of the B- or T-cell nature of ML, but cannot detect variations of the SM pattern which seem to affect the clinical behavior of these neoplasias. Thus, while the L-C classification seems immunologically sound, its clinical relevance still needs to be demonstrated.


Regression of established oral tumors after intralesional injection of living BCG or BCG cell walls. Oral tumors with associated cervical lymph node metastases developed after injection of tumor cells into buccal pads of inbred guinea pigs. Intralesional injection of living BCG or BCG cell walls (CW) caused regression of established tumors, prevented the development of cervical lymph node metastases and led to the development of host resistance to the growth of subsequent tumor transplant.


Immunological characterization of mononuclear cells in peripheral blood and regional lymph nodes of breast cancer patients. Mononuclear cells from peripheral blood and draining lymph nodes of 40 patients with invasive locoregional breast cancer were examined for immunological cell surface markers (E, EAhuman, EAox, EAC, SIg pos.). Concomitantly, blood lymphocytes from 36 healthy women and axillary and mesenteric lymph-nodes from patients without malignant diseases were tested as controls. In peripheral blood of tumor patients E rosette-forming cells were slightly diminished as compared to the control group, whereas EAox and EAC rosette-forming cells were increased. These differences may be age-dependent rather than tumor-related. In the draining lymph nodes of breast cancer patients as well as in the control lymph nodes, the percentages of EAC rosette-forming cells and SIg positive lymphocytes were significantly increased compared to peripheral blood, whereas E and EAhuman rosette values remained unchanged. Percentages of EAox rosettes on the other hand were strongly diminished in the draining lymph nodes, suggesting that the EAhuman and EAox rosetting techniques detect 2 types of Fc-receptor bearing cells. No significant differences were found between the cell surface marker analysis of tumor-free and metastatic lymph nodes of breast cancer patients and the control lymph nodes.


Immunocytochemical localization of calcitonin-producing cells in a strumal carcinoid with amyloid stroma. A nonfunctioning strumal carcinoid arising in a 49-year-old woman was studied by histochemical and immunocytochemical techniques. All tumor cells, irrespective of their architectural arrangement, showed properties of neuroendocrine-programmed cells, without any evidence of thyroid follicular cell differentiation. Foci of calcitonin-producing C-cells were demonstrable by immunocytochemical technique and were closely associated with areas of amyloid stroma of the tumor. Efforts at localization of insulin and gastrin within the tumor cells gave negative results. While the results in the present case offer additional support for an APUD cell origin of strumal carcinoids, the presence of the calcitonin-producing C-cells within the tumor raises interesting histogenetic possibilities as to whether these lesions are derived from C-cells or represent an ovarian carcinoid with foci of C-cell differentiation.


Strumal carcinoid of the ovary: an analysis of its components. A strumal carcinoid of the ovary was studied by light and electron microscopy. Thyroglobulin was demonstrated within the strumal element by immunofluorescence, thus establishing the identity of the thyroid tissue. The carcinoid fulfilled the light and electron microscopic criteria for a mixed insular and trabecular example of this tumor. Intermediate zones between the two tissue elements showed mixed characteristics. No amyloid was found. Immunoreactive calcitonin was demonstrated in the tumor, suggesting the presence of C-cells or medullary carcinoma of the thyroid.


Sedimentation versus cytocentrifugation in the cytologic study of craniospinal fluid. A sedimentation technique for cytologic study of CSF was compared with the standard cytocentrifugation method. Seventy-five samples from 37 children with leukemia and non-Hodgkin's lymphoma were processed by both methods. Total yield of cells and cytomorphology with differentials were analyzed. The techniques are comparable and both allow good cytologic study of the CSF even with very low cell counts/mm3. The sedimentation method can be used as an alternative, especially if a cytocentrifuge is not available. When both methods are used, the possibility of negative cell yield is decreased.


Nonspecific immune determinants in the patient with unresectable gastrointestinal carcinoma. Assays of immune function (recall skin tests to microbial antigens; total circulating lymphocytes, T-cells, B-cells; lymphocyte blastogenesis with PHA, Con A, and pokeweed mitogens; and serum immunoglobulins IgA, IgM, IgG) were obtained in 408 patients with unresectable gastrointestinal carcinoma. The overall patient population, in comparison to normal controls, was characterized by reduced response to recall skin tests, reduced total lymphocyte and T-cell counts, reduced lymphocyte blastogenesis assays, increased B-cell counts and increased IgA and IgM. Significant immunosuppression was associated with prior radiation or chemotherapy, and with impaired patient performance status. There was no apparent correlation between extent of clinically evident malignant disease and immune function within this patient population. No assay of immune function matched the prognostic value of the more readily available and less expensive determinations of performance status, serum alkaline phosphatase, or SGOT. Only reactivity to recall skin tests had a significant correlation to patient survival independent of performance status. Among patients with little or no disability, only intensity of skin test reactivity correlated significantly with survival; and among those with greater disability, there was correlation only with proportion of skin tests positive. The combination of candida and streptokinase antigens provided the best recall skin test survival correlation. Adding a third, fourth, or fifth antigen did not add to prognostic value. From an overall standpoint, the immune determinants which we studied do not appear to provide useful additions to the evaluation of the patient with unresectable gastrointestinal cancer.


Intracerebral involvement in Hodgkin's disease: a report of 6 cases and review of the literature. Intracerebral involvement in Hodgkin's disease is an unusual complication. Only 28 cases have been reported. During the past twenty-four months, we have seen six patients with intracranial involvement. Five of the six patients were male and all had mixed cellular histology. We have found the cytocentrifuge examination of the cerebrospinal fluid, brain scan, angiography, and computerized axial tomography to be the most important diagnostic examinations. We feel that intracranial disease will be seen with increasing frequency as patients are living longer.


Active specific immunotherapy with tumor cells and Corynebacterium parvum: a phase I study. Autologous, irradiated (10,000 rads) tumor cells mixed with C. parvum were given as weekly intracutaneous injections to fifteen patients with residual malignant disease. The toxicity was minimal and distinctly less than has been seen with tumor cell-BCG immunotherapy. A goal of 4 injections of 10(7) cells each was possible in only 4 patients because of limitations in methods of disaggregation and quantity of tumor available. The feasibility aspects are discussed and a case report of a prolonged regression is presented.


Rheumatoid factor in melanoma patients: alterations of humoral tumor immunity in vitro. Rheumatoid factors (RF) were associated with alterations of antibody reactions to melanoma cells in vitro by two serologic assays. Removal of RF from melanoma patients' sera by absorption with Cohn's Fraction II coated latex particles enhanced seroreactivity in the Immune Adherence (IA) assay and diminished IgM detection by the Indirect Membrane Immunofluorescence (IMI) assay. The addition of serum with high titers of RF to these assay systems led to diminution of IA reactivity and enhancement of IgM detection by IMI. Since these factors are found in cancer patients' sera and can alter humoral immune reactions directed against antigens on the membranes of tumor cells, their presence should be recognized when performing assays with tumor target cells. RF may be of significance in the host-tumor relationship in vivo.


Prospective comparison of intralesional and multipuncture BCG in recurrent intradermal melanoma. Fifty-nine patients with metastatic melanoma predominantly localized in the skin were randomly assigned to treatment with BCG given either intralesionally (IL-BCG) or by multiple puncture vaccination at a nontumor bearing site in the skin (MPV-BCG). Half the patients with IL-BCG experienced moderate fever, chills and malaise, suggesting systemic exposure to this live organism. However, only three of these patients required systemic antituberculous chemotherapy and all responded to it. MPV-BCG treated patients experienced significantly less systemic toxicity. Among fully evaluable patients 45% objective response rate was seen in the IL-BCG group and a 9% response rate in the MPV-BCG group, a significant difference. The only complete responses were seen in the IL-BCG group. Among fully evaluable patients, median survival was 21.1 months in the IL-BCG group and 13.3 months in the MPV-BCG groups (NSD). No patients with pretreatment anergy to all skin tests utilized, experienced objective response to BCG.


Primary gastrointestinal lymphomas: a classification of 66 cases. Using routine histology, resin embedded sections and immunohistochemical techniques on formalin-fixed, paraffin processed tissue, 66 cases of primary gastrointestinal lymphoma have been classified. This study necessitated the development of reliable criteria to separate lymphomas of true histiocytic origin from those of lymphocytic origin. Among the morphologic properties of malignant histiocytes were complex pleomorphic nuclei, abundant well delineated cytoplasm and phagocytosis. These cells were shown to contain all major immunoglobulin chains, C3, lysozyme and in some cases alpha 1 antitrypsin. Malignant lymphomas derived from histiocytes could be divided into two groups: malignant histiocytosis of the intestine (MHI), a recently described diffuse pleomorphic lymphoma associated with villous atrophy of the small intestine, and histiocytic lymphoma (HL) which forms solid tumor masses in a similar manner to lymphocyte derived tumors. Immunohistochemical studies of lymphocyte derived tumors were negative apart from one case with plasmacytoid differentiation. Of the 66 cases, 50% were of histiocytic origin (33% MHI, 17% HL) and 41% of lymphocyte origin, there was one case of Hodgkin's disease and five cases were unclassified. The role of the histiocyte in gastrointestinal mucosa deserves further study.


Coexistence of leukemic reticuloendotheliosis and histiocytic lymphoma: a case report. A 65-year-old woman had pancytopenia, splenomegaly, and an inaspirable bone marrow. Diagnostic evaluation demonstrated that she had both leukemic reticuloendotheliosis (LRE), or hairy cell leukemia, and an additional lympho-reticular neoplasm, most likely a "histiocytic" lymphoma. The diagnosis of LRE was based on the histopathology of spleen tissue and of a bone marrow biopsy specimen. The diagnosis of diffuse "histiocytic" lymphoma was based on the histopathology of a splenic hilar and a mesenteric lymph node, tumor nodules in the kidney and spleen, and tissue from a mass obstructing a ureter. This is the first well-documented association of a second lympho-reticular neoplasm with LRE. Even relatively gently treatment of the "histiocytic" lymphoma resulted in fatal pancytopenia, illustrating the restricitons on therapy imposed by the marrow impairment due to the LRE.


Erythroleukemia in a renal transplant recipient. A 53-year-old male developed acute erythroleukemia three years after renal transplantation. He had received three years of immunosuppressive therapy with azathioprine. A preleukemia phase associated with chromosome abnormalities was recognized. Azathioprine has been associated with chromosome abnormalities. The chronic stimulation of an abnormal erythroid clone by transplantation may have hastened the development of erythroleukemia.


Interaction of drugs, hormones, and nutrition in the causes of cancer. Hormones may act as promoters in the carcinogenic process, and occasionally their metabolites may act as antihormones or have new physiologic effects. Drugs can interact with the endocrine system in many ways. They can promote secretion of a hormone, alter its rate of removal from plasma, change plasma protein-binding characteristics, or modify routes of metabolism. Estrogens have a preparative effect on the uterine endometrium. There are biologic, clinical and epidemiologic reasons for believing that estrogen administration to postmenopausal women increases the risk for endometrial cancer. Although there are similar biologic reasons to associate prolonged estrogenic stimulation with breast cancerr, evidence for such an association is weak. Oral contraceptive use has been associated with a variety of hepatocellular tumors. Although estrogens, per se, can effect several hepatic functions, it seems likely that the 17 alpha-alkyl and 17 alpha-ethinyl functions of the progestins and estrogens are involved in this process. The role of estrogen use during pregnancy in the causation of vaginal cancer in female offspring and the role of androgens in prostate cancer have been discussed.


Mechanism of action of diet as a carcinogen. Stomach cancer in the United States has decreased over the last 50 years. It is still a major type of neoplasm in Japan, Eastern and Northern Europe, and parts of Latin America. Current concepts suggest that the reduction of gastric cancer in the U. S. stems from an increased consumption of foods with vitamin C on a year round basis, which is shown to antagonize the formation of putative gastric carcinogens. Risk factors for large bowel, breast, and prostate cancer are totally different from those for gastric cancer and thus are amenable to independent controls, with the goal of ultimately reducing the risk and preventing these major cancers in man. Current research aims to identify the nature of the mutagenic materials obtained during the frying of protein-containing foods. This process may be involved in the generation of carcinogens for cancer of the colon, breast, and prostate. Cancer of the colon is subject to somewhat different controlling elements than cancer of the breast because of the nature of the cell kinetics governing these tissues. Thus, the mechanism of action of diet involves lifestyle. The type, quality, and mode of cooking of food, particularly, play important roles in the etiology of the main human cancers in the gastrointestinal tract and the endocrine-sensitive organs.


Cancer cachexia.

Cancer cachexia. Cancer cachexia is characterized clinically by anorexia, early satiety, weight loss. anemia, and marked asthenia. The syndrome is not the result of semistarvation alone but it represents a complex metabolic problem. In the host there are abnormalities in metabolism of energy, carbohydrate, lipid and protein, in water content, in acid-base balance, in electrolyte, mineral and vitamin concentrations, alterations in the activity of host tissue enzymes and changes in endocrine homeostasis and immunologic mechanisms. The cancer initiates and contributes to the genesis of the syndrome but complications of the disease and the treatment may also play a role. Only the control of the cancer can reverse completely the syndrome. It was proposed that cancer peptides throw the host metabolism into a chaotic biochemical state by activating and inactivating host enzymes. This results in increased energy expenditure; the released host metabolites and trapped by the growing cancer.


Effects of cancer on nutrition: impaired organ system effects. The specific organ system effects of cancer and its treatment have been reviewed from the standpoint of nutritional impact. Nutritional impairment may occur as the result of specific organ system malfunction, and malnutrition itself may impair organ system functions in such a way as to compound these deficits. Nonmalignant, acute, and chronic illnesses resemble cancer in many ways, particularly in their ability to produce malnutrition and these organ system malfunctions. It is apparent that there is nothing particularly unique about many of these cancer states, from the standpoint of nutritional deficiency, that is not found in nonneoplastic conditions.


Metabolic response to surgery in the cancer patient: consequences of aggressive multimodality therapy. The metabolic response to uncomplicated surgery in the patient undergoing primary therapy for malignancy is no different than the response to surgery of similar magnitude for benign disease. Hemodynamic, nutritional-endocrine, and convalescent changes are similar. However, with current aggressive approaches to the management of cancer, the patient often comes to surgery with evidence of major debilitating side effects from his progressive malignancy or from aggressive multimodality therapy. The surgeon must be aware of the consequences of the use of combination therapies on the expected metabolic response to surgery. Awareness of such problems such as the nutritional deficit will allow preventive methods to supercede metabolic salvage procedures.


Nutrients, vitamins and minerals in cancer prevention: facts and fallacies. In this paper, a summary is first presented of the important facts that have linked diet and dietary habits to human cancers, with the purpose of identifying the sources and extent of food fallacies that associate "nutrients, vitamins, and minerals" in cancer prevention. Then examples are presented of the many fallacies that persuade consumers to make dangerous, inappropriate and/or ineffective dietary choices. Minimizing food faddism and dietary quackery with its false claims about diet and cancer requires an important counterchallenge on the part of health professionals. There is a great need to determine the possible role of nutrients and dietary components in the development of neoplastic disease in human populations in order to develop rational and safe food and nutrition policies. Concurrently, nutrition education should receive increased research support in order to improve techniques and approaches for informing policy makers, the food industry and public accurately and objectively of the recent advances in the study of nutrition and cancer prevention and their practical and health significance.


Nutrients, vitamins and minerals as therapy. Nutrients as therapy for patients with cancer are important as adjunctive therapy, i.e., adequate nutrition may be important for the success of whatever form of therapy is administered. Diets deficient in certain amino acids have some selectivity when tested against experimental tumors propagated in vivo. Such diets have had limited clinical trial and have been characterized by poor patient acceptance. Enzymes that produce deficiencies of certain amino acids, e.g., asparaginase, glutaminase, methioninase appear to offer a more reasonable approach to development of selective amino acid deficiencies in man. Trace metals in excessive amounts may be toxic or carcinogenic to the host. Two heavy metal salts, Cis-diamine dichloroplatinum and gallium nitrate, have recently been shown to have anti-neoplastic effects in man. There is no conclusive evidence that vitamins, administered in large doses, have significant antineoplastic effects although large doses of vitamin A, vitamin C, and vitamin B12 have been used for this purpose. In contrast, certain vitamin analogs such as folate antimetabolites can cause tumor regression and are useful clinical treatment. An enzyme, carboxypeptidase G1, by splitting naturally occurring folates, may also have promise as a method of producing enzymic folate deficiency.


Dietary and nutritional implications in the multifactorial etiology of certain prevalent human cancers. It has been estimated that 80--90% of the cancer rate in the U. S. can be attributed to environmental factors. For the last 20 years the role of smoking has been recognized by the scientific community. However it is only recently that the role of diet, i.e., food and beverages in carcinogenesis has begun to be recognized. It is likely that diet is more important than smoking in cancer causation. Both human and animal studies support this assumption. The study of special populations in the U. S. such as the Mormons and the Seventh Day Adventists also point to the potential of reducing U. S. cancer rates and individual risk factors through the modification of dietary habits. The major hypotheses of the role of dietary and nutritional factors in cancer etiology are examined in light of current scientific knowledge. General guideline for the reduction of risk from the major chronic diseases are also discussed.


Improvement in the therapeutic, immunological, and clearance properties of Escherichia coli and Erwinia carotovora L-asparaginases by attachment of poly-DL-alanyl peptides. The chemical modification of both Escherichia coli and Erwinia carotovora asparaginases by a DL-alanine-N-carboxyanhydride polymerization technique produced modified enzymes which had greater protease stability, retained most of their catalytic activity, and demonstrated a 7- to 10-fold prolongation in plasma clearance properties in normal mice and rats. Concomitantly, plasma substrate depletion was also extended 5 to 13 days longer for the modified as compared with the native enzymes. For preparations of modified enzymes with plasma half-lives longer than 24 hr, the therapeutic activity was superior to that of the native enzymes. In addition, the modified E. coli preparations were less immunogenic in mice than was the native enzyme, and they cross-reacted with antibodies developed to the native enzyme to a 300-fold lesser degree, such that the modified enzyme still showed prolonged clearance in an animal which had been immunized previously to the native enzyme. The native enzyme was immediately cleared from the plasma of such immune animals, although hyperimmune animals would rapidly clear both the native and modified enzymes. Similarly, the modified E. carotovora enzyme would cross-react to a 500-fold lesser degree with antibodies developed against the native E. carotovora enzyme.


Antibody-induced movement of common melanoma membrane antigens on the surface of unfixed human melanoma cells. Antisera to common human melanoma antigens were obtained from melanoma patients receiving autologous immunization with their own irradiated cultured melanoma cells and Bacillus Calmette-Guérin. The antibody thus derived was used to detect common antigens on the plasma membrane of three different human melanoma cell lines by membrane immunofluorescence. The antigen-antibody complexes on the surface of melanoma cells would move to a pole (capping) and would subsequently be extruded into the extracellular milieu at room temperature. Approximately 25 to 30% of viable cells were positive by immunofluorescence. However, when the cells were fixed with methanol, 60 to 70% of cells demonstrated membrane binding. Capping was inhibited at 0 degrees or when the cells were pretreated with vinblastine sulfate. It can be concluded that common tumor antigens exist on the surface of viable human melanoma cells and that the redistribution of antigen-antibody complexes is an active process. The extrusion of antigen-antibody complexes in vitro may represent a mechanism of antigenic modulation in vivo and could indicate a basic method of tumor survival since presumably the antigen-denuded cell is viable and capable of replication but not of recognition by subsequent effector immune events.


Kinetics of cell kill by hyperthermia.

Kinetics of cell kill by hyperthermia. A review of published reports showed that there was surprisingly good agreement between different authors on the heat sensitivity of a particular cell line. For several cell lines, there was a marked difference in the heat of inactivation above 43 degrees (deltaH = 148 kcal/mol) and below 43 degrees (deltaH = 365 kcal/mol). This may indicate different mechanisms of cell killing above and below this temperature. With all cell lines tested, M- and S-phase cells were much more heat sensitive than were G1 or G2 cells. The heat sensitivity of S-phase cells is in contrast to the resistance of these cells to X-rays. The effect of hyperthermia on cell progression is discussed. The possibility of greater sensitivity of neoplastic cells to hyperthermia as compared to normal cells seems very promising.


Possible benefits of hyperthermia to chemotherapy. The advantages of hyperthermia for chemotherapy are discussed in detail. These advantages are (a) synergy with chemotherapeutic drugs and also with ionizing radiation, (b) low host toxicity, (c) ease of control (heating precisions in the range of +/- 0.1 degrees C and specific definable localized areas), and (d) low resistance (chemotherapeutic resistance and hyperthermic resistance). The potential for hyperthermia and chemotherapy in the treatment of specific human cancers, both disseminated and solid tumors, are discussed with respect to current therapy and the possible benefit of hyperthermia treatment.


Assessment of current hyperthermia technology. The current state of the art in techniques for the production and control of whole-body and local hyperthermia is discussed. Techniques of radio-frequency, microwave, and ultrasonic local hyperthermia are considered and compared. Problems of thermometry and control system integration are defined, and requisite biophysical data requirements are established. A bibliography is provided to serve both as an introduction to the hyperthermia literature for researchers from other fields and as a convenient compendium of original sources for scientists currently engaged in hyperthermia research.


Quantitative tumor cytochemistry--G.H.A. Clowes Memorial Lecture. Quantitative optical cytochemistry permits the determination of many different parameters in whole cells or parts of cells. Total amounts of DNA, RNA, and protein and/or the amounts of these substances in nucleus or nucleolus are examples. Techniques in this field have contributed considerably to the development of our present conceptions of normal cell growth and regulation. Normal cell study has, however, predominated so that tumor work has not yet been very extensive, even though quite eqrly on, in the 1940's, a conspicuous cytochemical peculiarity was found in cancers, namely, a pronounced variability between cells with regard to several measurable parameters. The result has been different kinds of technical difficulties, which are especially great in work on tumor material. However, as years passed, a fair amount of information was accumulated from studies of different parameters in tumors. Only a few years ago this experience clearly indicated that, provided very considerable improvements were made in technique, several cytochemical methods could be used as efficient supplements to morphological cytodiagnostic work, especially in such important clinical fields as preneoplasia identification, malignancy grading, and judgment of the state of growth of for instance, hormone-stimulated populations and also the distinction, so difficult in morphology, between "atypical hyperplasia" and "truly malignant" states. In an effort to eliminate the foremost of these technical difficulties, during the last few years we have developed a comprehensive system for large-scale uni- and multiparameter measurements aimed specifically at the types of specimens encountered in cytopathological work. The system is based on cytophotometry in ultraviolet and visible light, interferometry, and fluorometry and also encompasses special arrangements to simplify the identification and recovery of individual cells for different types of study. Instruments for facilitation of the comparison of cytochemical results with morphological findings are also included.


Carcinogenicity of 2-hydroxybenzo(a)pyrene and 6-hydroxybenzo(a)pyrene in newborn mice. Benzo(a)pyrene (BP), 2-hydroxybenzo(a)pyrene (2-HOBP), and 6-hydroxybenzo(a)pyrene (6-HOBP) were tested for tumorigenicity by i.p. injection into newborn mice. The mice were treated sequentially with 200, 400, and 800 nmol of compound on the first, eighth and fifteenth day of life, and the animals were killed at 24 weeks of age. Treatment with 2-HOBP caused about 4-fold more pulmonary tumors than BP, while 6-HOBP had little or no tumorigenic activity. Newborn mice treated with 2-HOBP, BP, and 6-HOBP had a 98, 81, and 11% incidence of pulmonary adenomas with an average of 24, 6.4, and 0.11 adenomas per mouse, respectively. In the control group, 7.5% of the animals had pulmonary adenomas with an average of 0.08 adenoma per mouse. When 25, 50, or 100 nmol of BP or 2-HOBP was applied to mouse skin once every 2 weeks for 60 weeks, both compounds had about the same carcinogenic activity. These results demonstrate the importance of evaluating the carcinogenic potential of chemicals in more than one tumor system. BP and 2-HOBP were tested for mutagenicity towards two strains of Salmonella typhimurium and towards Chinese hamster V79 cells in the presence of hepatic microsomes from rats pretreated with Aroclor 1254. The products formed during the metabolism of 2-HOBP or BP by liver microsomes had significant mutagenic activity.


Protective effect of oral Salmonella enteritidis 11RX infection against colon tumor induction by 1,2-dimethylhydrazine in mice. Infection of mice with Salmonella enteritidis 11RX has been shown previously to cause nonspecific immune stimulation and, consequently, resistance to subsequent challenge with a variety of transplantable tumors. The present study has examined the effect of infection with this organism in a chemical carcinogenesis system. Colonic tumors were induced in LACA and BALB/c x C57BL/6JF1 mice by weekly s.c. injection of 1,2-dimethylhydrazine (15 mg/kg) for 28 weeks. Infection of mice p.o. with live S. enteritidis 11RX at 8-week intervals during 1,2-dimethylhydrazine administration protected both strains against colon tumorigenesis. Significantly fewer infected than control BALB/c x C57BL/6JF1 mice had colonic tumors at or before termination of the experiment (34 or 40 weeks) (p less than 0.001 in all cases). Comparable results were obtained with both male and female mice. The difference in tumor incidence between control and infected LACA mice was not statistically significant, however; the number and size of the lesions was greater in control mice (p less than 0.02). Although it has not been proven that the protective effect is mediated by the immune system, the results are consistent with the operation of a macrophage-mediated surveillance system. It is suggested that enteric infections should be considered as a possible contributing factor in the epidemiology of human colonic cancer.


Measurements of drinking patterns in the general population and possible applications in studies of the role of alcohol in cancer. Quantitative information on alcohol consumption patterns derives from four possible sources: indirect measures, observational studies, aggregate consumption statistics, and sample surveys of general populations. The potentials and problems of each method are briefly discussed, with primary attention to the various traditions of survey questioning and data analysis. While medically oriented epidemiologists have often used only an overall drinking volume measure, social scientists have pointed to the importance also of variability in characterizing drinking, particularly in relation to social and casualty as opposed to chronic health problems with drinking. The dimensions of drinking patterns which might be relevant to hypothesized linkages of alcohol and cancer are discussed. It is suggested that measurement will need to extend beyond volume of drinking and may indeed involve studies of new kinds of dimensions in the patterning of drinking.


Etiological and preventive implications in alcohol carcinogenesis. The current state of knowledge of the epidemiological association of alcohol and tobacco consumption with cancers of the head and neck in humans is reviewed. The possible involvement of alcohol-associated nutritional deficiencies in the etiology of head and neck cancer is considered. Data are presented which indicate that in vitro metabolism of the hepatocarcinogen N-nitrosopyrrolidine is increased in microsomal fractions isolated from ethanol-consuming hamsters. Relevant studies in experimental animals are discussed in the context of possible mechanisms that could account for the increased risk of cancer in heavy drinkers who smoke.


Current status of experimental chemical carcinogenesis and its applications to human cancer risk. The history of chemical carcinogenesis is a record of the observations of physicians and epidemiologists of the relation between the occurrence of uncommon cancers in humans and the exposures of those people to certain chemical agents. In parallel with some of these findings, experimental animal models were developed to imitate the findings in humans. From these experimental studies has been obtained most of the information we have about the mechanisms of chemical carcinogenesis. Many of the biochemical studies have focused on liver cancer which might be an inappropriate general model for chemically induced cancer, liver cancer being comparatively rare in humans. It is not known to what extent exposures to any particular chemical carcinogens are responsible for the major human cancers, and the agents responsible for most of them are not known. It is probable that many noncarcinogenic chemicals act as promotors of carcinogenesis, and among these alcohol can be included as in important contributor.


Simulation experiments of tumor measurement in clinical trials. A simple model of tumor growth involving stochastic growth factors as well as measurement errors in explored in the context of a simulated "clinical trial" comparing two treatments. The model shows how treatment effects on tumor growth translate themselves into "improvement rates" derived from measurement on diameters. Furthermore, it shows that treatment contrasts of considerable magnitude (such as doubling of mass or volume versus shrinkage to one half) may escape recognition in clinical trials. A number of "power" tables are presented that provide the probability of making correct judgments of treatment effects. The tables indicate that the actual power in trials of this nature is in satisfactory agreement with that claimed in the standard power tables which are currently used in guiding trial strategy based on improvement rates.


Therapeutic effect of tamoxifen versus tamoxifen combined with medroxyprogesterone acetate in advanced breast cancer in postmenopausal women. Postmenopausal patients, those less than 68 years of age resistant to chemotherapy and those greater than 68 years of age with or without resistance to chemotherapy, entered this trial. Among 101 eligible patients, 46 were randomized to treatment with tamoxifen at a dose of 10 mg 3 times daily and 55 were randomized to treatment with tamoxifen at a dose of 10 mg 3 times daily plus medroxyprogesterone acetate at a dose of 100 mg once daily. Remission (partial plus complete) was obtained in 20 patients (45%) with tamoxifen compared to 14 patients (26%) with tamoxifen plus medroxyprogesterone acetate; however, this difference is not significantly different. The median duration of remission was also not significantly different between the two treatments: 10 months for the single drug compared with 9 months for the combined treatment. Response rates correlated with the presence of estrogen receptor, with no differences between the two treatment groups. Side effects occurred in 12 patients and in only one patient did they cause discontinuation of treatment. In conclusion, these results and theoretic considerations indicate that combined treatment with tamoxifen and medroxyprogesterone acetate is not better than treatment with tamoxifen alone.


Procarbazine, vinblastine, and actinomycin D in stage III and IV melanoma with or without methanol-extracted residue of Bacillus Calmette-Guérin. Patients with stage III and IV melanoma were randomly assigned to receive procarbazine (100 mg/m2, Days 1--10), vinblastine (5 mg/m2, Days 1 and 8), and actinomycin D (0.5 mg/m2, Days 1 and 8) with or without methanol-extracted residue (MER) of bacillus Calmette-Guerin (200 micrograms in five sites). In patients with measurable disease, 20% (eight of 40 patients) responded with only the combination chemotherapy while 15% (six of 39 patients) responded with the MER added. Toxicity was tolerable except for some instances of severe, gastrointestinal toxicity associated with procarbazine. MER as given in this study, failed to either increase the response rate or prolong survival.


Treatment and immunodiagnosis of advanced ovarian adenocarcinoma: a preliminary report. High-dose methotrexate with leucovorin rescue plus cyclophosphamide resulted in a 66.6% objective response rate with a 50% complete response rate. These preliminary results are higher than our previous results with melphalan alone or actinomycin D, 5-fluorouracil, and cyclophosphamide in women with advanced ovarian adenocarcinoma. Circulating ovarian cystadenocarcinoma-associated antigen serum levels were positive in 69.8% of patients and correlated with response to chemotherapy in 70% of patients. To date, all of the patients with advanced ovarian adenocarcinoma were found to have elevated galactosyltransferase levels. Galactosyltransferase levels correlated with response to therapy in the first five patients followed serially.


Status report of 376 mycosis fungoides patients at 4 years: Mycosis Fungoides Cooperative Group. The frequency and prognostic importance of various characteristics of patients registered by the Mycosis Fungoides Cooperative Group between November 1974 and December 1977 are reported. Variables which were considered include demographic and historical factors, symptoms, extent of disease, and other physical findings. A staging system which is based on the extent of skin involvement and the number of nodal sites clinically involved is described. Finally, a description of therapeutic results to date for patients randomized into Mycosis Fungoides Cooperative Group protocols is presented.


Exercise stress testing--current status. This paper is a review of the stress testing literature applying current methods of evaluation and analysis of exercise stress testing data to modern practice. Advantages and disadvantages of various methods for stress testing are discussed. Interpretation of the exercise stress test and an extensive discussion of 'false positive tests' as well as 'false negative tests' and correlation of stress testing results with other parameters of coronary heart disease provide the reader with material which is particularly relevant to frequently encountered clinical situations. The implications of a negative and adequate stress test as well as various degrees of positivity of results are reviewed. Emphasis is placed on subgrouping patients with coronary artery disease by exercise stress testing results into reasonably homogeneous and clinically relevant subgroups. The usefulness of exercise stress testing in other conditions such as valvular heart disease, cardiac rehabilitation, postoperative coronary bypass evaluation and application of radionucleotide scanning are reviewed.


Prostacyclin (PGI2) induces coronary vasodilatation in anaesthetised dogs. Prostacyclin (PGI2), the predominant metabolite of arachidonic acid in isolated hearts, relaxes strips of bovine coronary artery and is a potent vasodilator in isolated perfused hearts. We have examined the actions of prostacyclin on coronary blood flow in open chest dogs anaesthetised with chloralose. An electromagnetic flow probe was fitted to the left circumflex artery and phasic coronary flow, mean coronary flow (a measure of coronary volume flow over 4 s intervals), and coronary vascular resistance were recorded together with aortic pressure and heart rate. Intravenous infusion of prostacyclin (0.05 to 1.0 microgram.kg.1.min.1), reduced coronary vascular resistance and aortic pressure according to dose, but had only small effects on phasic coronary flow or mean coronary flow. Both tachycardia and bradycardia occurred during infusion of prostacyclin, but 6-oxo-prostaglandin F1alpha (infused at 10 micrograms.kg-1.min-1), the stable degradation produce of prostacyclin, had no cardiovascular effects. The coronary vasodilator effects of prostacyclin were clear when it was injected into the left circumflex artery via a fine catheter distal to the flow probe. Prostacyclin (0.05 to 0.5 microgram) increased phasic coronary flow and mean coronary flow up to 3 fold and reduced coronary vascular resistance without affecting aortic pressure or heart rate, although higher doses had systemic effects. Prostaglandin E1 (0.1 to 0.5 microgram), which also dilated the coronary vessels, had a longer lasting effect and was 1 to 4 times more potent than prostacyclin. Prostaglandin E2, (0.5 to 4 microgram) was less potent than prostacyclin. In four dogs prostacyclin (20 to 500 micrograms) applied epicardially to the left ventricle caused marked and prolonged coronary vasodilatation. Epicardial application of prostacyclin (10 to 25 micrograms) to the right ventricle increased coronary sinus oxygen content with minimal changes in blood pressure. The endoperoxide prostaglandin H2 was a coronary vasodilator of similar potency to prostacyclin, but its analogue U46619 is a vasoconstrictor. Inhibition of cyclo-oxygenase with indomethacin (5 mg.kg-1 i.v.) or sodium meclofenamate (2 mg.kg-1 i.v.) potentiated the coronary dilator effects of prostacyclin given intravenously or into the coronary artery. Cyclo-oxygenase inhibition did not alter the hypotensive effects and increased the coronary vasodilator potency of prostacyclin relative to prostaglandin E2. Thus the sensitivity of the coronary vascular bed to prostacyclin is enhanced when endogenous biosynthesis of prostaglandin-like substances is inhibited. Although the importance of arachidonic acid metabolites in the coronary circulation still requires validation in vivo, it is clear that prostacyclin, and not prostaglandin E2, is the prostaglandin most likely to be involved.


Control of chloroplast formation by light. Light controls the formation of plastid ultrastructure and the synthesis of chlorophyll, plastid membrane constituents and Calvin cycle enzymes. A respective light-mediated regulation of the genetic apparatus in the nucleus and the plastid compartment has been reported. Three photoreactions are involved in the regulation: (1) the protochlorophyll (ide) leads to chlorophyll (ide) a photoconversion, (2) the formation of physiologically active phytochrome and (3) light absorption by a blue light receptor (cryptochrome). The chloroplast formation in higer plants is chiefly controlled by active phytochrome, while in lower plants cryptochrome is the prevailing regulatory factor.


Distribution, surface density, and membrane area of diadic junctional contacts between plasma membrane and terminal cisterns in mammalian ventricle. The surface density of diadic junctional complexes (DJC) between plasmalemma and terminal cisternal membrane, as well as the areas of plasmalemmal and cisternal membrane involved in DJC, have been determined morphometrically in external plasmalemmal envelope and T-system of rabbit, rat, and mouse ventricular heart muscle. In all three species, both the surface density and the plasmalemmal area of DJC are 4- to 6-fold greater in the T-system than in the external plasmalemmal envelope. The surface density and DJC membrane area per unit cell volume and per unit myofibrillar volume increase in the order rabbit less than rat congruent to mouse and are not related simply to basal heart rate or intraventricular pressure. The results show that if Ca2+ release is a function of terminal cisterns, then, in ventricular heart muscle, most of the Ca2+ thus released for myofibrillar activation must originate from cisterns associated with the T-system. They make it necessary to consider the possibility that the 20--50% of plasmalemma in the T-system that is involved in excitation-contraction coupling may be unavailable for other processes; and they show that interspecies differences in surface density and membrane area of DJC/unit cellular and myofibrillar volume correlate with differences in Ca2+- activated Ca2+ release in skinned fibers and with differences in rate of tension development described for intact rat and rabbit ventricular muscle.


Increased sheep lung vascular permeability caused by Escherichia coli endotoxin. We infused Escherichia coli endotoxin, 0.07-1.33 microgram/kg, intravenously into chronically instrumented unanesthetized sheep and measured pulmonary arterial and left atrial pressures, lung lymph flow, lymph and blood plasma protein concentrations, and arterial blood gases. Endotoxin caused a biphasic reaction: an early phase of pulmonary hypertension and a long late phase of steady state increased pulmonary vascular permeability during which pulmonary arterial and left atrial pressures were not increased significantly and lung lymph flow was 5 times the baseline value. Lymph: plasma total protein concentration ratio during the late phase (0.76 +/- 0.04) was significantly (P less than 0.05) higher than during baseline (0.66 +/- 0.03). The lymph response was reproducible. Lung lymph clearance of endogenous proteins with molecular radii (r) 35.5 to 96 A was increased during the steady state late phase of the reaction, but, as during baseline, clearance decreased as r increased. The endotoxin reaction was similar to the reaction to infusing whole Pseudomonas bacteria, except that endotoxin had less effect on pressures during the steady state response and caused a relatively larger increase in lymph clearance of large proteins. We conclude that E. coli endotoxin in sheep causes a long period of increased lung vascular permeability and may have a greater effect on large solute pathways across microvessels than do Pseudomonas bacteria.


Changes in diastolic time with various pharmacologic agents: implication for myocardial perfusion. Diastolic time (DT) is calculated as the cycle length (RR) minus electromechanical systole (QS2). The ratio of DT (RR-QS2) to RR interval times 100, or the percent diastole (%D), varies nonlinearly with heart rate (HR), increasing rapidly with decreasing HR. The effect of commonly used cardioactive agents on %D was studied in five groups of normal subjects. In group 1 (n = 12), propranolol (160 mg daily) increased %D from 55.9 +/- 1.7 to 64.7 +/- 1.3 (p less than 0.001) by slowing HR. In group 2 (n = 12), dobutamine (2.5 micrograms/kg/min) increased %D from 56.4 +/- 1.4 to 61.8 +/- 1.3 (p less than 0.005) by shortening the QS2. In group 3 (n = 10), Cedilanid-D (1.6 mg i.v.) increased %D from 55.5 +/- 1 to 63.2 +/- 0.7 (p less than 0.001), both by slowing the HR and shortening the QS2. In group 4 (n = 12), isoproterenol (2 micrograms/min) increased HR and shortened the QS2 significantly. The net result was a significant reduction of %D from 56.1 +/- 1.4 to 53.5 +/- 1.1, (p less than 0.05). In group 5 (n = 15), a 100-mg bolus of i.v. lidocaine did not have a significant effect on %D. This study indicates that cardiovascular drugs may have significant effects on the relative duration of diastole either by affecting HR or the duration of systole. This may have clinical implications for patients with coronary artery disease and patients with left ventricular hypertrophy, since in both cases coronary flow in mostly diastolic.


Normal left ventricular function.

Normal left ventricular function. The Starling relationship in the normal human ventricle may be different than usually portrayed. In normal, resting, supine man the ventricular function curve is at its peak at a left ventricular end-diastolic pressure of approximately 10 mm Hg. Below this point is a strong direct relation between filling pressure and stroke work, while at higher filling pressures, a plateau occurs. Limitation of ventricular response is related to a sharply rising ventricular pressure-volume curve at a normal level of filling pressure. Thus, in the supine position, the normal heart is not on the active portion of the ventricular function curve, but is in a unique position in which cardiac output is probably controlled by factors other than ventricular filling pressure. In ventricular failure, the peak of the ventricular function curve is displaced to a higher level.


Veterans Administration cooperative study of surgery for coronary arterial occlusive disease: view from a noncooperating hospital. Wadsworth Veterans Administration Hospital (VA-W) dropped out of the VA Coronary Cooperative Study (VA-Coop) in 1971 because of difficulty adhering to selection criteria, and because of the lack of standardization of surgical methods. Comparison of results from 1972-1974 showed the following differences: cardiopulmonary bypass time per graft, 61 minutes (VA-Coop) vs 33 minutes (VA-W); perioperative myocardial infarction (MI), 18% vs 6%; hospital mortality, 6% vs 1%; revascularization index (patent grafts per patient determined by postoperative angiography divided by diseased arteries per patient), 0.55 (VA-Coop) vs 0.84 (VA-W). However, the slopes of the actuarial survival curves were similar after the first year. In a group of patients operated on at UCLA and VA-W (UC-VA) during 1969-1971, the 1-year survival rate was 85%, but the annual death rate thereafter was also approximately 2% per year. The survival of VA-Coop surgical patients with three-vessel disease without left main lesions was significantly better (p less than 0.05 by Wilcoxon test) than the medical group with the 6-month (surgical) mortality adjusted to a more acceptable level (5%). These results indicate that coronary bypass surgery produces an annual mortality of approximately 2% per year after the first year. Differences in survival rates are due primarily to variations in first-year mortality, which is influenced by operative mortality as well as morbidity, incomplete revascularization, and low graft patency rate. In our view, the surgical results reported by the VA Cooperative Study are representative of an intermediary step in the development of coronary bypass surgery. The data, however, still indicate that surgical treatment results in better survival in patients with multivessel coronary disease.


Effect of septal myotomy and myectomy on left ventricular systolic function at rest and during exercise in patients with IHSS. Patients with idiopathic hypertrophic subaortic stenosis (IHSS) have supernormal left ventricular systolic function at rest. Septal myotomy/myectomy reduces outflow obstruction and symptoms. However, it has been proposed that operation causes myocardial damage, with consequent reduction in left ventricular function and potentially deleterious long-term consequences, despite relief of symptoms. To evaluate the effect of myotomy and mylectomy on left ventricular function, we employed noninvasive radionuclide cineangiography at rest and during maximal exercise in21 consecutive patients with IHSS, before and 6 months after operation. In 30 normal subjects, the ejection fraction (EF) was 57 +/- 2% at rest and 71 +/- 2% during exercise. Before operation in patients with IHSS, the EF was supernormal at rest (76 +/- 2%, p less than 0.001), and normal during exercise (71 +/- 3%, NS). All patients improved from NYHA functional class III-IV preoperatively to class I-II postoperatively; the maximal provocable gradient invariably diminished (average, 100 +/- , mm Hg preop, 33 +/- 9 mm Hg postop, p less than 0.001). Postoperatively, the EF at rest was 67 +/- 2%, still supernormal, but less than that noted preoperatively (p less than 0.001). During exercise, the EF was 66 +/- 4%, only mildly diminished (p less than 0.01) from that preoperatively. We conclude that muscle resection during myotomy and myectomy usually does not cause any important impairment of global left ventricular function at rest or during exercise stress.


Long-term follow-up of the Hancock bioprosthetic heart valve: a 6-year review. Clinical experience with the Hancock porcine bioprosthetic heart valve was reviewed in 467 patients (254 men and 213 women, 18--84 years old, average, 56 years) who received 528 valves from January, 1972, to January, 1978. Associated procedures, including coronary bypass graft, ascending aortic aneurysm, and valvuloplasty were done in 102 of the 467 patients (22%). The overall operative mortality was 25/467 (5.6%), 12/226 (5.3%) for aortic valve replacement (AVR), 11/183 (6%) for mitral valve replacement (MVR), and 2/58 (3.4%) for multiple valve replacement. The first 323 patients with a minimum follow-up of 16 months (16--75 months, average 33 months) were analyzed for survival and thromboemboli. Actuarial survival at 66--75 months was 75.7% for AVR, 79% for MVR, and 75.8% for multiple valve replacement. Emboli per 100 patient-years was 0.55 for AVR (no anticoagulants), 3.9 for MVR, and 4.8 for multiple valve replacement (anticoagulants for atrial fibrillation patients only); emboli occurred only in patients with atrial fibrillation. There were seven of 528 primary dysfunctional valves (1.3%): calcification in two, tissue failure in two, and fibrosis in three. A hemodynamic study of four patients with a 21 mm Hancock Modified Orifice aortic valve prosthesis showed improved orifice areas (greater than 1.3 cm2) over the standard aortic valve. The Hancock porcine xenograft bioprosthetic heart valve has been a durable heart valve in excess of 6 years and has a low associated incidence of thromboemboli in patients off anticoagulants except in those with chronic atrial fibrillation.


Investigations with the 'individual pollen collector' and the 'Burkard trap' with reference to hay fever patients. Pollen collecting devices such as the 'Hirst' trap and the 'Burkard' apparatus provide information on average pollen content in the air during a certain time in a certain volume of air (e.g. 24 hr in 1 m3 air). They give no idea, however, of the allergenic particles to which individual hay fever patients are exposed to the course of a day. An 'Individual Pollen Collector', attached to the patient's clothing, showed that the counts varied considerably in different persons in the same place. They differed--quantitatively and qualitatively--from the values with the 'Burkard' pollen and spore traps at two places in Switzerland. The slides from the 'Individual Pollen Collector' frequently show 'clouds' of certain kinds of pollen grains, which could be responsible for hay fever attacks in moderately sensitized subjects.


RAST in the diagnosis of hypersensitivity to dog and cat allergens. A comparison of different extract preparations with clinical history, skin test and provocation tests. A comparison was made of clinical signs and provocation tests with the RAST for allergy to dog in eight and cat in twenty patients. Twenty-two had high IgE levels and all gave positive reactions to provocation tests. A commercially available dog epithelium extract gave more positive RASTs than five other dog allergen preparations, and there were no positive reactions to dog serum. The RAST was negative in patients with a low degree of sensitivity. All twenty patients allergic to cat gave positive intracutaneous test reactions and in the RAST the cat epithelial allergen showed 90% agreement with the in vivo findings.


Determination of plasma octopamine and its level in renal disease. A radioenzymatic assay method for the estimation of octopamine levels in plasma was developed. Preparation of the enzyme, phenylethanolamine-N-methyl transferase, dilution of the plasma sample, preparation of a suitable blank, and the assay conditions were found to have a significant effect on the sensitivity of the assay. Plasma octopamine levels were measured in a population of 33 normal individuals ranging in age from 19 to 94 years. Significantly higher plasma octopamine levels were found in the age group 70-90 years. Excluding those individuals over the age of 70 years, no significant differences in plasma octopamine levels were found for males or females, the range of values was 0 to 0.68 ng per ml, with a mean value of 0.23 ng per ml (n = 25). Examination of plasma octopamine levels in patients with severe renal disease requiring hemoperfusion dialysis, revealed a significantly higher level of plasma octopamine in renal disease (1.9 ng per ml), and an increase in plasma octopamine during dialysis; the mean level post dialysis being 2.7 ng per ml.


Enzyme immunoassay of theophylline with the Abbott ABA-100. The enzyme immunoassay of theophylline using the "EMIT" reagents was adapted to the Abbott ABA. The method greatly increases the maximum tests per kit. The correlation with high pressure liquid chromatography was 99%. No interference with bilirubin was found at 15 mg/dl. of total bilirubin. The method is useful for pediatric patients including newborns.


Liquid-chromatographic assay of diazepam and its major metabolites in plasma. We describe a method for simultaneous quantitation of diazepam and its metabolites, N-desmethyldiazepam and oxazepam, by reversed-phase liquid chromatography with ultraviolet detection at 254 nm. After extraction with chloroform at pH 11.0, the organic extract is evaporated, and the residue is reconstituted in a small volume of mobile-phase and chromatographed. Concentrations as low as 12 to 20 microgram/L can be detected after extraction of only 250 microL of plasma. The maximum within-day and day-to-day coefficients of variation for each compound at concentrations of 50, 250, and 1000 microgram/L are 8.0 and 10.3%, respectively. Of 14 commonly used anticonvulsant, sedative, and psychotherapeutic drugs, only carbamazepine and lorazepam may interfere with analysis for oxazepam or N-desmethyldiazepam, or both. Total chromatography time for a single sample is less than 10 min. Applicability of the method to diazepam disposition studies in children is illustrated.


Carbohydrate content of acid alpha-glucosidase (gamma-amylase) from human liver. The presence of carbohydrates in homogeneous preparations of human liver acid alpha-glucosidase has been established and the carbohydrate content of the enzyme determined. The enzyme was purified with the specific purpose of removing all low-molecular-weight carbohydrates. It was specifically adsorbed on Concanavalin A-Sepharose, eluted with methyl-alpha-D-mannopyranoside and gave a positive reaction with the phenol-sulphuric acid reagent. These facts taken together provide evidence that the enzyme studied is a glycoprotein. The analysis of the carbohydrate content of human liver acid alpha-glucosidase showed that there were 8.3 glucosamine, 13.2 mannose and possibly 3--4 glucose residues per molecule of the enzyme with a molecular weight of 98,000.


Influence of phenylethanolamine on octopamine plasma determination in hepatic encephalopathy. Octopamine and phenylethanolamine levels were measured by a radioenzymatic procedure in 30 cirrhotic patients with and without hepatic coma and in 15 normal controls. Octopamine data were obtained either by direct extraction with 40% isoamyl alcohol in toluene according to Molinoff et al. (Molinoff, P.B., Landsberg, L. and Axelrod, J. (1969) J. Pharm. Exp. Ther. 170, 253), or after pre-extraction of phenylethanolamine with 3% isoamyl alcohol in toluene. Phenylethanolamine was statistically correlated with the grade of hepatic encephalopathy. Octopamine levels also appeared to parallel the grade of coma, although the values obtained after pre-extraction were lower and less significant than those obtained with 40% isoamyl alcohol in toluene extraction. The higher values of directly extracted octopamine are due to contamination of other beta-hydroxylated phenylethylamines, among which is phenylethanolamine.


The technical variables associated with the frequencies of QFQ, RFA and CBG heteromorphisms of human chromosomes. In the 1971 Paris Conference (1972) it was established that certain regions of human chromosomes show remarkable heteromorphisms. These are the short arm of acrocentric chromosomes, the secondary constriction regions of chromosomes 1, 9, 16, and the distal 2/3rd of the long arm of the Y and the centromere of chromosomes 3, 4, and 5. There are several technical variables which affect the frequency of these heteromorphisms. These include quality of culture, age of slide, photography (filter, etc.), method of printing and method of scoring (criteria). Several other variables in the production of QFQ, RFA, and CBG heteromorphisms are discussed. In order to compare results from different laboratories these variables must be taken into consideration.


Malignant tumors of the pelvic girdle mimicking the herniated disk syndrome. Sarcomas of the pelvic girdle may produce signs and symptoms indistinguishable from those of herniated lumbar disks. Five patients are described in which the diagnosis was more difficult than in patients with intraspinal or vertebral neoplasms because they demonstrated isolated nerve root abnormalities, a positive history of trauma, an absence of radiographic abnormalities, and a lack of symptoms usually associated with malignancy. Four of the 5 patients underwent laminectomy for suspected herniated disks. In such cases a correct diagnosis often can not be made at the outset but the necessity for frequently repeated clinical and radiographic examinations cannot be overemphasized.


The operative treatment of intra-articular fractures of the lower end of the tibia. Intra-articular fractures of the lower end of the tibia are an interesting challenge. The best functional results in the past series were observed in patients treated according to the following 4 sequential principles: (1) reconstruction of the correct length of the fibula; (2) anatomical reconstruction of the articular surface of the tibia; (3) insertion of a cancellous autograft to fill gaps left by impaction and comminution; (4) stable internal fixation of the fragments by a plate placed on the medial aspect of the tibia. Seventy-five cases had a good or excellent late result (on average 6 years postoperatively) in 70% as compared to 43% to 55% in cases treated by closed and/or open methods.


Physical and biological aspects of fracture healing with special reference to internal fixation. Fracture healing is a repair process of a mechanical discontinuity loss of force transmission, and pathological mobility of bone. Through a sequence of changes of tissue development and geometry, the original structural integrity is restored. The recovery of rigidity and strength is related to tissue differentiation. In unified theory of non-operative and operative stabilized fractures, the mechanics of primary bone healing involves a complex interplay of physical and biological factors. The different patterns of bone repair respond to physical influences including strain tolerance.