Nucleotide clusters in deoxyribonucleic acids: sequence analysis of DNA using pyrimidine oligonucleotides as primers in the DNA polymerase I repair reaction. Pyrimidine oligonucleotides have been shown to prime the E. coli DNA polymerase I repair reaction, specifically and reproducibly. DNA molecules up to 30 nucleotides long have been obtained from the extension of oligopyrimidine primers, 9 to 11 nucleotides long isolated from the complementary (minus) strand of bacteriophage S13 RFDNA using S13 viral DNA as the template molecule. The sequences of the extended primers were determined from mobility shift following separation of partially extended primers by ionophoresis and homochromatography, and by a modification of the "plus" system of Sanger and Coulson (1975). The 3' leads to 5' exonuclease activity of E. coli DNA polymerase was utilized for the "plus" system in the presence of single dNTPs and also with two dNTPs in the reaction, to give a nearest neighbor type of analysis for sequence confirmation. The ready availability of oligopyrimidine primers from any DNA and the simplification of the "plus" method broaden the range of applicability of the primed DNA polymerase I repair reaction for DNA sequence analysis.


Photobinding of 8-methoxypsoralen to transfer RNA and 5-fluorouracil-enriched transfer RNA. The photobinding of [3H]8MOP to tRNA upon irradiation at 365 nm in the absence of O2 was determined by gel filtration. The maximum photobinding was found to be ca. 4 mol of 8MOP er mol of tRNA and 5FU-tRNA, with an overall quantum yield of 2.3 X 10(-3). The photobinding kinetics for 8MOP-tRNA showed an apparent induction period or sigmoidal kinetic curve, indicating a specific initial photobinding site on tRNA which was identified as 4-thiouridine at position 8 from the 5'-end of Escherichia coli tRNA. Photobinding of 8MOP to 5FU-tRNA proceeded without an apparent induction period. 8MOP-tRNA and 8MOP-5FU-tRNA adducts were characterized by absorption, fluorescence, and CD spectroscopy. A modified procedure was also developed to analyze the nucleoside composition in modified 8MOP-tRNA and 8MOP-5FU-tRNA. The results showed that 8MOP photochemically added mainly to pyrimidine bases. The photobinding of 8MOP changed the conformation (secondary in particular) of tRNA and inhibited aminoacyl-tRNA synthetase activity.


Kinetic studies of Escherichia coli transfer RNA (uracil-5-)-methyltransferase. The kinetic mechanism of a semipurified tRNA (uracil-5-)-methyltransferase (EC 2.1.1.35) preparation obtained from Escherichia coli has been studied at pH 9.0 in the presence and absence of products. The initial velocity and product inhibition patterns are consistent with a random order of addition of adenosylmethionine and transfer RNA to separate and independent binding sites on the enzyme. Values have been determined for the Michaelis and product inhibitor constants.


The plasma membrane of Saccharomyces cerevisiae. Isolation and some properties. The isolation of Saccharomyces cerevisiae plasma membrane was carried out after hypotonic lysis of yeast protoplasts treated with concanavalin A by two independent methods: a, at low speed centrifugation and b, at high speed centrifugation in a density gradient. Several techniques (electron microscopic, enzymic, tagging, etc.) were used to ascertain the degree of purification of the plasma membranes obtained. The low speed centrifugation technique as compared with the other method gave a higher yield of plasma membranes with a similar degree of purification. Analysis of the yeast plasma membrane of normally growing cells by sodium dodecyl sulphate polyacrylamide gel electrophoresis showed at least 25 polypeptide bands. Twelve glycoprotein bands were also found, and their apparent molecular weights were determined. Treatment of the protoplasts with cycloheximide resulted in a significant decrease in the carbohydrate and protein content of the plasma membrane. The electrophoretic pattern of the plasma membrane of cycloheximide-treated cells showed a redistribution of the relative amounts of each protein band and a drastic reduction in the number of Schiff-positive bands. The isoelectric point of the most abundant proteins was low (pI 4) or lower than expected from previous data. A large part of the mannosyl transferase activity found in the cell (80%) was associated with the internal membranes, the remaining activity (20%) was located in the plasma membrane preparation. Part of the mannosyl transferase activity of the cells is located at the plasma membrane surface. Invertase (an external mannoprotein) is found in both the plasma and internal membranes, and as the specific activity dropped significantly following cycloheximide treatment of the cells, it is suggested that these membranes systems are the structures for the glycosylation of a precursor invertase and its subsequent release into the periplasmic space. Other transferase found in the plasma membrane preparation transfers glucose residues from UDPglucose to a poly(alpha(1 leads to 4) polymer identified as glycogen.


Binding of [3H]narciclasine to eukaryotic ribosomes. A study on a structure-activity relationship. [3H]Narciclasine is a specific inhibitor of peptide bond formation on eukaryotic ribosomes and binds to 60-S ribosomal subunits. Binding of [3H]-narciclasine to yeast ribosomes is inhibited by many other inhibitors of peptide bond formation including anisomycin, several sequiterpene antibiotics (trichodermin, trichothecin, fusarenon X and verrucarin A) several Cephalotaxus alkaloids (harringtonine, homoharringtonine and isoharringtonine), several Amaryllidaceae alkaloids (pretazettine, haemanthamine, lycorine, pseudolycorine and dihydrolycorine) and the narciclasine derivatives trans-dihydronarciclasine, trans-dihydronarciclasine acetonide and isonarciclasine. Binding is also inhibited, although to a very small extent, by methylnarciclasine and cisdihydronarciclasine. In contrast, no inhibition of [3H]narciclasine binding was observed in the presence of certain other inhibitors of peptide bond formation including blasticidin S, gougerotin, sparsomycin and puromycin.


Inhibition of phosphoglycerate kinase by salicylates. A kinetic analysis has been performed on the inhibition of the yeast phosphoglycerate kinase (APT:3-phospho-D-glycerate 1-phosphotransferase, EC 2.7.2.3) reaction by 2-hydroxybenzoate (salicylate) and two of its iododerivatives, 2-hydroxy-5-iodobenzoate and 2-hydroxy-3,5-diiodobenzoate. The results give evidence that the salicylates mimic the nucleotide binding at the catalytic centre. The enzyme has an affinity for salicylate that dramatically increases for each iodine atom introduced to the benzene ring. Parabolic inhibition give evidence for two inhibitor binding sites per enzyme molecule. The two Ki values are 10 and 180 mM for salicylate, 0.60 and 13 mM for iodosalicylate and 0.064 and 0.70 mM for diiodosalicylate. The 2'-OH of the nucleotide substrate appears to be important for the catalytic events.


Biosynthesis and characterization of large dolichyl diphosphate-linked oligosaccharides in Saccharomyces cerevisiae. Yeast membranes incorporate radioactivity from GDP[14C]mannose into various glycolipids. These can be separated by thin layer chromatography into at least seven components. The major component has been identified previously as dolichyl monophosphate mannose. Only one additional component is not sensitive to mild alkaline saponification, but is hydrolyzed instead under mild acidic conditions. This latter glycolipid has all the characteristics of a polyprenyl diphosphate oligosaccharide with a sugar moiety of more than 12 hexose units. It runs like dolichyl diphosphate derivatives on a DEAE column and evidence is presented that the lipid moiety is a polyprenol. When radioactive Dol-PP-di-N-acetylchitobiose is incubated with yeast membranes in the presence of non-radioactive GDPmannose a small amount of a larger lipid oligosaccharides is formed besides the previously-described Dol-PP-(GlcNAc)2 mannose. This oligosaccharide has all the properties of the glycolipid described above. Its formation is greatly increased when Triton is omitted from the incubation. Radioactivity of the polyprenyl diphosphate [14C]oligosaccharide is transferred to ethanol-insoluble material, most likely endogenous membrane glycoproteins.


[Characterization of the membrane attached to the folded chromosome isolated from Escherichia coli]. Phospholipid analysis of the membranes associated with fast sedimenting folded chromosomes prepared by lysis of E. coli CR 34 shows that both inner and outer membranes are parts of the complex, in proportions not very different from that found in the whole bacteria. During the preparation of the folded chromosomes, the most recently synthesized molecules of phosphatidylglycerol and phosphatidylethanoamine are more sensitive to solubilisation, particularly those from the cytoplasmic membrane. Identification of a dominant fraction, the outer membrane, in some complexes, results from a preferential solubilization of the inner membrane. These results do not favor any specific association between the folded chromosome and the membranes.


[The autonomic transfer of mitochondrial factors (cytoduction) during crossing of Saccharomyces cerevisiae cells]. When crossing the genetically marked yeast strains obtained from the Gif collection we observed the appearance of haploid nucleo-cytoplasmic hybrids carrying the 3 nuclear markers of the rho- parent and the mitochondrial markers (rho+ ER CR) of the other parent. The frequency of such cytoduction was about 1 per cent. The mitochondrial markers ER and CR were transmited to cytoductants together and did not segregate. The possible mechanisms of the cytoduction and its significance are discussed.


A selected bibliography of biomedical and environmental applications of stable isotopes. I--Deuterium 1971-1976. A compilation of selected references to the use of deuterium in biochemical, pharmacological, clinical and environmental applications for the period 1971-1976 is presented. As a further aid, author and subject indices have been compiled.


[Edema of the paws of white mice--test for assessing the activity of E. coli enterotoxins]. The authors studied the paw edema test in mice for detection of the E. coli (strain P-99) enterotoxins activity. This test proved to be simple, sensitive and reproducible; it permitted to determine the activity of thermostable and thermolabile enterotoxins and endotoxin; the mentioned test was particularly useful in testing various preparations of enterotoxins obtained during their extraction and purification.


[Microcinematographic study of pancreatic islet cells from fetal cattle]. The growth characteristics of pancreatic islet cell cultures of bovine fetuses were investigated by the method of time-lapse cinemicrography. These monolayer cultures consisted of epithelial cells only. Under the influenc of high glucose concentration in the growth medium (up to 300 mg per 100 ml) there occurred an activation of mitochondrial apparatus of the islet cells, stimulation of cytogranulokinesis, and intensification of accumulation of the secretory granules with the subsequent degranulation of the islet cells. These data were compared with the results of cytological control of fixed and stained culture.


[Immunomorphologic study of the early stages of amyloidogenesis]. Early stages of amyloidogenesis were studied in mice with experimental amyloidosis. According to indirect Coons' method the cryostat sections of the spleens and other organs of mice were incubated first with pure rabbit fibrillar protein antiamyloid antibodies, and then with pure fluorescein-labeled foat antirabbit IgG antibodies. At the early period after 1--2 casein injections there appeared amyloid protein in the intercellular space and in the blood filling the spleen and liver sinuses. Formation of the typical amyloid deposits in the spleen were completed by the 5th--7th day of the experiment after 3--4 casein injections.


Platelet factor VIII-related antigen: studies in vivo after transfusion in patients with von Willebrand disease. Four unrelated patients with a severe form of von Willebrand disease showed no detectable factor VIII-related antigen (VIIIR:AG) in either their plasma or their platelets. They received cryoprecipitate infusions, three patients in a single injection each and one every day for 9 days before and after surgery. Platelet VIIIR:Ag was studied at different times during and after transfusion using electroimmunoassay of platelet extracts and electron microscopy of the platelets incubated with anti-VIIIR:Ag antibodies coupled to peroxidase. No VIIIR-Ag was detected in or around the patients' platelets, although this antigen was detected in the circulating blood. These results that there was no VIIIR:Ag uptake from the plasma by the platelets and that platelet VIIIR:Ag came from megakaryocytes.


[Polychemotherapy of advanced breast cancer. Triple combination with doxorubicin. Analysis of 209 observation]. Two hundred and nine patients with breast cancer in an advanced stage were treated according to a chemotherapeutic regimen associating doxorubicin, vincristine and methotrexate, administered in courses of 5 days every three weeks. This analysis deals only with the short range results; they confirm those of a previous randomized study. A global objective response was obtained in 187 cases (89%) and a measurable regression of the lesions in 150 cases (71%); in these later cases 90 (43%) had a regression of more than 50 per cent. The most striking effects, often rapidly observed, involve sites which are not generally sensitive: liver (40%), pleura (24%) and bone (only 6%, but 8 times out of 10 a definite action on the pain syndrome). Side effects were, on the whole, acceptable (only one severe hematologic complication); however, the risk of myocardiac toxocity due to the accumulation of doxorubicin limits the utilization of this association. It thus needs to be relayed by other drug regimens which are included in a program of long term action, but has interesting characteristics as induction chemotherapy.


Metabolic effects of heavy physical training on female 'age-group' swimmers. Twelve female age-group swimmers and twelve female controls, aged ten to sixteen, performed a pre-training discontinuous maximal cycle ergometer test to determine the capacities of their anaerobic (alactacid and lactacid) and aerobic energy systems. Heart rate and oxygen uptake were determined during rest, exercise, and recovery. Blood samples were collected before and after exercise for determination of blood lactic acid concentrations. Tests were readministered to both groups immediately following the swimmers' competitive season. It was concluded that female swimmers possess significantly superior oxygen transport systems as compared to the untrained controls and that the high level of aerobic fitness is maintained throughout their training programme.


Clinical trial of four pancreatic scanning agents. Four 75Se-labelled amino acids have been tested in 22 patients. In 11 of the patients pancreatic function was estimated by the Lundh test. Scans at varying time intervals up to 30 hours from isotope administration were assessed by blind marking. Pancreatic visualization with all four agents was markedly poorer than would have been expected with 75Se-selenomethionine. Whole-body retention was estimated for all four agents; two showed faster 75Se clearance than selenomethionine. Radioactivity in duodenal aspirate was measured for two of the agents.


Controlled clinical trial of arginine for infertile men with oligozoospermia. 64 infertile men with oligozoospermia took part in a double blind cross-over trial. Each patient received matching capsules of a placebo and arginine for periods of 12 weeks. There was no difference in the conception rates of the wives or changes in the quality of the semen during each period of treatment.


Lichenoid tattoo hypersensitivity.

Lichenoid tattoo hypersensitivity. Four patients are described who developed granulomatous reactions in the red portions of their tattoos. Histopathological and immunofluorescence studies showed features of lichen planus. Mercury was identified in only one patient's lesion, and hypersensitivity to mercury was shown by patch testing in one other patient. Tattooing may provide a localised antigenic challenge resulting in spontaneously occurring lichen planus.


Interaction of chlorambucil with tRNA.

Interaction of chlorambucil with tRNA. Preincubation of purified mixed tRNAs from Escherichia coli K12-MO with 2.94 mM chlorambucil (CAB) for 2 h at 37 degrees C results in the inhibition of the capacity of mixed tRNAs to accept alanine, arginine, asparagine, aspartic acid, glutamic acid, glutamine, glycine, histidine, isoleucine, leucine, lysine, methionine, phenylalanine, proline, serine, threonine, tyrosine, and valine by 100, 71, 100, 100, 100, 95, 32, 88, 36, 26, 96, 78, 44, 31, 34, 98, 38, and 17% respectively. Preincubation of tRNA with 0.75 mM and 0.29 mM CAB inhibited aminoacylation by aspartic acid to the extent of 69 and 17% respectively. CAB has no apparent effect upon the capacity of ATP to function in the formation of aminoacylated tRNALeu.


New drugs in hypertension.

New drugs in hypertension. Clonidine, propranolol, bethanidine and debrisoquine effectively decrease blood pressure by suppressing renin secretion or interfering with function of the sympathetic nervous system. In man these compounds exert an antihypertensive effect within several hours or days and their duration of action is sufficient to permit administration twice or thrice daily. Clonidine and propranolol are especially useful if sexual dysfunction or postural hypotension is undesirable. Although bethanidine and debrisoquine may produce these adverse effects, they are beneficial in severe hypertension and produce fewer side effects than guanethidine. Clonidine frequently causes sedation, and rebound hypertension may occur with sudden cessation of therapy. Injudicious use of propranolol may provoke heart failure or asthma in susceptible individuals. The combination of a thiazide diuretic with propranolol and one of hydralazine, bethanidine and debrisoquine may be used to treat severe or complicated hypertension.


5. New approaches to the management of flail chest. Although continuous positive-pressure ventilation (internal pneumatic fixation) was a great advance in the treatment of flail chest and is now the standard treatment of this condition, early and late complications related to tracheostomy and long-term ventilation are associated with this method. These complications can be avoided by use of three recently adopted techniques--expectant therapy, intermittent mandatory ventilation with positive end-expiratory pressure, and early surgical stabilization of fractures. All patients should continue to be treated in intensive care units so that impending respiratory failure can be identified and treated. These newer forms of therapy not only have the advantages of avoiding complications inherent in tracheostomy and prolonged ventilation, but also decrease the length of hospital stay and expense of treatment.


7. The groin flap: a new technique to repair traumatic tissue defects. Tissue loss from trauma, particularly in the hand and forearm, occasionally requires immediate skin-flap coverage to ensure optimal healing. A consistently safe technique of skin-flap coverage is use of a groin flap. Anatomic studies of this flap have revealed the reliability of blood supply by the superficial circumflex iliac vessels to an area of skin and subcutaneous tissue running paralle to the inguinal ligament lateral to the femoral artery, and the axial relation of the vessels to the flap allows the surgeon to take a longer flap than usual without fear of vascular embarassment. Three case reports illustrate the value of the groin flap in primary soft-tissue closure and in the treatment of acute traumatic injuries.


Results of 12 years' treatment of chronic renal failure by dialysis and transplantation. The survival of 305 patients with chronic renal failure treated at the Vancouver General Hospital by centre and home peritoneal dialysis, centre and home hemodialysis and cadaver renal transplantation over a 12-year period was analysed. There was decreasing survival with age except in patients undergoing home dialysis. Hypertension and analgesic nephropathy as primary causes of renal disease were associated with a poor prognosis. Hence age and diagnosis appear to be two of the main determinants of survival. Cardiovascular disease was the commonest cause of death but seven deaths were due to dialysis dementia. The results compare favourably with other published statistics.


Cigarette smoking and reactions to air pollutants. There are many mechanisms whereby recent exposure to cigarette smoke augments the toxicity of common air contaminants: the total pollutant burden is increased, there is cumulative irritation of the airways, pollutants are deposited selectively in the airways, ventilatory patterns are altered, mucus production is increased, ciliary function is depressed, mucosal characteristics are altered, macrophage activity is depressed and specific allergic reactions may occur. In the longer term adverse changes of form and function may develop in the lining of the airways.


Subacute sclerosing panencephalitis and multiple sclerosis: in vitro measles immunity and sensitization to myelin basic protein. Three children with subacute sclerosing panencephalitis (SSPE), 12 patients with multiple sclerosis (MS) and 12 healthy persons were studied by the macrophage migration inhibition factor (MIF) assay with measles and rubella antigens and with myelin basic protein. For the SSPE patients the mean migration indexes +/- standard deviation were 44.1 +/- 10.9 for measles antigen, 38.7 +/- 12.3 for rubella antigen and 49.8 +/- 25.7 for myelin basic protein; for the MS patients the indexes were 103.0 +/- 10.6, 93.8 +/- 15.0 and 89.3 +/- 19.9; and for the healthy subjects the indexes were 68.8 +/- 22.6, 77.7 +/- 31.3 and 100.1 +/- 6.5. The results of this study showed increased cellular immunity to measles and rubella in SSPE patients as compared with healthy persons, and absence of immunity to measles in MS patients. Patients with MS showed hypersensitivity to myelin basic protein during clinical exacerbations that was not associated with changes in immunity to measles, whereas all SSPE patients showed a significant response regardless to stage of illness.


Postdiarrheal arthropathy of Yersinia pseudotuberculosis. Two patients with acute gastroenteritis in whom polyarthritis subsequently developed were found to have positive serologic results for Yersinia pseudotuberculosis. With resolution of the arthropathy the antibody titres decreased. While the patient without the histocompatibility antigen HLA-B27 had an acute, self-limited arthritis, the patient with this antigen had a more chronic arthritis. Serologic typing and stool culture for Y. pseudotuberculosis should be done in cases of postdysenteric arthritis.


Combination antibiotic therapy in an outbreak of prosthetic endocarditis caused by Staphylococcus epidermidis. The efficacy of combination antibiotics in vivo and in vitro was studied during an outbreak of prosthetic endocarditis caused by Staphylococcus epidermidis in 10 patients. The epidemic curve suggested that patients were infected at the time of their operation, with an interval from that time until diagnosis of 11 days to 20 months. The overall mortality was 50%. Four of six patients treated with gentamicin in combination with a penicillin analogue, a cephalosporin or clindamycin survived without reoperation. One of four patients survived when treated with regimens that did not include gentamicin. In vitro studies showed a median minimum inhibitory concentration for methicillin of 8.0 microgram/mL, compared with 0.1 microgram/mL for cephalothin, clindamycin and gentamicin, and a synergistic bactericidal effect between gentamicin and methicillin, cephalothin or clindamycin. These data suggest that gentamicin is a valuable component of combination antibiotic therapy in prosthetic endocarditis caused by S. epidermidis.


Role of the adrenal cortex and sodium in the pathogenesis of human hypertension. After 30 years of continuous research into the mechanisms of human hypertension, we summarize the results obtained by the members of the multidisciplinary research group on hypertension of the Clinical Research Institute of Montreal on the disturbances of minerlocorticoid activity in a rigorously selected group of patients with early, mild essential hypertension. We attempt to integrate these findings with those of many other groups working on other aspects of hypertensive cardiovascular diseases. On the assumption that the increased peripheral resistance responsible for hypertension results from an imbalance or a disturbance of the equilibrium between the sympathetic nervous system and norepinephrine on one hand, and the vascular tone, sensitivity and responsiveness of the arterial smooth muscle to norepinephrine and to angiotensin II on the other hand, three models that fit the experimental and clinical facts as known at present are described.


Combination chemotherapy in metastatic malignant melanoma: a randomized study of three DTIC-containing combination. The activity of three DTIC-containing combinations was compared in a prospective randomized study. Of 101 patients randomized to receive one of the three regimens, 95 received adequate trials. Response rates were as follows: DTIC + cyclophosphamide 7/29 (24%); DTIC + vinblastine 6/34 (18%); DTIC + procarbazine 4/32 (13%). None of these response rates is significantly superior to any of the others. When the activity of the combination is analyzed by sex, DTIC + cyclophosphamide appears more active in females than the other regimens, but the difference is not statistically significant. Response to treatment is associated with significant prolongation of life; the median survival among responders was 11 months, while those who progressed lived a median of 4 months from the start of therapy. Toxicity of all regimens appeared to be about the same; therapy with DTIC + procarbazine was associated with significantly more nausea and vomiting. This study has failed to demonstrate clearly that any of three combinations is superior to any of the others.


Diffuse histiocytic lymphoma complicating chronic lymphocytic leukemia. Nine patients with chronic lymphocytic leukemia (CLL) who also developed diffuse histiocytic lymphoma (DH) are described. The incidence of patients with CLL developing DH was at least 3.3%. CLL existed for a median of 2 years before the diagnosis of DH. DH presented in 8 patients with abdominal symptoms and/or enlarging lymph nodes, spleen and liver. There were no consistent laboratory abnormalities associated with the onset of DH. In 4 of the patients the DH appeared to be localized. Eight of the 9 patients have died with a median survival of 2 months from the diagnosis of DH. Whether DH occurs as a result of "blastic transformation" of pre-existing CLL or is a second, unrelated malignancy is not certain. It is hypothesized that utilizing current therapies for DH might favorably influence survival.


Pleomorphic adenoma ("mixed" tumor) of human female breast mimicking carcinoma clinico-radiologically. A case of pleomorphic adenoma ("mixed" tumor) of the breast is described Although rare, this is a distinctive primary neoplasm which can be mistaken for a malignant tumor both clinically and radiologically. Brief reviews of the pertinent literature and of the possible origin of the tumor are presented.


Anaerobic liver abscess and intrahepatic metastases: a case report and review of the literature. A patient is described in whom the first recurrence of a cloacogenic carcinoma of the rectum was an intrahepatic metastasis associated with an hepatic abscess caused by the anaerobic bacterium Peptococcus prevotii. Three previously reported cases of infection associated with hepatic tumor nodules have been found in which bacteriologic data were provided, and in all three cases anaerobic bacteria were the primary or only infection organisms. Experimental data exist which document the ability of certain anaerobic bacteria to grow selectively in tumor nodules, but not in the normal tissues of a tumor-bearing host. Since 23% of patients with liver metastases have fever and offer a clinical picture compatible with infection, occult anaerobic infection associated with liver metastases may be more common than previously recognized.


Granulocytic sarcoma of the uterus.

Granulocytic sarcoma of the uterus. The presenting features of vaginal bleeding and abnormal cytologic smears in a elderly patient with simultaneously occurring acute myelogenous leukemia (AML), were due to massive infiltration of the uterine cervix and endometrium by immature myeloid elements or granulocytic sarcoma. The abnormal cytologic smears and uterine mass were initially believed to represent a poorly differentiated lymphocytic lymphoma. The diagnosis of granulocytic sarcoma was confirmed with the naphthol AS-D chloroacetate stain that demonstrated activity in the cytoplasm of the neoplastic cells.


Evaluation of two plasma fucosyltransferases as marker enzymes in non-Hodgkin's lymphoma. Levels of two fusosyltransferases were measured in plasmas of patients with non-Hodgkin's lymphoma at different phases of the disease. The level of a GDP-fucose: galactoside fucosyltransferase (EC 2.4.1.69) was found elevated in nonresponding patients and was correlated with estimated tumor burden. Enzyme levels in the normal range were found in patients in remission, maintained on chemotherapy, or unmaintained. The plasma level of a GDP-fucose; N-acetylglucosaminide fucosyltransferase (EC 2.4.1.68) was elevated in all individuals receiving drug therapy regardless of diesease status, but returned to normal levels during unmaintained remissions.


2alpha, 3alpha-epithio-5alpha-androstan-17beta-yl 1-methoxycyclopentyl ether in the treatment of advanced breast cancer: Japanese Cooperative Group of Hormonal Treatment for Breast Cancer. A new antiestrogenic steroid, 2alpha, 3alpha-epithio-5alpha-androstand-17beta-yl 1-methoxy-cyclopentyl ether, mepitiostane, given orally 10 mg b.i.d. to 50 patients with advanced breast cancer, produced objective regression of the tumor in 17 cases (34%). Objective regression of the metastases was seen in 20 of the 48 control patients given fluoxymesterone, 10 mg b.i.d. orally (47.7%). These figures do not differ significantly. The study was a prospective, randomized, double-blind trial employing the protocol of the Cooperative Breast Cancer Group. There was a significantly lower incidence of hepatotoxicity in the patients given mepitiostane.


Fanconi syndrome associated with cephalothin and gentamicin therapy. A case is reported of Fanconi syndrome and nonliquric renal failure, following a brief course of cephalothin and gentamicin, in a patient with diffuse histiocytic lymphoma. These drugs, especially when used in combination, have been associated with nephrotoxicity manifested as acute tubular necrosis and altered proximal tubular function, but biochemical evidence for generalized proximal tubular dysfunction has not been accurately defined. Thus far, only two other antibiotics, degraded tetracycline and streptozotocin, have been implicated in producing an acquired Fanconi syndrome.


A new analytical method for determining duration of phases, rate of DNA synthesis and degree of synchronization from flow-cytometric data on synchronized cell populations. L-cells synchronized by mitotic selection were investigated by flow-cytometry and the fractions of cells in the various cell cycle compartments were determined as a function of time. A new analytical evaluation procedure was developed, by which the mean transit-times of cells through various cell cycle phases can be calculated from these data. Three examples for application of the method are presented: (1) determination of the duration of G1, S, G2 + M and of the whole cell cycle; (2) calculation of the rate of DNA synthesis in several subcompartments of the S-phase; and (3) evaluation of the degree of synchronization at different stages of the cell cycle.


Endocrine cells in the oesophagus of the ascidian Styela clava, a cytochemical and immunofluorescence study. Immunocytochemical studies have demonstrated the occurrence of an insulin-immunoreactive cell type in the oesophageal epithelium of the Ascidian Styela clava. Staining with aldehyde fuchsin has demonstrated a number of similar small, triangular, cells located on the basement membrane, which may have an endocrine function. Argyrophilic cells have also been found, suggesting the presence of a second endocrine cell type. The absence of argentaffin cells has led us to believe that the cells so far observed do not produce biogenic amines such as 5-HT (5-Hydroxytryptamine). The nature of these cells is discussed with reference to endocrine-like cells found in the digestive tracts of other protochordates.


Different myosins in myoid and entodermal reticular epithelial cells of the thymus. An immunocytochemical study using specific antibodies against striated and smooth muscle myosin. A sensitive immunofluorescence microscopical technique employing specific antibodies against highly purified actin and (smooth muscle type) myosin from chicken gizzard and myosin from human striated muscle was used to localize these contractile proteins in the thymus of rat, guinea-pig, cat and chicken. Myoid cells were seen to react with antibodies to striated, but not to smooth muscle type myosin, whereas reticular epithelial cells contained smooth, but not striated type myosin. Actin immunoreactivity was found in both myoid and reticular epithelial cells.


Immunofluorescence of somatostatin-producing sites in the hypothalamus of the tadpole, Alytes obstetricans Laur. Three sites of somatostatin-synthesizing perikarya, or a related antigen, were determined by immunofluorescence in the hypothalamus of the tadpole, Alytes obstetricans (Amphibia, Anura). Two sites of neurosecretory perikarya were localized in the preoptic nuclei of the anterior hypothalamus; the axons extended either to the anterior diencephalon or to the median eminence and the pituitary. The third site was found in the posterior hypothalamus. These neurosecretory cells showed a strong immunofluorescent reaction; their axons all terminated at the level of the median eminence. Somatostatin cells were only found in intact or hypophysectomized tadpoles given somatotropin (STH). The strong reaction observed in hypophysectomized tadpoles was possibly due to the loss of the terminal portion of the neurosecretory pathway (median eminence and pituitary) by which the agent is transported to the site of discharge.


Ultrastructural immunocytochemical distribution of tubulin in cultured cells treated with microtubule inhibitors. Microtubules in tissue cultured cells are stained immunocytochemically with the PAP-method using a purified antitubulin antibody. Treatment of the cells with microtubule inhibitors (colchicine, nocodazole, vinblastine) results in the disappearance of microtubules. The diffuse cytoplasmic staining is strongly increased in the cells by colchicine and nocodazole. Vinblastine produces paracrystalline aggregates that are strongly stained and macrotubules that are unstained. The diffuse staining is much less in vinblastine-treated cells. The bundles of intermediate filaments that are induced by all microtubule inhibitors do not bind the antitubulin antibody.


Active chromatin structure.

Active chromatin structure. Active gene sequences are present in the nucleosomal fraction of chromatin. Histones are attached to the DNA of transcribing non-ribosomal genes, and EM images suggest that their conformation is related to that of nucleosomes, or is readily converted to that structure on preparation for microscopy. Active nucleosomes do have, however, a changed conformation, since their DNA is more susceptible to endonucleolytic attack by DNase I. This alteration appears to reflect potential rather than actual transcriptional activity. Mechanisms for nucleosome disassembly to allow transcription without histone have been proposed. These involve alterations in histone-histone interactions without perturbation of histone-DNA contact.


A study on the microbial filtration efficiency of surgical face masks--with special reference to the non-woven fabric mask. With the experimental apparatus designed and made available by Nicholes, we evaluated the bacterial filtration efficienty (B.F.E.) of the non-woven fabric and cotton cloth masks. The apparatus was supplied by Nicholes (U.S. Military Specification 36954 C mask, surgical, disposable). The study presented here was performed as a round robin test with Nicholes. By using this apparatus, comparison was made as to the B.F.E. of the six different kinds of surgical face mask before and after prolonged use. The result was obtained that the disposable mask made of glass fiber mat combined with non-woven fabric proved to be the highest in performance with a B.F.E. of 98.1-99.4%. It is useful both in preventing hospital infection and in general clinical practice. The B.F.E. of the conventional cotton cloth masks is not only lower but variable over a wide range of 43.1-93.6%.


Quantitative toxicology: interlaboratory and intermethod evaluation in New York State. The New York State Department of Health has conducted a proficiency evaluation program in quantitative toxicology since 1974. Serum samples containing a barbiturate and phenytoin, together with either glutethimide, procainamide, or theophylline, are sent to participating laboratories quarterly. Within the first two years of the program the percentage of laboratories able to quantitate 75% of the test samples to within 25% of the gravimetric values increased from 25 (1974-1975) to 40% (1975-1976). This improvement was partly due to licensure requirements, improved technology for sample preparation and analysis, and the availability of better quality-control practice. An obstacle to obtaining uniform accuracy is the lack of adequate calibration or testing materials. To overcome these obstacles, pure drugs are weighed into a bovine serum matrix, and the weights are confirmed by reference laboratories and used as the target values in the testing program. Comparison of the methods used by participants in this program for barbiturate and phenytoin yielded equations different from those found in other method evaluations.


Hyperlipidemia in uremic children: response to peritoneal dialysis and hemodialysis. Hemodialysis and hyperlipidemia have been associated in both adults and children. The present study indicates hyperlipidemia in uremic children treated with peritoneal dialysis and implies that the cardiovascular risk felt to exist with hemodialysis also exists in peritoneal dialysis. Thirty-eight children with chronic renal insufficiency or end-stage renal disease were followed serially under varying conditions of medical management, hemodialysis, peritoneal dialysis, and transplantation. Serum triglyceride concentrations in patients on peritoneal dialysis were not significantly different from those in patients on hemodialysis, but both were significantly higher (P less than 0.01) than concentrations in patients on medical management and transplantation.


Prolonged survival after renal transplantation in primary hyperoxaluria of childhood. Cadaver renal transplantation was performed in a 14-year-old girl with primary hyperoxaluria. Acute tubular necrosis was present initially, and a moderate rejection crisis occurred at 6 weeks. Renal biopsy performed at 4 months showed considerable deposition of calcium oxalate. Urinary excretion of oxalate varied between 315-371 mg/24 hr per 1.73 m2 (normal less than 50 mg). Despite these unfavourable factors, renal function has remained stable for the last 2 1/2 years; the serum creatinine is 1.5 mg/100 ml at 3 years. This is the longest surviving graft reported so far in documented primary hyperoxaluria. Graft failures in previous reports could in part be explained by additional complicating factors. It is concluded that renal transplantation is not necessarily contraindicated in primary hyperoxaluria.


Collagens, elastin and noncollagenous protein of the intervertebral disk. This is a review of the recent developments in collagens, elastin, and noncollagenous protein of the normal and abnormal intervertebral disk. Much progress has been made on the chemistry of the normal disk constituents. However, little work has been done to date on the essential lesion of the early degenerative disk in humans; a major effort in this field is indicated in the next decade. The reasons are obvious, for in the unraveling of the etiology of degeneration of the intervertebral disk lies the hope and expectation of prevention of disk failure.


Biomechanics and biochemistry of the intervertebral disks: the need for correlation studies. The literature on the biomechanics of the intervertebral disk is reviewed with emphasis on biomechanical--biochemical--morphological correlative studies. The deficiency of definitive correlative studies is apparent and an appeal is made to interested investigators to fill in the voids in this extremely important area of study. A comprehensive theory of intervertebral disk failure awaits application of existing biomechanical, biochemical and morphological techniques in a detailed and methodical manner to the normal and early degenerative human intervertebral disks.


Analgesic activity of floctafenine after cholecystectomy. In a double-blind, crossover study involving 40 post-cholecystectomy patients, the analgesic activity of a new oral nonnarcotic agent, floctafenine, was compared with that of oral meperidine and oral propoxyphene. A behavioral approach to the measurement of pain relief, i.e., the measurement of pain on movement or coughing, was used in addition to the accepted subjective method. Floctafenine 200 mg was found to have analgesic activity intermediate between that of meperidine 75 mg and propoxyphene 65 mg. Patients reported the fewest side effects after floctafenine. Initial pain level was found to affect the final pain score. Effects on pain relief due to age, sex, time of the day, and carryover effects were also examined and not found to be significant.


The Herbert total knee replacement: a longer than three year follow-up. Thirty personally performed Herbert total knee replacements, evaluated during a 3-year follow-up, were found not to function well. At the end of one postoperative year 6 knees had symptomatic metal synovitis and required replacement. By the end of 3 years the Herbert total knee replacement had functioned in only 12 patients. The largest single follow-up complication was foreign body synovitis, inflammation of the synovium secondary to small free metal fragments produced by the 2 components rubbing against each other during gait.


Fendosal and aspirin in postpartum uterine pain. The analgesic efficacy of fendosal, a new nonsteroidal anti-inflammatory agent structurally related to salicylic acid, was compared with that of aspirin and placebo in 100 patients with postpartum uterine pain in a single oral dose, parallel, stratified, randomized, double-blind design. With 650 mg aspirin and with 200 or 400 mg fendosal, but not with 100 mg, analgesic effects, as measured subjectively by mean pain intensity scores, began within 1 hr and had similar time-effect patterns for the first 4 or 5 hr. Thereafter with the 2 higher doses of fendosal analgesia contimued to increase, reaching a peak at 6 hr (p less than 0.05) and persisting beyond 7 hr (p less than 0.01), whereas there was no aspirin analgesia after the fifth hour. With 100 mg fendosal time of onset tended to be delayed 2 hr or more, and duration was short. The most effective treatment (largest mean 7-hr sum of pain intensity difference [SPID] scores) was 400 mg fendosal (p less than 0.01); 200 mg fendosal was rated second (p less than 0.01), 650 mg aspirin, third (p less than 0.05), 100 mg fendosal, fourth, and placebo, fifth. There was no significant side effects. These results demonstrate the efficacy of single doses of fendosal as well as the dose-dependent magnitude and time course of effects on postpartum uterine pain.


Autoradiography and histology in a case of idiopathic femoral head necrosis. The necrotic femoral head in a patient with a transplanted kidney was examined autoradiographically (with fluorine--18 and Technitium--99 m--Polyphosphate) and histologically (i.e. with long interval Tetracycline labellings). A well circumscribed area of necrotic bone was demonstrated in the weight bearing part of the caput giving evidence of a solitary infarction. The demarcation zone showed revascularization, and appositional bone formation accounted for the increased density. Foci of necrotic bone were observed further away from the necrotic area indicating an originally more extensive vascular insufficiency. In the subchondral bone a fissure had arisen probably due to rarefaction of bone during the process of revascularization. It is suggested that the vascular insufficiency was a result of a reduced resistance of the bone tissue altered by steroid therapy.


Effect of a nitrogen analog of tetrahydrocannabinol on cancer pain. Two consecutive, randomized, double-blind trials were performed to test the analgesic properties of a synthetic nitrogen analog of tetrahydrocannabinol (NIB). In the first trial, the test preparation was superior to placebo and approximately equivalent to 50 mg of codeine phosphate. In the second study, the tetrahydrocannabinol analog was superior to placebo and to 50 mg secobarbital. NIB is not useful clinically because of the frequency of side effects.


Gastrointestinal microbleeding after aspirin and naproxen. Gastrointestinal bleeding is the most serious side effect encountered with the anti-inflammatory antirheumatic drugs. Using the 51Cr labeling technique, the comparative quantity of blood loss with aspirin or naproxen has been previously done on normal volunteers. With the present study, 12 rheumatoid arthritic patients were controlled in a double-blind crossover study with the same radioactive technique. There is a difference in favor of naproxen. The difference between the baseline period and naproxen administration was not statistically significant.


Newer knowledge of skeletogenesis: macromolecular transitions in the extracellular matrix. Morphogenesis of skeletal tissues is accompanied by dramatic changes in the types and amounts of extracellular macromolecules synthesized. These changes correlate with the morphological and structural characteristics of each tissue type involved in skeletogenesis, viz. mesenchyme, cartilage and bone. At the beginning of skeletogenesis, a hyaluronate-rich extracellular matrix may provide a beneficial milieu for mesenchymal cell migration and proliferation, and prevent precocious differentiation. This matrix also contains type I collagen and possibly a unique sulfated proteoglycan. Cartilage differentiation, during endochondral osteogenesis, involves the removal of hyaluronate and the production of large amounts of type II collagen and a characteristic chondroitin sulfate-proteoglycan. Further complex transitions in arrangement and concentration of proteoglycan occur in the epiphyseal growth plate followed by sudden depletion at the site of initiation of bone formation. In addition, at this site, the type of collagen synthesized reverts from type II back to type I. Bone formation at periosteal sites also involves removal of proteoglycan. The collagen component of both osteoid and bone matrix is type I but the level of hydroxylation of lysine moieties may be significantly higher in osteoid. It is proposed that changes in extracellular matrix composition are important factors in the control of morphogenesis as well as in providing suitable structural properties to the developing skeletal tissues.


Safety evaluation of medical plastics.

Safety evaluation of medical plastics. At present, there is no evidence of toxicity from the use of PVC plasticized plastics in medical practice. The major components of plasticized PVC have been examined over a span of years and each passing year sees a confirmation of the lack of toxicity. From time to time, misconceptions of new workers in the field may raise issues that have been examined and found to no longer be issues. Considering all the factors of cost, convenience, and safety, it appears that plasticized PVC containers continue to have a valuable place in medical practice.


The development of Chinese herbal medicine and the Pen-ts'ao. Chinese medicine employs complex mixtures of remedies and does not appreciate the advantage or effectiveness of a single drug entity. Chinese herbal remedies are derived from animal, mineral, as well as arboreous and herbaceous sources. At least 1,500 different herbal drugs have been tested, analysed, and used in Chinese medicine; this is well documented in more than 50 different or revised editions of Pen-ts'ao. Both Sheng-nung Pen-ts'ao Ching, the earliest Chinese materia medica book, and the latest Pen-ts'ao Kang-mu are well-known and valuable compendia of herbal drugs.


Current developments in bovine mastitis treatment and control. Mastitis in its complexity has managed to forestall all efforts of eradication in spite of years of research, antibiotics and practical control measures. This minisymposium will touch on seven topics current to treatment and control of this economically important disease.


Small animal reproductive problems.

Small animal reproductive problems. Reproductive problems in the dog and cat are an important segment of the total case load in many veterinary practices. The interest in pet population control, estrus control, artificial insemination and planned pregnancies of pets as well as the advanced knowledge and technology in immunology, microbiology, pathology, physiology and related sciences are expanding the knowledge concerning pet reproduction. The use of radioimmunoassays (RIA) to detect minute amounts of hormones in the serum or plasma of animals has given the physiologist a precise biological measuring stick. As hormone testing laboratories become available, the RIA will become a valuable aide to the veterinary clinician, clients and their pets in diagnosing and possibly preventing or treating reproductive disorders. Knowledge of the normal canine and feline reproductive physiology, pathogenesis of reproductive disorders and a thorough history, genital tract examination, collection and examination of specimens for diagnosis and realistic treatments are all fundamental to a successful management of these disorders.


A comparison of sodium fusidate ointment ('Fucidin') alone versus oral antibiotic therapy in soft-tissue infections. A study was carried out in 90 patients with superficial, soft-tissue infections to compare the effectiveness of topical treatment with 2% sodium fusidate ointment used alone, and oral antibiotic therapy (clindamycin, erythromycin, or flucloxacillin) plus a placebo ointment. The results showed that the number of days for healing to take place was significantly shorter with sodium fusidate ointment, and there was also a highly significant preference for it over oral antibiotic therapy in the subjective assessment of clinical response. Bacteriological investigations of swabs from 58 of the patients showed Staphylococcus aureus to be the most frequently isolated pathogen: 72% of the strains were penicillin-resistant but all were sensitive to sodium fusidate. It is suggested that oral antibiotic therapy should be reserved for those cases where there is evidence of systemic spread of the infection and that sodium fusidate ointment, with or without surgical drainage, should be the standard initial treatment in the out-patient and general practice situation.


Is vitamin E involved in the autoimmune mechanism? Autoimmune diseases are characterized by an alteration of the body's defense mechanism, designed for protection against infections and toxic injuries, which for unknown reasons attacks and destroys normal tissue. Some evidence strongly suggests that such diseases are the result of hydrolytic enzymes that escape from lysosomes whose membranes have been damaged by lipid peroxidation or other causes and that combine with and denature normal tissue proteins--in effect converting them into foreign proteins--to which the body then reacts by producing antibodies. During the past ten years, in a private dermatologic practice, we have conducted clinical investigations on the possible therapeutic value of vitamin E in the management of a number of disabling skin diseases of unknown etiology as well as several muscular disorders. Among the diseases that were successfully controlled were a number in the autoimmune category, including scleroderma, discoid lupus erythematosus, porphyria cutanea tarda, several types of vasculitis, and polymyositis. Since vitamin E is a physiologic stabilizer of cellular and lysosomal membranes, and since some autoimmune diseases respond to vitamin E, we suggest that a relative deficiency of vitamin E damages lysosomal membranes, thus initiating the autoimmune process.


Tolmetin in osteoarthrosis of the hip and knee: double-blind crossover trials. A double-blind crossover study was carried out in 24 patients with osteoarthrosis of the hip or knee to compare the efficacy of a 1200 mg tolmetin daily dose with a 600 mg daily dose, each given for 2 weeks. Both regimens were well tolerated and appeared to give satisfactory relief of pain, but no differences in response between the two dosages were noted either because the number of patients involved were small or because the methods of monitoring clinical improvement were not sufficiently sensitive. A further double-blind crossover study was carried out in 40 patients to compare the efficacy of 1200 mg tolmetin daily with 150 mg ketoprofen daily, each drug being given for 2 weeks after an initial 1-week period on placebo. Pain was monitored using a visual analogue line technique and significant differences were found between both active and placebo periods. Analysis of the biochemical monitoring of both trials showed statistically significant rises in blood urea for all active treatment periods. There were no concomitant changes in serum creatinine, suggesting this effect to be extra-renal in origin. In general, side-effect incidence was low; 1 patient withdrew from ketoprofen treatment because of weight increase and urine retention.


Comparison of 0.1% halcinonide with 0.05% betamethasone dipropionate in the treatment of acute and chronic dermatoses. A 4-week, bilateral, controlled study was carried out in 53 patients with various acute and chronic dermatoses to compare the effectiveness of 0.1% halcinonide in a water-miscible base, applied once daily, with 0.05% betamethasone dipropionate cream applied twice daily. Patients' response to treatment was assessed at the end of each week. Halcinonide proved to be equally as effective as betamethasone dipropionate in most and superior in some patients with psoriasis, lichen chronicus simplex, and atopic and neurodermatitis. There was also a prompt response to once daily treatment with halcinonide in patients with contact dermatitis, eczema of the hands, and more serious cases of eczema nummulare and allergic skin reactions, many of whom had failed to respond to previous topical steroid therapy. Both preparations were well tolerated and side-effects were noted in only 1 patient with psoriasis whose condition was aggravated by halcinonide. Only 3 patients had a relapse during the 1-month follow-up period after treatment was stopped.


Double-blind cross-over study of levamisole as immunoprophylaxis for recurrent herpes progenitalis. A double-blind cross-over study of the immunoprophylactic influence of levamisole was undertaken in a study of forty patients with chronic, recurrent herpes progenitalis. Clinical records failed to show significant reduction in the frequency or severity of attacks in levamisole-treated patients when compared with placebo-treated control patients. At evaluation six months after levamisole administration, there was no essential alteration in the course of the disease in the initial treatment group.


Relative potency of the atropine-like effects of a new parasympatholytic drug, scopolamine-N-(cyclopropyl methyl) bromide and those of hyoscine-N-butyl bromide. A double-blind crossover trial with a 4-point bioassay was carried out in 8 convalescent in-patients  to study the relative potency of scopolamine-N-(cyclopropyl methyl) bromide (DA 3177), a new parasympatholytic drug, administered at doses of 2.5 mg and 5 mg i.v., and hyoscine-N-butyl bromide, administered at doses of 10 mg and 20 mg i.v., in producing atropine-like effects. The results showed that the effects on heart rate and near point of accommodation were slightly less with DA 3177, while its effects on salivary secretion were a little greater than those of hyoscine-N-butyl bromide. It is suggested that study of the pharmacodynamic effects of parasympatholytic drugs is a relatively simple way of predicting which doses should be effective spasmolytically.


Coexistent bullous pemphigoid and systemic lupus erythematosus. A case of coexistent bullous pemphigoid and systemic lupus erythematosus is reported. Evidence for an immunologic pathogenesis is reviewed for both disorders. It is suggested that the coexistence of bullous pemphigoid and systemic lupus erythematosus may represent a similar pathomechanism.


A double-blind comparison of 1% hydrocortisone plus 10% urea ('Alphaderm') and 0.1% betamethasone 17-valerate in the treatment of non-infective inflammatory dermatoses. A double-blind controlled trial was carried out over a period of 3 weeks to assess the effectiveness of 1% hydrocortisone, in a specialized carbamide drug delivery system, compared with 0.1% betamethasone 17-valerate cream in the treatment of 21 patients with bilateral, symmetrical, non-infective inflammatory dermatoses. The trial preparations were applied topically twice daily, each to one side only during the trial. Although overall patient preference tended to favour betamethasone 17-valerate, the physician's assessment of clinical improvement, based on severity rating scores, indicated that both preparations were equally effective and there were no significant differences between the calculated mean percentage clinical improvements at the end of each week.


Desoximetasone--a new topical corticosteroid: short- and long-term experiences. A new potent topical corticosteroid, desoximetasone, was clinically evaluated in several hundred patients with steroid-responsive dermatoses. Both short-term and long-term comparative studies showed desoximetasone emollient cream (0.25 percent) to be highly effective. Studies comparing betamethasone valerate cream C0. p1 percent) with desoximetasone emollient cream (0.25 percent) showed the new topical steroid to be clinically superior in the relief of moderate and severe inflammatory manifestations of psoriasis and atopic dermatitis. In addition, desoximetasone was found to be safe, well tolerated, and accepted by the patients.


Nuclear envelope transport capacity and the cell cycle in yeast (Saccharomyces cerevisiae). Changes in the nuclear envelope transport capacity, as measured by the number of nuclear pore complexes/unit nuclear volume/cell, were followed during the Saccharomyces cerevisiae cell cycle using data obtained by freeze-fracture electron microscopy. Pore number per unit nuclear volume decreased sharply in early G0, remained steady from mid-GO through S to G2, and showed a further slight decrease at M and G1. These periods of decline apparently resulted from nuclear enlargement without sufficient formation of new nuclear pore complexes to maintain the pore number to nuclear volume ratio. However, marked nuclear pore formation did accompany both increases in nuclear volume. The significance of these changes in relation to other events in the cell cycle is discussed. The validity of using nuclear pore number/unit nuclear volume and other pore number data as indices of nuclear envelope transport capacity and cell activity is critically examined.


Clinical comparison of fenoterol and albuterol administered by inhalation. A double-blind study. The effects of inhaling 0.4 mg of fenoterol hydrobromide (Berotec), 0.2 mg of albuterol (salbutamol), or placebo were compared in a double-blind three-way crossover study in a group of 12 asthmatic patients. After inhalation of fenoterol, the maximum increase in the forced expiratory volume in the first second (FEV1) was 0.76 L (48 percent) and in the peak expiratory flow (PEF) was 100 L/min (47 percent). The corresponding figures after inhalation of albuterol were 0.68 L (46 percent) and 98 L/min (48 percent), respectively. In comparison with administration of placebo, the FEV1 was significantly increased until six hours after inhalation of either drug. From three to six hours after inhalation, the effect of administration of fenoterol (as measured by FEV1 or PEF) significantly exceeded that of albuterol. Administration of either drug resulted in approximately equal bronchodilation (as measured by the increase in FEV1 or PEF), the effect of inhalation of fenoterol being of longer duration.


The validity of determinations of pulmonary wedge pressure during mechanical ventilation. Changes in the mean pulmonary wedge pressure were measured during temporary disconnection from a ventilator in 29 patients to assess the effects of therapy with controlled-volume ventilation on determinations of pulmonary wedge pressure. In 16 observations performed during therapy with intermittent positive-pressure ventilation, the mean value for the pulmonary wedge pressure was the same (10.3 mm Hg) with the patients connected to or disconnected from the ventilator. Thirteen of the patients were also maintained on therapy with positive end-expiratory pressure (PEEP); the mean (+/- SD) of 17 measurements of pulmonary wedge pressure did not show a significant variation on cessation of mechanical ventilation (12.5 +/- 6.7 mm Hg vs 11.7 +/- 6.9 mm Hg; P greater than 0.05). We conclude that pulmonary wedge pressure can be measured accurately at the end of exhalation during the administration of positive-pressure ventilation with 10 cm H2O of PEEP. The suggested practice of discontinuing mechanical ventilation in order to obtain a more exact measurement is not warranted.


Corticosteroids in chronic bronchitis and pulmonary emphysema. Chronic bronchitis and emphysema (chronic obstructive pulmonary disease [COPD]) represent a major health problem in this country. Corticosteroids have provided an important advance in the management of bronchial asthma, but the role of these drugs in the therapy for COPD has not been defined clearly. To gain further insight into this problem, an overview of the pharmacologic properties and mechanisms of action of corticosteroids on the cellular systems of the lung and a critical analysis of the 17 studies evaluating the efficacy of therapy with corticosteroids in COPD were done. There are several theoretic reasons why corticosteroids might be useful in treating COPD; however the majority of studies have not demonstrated a positive effect, yet individual patients have attained marked improvement. An objectively monitored, finite trial of therapy with corticosteroids in the patient with COPD who has worsening symptoms is warranted, as the benefit is high in responsive individuals and the risk is low in nonresponders.


Deposits of immunoglobulin and complement in the pulmonary tissue of patients with "heroin lung". Pulmonary tissues from six patients who died with a clinical diagnosis of "heroin lung" (heroin-induced pulmonary edema) were examined with the light microscope and electron microscope. Immunofluorescent microscopic analysis revealed multifocal granular alveolar septal deposits of IgM in all patients, C3 complement in five patients, IgG in four patients, fibrinogen in three patients, and IgA in two patients. IgM, IgG, IgA, and C3 complement were eluted from the lungs of these addicts with citrate buffer with a low pH. No deposition of albumin was found in any of the specimens. These findings are believed to represent the first report of immune complexes in the alveolar capillary membrane in patients with heroin-induced pulmonary edema. Electron-microscopic studies revealed a proteinaceous plasma-like fluid in the alveolar spaces, thereby confirming the heroin induced pulmonary edema. Mechanisms of transport of edematous fluids from alveolar capillaries to alveolar spaces in lungs from heroin addicts are considered.


Aerosol therapy with Sch 1000. Short-term mucociliary clearance in normal and bronchitic subjects and toxicology in normal subjects. The anticholinergic bronchodilator drug, Sch 1000, was administered as an aerosol by a metered-dose inhaler (200 microgram) to six normal and six bronchitic subjects. The short-term effect on mucociliary clearance was assessed and compared to a placebo (propellant and dispersal agent) in a double-blind crossover study. Mucociliary clearance in the normal group was significantly faster with administration of Sch 1000 than with placebo (P less than 0.01). There was no significant difference between the effects of administration of Sch 1000 and placebo on mucociliary clearance in the bronchitic group. Pulmonary function was significantly increased by therapy with Sch 1000 (as compared to administration of placebo) in the bronchitic group for two hours (P less than 0.05) and in the normal group for one hour (P less than 0.05). In another study, 12 normal subjects inhaled aerosols containing 40 microgram of placebo or 400 microgram of Sch 1000 from metered-dose inhalers on separate days in a randomized double-blind fashion. A significant sustained improvement in pulmonary function (P less than 0.05) and a transient fall in diastolic blood pressure were observed after administration of Sch 1000.


Symptomatic unilateral cannon "a" waves in a patient with a ventricular pacemaker. A 64-year-old woman was referred because of intermittent pulsations of the left side of the neck, face, and scalp that were first noticed after the insertion of a ventricular pacemaker. The pacemaker had been inserted because of symptomatic 2:1 atrioventricular block. Right cardiac catherization showed cannon "a" waves, and phlebographic studies revealed stenosis of the right innominate and internal jugular veins. The symptoms were abolished by conversion to an atrial synchronous pacing system. Comments are offered on the hemodynamic findings, the "pacemaking syndrome", and the use of atrial synchronous pacing.


Detoxification from methadone maintenance: double-blind comparison of two methods. A well-rehabilitated group of 22 methadone maintenance patients were detoxified under ambulatory and double-blind conditions, over 42 days, either by decreasing the daily dose of methadone and supplementing it by propoxyphene napsylate (M--PN), or by decreasing the daily dose of methadone administered in two equal doses given 12 hours apart (M--M). All of 12 (100%) M--M and 5 of 10 (50%) M--PN subjects were able to temporarily withdraw from methadone maintenance, although two of the M--PN patients required maintenance with propoxyphene napsylate to cease methadone maintenance. In our experience both detoxification methods employed appear superior to the standard withdrawal technique of simply reducing the daily methadone maintenance dose in a step-wise fashion.


Purification of the gonadotropin-releasing hormone-degrading enzyme by affinity chromatography. A crude preparation of Kallikrein inactivator, which inhibits the gonadotropin-releasing hormone (GnRH)-degrading enzyme(s) from rat hypothalamus and anterior pituitary, was fractionated by passage through an ion-exchange column. The enzyme-inhibiting fraction was coupled to Sepharose and the resin obtained was used for, affinity-chromatography purification of the GnRH-degrading enzyme. The enzyme from crude tissue preparations was retained on this column and eluted by 0.05 M phosphate buffer. A 9-12 fold increase in the specific activity of the enzyme was achieved. Bacitracin, an effective peptide inhibitor of the degradation of GnRH, was also coupled to Sepharose. Three different such Sepharose-bacitracin conjugates were synthesized, two of which inhibited the degradation of GnRH by hypothalamic and pituitary extracts. They all failed, however, to separate the active enzymic fraction from the bulk of accompanying proteins, using affinity chromatographic techniques.


Insulin and glucagon secretion and the insulin sensitivity of peripheric organs of colony-bred sand rats fed with pellet diet after weaning. Colony-bred sand rats were fed with rat pellet chow in restricted quantities or ad libitum for 8--10 or 28--31 weeks after weaning. The changes of glucose metabolism were characterized by an intraperitoneal glucose tolerance test. The daily food intake and the average weight gain differed only in the first 5--7 weeks of pellet nutrition. In the impaired glucose tolerance tests of all sand rats the high basal plasma IRI levels were not significantly increased by the grossly enhanced blood glucose concentrations. The insulin secretion of either acutely incubated or for 8 days cultivated isolated pancreatic islets, however, was stimulated already by low (1.7 and 5 mM) glucose concentrations in all diet groups. Otherwise the glucagon secretion of isolated islets was not suppressed by high glucose concentrations. No changes of insulin or glucagon contents of islets were found in the different diet groups. The adipocytes of all animals revealed a complete ineffectiveness of insulin on the glucose utilization to CO2 and triglycerides. The basal glucose conversion  to CO2 and glycogen in skeletal muscle and the stimulatory potency of insulin was low and not distinctly different in all groups. In liver glycogen and triglyceride contents as well as gluconeogenic enzyme activities were not influenced by feeding of different quantities of pellet diet at the investigated time points. The time course of the metabolic and clinical alterations demonstrates that the peripheral organs become insensitive to insulin in the first weeks after weaning.


Transitional steady-state investigations during aerobic-anaerobic transition of glucose utilization by Escherichia coli K-12. Transitional steady-state investigations during changes in oxygen tension under aerobic and during aerobic-anaerobic transition conditions were carried out with the aim of finding an indicator system which separates the equilibrium from the non-equilibrium state. Of the parameters used i.e. biomass formation, CO2 production, Q02, NADH oxidase, succinate dehydrogenase, phosphofructokinase, glyceraldehyde-3 phosphate dehydrogenase, 6-phosphogluconate dehydrogenase and 2-oxoglutarate dehydrogenase, only the three enzymes requiring NADH or NADP for their function fulfilled the requirements. Biomass production and CO2 formation were useful only during the aerobic-anaerobic transition period. In each case the response was immediate and the indicator systems demonstrated that a new steady state of oxygen was always obtained after 11 h which, at the specific growth rate used, was equivalent to at least two volume replacements of the growth vessel.


Bromocryptine in levodopa response-losing parkinsonism. A double blind study. 23 patients with advanced Parkinson's disease were allocated in a double-blind study of bromocryptine. These patients had an insufficient or deteriorating response to levodopa treatment. The dosages of levodopa were optimal and stabilized 3 months prior to and during this 5-month study. The addition  of bromocryptine in high doses (average daily dose 71 mg) induced a significant improvement in the total score of the Webster and the NUDS scales. The global assessment, both by the investigator and by the patients, also showed significant improvement. The efficacy of bromocryptine in these type of parkinsonian patients in a double-blind trial has not yet been established. The conclusion of this trial is that bromocryptine significantly increases the therapeutic effectiveness in these poorly levodopa responding parkinsonian patients.


Plasma kallikrein activity and prekallikrein levels during endotoxin shock in dogs. Endotoxin shock (ES) was induced in Labrador retriever dogs by infusion of a lethal dose of Escherichia coli endotoxin. Spontaneous plasma kallikrein activity and prekallikrein levels were determined during subsequent stages of the shock both by an esterolytic assay (BAEe) and a new amidolytic assay utilizing a chromogenic tripeptide derivative (Chromozym PK, Prntapharm AG, Basel Switzerland). During the late stages of shock characterized by a substantial decline of blood pressure, plasma prekallikrein levels determined by the amidolytic assay were considerably reduced. In this phase of the shock both the esterolytic and the amidolytic assays revealed a significant elevation of spontaneous activity. Plasma prekallikrein determined by the esterolytic assay was found to be elevated vs. control values for the whole duration of ES. The findings made seem to associate activation of the plasma kallikrein-kinin system to the circulatory collapse of endotoxin shock in dogs.


Antibody-coated bacteria and pregnancy.

Antibody-coated bacteria and pregnancy. A study is made of 158 pregnant patients, between 3 and 9 months pregnant, in order to determine, by means of urine culture and ACB, the index of subclinical infections during pregnancy involving the renal parenchyma. The conclusion is reached that these infections occur in 4.42% of cases and out of those cases 57.14% were later shown to have an organic pathology of the excretory tracts.


Graft rejection in earthworms: an electron microscopic study. Graft rejection in the earthworm, Lumbricus terrestris, is mediated by granulocytic coelomocytes (neutrophils, by light microscopy). Within 1--3 days post-transplantation of body-wall xenografts, granulocytic coelomocytes migrate to the transplant site, penetrate the graft matrix, and actively phagocytize viable muscle fibers. Destruction of muscle tissues may be augmented by lymphocytic coelomocytes (basophils, by light microscopy), but these cells participate in a minor way and do so very late in the rejection process (days 11--13). Xenografts, autografts and sham-operated controls display generalized inflammatory reactions, including coelomyocyte infiltration into the grafted tissues. In autografts, however, granulocytes only penetrate the inner longitudinal muscle layers and extensive infiltration, persistence and complete destruction never occur. Lymphocytic coelomocytes are not observed in autografts or sham-operated controls. Grafts rejection by leukocytes in an advanced invertebrate confirms that aspects of cell-mediated immunity evolved early in phylogenetic history.


Endotoxin-induced acceleration of ovum transport in rabbits. Salmonella enteritidis-Boivin endotoxin (1--20 microgram/kg) induced accelerated oviductal ovum transport in rabbits in a dose-related manner. Indomethacin prevented this effect. Levels of prostaglandin E and F in uterine vein blood increased following endotoxin injection.


Microtubules, interkinetic nuclear migration and neurulation. The hypotheses dealing with mechanisms of neurulation are reviewed briefly. The phenomenon of interkinetic nuclear migration is thought to be an important factor to be considered in the invagination of the neuroepithelium in the chick embryo. Evidence is presented that implicates cytoplasmic microtubules in this phenomenon. It is suggested that microtubules not only participate in cell elongation but also that they are involved, through interkinetic nuclear migration, in the broadening of the basal region of the cells; this widening progressively creates the strain that ensures the invagination of the neuroepithelium.


Immunofluorescence localization of thyroglobulin autoantibody producing cells in various organs of obese strain (OS) chickens. All major lymphoid organs from animals of the Obese strain (OS) of chickens which develop a spontaneous autoimmune thyroiditis with circulating thyroglobulin autoantibodies (Tg-AAb) were investigated for Tg-AAb producing cells using the immunofluorescence method (IF). No Tg-binding cells could be detected in spleen, bursa. Harderian glands, thymus, coecal tonsils or bone marrow. The infiltrated thyroid gland was shown to be the only site of Tg-AAb production detectable by IF.


Immunological enhancement of muscle allografts induced by serum from tolerant rats. Serum from tolerant animals induced immunological enhancement of muscle allografts. Serum from both animals bearing tolerated skin allografts and animals in which tolerance to skin grafts disappeared was effective. No significant differences between these two types of allografts were found with respect to contractile and histochemical behaviour. Serum from animals in which skin allografts survived transiently following non-specific treatment induced weak immunological enhancement. The changes in contractile and histochemical properties of muscle allografts serve as adequate parameters for assessment of the success of immunological enhancement.


[Effect of caerulein on pancreatic endocrine and exocrine secretion from the perfused rat pancreas (author's transl)]. Several investigations in vivo and in vitro have shown that gastro-intestinal hormones stimulate insulin secretion. However, the reports on the insulinotropic activity of pancreozymin are contradictory. The conflicting results are probably due to the fact that pure native preparation of this hormone has not been obtained in "physiologic" doses. In the present study this problem has been investigated by exposing rat pancreas to caerulein in vitro. Caerulein, an active decapeptide isolated from the skin of the Australian amphibia Hyla caerulea, resembles pancreozymin in chemical structure, including C-terminus. This active polypeptide of nonmammalian origin has been shown to possess all the biological activities of pancreozymin. The present investigation was undertaken to evaluate the significance of the interactions of exocrine and endocrine pancreas using perfused rat pancreas in vitro. Biphasic insulin release was demonstrated with caerulein at concentrations higher than 1 ng/ml. Insulin response of the first phase was proportional to the dose up to 1 microgram/ml. The second phase of insulin release was, however, almost constant, regardless of the concentrations of caerulein. Release of glucagon was stimulated by the same concentrations of caerulein which stimulated insulin release. Maximal response of the pancreatic amylase and pancretic juice output were observed with 1 ng/ml of caerulein. With higher doses, significantly less secretory responses were observed. The dissociation of the response to caerulein between endocrine and exocrine pancreas was found.


A controlled study of Trancopal in sleep disturbances due to rheumatic disease. A placebo controlled, double-blind study was carried out in six centres in general practice to assess the effectiveness of Trancopal in treating sleep disturbances due to rheumatic disorders. Eighty-five patients received a usual dose of two tablets of Trancopal or matching placebo at night for two weeks. Patients were assessed weekly and kept a daily record of the quality of sleep. All ratings showed that patients slept significantly better on Trancopal than on placebo. Day-time rheumatic stiffness however was not significantly reduced. Six patients receiving Trancopal reported side-effects chiefly drowsiness (five patients) which was controlled by dose reduction. It was concluded that for rheumatic patients Trancopal offers an acceptable alternative to current hypnotics over which it may prove to have some advantages, particularly for the elderly.


A controlled study of Trancopal in the treatment of sleep disturbances due to anxiety. Sixty-eight patients presenting with sleep disturbances due to mild neurotic anxiety were treated for two weeks with a single night-time dose of 400 mg trancopal or matching placebo under double-blind conditions. Patients kept a daily record of the quality of their sleep and the observer carried out a weekly rating of anxiety using a modified Hamilton scale. By Day 7 patients receiving Trancopal had a significantly better rating for sleep and mean Hamilton scores for day-time anxiety than the placebo group. Side-effects were minimal. It was concluded that for patients with sleep disturbances due to neurotic anxiety Trancopal is a well tolerated and effective alternative to the hypnotics.


A comparison of the relative efficacy of Serenace and chlorpromazine in the treatment of chronic schizophrenics. A study designed to assess the relative efficacy of chlorpromazine and Serenace in the control of chronic schizophrenics is described. Twenty-five cases were selected for the study and were randomly allocated to treatment. The condition of the patients was assessed at fortnightly intervals over the eight-week duration of trial period. No significant differences in side-effects emerged in patients on chlorpromazine and Serenace in the dosages administered. The statistically significant trends all showed a superiority of Serenace above chlorpromazine which was in accord with the clinical picture.


Randomized controlled trial of Syn-Ergel and an active placebo in the treatment of heartburn of pregnancy. A randomized controlled trial was performed to study the efficacy of Syn-Ergel with an active placebo in the treatment of heartburn of pregnancy in ninety-two patients completing 7 days of therapy. Syn-Ergel was significantly better (p less than 0.001) in all groups of pre-treatment pain severity in relieving the symptoms, and had a longer duration of action, than the active placebo. Complete relief of pain was achieved in 79.5% of Syn-Ergel treatments with a further 10% of treatments resulting in marked easing of discomfort at 1 hour following administration. The corresponding figures for the 'active placebo' were 56% and 20%. The combination of an antacid and a protective mucosal coating agent would appear to be a useful approach in the treatment of heartburn of pregnacy.


A comparison of naproxen, indomethacin and acetylsalicylic acid in pain after varicose vein surgery. Oral naproxen in doses of 500 mg and 750 mg daily was compared with oral indomethacin, 75 mg daily, in a double-blind, completely randomized study of patients with post-operative pain after out-patients varicose vein surgery. Altogether, 120 patients were studied. In the study 750 mg naproxen proved to be equal in respect of analgesic efficacy to 75 mg indomethacin, and it was clearly superior to 1500 mg acetylsalicylic acid. Naproxen, 500 to 750 mg daily, afforded adequate post-operative analgesia in 98% of patients. The side-effects were mild. On the basis of the study, naproxen can be recommended as a pain-relieving drug after minor surgery, particularly when an antiphlogistic effect is also desirable.


A trial of trimebutine in spastic colon. In a double-blind crossover trial of three days duration on each drug, trimebutine in a dose of 200 mg three times daily was significantly more effective than placebo in relieving the symptoms of mild to moderate degrees of spastic colon (p less than 0.001). The only side-effect necessitating discontinuation of treatment was one case of vomiting.


Enhancement of the antibody response in vitro by BCG. The addition of heat-killed BCG to mouse spleen cells in Marbrook cultures causes an enhanced in vitro antibody response against sheep red blood cells, the extent depending on BCG concentration and on whether the spleen cells have been previously primed with BCG in vivo. Moreover, a factor is produced by spleen cells incubated in vitro with BCG which enhances the antibody response of spleen cells from normal untreated mice, the extent of enhancement again depending on BCG concentration and the origin of the spleen cells producing the factor. Filtration through a 0.22 mu filter removes the enhancing activity of the bacteria but not of the factor produced by spleen cultures in the presence of the bacteria. The cellular basis of the enhancement of the antibody response will be discussed.


Effects of drugs on immune responsiveness in rabbits. The effects of chemotherapeutica: 6 mercaptopurine (6 MP), nitrogen mustard (HN2) and cyclophosphamide (Cy) on T and B cells were studied in standardized experimental systems. From the histological and immunological results it was concluded that: (a) A course of 9 daily 6 MP injections affected antibody production only when given after antigenic stimulation. Histologically figures of mitotic death were found among proliferating cells of plasmacellular-germinal centre-and specific cellular reactions. It was concluded that a net mitotic death of 50% would account for the observed immunological and histological effects; (b) HN2 and Cy affected antibody production itself when administered during a very restricted period (1 through 3 days after ag.). Histologically only morphological changes were found in differentiating immature plasmacells and interphase death of cells involved in germinal centre reactions. Loss of responsiveness depended on the degree of interphase death of follicular elements. Cy interfered with the formation of T helper cells in thymus-dependent antibody production; (c) L-Asparaginase (1,000 U) only prevented the origination of T-helper cells. Neither antibody-producing cells nor their precursors were affected.


Host responses in adjuvant contact suppression of experimental rat tumours. BCG (Glaxo) and C. parvum (Wellcome CN 6134) have been examined for suppression of growth of a range of syngeneically transplanted rat tumours, both carcinogen-induced and of spontaneous origin. Treatment by locally applied adjuvant controlled growth of both immunogenic and non-immunogenic tumours, and the response to highly immunogenic tumours was not abolished by host immunosuppression with whole body irradiation known to abrogate induction of tumour-specific immunity. In addition, rat tumour xenografts in congenitally athymic mice were suppressed by admixture with BCG or C. parvum. In contrast to these findings in immunoincompetent animals, host phagocytic cell depletion, by systemic administration of silica, a known macrophage poison, abrogated adjuvant contact suppression of tumours in syngeneic rats and athymic mice. These findings suggest that tumour suppression by regionally applied adjuvants may be more dependent upon local activation of host macrophages than upon generalized stimulation of lymphocyte mediated responses. This is further supported by the market correlation, within a range of tumours, between susceptibility to regionally applied BCG and normal levels of host macrophage infiltration, and in addition the facilitation of tumour suppression achieved by macrophage enrichment of tumour cell: BCG inocula.


Unanticipated effect of BCG in mice treated by radiotherapy. Female C57 Bl/6 mice (6-8 weeks old) bearing the Lewis or the MBL-2 tumor received a localized irradiation (1,600 Rads; Cobalt 60) three days after the tumor implantation. We compared the association of irradiation and Immuno-BCG-F (1 mg/mice i.v.) with three control groups (no treatment, irradiation alone, Immuno-BCG-F alone). The timing and number of BCG injections varied in the different sub-groups. Results were improved in the Lewis tumor system when BCG was injected just after the end of the irradiation. Efficiency improved with the number of injections (P less than 0.05). In the MBL-2 system, depending on the timing of BCG injections we observed significant survival prolongation (irradiation + BCG) as compared to control groups. It has to be noted that the use of BCG alone enhanced tumor growth in two models.


Various modalities of local administration of bacterial immunostimulants in transplantable rat tumours and in primitive methylcholanthrene mouse tumours. The frequent use of intra-lesional injection of bacterial immunostimulants is hampered by apparent rarity of susceptible tumours, absence of therapeutic effect on large tumours, lack of variety of experimental models, eventual traumatism which is feared in case of intra-lesional, and injection in visceral cancers. (1) Methylcholanthrene induced primitive tumours in mice are more frequently susceptible when the carcinogen induction dosage is low (0.01 mg). (2) Using transplantable rat tumours, one susceptible and one resistant to intra-tumoral BCG or Corynebacterium parvum therapy, we have shown that both are resistant to systemic administration of immunostimulants. For the susceptible tumour, subcutaneous peritumoral multiple injections have the same efficacy as intra-tumoral injection in curing small tumours and ipsilateral distant tumours, when the rats receive a double graft of the same tumour. Superficial multifocal intratumoral injections can cure more voluminous susceptible tumours. The association of peritumoral and intra-tumoral injections rendered susceptible the usually resistant tumours.


A phase I study of a multi-modal schedule with Corynebacterium parvum. A Phase I study of an immuno-chemotherapy regime was carried out using C. parvum as an immune-modulator. 14 women were studied. All received doses of C. parvum ranging from 2.5 mg to 21 mg administered in 1 litre of dextrose saline over 4 h. No evidence of tumour enhancement was observed.


Monitoring of a multi-modal schedule for the treatment of disseminated breast cancer. 39 women and 1 man have been monitored by sequential CEA, immunoglobulin, lymphocyte and monocyte readings, hydroxyproline excretion, scans and x-rays. CEA is shown to be a useful monitor of disease. The significance of the lymphocyte counts is discussed.


Clinical trial with Corynebacterium parvum. Corynebacterium parvum was administered to sixteen patients with malignant tumors submitted to repeated chemotherapy courses. A total of 428 injections of C. parvum at a dose of 3.5 mg/m2 in weekly, biweekly and monthly administration was given between the chemotherapy courses. Injection of C. parvum was followed by fever and local pain in 15/16 patients. Three patients presented a local ulceration during the initial period of weekly injections. Splenomegaly was observed after the second month of treatment, peripheral and bone-marrow monocytic infiltration after the second month. The decreased lymphocyte stimulation by PHA observed during the first two months was followed by an increased response. Cutaneous reactions to three antigens increased progressively in most patients and negative pre-treatment tests became positive after treatment.


On the role of the proinsulin C-peptide. Intracellular cleavage of protein and polypeptide precursors is now recognized as a widely occurring biosynthetic mechanism. As this field has developed, proinsulin and its cleavage patterns and secretory products have served as useful models for investigations of other systems. A particularly relevant aspect of the proprotein concept is the simple mechanism it provides for the coördinate synthesis and discharge of related peptides from endocrine or other secretory cells. This report reviews briefly the role of the proinsulin C-peptide, first in terms of its special biosynthetic functions, which are unique to the assembly of the two-chain insulin structure, and then with regard to its more general implications for other biosynthetic and secretory systems.


Experience with BCG adjuvant immunotherapy in stage II malignant melanoma. 23 "high risk" melanoma patients treated with BCG-AIT are compared with a non-randomized control group of 35 Stage II melanoma patients receiving other treatment. The results are discussed. It has been noted that patients with weak initial BCG reactions survived longer than patients with strongly positive first BCG reactions. This observation could be interesting for the choice of immunotherapy.


Clinical studies with Corynebacterium parvum. In a pilot study twelve patients with malignant disease were treated with Corynebacterium parvum. The clinical results were encouraging. A prospective randomised controlled clinical trial of C. parvum therapy in the treatment of patients with carcinoma of the bronchus began in August 1976. 22 pateints have been admitted to the trial and 11 treated with C. parvum. Clinical progress is reported. Radiological, haematological, biochemical and immunological measurements have been made and these results are presented with emphasis on the immunological data. Marked elevation of C. parvum antibody titre occurs. Lymphocyte reactivity, assessed by responses to phytohaemagglutinin and poke-weed mitogen and by the formation of T and B-cell rosettes, was significantly depressed in all patients compared to healthy volunteers, but in patients receiving C. parvum there is a relative increase in B-lymphocyte activity. Mild platelet depression occurs. No alteration to complement activity has been detected.


Randomized trial of chemoimmunotherapy for resectable and non-resectable gastrointestinal cancer. Two trials were carried out in order to compare, in two similar groups of patients, the efficacity of 5-fluorouracil (5FU) with or without BCG. The first trial comprised 159 patients with different forms of carcinoma. The differences in survival rate between the 77 patients treated with 5FU and the 82 patients who had received 5FU and BCG seem to be in favour of the combined treatment, but are not statistically significant. The second trial (20 cases treated with 5FU and 23 cases treated with 5FU and BCG) concerned patients with Dukes' Stage B and C colorectal cancer; the results of the combined treatment are clearly more favourable.


Residual beta-cell function and its metabolic consequences. Improvement in the sensitivity and specificity of the C-peptide immunoassay and studies of larger groups of patients have increased our knowledge of the importance of residual beta-cell function and its metabolic consequences in insulin-treated diabetic patients. During the first five to 10 years after the onset of diabetes mellitus residual beta-cell function is demonstrable in the majority of insulin-treated patients irrespective of the severity of the initial symptoms and only partly dependent on the patient's age at diagnosis. Residual beta-cell function facilitates good control. Stable patients have a higher C-peptide concentration in plasma than unstable ones, but unmeasurable C-peptide is not always associated with poor control. More data are needed before the full significance of an even minimal reserve of beta-cell function is elucidated. It also remains to be shown whether the reductive in beta-cell function in diabetic patients has a qualitative as well as quantitative component.


Randomized trial in advanced breast cancer using combination chemotherapy with or without C. parvum; preliminary results. In a prospectively randomized cooperative study patients with metastatic breast cancer were treated with or without Corynebacterium parvum (C.p.)5 mg/sc/m2 on day 1 in addition to CAO/CMF (Cyclophosphamid (C) 150 mg/m2/d per os X 5 d and Adriamycine (A) 50 mg/m2 i.v. d 1 and Oncovin (O) 1.0 mg/m2 i.v. d 1. 6 CAO-cycles q 28 days later were followed by monthly CMF cycles q 28 d with Cyclophosphamide (same dose), Methotrexate 30 mg/m2 i.v. 1 and 5-fluorouracil 600 mg/m2 i.v. d 1). 76 patients entered the study until January 1, 1977. The patients' characteristics (age, cytostatic pretreatment, tumor free interval, metastatic sites and mean doses of CA) were well balanced in the two groups. The lowest values of WBC and platelets on d 14 of the monthly CAO-cycles show a mean nadir of 1,630/mm2 and 122'850/mm3 respectively in the C.p.-group and of 1,890/mm2 and 141'760/mm3 in the group without C.p. GI-toxicity was seen more frequently in the C.p. group. An improvement of symptoms was observed in 88% of the C.p.-CAO/CMF treated group and in 77% of the group without C.p. Complete and good partial remissions (greater than 50% tumor size reduction) were seen in 53% of the CAO-C.p. treated patients and in 34% of the patients in the control group without C.p. Survival data presently show a trend of improvement by the addition of C.p. to the CAO-CMF-chemotherapy regimen.


beta-cell function in children with diabetes. Although it is generally believed that insulin secretion is minimal or absent in juvenile-onset diabetes, we have found appreciable levels of C-peptide at the time of onset in 12 patients, 4 to 16 years old (9.3 +/- 4.2). Ten of them had ketonuria but none severe ketoacidosis. All entered a remission period. Most of the patients had near normal C-peptide levels during the remission, and their beta cells had the capacity to respond to a breakfast stimulation with increased insulin secretion. C-peptide and proinsulin were also determined in 98 juvenile diabetics with age at onset of 1 to 16 years (6.8 +/- 3.9) and a duration of diabetes between two and 17 years (6.7 +/- 3.4). Many were found to have persisting beta-cell function, which seems to be of importance for ensuring stability in metabolic control. Although little is known about factors that may slow or reverse the process leading to beta-cell failure, our results suggest that early detection and intensive treatment of diabetes before severe metabolic disturbances have occurred may help preserve beta-cell function.


Clinical experience in the use of C. parvum in the treatment of locally advanced carcinoma of the breast. Twenty-one patients with locally advanced breast cancer which had failed to respond to conventional therapy have been treated by infusion of C. parvum (strain CN 6134, Wellcome Research Laboratories) in 5% Dextrose. Thirteen patients had a single dose of 15 mg. C. parvum over 4 h and 8 patients received 5 daily infusions of 4 mg C. parvum over 1 h. In 3 patients there was some evidence of tumour regression. Pyrexia, often associated with rigors, headaches, vomiting and variations in blood pressure occurred in most patients receiving either schedule, although the severity of the side effects decreased daily in those receiving 5 treatments. One patient became comatose within 24 h of treatment and died two weeks later. Progressive swelling of the arm on the side of the tumour and inflammation of the primary lesion were prominent in those receiving 5 daily treatments. These results show that caution must be exercised in the clinical use of C. parvum and the search for an ideal schedule should continue.