Membrane asymmetry and enhanced ultrastructural detail of sarcoplasmic reticulum revealed with use of tannic acid. Fixation of purified sarcoplasmic reticulum (SR) membrane vesicles, using glutaraldehyde supplemented with 1% tannic acid, reveals newly visualized ultrastructure in thin sections. The trilaminar appearance of the membrane is highly asymmetric; the outer electron-opaque layer is appreciably wider (70 A) than the inner layer (20 A). The asymmetry is not referable to lack of penetration of the tannic acid since: (a) SR vesicles made permeable with 1 mM EDTA, pH 8.5, show similar asymmetry; (b) treatment of SR with trypsin results in progressive loss in protein content and decrease in the thickness of the outer layer, until in the limit the trilayer has a symmetric appearance; (c) within the same muscle section, the SR membrane appears highly asymmetric whereas the sarcolemma has a more symmetric appearance; (d) reconstituted SR vesicles have a symmetric appearance with equally broad inner and outer layers (approximately 70 A); the symmetric structure is confirmed by freeze-fracture and negative staining electron microscopy. Heavy and light SR vesicles obtained by isopycnic density sedimentation of purified SR have the same asymmetric appearance of the membrane and seem to differ mainly in that the heavy vesicles contain internal contents consisting largely of Ca++-binding protein. The asymmetry of the SR membrane is referable mainly to the unidirectional alignment of the Ca++ pump protein, the major component (90% of the protein) of the membrane. The asymmetry of the SR membrane can be visualized now for the first time in situ in thin sections of muscle.


Intermediate filaments in nervous tissues. Intermediate filaments have been isolated from rabbit intradural spinal nerve roots by the axonal flotation method. This method was modified to avoid exposure of axons to low ionic strength medium. The purified filaments are morphologically 75-80 percent pure. The gel electrophoretogram shows four major bands migrating at 200,000, 145,000, 68,000, and 60,000 daltons, respectively. A similar preparation from rabbit brain shows four major polypeptides with mol wt of 200,000 145,000, 68,000, and 51,000 daltons. These results indicate that the neurofilament is composed of a triplet of polypepetides with mol wt of 200,000, 145,000, and 68,000 daltons. The 51,000-dalton band that appears in brain filament preparations as the major polypeptide seems to be of glial origin. The significance of the 60,000- dalton band in the nerve root filament preparation is unclear at this time. Antibodies raised against two of the triplet proteins isolated from calf brain localize by immunofluorescence to neurons in central and peripheral nerve. On the other hand, an antibody to the 51,000-dalton polypeptide gives only glial staining in the brain, and very weak peripheral nerve staining. Prolonged exposure of axons to low ionic strength medium solubilizes almost all of the triplet polypeptides, leaving behind only the 51,000- dalton component. This would indicate that the neurofilament is soluble at low ionic strength, whereas the glial filament is not. These results indicate that neurofilaments and glial filaments are composed of different polypeptides and have different solubility characteristics.


Effect of dibutyryl cyclic AMP on leucine incorporation in L5178Y cells. II. Effect of actinomycin and heat shock. 3H-leucine incorporation was assayed in L5178Y cells as a measure for protein synthesis. Protein synthesis was inhibited by short duration heat shock, actinomycin, cordycepin or a combination of these agents. Dibutyryl cyclic AMP had little or no effect upon protein synthesis in control cells. Dibutyryl cyclic AMP, however, stimulated protein synthesis in cells previously heat shocked and/or inhibited by actinomycin or cordycepin. The results have been interpreted to indicate that the cyclic nucleotide stimulated protein synthesis by influencing the metabolism of some species of RNA which may regulate translation.


Plasminogen activator synthesis by cultured human embryonic lung cells: characterization of the suppressive effect of corticosteroids. The synthesis of plasminogen activator (PA) by cultured human embryonic lung (HuEL) cells has been examined. The production of PA by these cells was found to be reversibly inhibited by physiological levels of glucocorticoids. The suppression of PA synthesis in HuEL cells was not accompanied by an inhibition of cell growth. Moreover, the glucocorticoid induced deinduction of plasminogen activator synthesis occurred in both growing and non-growing cells. The inhibition of PA production by corticosteroids appeared to have a requirement for DNA-dependent RNA synthesis since the inhibition of DNA-dependent RNA synthesis at the time of exposure of cells to corticosteroids prevented the deinduction of PA.


RNA synthesis by nuclei and nucleoli from ischemic liver cells. Nuclei and nucleoli were isolated from rat livers subjected to an interruption of the blood supply for periods of different duration, as well as after restoration of the blood supply. They were assayed for RNA synthesis under conditions of diverse ionic strengths, and in the presence of an exogenous template, such as poly d (A-T), and actinomycin to inactivate the endogenous template; alpha-amanitin was made used of to distinguish polymerase I and polymerase II dependent RNA synthesis. Nuclei and nucleoli from ischemic livers showed a severe impairment of RNA synthesis, which is likely to be due to decreased initiation frequency of the engaged polymerases, while free polymerases were essentially unchanged. Both form I and II polymerase were equally involved. After restoration of the blood supply RNA synthesis recovered with an overshooting well above normal levels of activity, lasting for at least 24 hours. Increased RNA synthesis was not followed by thymidine incorporation into DNA.


Immune response in urinary tract infection determined by radioimmunoassay and immunofluorescence: serum antibody levels against infecting bacterium and Enterobacteriaceae common antigen. A solid-phase radioimmunoassay (RIA) procedure was compared with the indirect fluorescent antibody (IFA) test in a serological study of 76 female adults with urinary tract infections. Relative serum antibody activity was determined against patients' homologous infecting enterobacteria by RIA and IFA and against heterologous enterobacterial common antigen (Escherichia coli O14) by RIA. There was marked correlation between results of the IFA and RIA methods using the homologous system; 22 of 51 patients (43%) with pyelonephritis had significantly elevated serum antibody activity by both IFA (titers greater than or equal to 512) and RIA (binding ratio greater than or equal to 2.0) when compared with normal serum controls; three had significant antibody activity detectable by RIA only. Eighteen (72%) of 25 patients with pyelonephritis had RIA binding ratios of greater than or equal to 2.0 against their homologous bacterial isolates and the enterobacterial common antigen; an additional 6 patients had binding ratios of greater than or equal to 2.0 against the antigen only. All 25 patients with cystitis had low serum antibody levels by IFA and RIA when tested against their own isolate as well as enterobacterial common antigen. The RIA procedure was objective, quantitative, and less tedious to perform than IFA.


Broadly reacting precipitating and agglutinating antigen of leptospirae. A saprophytic Leptospira biflexa strain of equine origin was found which cross-reacts with immune rabbit antisera to 14 pathogenic Leptospira interrogans serotypes. Sera from goats experimentally inoculated with the saprophyte showed multiple low-level cross-agglutination reactions against a battery of live L. interrogans serotypes. Sonically treated and saline-extracted suspensions of the L. biflexa strain and serotypes canicola, icterohaemorrhagiae, and pomona yielded a common precipitating protein antigen that was detected by immunodiffusion and immunoelectrophoresis with all of the antileptospiral sera examined. In cross-absorption and gel diffusion tests, the precipitinogen from each of the strains was shown to be identical. Formaldehyde treatments and heating at 100 degree C suggest that the cellular location of the common antigen is either somatic or subsurface, and Sephadex G-200 gel filtration enabled the isolation of the active fraction of the L. biflexa antigen. Monoprecipitin sera against the common antigen of L. biflexa were produced by immunizing rabbits with specific precipitates in agar. In gel diffusion and immunoelectrophoresis tests the antisera with each of the soluble antigens developed a single precipitin formation, and the antisera agglutinated formolized and heated whole-cell suspensions of serotypes canicola, icterohaemorrhagiae, and pomona at low dilutions. The soluble L. biflexa antigen was evaluated as an immunogen and in passive immunity tests for protection against death and kidney infection in hamsters. No cross-protection occurred when the hamsters were challenged with virulent leptospires. In contrast, the animals vaccinated or administered hamster immune serum before challenge died earlier than the control animals.


Improvement in vowel articulation of deaf children. Three deaf adolescents who had poorly developed skills in oral communication were given specialized instruction designed to improve their ability to articulate vowels. This instruction was given for 1 hour weekly over a 5-month period, and it led to an improvement in vowel articulation that was substantial enough to be measured acoustically. The instruction emphasized articulatory relations between vowel sounds that are particularly difficult for the deaf to perceive visually or vibrotactually. The formant frequencies of five vowels were measured spectrographically before and after training. The measurements showed that all three children improved in their ability to articulate vowels as indicated by an increased frequency range of the second formant, a reduced amount of overlap in the frequency plots of adjacent vowels, and in more appropriate formant frequency values for individual vowels.


Combined methenamine-silver nitrate and hematoxylin & eosin stain for fungi in tissues. Initial examination of hematoxylin & eosin-stained tissue from a human brain specimen did not reveal the fungi which were seen in subsequent tissue sections stained with methenamine-silver nitrate. Microabscesses seen in the hematoxylin & eosin-stained sections were not apparent in the methenamine--silver nitrate-stained tissue. Staining with methenamine--silver nitrate and counterstaining with hematoxylin & eosin proved excellent not only for detecting fungus cells, but also for revealing their relationship to the host cellular response in this case and in examples of experimental murine coccidioidomycosis and histoplasmosis.


Transfer of contact sensitivity to beryllium using dialyzable leukocyte extracts (transfer factor). Transfer factor derived from lymphocytes of donors with strong cellular immunity against beryllium was intradermally or subcutaneously injected into unprimed or subclinically primed human recipients who were patch test-negative. These recipients were challenged with beryllium at weekly intervals thereafter. Subjects who had been subclinically primed and received transfer factor either intradermally or subcutaneously showed transient patch test reactivity to the challenge. Subjects who received transfer factor but were not primed and subjects who had been primed but did not receive transfer factor showed no such conversion. This is the first demonstration of transfer of contact sensitivity in man using transfer factor, and it suggests that subclinical priming is necessary for such transfers.


Cockroach cause of allergic asthma. Its specificity and immunologic profile. To assess the etiologic role of cockroach antigen in bronchial asthma, 46 asthmatic subjects were studied using in vitro assays for total and cockroach-specific IgE antibodies (IgEcr) and the responsiveness of the skin and bronchial tree to the antigen challenge in vivo. Asthmatic subjects were divided into skin test-positive (PCR) and skin test-negative (NCR) groups according to immediate skin response to cockroach antigen. The 28 in the PCR group showed high total IgE (1,901 ng/ml) and a high cockroach-specific IgE antibody level (329%) in the serum compared to the 10 in the NCR group (IgE: 915 ng/ml, IgEcr:84%) (p less than 0.001). Bronchial challenge with the antigen revealed immediate asthmatic reaction (30/33) and late asthmatic reaction (16/33) in the PCR asthmatics, whereas the NCR asthmatics showed neither immediate asthmatic reaction (2/13 showed questionable decrease in FEV1) nor late asthmatic reaction (p less than 0.001). A marked increase in peripheral eosinophils (758% vs 121%) was noted following antigen inhalation in the skin test-positive asthmatics (p less than 0.025). The results indicate that cockroach antigen causes antigen-specific IgE-mediated bronchial asthma and peripheral eosinophilia in specifically sensitized asthmatic subjects.


Feulgen-DNA absorption spectrum of euchromatin and constitutive heterochromatin. When the heterochromatin and euchromatin of Triatoma infestans are maximally depurinated, their Feulgen-DNA spectral profiles exhibit a shoulder at about lambda = 530 nm. The shoulder is especially prominent in the curves of the heterochromatin. It is assumed that this pattern is related to richness in repetitive DNA in the heterochromatin, favoring appearance of Schiff reagent molecules di-substituted with adjacent apurinic acid aldehydes.


Atrial specific granules of the rat heart: light microscopic staining and histochemical reactions. An investigation was carried out to determine general staining and histochemical properties of rat atrial specific granules. It was found that these granules may be demonstrated using aldehyde fuchsin after pretreatments which involve oxidation or thiosulfation. This new way of demonstrating atrial granules is compared to other staining methods in terms of sensitivity and selectivity as well as to the nature of reactive groups that may be involved in the staining reactions. No lipid or carbohydrate were detected histochemically. Overall assessment of reactions suggests that atrial granules are a site of storage for a protein or polypeptide. Some of the tests indicate that these may contain tryptophan and sulfur-containing amino acids.


Immunochemical characterization and cellular localization of pepsinogens in cat and dog. The antigenic relationships and cellular localization of cat and dog pepsinogens were investigated by electrophoretic analysis, immunodiffusion, immunoelectrophoresis, immunoabsorption, and by immunofluorescence, respectively. Rabbit antiserum to human and hog group I (Pg I) and group II pepsinogens (Pg II) had been previously prepared. Electrophoretic analysis revealed at least eight distinct proteases in extracts of gastric and proximal duodenal mucosa, resistant to alkalinization but destroyed by sequential accidification and neutralization. Rabbit antiserum to Pg I (anti-Pg I) and Pg II (anti-Pg II) produced a single precipitin arc against each extract forming a line of nonidentity. Immunoelectrophoresis of extracts produced a single precipitin arc against anti-Pg I or anti-Pg II. The specificity of the antibodies for the group I or group II pepsinogens was confirmed by immunoabsorption. By immunofluorescnece, both Pg I and Pg II were present in mucous neck and chief cells in fundic mucosa, in the pyloric gland cells in antral mucosa, and Brunner's glands in the proximal duodenum. The results indicate that canine and feline pepsinogens are electrophoretically heterogenous, that canine and feline Pg I share antigenic determinants with each other but not with Pg II, that a similar positive relationship exists for Pg II, and that both Pg I and Pg II are localized to the peptic cell mass, consisting of four types of cells.


Priming potency of the products of individual regions of the H-2 complex and their role in the restimulation in secondary MLC. Genetic analysis of the determinants causing an early proliferation in MLC after priming with allogeneic cells in vivo was performed. The active determinants were localized in the I-A subregion of the H-2 complex by using appropriate recombinant mouse strains. Upon priming with antigens coded by the whole H-2 complex, the lymphocytes gave a strong MLC response only to the priming stimulator cells and cells sharing the I-A subregion determinants of the latter. The response to third party stimulator cells and cells not sharing I-A subregion determinants was low. Upon priming with various H-2 region products, only lymphocytes primed against I-A subregion products gave an early proliferative MLC response to the priming stimulator cells, whereas lymphocytes primed against other H-2 region products gave none.


Histocompatibility difference between C3HfeB/HeN and C3H/HeN mice: tumour induced in C3HfeB/HeN mice expresses C3H/HeN-associated alloantigen. A transplacentally induced lung tumour of C3HfeB/HeN mouse origin expresses, as a tumour-associated antigen, a normal tissue component of strain A mice. The genetic locus coding for this alloantigen has been shown to be linked to the H-2 major histocompatibility complex. In the present study we demonstrate that this antigen is also expressed on normal tissues of C3H/HeN mice. Skin grafts exchanged between C3HfeB/HeN and C3H/HeN mice are reciprocally rejected at approximately 3 weeks after grafting. C3HfeB/HeN mice were derived from C3H/HeN mice in 1945. These strains have apparently deviated since then in their genetic regulation of the expression of the MHC-linked genetic locus. The finding of the C3H/HeN-associated antigen on a C3HfeB/HeN mouse-derived lung tumour indicates that this deviation is reversible.


The influence of postoperative chemotherapy with bleomycin, methotrexate and vincristine on the outgrowth of nerve axons after microsurgical nerve reconstruction. An experimental study. Surgical therapy of epidermoid carcinoma of the maxillo-facial region often makes it necessary to sever important nerves (accessory, facial, mandibular). Microsurgical technique has made it possible to restore this damaged function by nerve transplantation. On the other hand, postoperative anticancer chemotherapy may inhibit axonal outgrowth after such transplantation procedure and thereby destroy the functional restoration. A single course of bleomycin, methotrexate and vincristine therapy in rats with previously created sciatic nerve anastomoses caused only a delay of axonal outgrowth in the case of vincristine therapy. The other two drugs showed no similar effect. From this it follows that postoperative chemotherapy does not definitely compromise the result of nerve restoration in connection with tumour resection.


Chemotherapy in the treatment of osteogenic sarcoma of the maxilla (case report). A case of osteogenic sarcoma of the maxilla is described. The tumor was excised by a hemimaxillectomy but recurred in 3 months. The patient died 8 months after the initial onset of symptoms. Chemotherapy and radiation were ineffective with the exception of bleomycin, which caused necrosis of the tumour, with no apparent increase in growth, and a decrease of the serum alkaline phosphatase level to less than half of the maximum value. There was a close correlation between the fluctuating pattern of the serum alkaline phosphatase level and the growth and remission of the tumour during the entire course of treatment.


Rapid determination of proteins in serum and cerebrospinal fluid by laser-nephelometry. The Laser-nephelometric technique is characterized by its easy handling, accuracy, good reproducibility and especially by the short time in which reliable results are available. A very good correlation was found between the results obtained by the electroimmunoassay and those obtained by Laser-nephelometry. In both techniques alpha2-macroglobulin is the largest serum protein that can be determined in normal unconcentrated cerebrospinal fluid (CSF). This is of diagnostic significance, since the serum/CSF ratios of both albumin and alpha2-macroglobulin are used as a parameter for the blood-CSF barrier condition.


Characterization of a retrovirus isolated from normal mink cells co-cultivated with a dog mammary tumour. A retrovirus antigenically distinct from known type C, B and D viruses was isolated from normal mink (Mustela vison) lung cells that had been co-cultivated with 5-iododeoxyuridine- and dexamethasone-treated dog mammary tumour cells. Cytogenetic studies of the virus-releasing co-culture showed mitotic figures identical to the normal mink cell line (MvlLu) with the exception of a low frequency of cells with extensive chromosomal breakage and uncoiling. The new virus bands at a buoyant density of 1.16 g/ml, contains 60S RNA and a reverse transcriptase which prefers Mn2+ over Mg2+ for the synthesis of DNA. This enzyme utilizes poly(rA).oligo(dT) more efficiently than poly(dA).oligo(dT) and is also able to synthesize DNA copies from the endogenous RNA. Morphologically, it is a typical type C virus. Filtered virus readily infects mink, dog and other mammalian cells indicating the amphotropic nature of its cell growth requirement. Hybridization studies showed that normal mink DNA contains multiple copies of proviral sequences of this newly isolated virus. Serological analyses indicate that the mink endogenous virus contains in its core protein, in addition to the interspecies type-C determinant, an antigenic component related to one of the determinants found in the feline leukaemia virus p30 protein. This determinant is not present in the Rauscher leukaemia virus, RD114 virus or simian sarcoma virus.


The tumor-producing effect of automobile exhaust condensate and fractions thereof. Part II: animal studies. The induction of squamous cell carcinomas and papillomas in a total of 1,950 mice in a lifelong skin-dropping experiment with different doses of automobile exhaust condensate and its fractions is described. Results of the dose-response studies reported indicate that local oncogenic activity of automobile condensate is contained primarily in its polycyclic aromatic hydrocarbon-fractions. In addition, findings in lung tumor incidences are given. Results of the sebaceous gland suppression screening test were found to be comparable to findings of the skin-dropping experiments.


The tumor-producing effect of automobile exhaust condensate and fractions thereof. Part III: mathematical-statistical evaluation of the test results. This paper deals with the mathematical-statistical evaluation of experiments devoted to the following problems: 1. To what extent is the carcinogenic potency of automobile exhaust gas condensate dependent on the dose? 2. What fractions (groups of substances) of the automobile exhaust gas condensate are mainly responsible for the carcinogenic potency? 3. To what extent can the potency be explained by fractions (or single substances)? In order to answer the above questions, the working group planned animal experiments (cf. Misfeld and Timm, 1973) and obtained, prepared, and fractionalized automobile exhaust gas condensate (Grimmer, 1978). The exhaust gas condensate and its fractions were dropped onto the skin of female CFLP mice (Brune et al., 1978). In view of the problems posed above, the aim of the mathematical-statistical evaluation was to establish the dose-response relations, to assess the combined effect, and to estimate the relative potency and the assumed potency. In particular, the hypothesis (basis for the separation process) that the potency of the entire exhaust gas condensate is mainly attributable to the fraction which contains the polycyclic aromatic hydrocarbons (nitromethane phase) was examined.


Circulating antibody to myelin basic protein in relapsing-remitting multiple sclerosis? A comparative group and sequential study by radioimmunoassay. Sera from multiple sclerosis patients with relapsing-remitting disease and normal subjects were tested for antibody to myelin basic protein by a sensitive radioimmunoassay. The results showed a marginally decreased titre in multiple sclerosis superimposed on a seasonal variation. There was no correlation with the clinical state of the patients. Results are discussed briefly in relation to humoral antibody function in multiple sclerosis and experimental autoimmune encephalitis.


CSF protein examinations with thin-layer isoelectric focusing in multiple sclerosis. Thin-layer IEF, due to its extremely high resolving capacity, has been found to be quite valuable for CSF protein examinations, one important advantage of the technique being its excellent capacity for separation of immunoglobulins. The CSF and serum proteins of 230 patients with clinically verified or probable MS and 20 subjects with optic neuritis were examined with thin-layer IEF and the findings were compared with clinical data and results of other CSF examinations. All but 3 of the MS patients and about two thirds of the subjects with optic neuritis inhibited one or combinations of different CSF protein aberrations in the acidic and alkaline range. Oligoclonal bands and/or regional increases of Ig fractions, changes compatible with intrathecal Ig synthesis, were detected in respectively 95 and 80% of patients with clinically verified and probable MS and 30% of subjects with optic neuritis. Other aberrant CSF protein fractions (including transferrin, the taufraction and gamma-trace protein) were found in about half of the cases; some of these fractions had the highest occurrence in patients with the most extensive Ig abnormalities. The diverse CSF protein aberrations seemed to be influenced by the duration and course of the disorder as well as the probable sites of lesions; further factors might be the release of decomposition products from destroyed tissues, the genetically determined reactivity of the individual and the presence of possible agents.


The effect of silicate cement on the mitochondria and lysosomes of cultured cells assessed by quantitative enzyme histochemistry. The cytotoxic effect of the silicate cement "Silicap" was evaluated in an in vitro system which simulates the clinical usage of the material. BHK-21 (C-13) cells on cover slips were exposed to the freshly mixed material for 1h, and stained for the demonstration of succinic dehydrogenase and acid phosphatase. The mean stain density for succinic dehydrogenase and acid phosphatase in the experimental cells was 77% and 153% of the control values respectively. The mechanism of cytotoxicity of "Silicap" is discussed.


Healing of periodontal flaps following use of MBR 4197 (flucrylate) in rhesus monkeys. A clinical and histological evaluation. Experimental periodontal surgery was performed on six adult Rhesus monkeys, using the modified Widman flap technique. Each monkey provided four or six segments for flap surgery, and three different experimental time intervals were used. Flaps were immobilized after surgery by conventional sutures or by application of MBR 4197 cyanoacrylate spray. Each animal provided its own contralateral comparison, and the mode of flap immobilization was reversed in the corresponding segments in the other animal of each experimental group. One monkey died approximately 12 hours after surgery, and the other animals were sacrificed at 14, 35 and 180 days. Histological sections were prepared from all operated areas, and examined for the pattern of healing. A special staining technique was used to determine the presence of MBR 4197 within the tissues.


Pharmacologic characterization of the antiallergic activity of SK&F 78729-A. SK&F 78729-A, one of a series of pyranenamine compounds, was studied in several laboratory models of immediate-type hypersensitivity reactions. In vivo, SK&F 78729-A, i.v./p.o., inhibited the antigen-induced rat 48-hr passive cutaneous anaphylaxis by a mechanism other than end-organ antagonism to either histamine or serotonin. In vitro, the compound produced a concentration-related inhibition of the immunologic release of histamine and slow-reacting substance of anaphylaxis from passively sensitized fragmented rhesus monkey and canine lung, and modest inhibition of histamine release from passively sensitized fragmented rhesus monkey skin. Similarly, SK&F 78729-A inhibited the antigen-induced release of histamine from passively sensitized fragmented rat lung. Under certain conditions, SK&F 78729-A inhibited antigen-induced pathophysiologic pulmonary responses in in vivo canine and rhesus monkey models of allergic asthma. The results of these studies suggest that clinically, SK&F 78729-A should exhibit a pharmacologic profile consistent with that of a prophylactic antiallergic agent.


Effectiveness of community preventive programs on improving oral health. Although sizable community efforts in the United States have been made to educate children and adults about periodontal disease and its control, valid inferences regarding their effectiveness cannot be made because, for the most part, invalid methods of evaluation have been used. Confusion about these methods may exist because there has been little conviction that the available methods of control will stop the progress of periodontal pathology. Many recommended oral hygiene practices are probably applicable only to certain motivated individuals. An effective, comprehensive community-program for the prevention of periodontal disease remains to be developed. It is unlikely that sufficient sums of money and personnel could be diverted from the budgets of lesser-developed countries to initiate mass oral hygiene programs. Therefore, it appears that, organized community efforts appear to be promising only for the control of dental caries. However, it must be remembered that community fluoridation may not be applicable in many countries. Therefore, new strategies and vehicles to bring fluorides to all segments of the world's population are needed.


Stimulation of urinary acidification by aldosterone and inhibitors of RNA and protein synthesis. Urinary acidification by the urinary bladder of the toad (Bufo marinus) was stimulated, relative to control, by the in vitro addition of aldosterone (10(-7) M), actinomycin D (20 microgram/ml), puromycin (80 microgram/ml) or cycloheximide (5 microgram/ml). The action of the inhibitors of RNA or protein synthesis was not additive with that of aldosterone. This is opposite to the situation with Na+ transport, where the stimulation by aldosterone is abolished by the same concentrations of these inhibitors. That all agents enhanced urinary acidification was verified by: (i) measurement of RSCC (reverse short-circuit current) in the absence of Na+ transport, (ii) inhibition of RSCC by acetazolamide, an inhibitor of carbonic anhydrase, and (iii) direct measurement of the pH change of the mucosal (urinary) fluid. As in the case of Na+ transport, spirolactone inhibited the action of aldosterone. Although not a unique model, the apparent paradoxical mimicry of aldosterone's stimulation of urinary acidification may be explained by a model which includes action of aldosterone and the inhibitors via their known effects on RNA and protein synthesis.


l/f noise in black lipid membranes induced by ionic channels formed by chemically dimerized gramicidin A. The noise behavior of lipid bilayer membranes, doped with a chemically dimerized gramicidin A, was investigated. In contrast to normal gramicidin A, which generates a Lorentzian type power spectrum due to the formation and disappearance of conducting dimers, the current power spectrum density Sm(f) obtained with this gramicidin A derivative showed over several orders of magnitude a clear l/f behavior. The intensity of this l/f component was analyzed as a function of the membrane-applied voltage, membrane resistance, electrolyte concentration, and composition. The relationship between the mean-square fluctuation in current and the membrane current mean value was found to follow Hooge's equation, i.e., deltaI2 = alphaI2m/Nf where N is the number of channels and alpha is a constant equal to 1.0 X 10(-2). It is suggested that a l/f type noise was observed because the chemically dimerized form of gramicidin A produces long lasting cation selective channels.


The role of radiotherapy in management of metastatic bone disease. Pain relief from bone metastases is achieved in 80 percent of patients by local irradiation. Response to local irradiation is much faster in metastases from breast and lung than in prostate bone metastases. Local irradiation is also very effective in preventing pathological fractures in lytic bone lesions, and healing of the pathological fractures by new bone formation.


Carcinogenicity of kepone.

Carcinogenicity of kepone. Five studies of the carcinogenicity of the chlorinated pesticide Kepone (chlordecone) in animals were reviewed. Examination of histological sections showed that Kepone is unmistakably carcinogenic in rats and mice. Kepone induced malignant tumors in the liver of rats and mice in the National Cancer Institute studies and in the liver in rats in the Medical College of Virginia study. Malignant tumors were also found in organs other than the liver rats, including those on the lowest dose, in both studies. Female rats given Kepone were more likely to develop malignant tumors than male rats. There also were toxic changes, particularly in male rats. These included interstitial fibrosis of the kidney; polyarteritis of the mesenteric, pancreatic, and other arteries; and atrophy of the testes. Such lesions generally interfere with the health of the rats and with the development of tumors. Atrophy of the testes also prevents reproduction.


The management of intractable pain in patients with advanced malignant disease. The Brompton mixture is a highly effective, flexible, safe and convenient means to control chronic pain of malignant disease. The mixture is a solution containing morphine, the dose of narcotic varying with the need for analgesia, and is given regularly, usually every 4 hours, with a phenothiazine. The main aims of therapy are prevention of pain rather than treatment, an unclouded sensorium and a normal effect. Terminally ill cancer patients were given the Brompton mixture and a phenothiazine in an attempt to control their pain. The mixture was administered to patients in 3 hospital environments: 1) a palliative care unit, 2) general wards and 3) private rooms. Pain was measured in 92 patients with the McGill-Melzack pain questionnaire. The Brompton mixture controlled pain in 90 per cent of patients in the palliative care unit and in 75 to 80 per cent of patients in the wards or private rooms. The differences in pain scores between patients in the palliative care unit and the other groups were significant. The mixture produced substantial decreases in the 3 major dimensions of pain: 1) sensory, 2) affective and 3) evaluative. Comparison of these results with data obtained in an outpatient pain clinic showed that the Brompton mixture was strikingly more effective than the traditional methods of managing cancer pain.


The pigtail ureteral stent in the cancer patient. Nephrostomy has been the standard procedure for urinary diversion when ureters are obstructed by cancer. However, recent reports have revealed significant problems related directly to the nephrostomy. The indwelling, internal ureteral stent eliminates many of these problems. We herein describe the course and survival of 20 patients in whom the pigtail ureteral stent was used to relieve ureteral obstruction caused by cancer. In these cases an over-all prolonged longevity, better quality of life and fewer complications have been noted when compared to cases of nephrostomy diversions.


The rationale of urinary diversion in cancer patients. A retrospective review of 218 consecutive nephrostomies done on uremic cancer patients has revealed an alarming incidence of postoperative morbidity and mortality. This review has raised legitimate questions regarding the value of palliative urinary diversion. We present a rationale to assist physicians in the management of this clinical problem.


Serum markers in testicular tumors.

Serum markers in testicular tumors. Certain cancer-associated substances are useful in the diagnosis and management of cancer. We have found that the estimation of serum alpha-fetoprotein and beta-human chorionic gonadotropin in patients with testicular tumors is useful. Of 17 patients with germ cell testicular tumors found to have elevated serum markers 3 had seminoma of the testis and all 3 had elevated beta-human chorionic gonadotropin. It is not possible, however, to correlate the histology of testicular tumors and the type of serum markers. All of our patients with elevated markers had active tumor. However, 3 patients with metastatic deposits in the para-aortic lymph nodes did not have elevated serum markers.


Assay of nuclear androgen receptor in human prostate. Nuclei were recovered from normal and hyperplastic human prostates and from well differentiated carcinoma using triton N-101 and discontinuous sucrose density gradient centrifugation. The nuclei were sonicated and dissolved in 2-([2-hydroxy-1,1-bis(hydroxymethyl)ehtyl]amino)ethane sulfonic acid buffer, pH 7.0, containing 0.6 M. sodium chloride. After incubation of the nuclear extract in the presence of 2 to 20 nM. 3H-dihydrotestosterone at 4C for 18 hours, an androgen receptor was isolated by Sephadex G-25/G-200 dual-column chromatography. The receptor demonstrated greater specificity for testosterone and dihydrotestosterone than for cortisol, progesterone and 17beta-estradiol. It was characterized by a sedimentation coefficient of 3 S and a Kd of 4.5 x 10(-9) M. The mean concentration of the nuclear androgen receptor, in terms of molecules per nucleus, was normal prostate-1,000, hyperplastic prostate-1,400 and well differentiated carcinoma-1,900. With this assay the problems associated with the measurement of a cytoplasmic androgen receptor can be avoided.


False-positive Gram-stained smears.

False-positive Gram-stained smears. The rate per 1,000 smears showing nonviable Gram-negative bacilli (false-positive smears) increased from a baseline of 10.8 to 38.5 following purchase of new culture-collection devices; the rate decreased to 8.0 following replacement of contaminated culture sets. False-positive reports led to changes in therapy for five patients. In addition to being sterile, commercial culture-collection devices should be certified by the manufacturer as being free of stainable microorganisms or as unsuitable for preparation of Gram-stained smears.


[Histological appearances of cancer of the head and neck treated with pepleomycin (NK 631) (author's transl)]. Clinical findings and histopathological appearances in the patients with cancer of the head and neck treated with a new anti-tumor agent, pepleomycin, are reported. The total dosage of the new drug was within 100 mg on the average; however, the responses to chemotherapy were considerably favorable in general. Pepleomycin was markedly effective in two patients, moderately effective in seven, and ineffective in one. Microscopic evidences of regression of cancer cells were demonstrated in six surgical materials. Pepleomycin was shown to have an even more selective action on squamous cell carcinoma than bleomycin. The reactions of the surrounding tissue and skin to combination therapy, including pepleomycin, remained comparable to those to bleomycin. Side effects of the drug were slight fever and transient anorexia. No fibrosis of the lung was seen during eight months of observation.


[Toxicological studies on pepleomycin sulfate (NK 631). I. Acute toxicity of pepleomycin in mice, rats and dogs (author's transl)]. Studies on acute toxicities of pepleomycin sulfate were carried out in both sexes of mice and rats, comparing with bleomycin, and male dogs. Pepleomycin was administered subcutaneously, intravenously and intraperitoneally in both sexes of mice and rats, and intravenously in male dogs respectively. Mice and rats, and intravenously in male dogs respectively. Mice and rats were observed respectively for 10 and 14 days after the administration. LD50 values were calculated by the method of Litchifield & Wilcoxon. LD50 values of pepleomycin were 4 approximately 6 times smaller than those of bleomycin in all routes of mice, but difference between them was not significant in all routes of rats. Additionally sex-difference of LD50 values was scacely recognized in all routes of both species. Toxicological findings observed in common to all routes of both species were ataxia, depression, tremor and epiphora, and only in all routes of mice, head-twitch, running-round and rolling were especially recognized as toxic behavior, which were not observed in bleomycin. Hepatic and renal lesions were recognized in biochemically and histopathologically in the survived rats. The dogs treated with pepleomycin 50 and 30 mg/kg had the decrease in food intake and the loss of body weight. They became moribund in 9 approximately 36 days after administration. In these dogs the lesions of liver and kidney were severely recognized in biochemical and histopathological findings. One of them which received 50 mg/kg recovered biochemically and histopathologically in 209 days after administration by the supplemental nutrition in early stage.


[Toxicological studies on pepleomycin sulfate (NK 631) II. Subacute toxicity of pepleomycin sulfate in rats (author's transl)]. Studies on subactute toxicity and its recovery of pepleomycin sulfate (NK631) were carried out in both sexes of rats. NK 631 was administered intraperitoneally in dose levels of 0.3, 0.9, 2.7. 8.1 and 24.3 mg/kg/day for 30 days. After finishing administration of NK 631 for 30 days, 5 animals of each group were proceeded to recovery test for 35 days. During the course of the experiment, the body weight gains were suppressed in all dose levels except in 0.3 mg/kg group of male rats. The deaths were found in the animals treated with doses over 24.3 mg/kg during treatment period and in those over 2.7 mg/kg during recovery period. In biochemical and urinary analysis, the increases of serum GPT, BUN, Mg, Ca and urine glucose were moderately recognized in 8.1 mg/kg group. Additionally, in macroscopical and histopathological findings, bone damage was found in the animals treated with doses over 2.7 mg/kg during treatment and recovery periods. From these results, the maximum safety dose of NK 631 in subacute toxicity using rats were estimated to be about 0.3 mg/kg.


[Toxicological studies on pepleomycin sulfate (NK631). III. Subacute toxicity of pepleomycin in dogs (author's transl)]. Subacute toxicity and its recovery of pepleomycin sulfate was studied in both sexes of beagle dogs. At dose levels of 2.4, 1.2 and 0.6 mg/kg, pepleomycin was administered intramuscularly to dogs for 30 successive days. Two dogs of the 1.2 mg/kg dose group were used for recovery test for 35 days. As general symptoms, the decrease of food intake, the loss of body weight, ulceration of foot pad, nail root necrosis and onychoptosic, ulcer of tongue and labia, and alopecia, dermatitis and necrosis at friction sites were observed the more severely in high dose groups, as those in bleomycin were. The death occurred in the 2.4 mg/kg dose group of both sexes. The lesions of liver and kidney were recognized in the 2.4 and 1.2 mg/kg dose groups of both sexes on biochemical, histopathological or urinary findings. Additionally slight fibrous change of lung was observed in all dose groups. Generally subacute toxicity of pepleomycin was revealed approximately in the same as or in a little stronger degree than that of bleomycin, and its recovery was hardly recognized during its period. The maximum safety dose in this studies is estimated to be between 0.3 and 0.6 mg/kg in dogs.


[Toxicological studies on pepleomycin sulfate (NK631), IV. Chronic toxicity of pepleomycin sulfate in rats (author's transl)]. Studies on chronic toxicity and its recovery of pepleomycin sulfate (NK 631) were carried out in both sexes of rats. NK 631 was administered intraperitoneally in dose levels of 0.15, 0.3, 0.6, 1.2 and 2.4 mg/kg/day for 180 days. After finishing administration of NK 631 for 180 days, animals of each group were proceeded for 35 days recovery test. During the course of the experiment, the body weight gains were suppressed in all dose levels except for 0.15 mg/kg group of female. The deaths were found in all dose levels except for 0.15 mg/kg level of male during treatment and recovery periods. In biochemical and urinary findings, the increase of serum BUN, Mg, inorganic P. and urine glucose were slightly recognized in the animals treated with doses over 0.6 mg/kg. Additionally, in macroscopical and histopathological findings, bone damage and renal lesions were found in the animals treated with doses over 0.6 mg/kg during treatment and recovery periods. From these results, the maximum safety dose of NK 631 in chronic toxicity study using rats were estimated to be at less than 0.15 mg/kg.


[Toxicological studies of pepleomycin sulfate. V. Short term intermittent toxicity in dogs (author's transl)]. The comparative studies in the short term intermittent toxicity of pepleomycin (NK631) and bleomycin (BLM) were performed on 10 beagle dogs of 13 approximately 15 months old. Two dogs per group were injected intravenously with NK631 and BLM in doses 5.0 and 2.5 mg/kg body weight every fourth day for 11 treatment. Two dogs served as control and were injected with saline solution. In the group of 5.0 mg/kg of NK631, one dog was sacrificed on day 37 of the treatment and another one dog died on day 33 of the treatment. All the dogs of other group survived until the end of the treatment. The toxicity to the hepatic and renal damage caused by NK631 was stronger than the BLM. On the contrary, the toxicity to lung and various mucocutaneous regions was weaker than the BLM. The grade of pulmonary fibrosis of NK631 was about 1/2 and 2/3 of the BLM in dose of 5 mg/kg and 2.5 mg/kg, respectively. Other toxicological changes such as anorexia and weight loss were almost similar to the BLM.


[Safety evaluation of NK 631. Antigenicity, effect on delated hypersensitivity, irritative effect on eye mucous membrane and mutangenicity of pepleomycin (NK 631) (author's transl)]. 1. Whether NK 631 is antigenic to guinea pigs and rabbits was studied by the methods of active and passive anaphylactic shock tests, Schultz-Dale reaction, passive cutaneous anaphylaxis, Ouchterlony, tanned red cell haemagglutination test and test according to the U.S. Appraisal of the Safety of Chemicals in Foods, Drugs and Cosmetics. However, none of the tests proved NK 631 to be antigenic. 2. The immunosuppressive effect of NK 631 was studied by delayed hypersensitivity to picryl chloride in normal and L-1210 tumor bearing mice. Therapeutic dosis of NK 631 was no immunosuppressed but toxic dosis of NK 631 was slightly decreased in ear thickness of delayed hypersensitivity. 3. The acute irritative effect of NK 631 and of bleomycin was studied by single instillation to the rabbit eye mucous membrane with 0.1 ml of either of 10, 33 and 100 mg/ml solution of the drugs in physiological saline. The irritative effect of NK 631 on the eye mucous membrane at each concentration was slightly severe than that of bleomycin at the same concentration. However, the manifestations were only mild to moderate dilatation of the conjunctival and nictating membrane blood vessels and eye mucous, and recovered or were mitigated 48 hours after the instillation. No severe changes such as corneal opacity, corneal desquamation, swelling and deaquamation of the conjunctival and nictating membrane were observed. The histopathological examination revealed no striking changes. 4. Mutagenicity of NK 631 and of bleomycin on Salmonella typhimurium strain TA 100 and TA 98 was studied. It was definitely shown that neither NK 631 nor bleomycin exerted any mutagenic action on either test strains.


[Studies on antitumor activities and pulmonary toxicity of pepleomycin sulfate (NK631) (author's transl)]. The antimicrobial and antitumor activities, and the pulmonary toxicity of pepleomycin (NK631) were studied in comparison with bleomycin (BLM). NK631 showed a broad antimicrobial spectrum against gram positive and gram negative bacteria equally to BLM, and its activity was about twice higher than BLM. NK631 showed higher activity on cultured HeLa S3 cells and higher antitumor effect on the transplanted tumors of Ehrlich solid carcinoma in mice, AH66 and AH66F ascites hepatoma in rats, and lower antitumor effect on Ehrlich ascites carcinoma in mice than BLM. Similarly to BLM, NK631 did not show satisfactory activity on L1210 leukemia in mice. NK631 showed marked effect on chemically induced squamous cell carcinoma, spontaneous lymph sarcoma of a dog, human and dog gastric cancer heterotransplanted in nude mice equally to BLM. Furthermore NK631 exhibited remarkably higher antitumor activity on lymph node metastasis of AH66 ascites hepatoma of rats and chemically induced gastric carcinoma of rats than BLM. Pulmonary toxicity of NK631 was low as 1/3 in incidence and 1/4 in grade of the BLM in old mice system. This trend was confirmed by chemical analysis of hydroxyproline in lung.


[Studies on organ distribution, absorption and excretion of pepleomycin sulfate (NK631) (author's transl)]. 1. Organ distribution of pepleomycin (NK631) in mice and rats was studied. NK631 was found at higher levels than bleomycin (BLM) in skin, lung, stomach, solid tumor, etc. in mice and rats. Furthermore NK631 was detected in the mesenteric and lumbar lymph node, esophagus and prostate in rats and also distributed at about twice as high levels as BLM in the AH109A hepatoma cell-metastasized lymph nodes. 2. For the elucidation of reason on low pulmonary toxicity of NK631 which is in spite of 1.5 times highly distribution in lung compared with BLM, inactivation of various BLMs by high molecular fraction of lung of mice and rats was determined. The order of inactivation rate of various BLMs in lung was as follows: BLM-M5196 greater than NK631 greater than BLM greater than BLM-HPE. There is an encouraging coincidence between index of pulmonary fibrosis in mice and inactivating rate in lung. 3. A comparative study on the serum level and urinary excretion of NK631 and BLM was performed in dogs. The blood level and urinary excretion rate of both drugs were almost similar. 4. The blood levels of NK631 were comparable to those of BLM in cancer patients.


[Absorption, excretion, distribution and metabolism of 3H-labelled pepleomycin sulfate (author's transl)]. Absorption, excretion, distribution and metabolism of pepleomycin sulfate (NK631) were investigated in rats after intravenous administration of 3H-NK631 by whole-body autoradiography, CM-Sephadex column chromatography and high performance liquid chromatography. The highest radioactivity was found in kidney, followed by cartilage, blood, lung, esophagus, adrenal gland and skin at 0.5 hour after the administration and little radioactivity was observed in central nerve system. The NK631 and deamide NK631 were identified as major (90%) and minor metabolites in the 24-hour urine.


[General pharmacological studies on pepleomycin sulfate (NK 631) (author's transl)]. Pharmacological actions of pepleomycin sulfate (NK 631) which is a new antitumor agent derived from bleomycin were studied and the following results were obtained. NK 631 had no significant influences on the central, motor and sensory nervous systems at relatively higher doses (5 approximately 10 mg/kg, i.v., i.p., s.c.). NK 631 (5 approximately 10 mg/kg, i.v.) caused a slight decrease in blood pressure in anesthetized rats and slight increases in blood pressure, heart rate and peripheral blood flow in anesthetized dogs. NK 631 (1 approximately 3 mg) given close-arterially caused a slight increase in the developing tension in the isolated blood-perfused papillary muscle. NK 631 slightly contracted the isolated guinea pig ileum and rat uterus but did not affect the contraction of isolated guinea pig trachea. NK 631 caused significant increases in urine output and Cl excretion in saline loaded rats at 20 mg/kg, i.p. By the local injection of NK 631, a slight edema of rat paw and an increase in rabbit cutaneous permeability were observed. The intraperitoneal injection of NK 631 caused a significant increase in leakage of dye injected intravenously into the peritoneal cavity of mice. NK 631 did not affect hemolysis and prothrombin time at 10(-4) g/ml. In pharmacological actions, significant differences between NK 631 and pepleomycin were not observed.


[Familial coincidence of hypertrophic cardiomyopathies and thyroxine-binding globulin deficiency (athyropexinemia) (author's transl)]. A twenty-five year old man was found to have simultaneous total deficiency of thyroxine-binding globulin ("thyropexin") and hereditary hypertrophic obstructive cardiomyopathy (HOCM). The thyroxine-binding capacity (RT3U), thyroid hormone levels, PB127I, PB131I and TBG (RIA) in serum were very low and TBG cap was zero. Trapping of radioiodine in the thyroid was enhanced. Clinically, the patient appeared euthyroid. The case seems to be similar to another one described earlier by Ingbar. An investigation of the family showed that in one uncle and two nephews of the patient thyropexin was absent whilst the mother, one sister and one female cousin had partial thyropexin deficiencies. One of these nephews also suffers from asymmetric septal hypertrophy (ASH), the mother of the propositus has a non-obstructive hypertrophic cardiomyopathy (HCM).


Influencing breastfeeding success.

Influencing breastfeeding success. Results of a study to evaluate factors that influence breastfeeding success, including teaching and nursing support, are reported. A slide-tape presentation was made to one group (experimental); the presentation plus nursing support was given to a second group (experimental); and a third group (control) received only routine hospital care. All subjects were then interviewed at 6 weeks postpartum. Of the control and first experimental groups, 50% were successful. Success increased to 80% in the second experimental group. The nursing support approach used with the second experimental group is described in detail in the latter half of the article.


Role of cyclic AMP in the regulation of renin release from the isolated perfused rat kidney. The role of cyclic AMP in the regulation of renin release (RR) was studied in isolated rat kidneys, which were perfused at constant pressure in a single-pass system with a modified Krebs-henseleit solution. Isoproterenol (IP) (2 x 10(-9) to 2 x 10(-6) M) and 3-isobutyl-1-methyl-xanthine (IBMX) (4 x 10(-7) to 7 x 10(-5) M) induced a dose-dependent increase of renal perfusate flow, glomerular filtration rate and urinary sodium excretion. RR was stimulated up to 10-fold above control values within 5 min. At the lowest concentrations IP stimulated RR, but did not affect renal haemodynamics. When IP and IBMX were administered concomitantly, a supraadditive stimulation of RR was observed. Dibutyryl-cAMP (db-cAMP) and 8-Br-cGMP (10(-6) to 10(-4) M) produced a similar dose-dependent vasodilation and natriuresis, but differed in their action on RR. Within 15 min after the start of the infusion, db-cAMP increased RR up to 4-fold, whereas 8-Br-cGMP was without an effect. These results suggest that IP, IBMX and db-cAMP stimulated RR by increasing the concentrations of cAMP in the epitheloid cells and independently of changes in renal haemodynamics and sodium excretion.


Mallory bodies: isolation of hepatocellular hyalin and electrophoretic resolution of polypeptide components. Mallory bodies (MBs) were obtained in purified form from human liver obtained at autopsy using a new procedure consisting of sedimentation through a Ficoll viscosity barrier. Preparations from six livers ranged in purity from 95 to 99 per cent. MB preparations were autofluorescent. MBs were strongly agglutinated by Concanavalin A. The presence of carbohydrate was also indicated by the fact that MBs bound fluorescently labeled Concanavalin A; no binding was observed in the presence of appropriate inhibitor monosaccharides. Direct analysis indicated that MBs contained variable amounts of neutral hexose (0.65 to 2.4 mumoles of glucose-equivalents per milligram of protein) but no sialic acid. Sodium dodecyl sulfate-polyacrylamide gel electrophoresis indicated that purified MBs contain five major polypeptides possessing apparent molecular weights of 56,000, 48,500 to 45,000 (triplet), and 32,500. Periodic acid-Schiff-positive components were not detected. Scanning electron microscopy of isolated MBs revealed the presence of a rough, fibrous surface, whereas conventional transmission electron microscopy indicated the filamentous nature of MBs.


Dimensions and specificities of recognition sites on lectins and antibodies. A comparison is made of the specific combining sites of a number of lectins and of antibodies with emphasis on those reacting with blood group A, B, and H determinants. The ranges of site sizes and specificities of both groups are similar both from immunochemical studies and from the limited x-ray diffraction data available.


Adriamycin, bleomycin, and CCNU as effective induction chemotherapeutic agents in advanced squamous cell carcinoma (COG Protocol 7333). Twenty-six member institutions of the Central Oncology Group entered 154 patients in this two-armed, phase III study comparing the effects of adriamycin, bleomycin, and CCNU against a variety of squamous cell carcinomas. The combination of adriamycin and bleomycin produced a 43% overall response rate in primary tumors of the head and neck, which included two complete responses. This compares favorably to the results obtained with methotrexate and other agents previously reported. The combination of adriamycin and bleomycin will probably be the most useful for induction chemotherapy because both drugs have cumulative toxicities and the duration of response to this combination is short.


Primary malignant melanoma of the rectum: rationale for conservative surgical management. A case of malignant melanoma arising in the rectum is described and the literature is reviewed. The natural history of melanoma of the rectum is distinctive from that of other tumors of the perineal area in that local recurrence is uncommon and systemic dissemination is frequent, with a low cure rate (2/66 in a literature review). Conservative surgical approaches (fulguration, local resection) are recommended in preference to abdominoperineal resection in that palliation is the realistic goal of surgical therapy.


Lack of correlation between mesenchymal cell death and morphogenesis after different extents of apical ectodermal ridge/rim ectoderm removal in the chick embryo wing bud. The removal of the apical ectodermal ridge (A.E.R.) subsequently causes distal deletion defects in the limb. There have been contradictory reports as to the appearance of cell death in the mesenchyme after A.E.R. removal, as well as to its morphogenetic significance. In our study the A.E.R./ rim ectoderm removal was varied to test whether different degrees of cell death would correlate with different degrees of distal deletions. From the right wing bud of stage 19 and 20 (HH) embryos the rim ectoderm was removed in four ways: all of the rim, the anterior third, the middle third (most of the A.E.R.), or its posterior third. The removal of all or of the anterior third caused a definite band of subwound mesenchymal cell death to appear. There was little or no cell death after removal of the middle or posterior thirds. Removal of the anterior third caused no distal deletion defects, and only a few were noted after removal of the posterior third. The proximo-distal level of the distal deletions, however, was the same after removal of all of the rim or only its middle third. As there was no difference in the degree of distal deletions after the removal of all or of the middle third of the rim but a definite difference in the mesenchymal cell death patterns we conclude that cell death is not part of the mechanisms of the distal deletion defect. Our findings also suggest that cell death does not play a role in the A.E.R.-mesenchyme reciprocal interaction that controls limb proximo-distal morphogenesis.


Further studies of the prospective fates of blastomeres at the 32-cell stage of Xenopus laevis embryos. Each blastomere in the marginal zone of Xenopus laevis embryos at the 32-cell stage was stained with Nile blue sulphate. Only specimens with the typical arrangement of blastomeres of morulae of this species were used, and special care was taken to prevent the dye from spreading to neighbouring cells and to determine the extent of stained areas. The prospective fate of each blastomere was studied and a new fate-map of the 32-cell embryo was drawn by tracing the movement of stain during the course of further development.


Transient hypoxaemia during sleep in chronic bronchitis and emphysema. Arterial oxygenation, breathing pattern, and electroencephalogram were studied during sleep in patients with chronic bronchitis and emphysema and in healthy subjects. All of the 10 "blue and bloated" patients had episodes of transient hypoxaemia lasting 1--100 min, when their oxygen saturation fell by more than 10%, whereas such desaturation did not occur in 2 "pink and puffing" patients or in 4 healthy subjects. Hypoxaemic episodes usually occurred during the rapid-eye-movement stage of sleep. It is suggested that these hypoxaemic episodes result from a combination of hypoventilation and impaired ventilation/perfusion relationships and that these episodes may contribute to the development of the pulmonary hypertension and secondary polycythaemia which characterises "blue and bloated" patients.


Accelerated ageing or selective neuronal loss as an important cause of dementia? Extensive biochemical analysis of whole temporal lobe from cases of dementia and controls suggests that Alzheimer's disease is a primary degenerative nerve-cell disorder and not the result of accelerated ageing. There is selective loss of neocortical cholinergic neurones. Transmitter systems apart from the cholinergic system appears to be affected, but to a lesser extent, and there are no significant changes in the caudate nucleus. The change in cholinergic neurones has been confirmed in biopsy samples.


Autoimmunity in diabetics induced by hormonal contaminants of insulin. Several commercial insulin preparations were found to contain significant quantities of pancreatic glucagon, pancreatic polypeptide (P.P.), vasoactive intestinal peptide (V.I.P.), and somatostatin, though these substances were effectively absent from the new highly purified or monocomponent insulins. Of 448 insulin-dependent diabetics receiving conventional insulins, 63% had circulating antibodies to human P.P., 6% antibodies to V.I.P., 6% to glucagon, and 0.5% to somatostatin. The antibodies were of high affinity and were commonest in the younger diabetics. No antibodies were detected in 167 maturity-onset diabetics, in 125 healthy controls, or in 22 patients treated only with monocomponent insulin. Immunocytochemical testing showed that antibody-positive diabetic plasma reacted specifically against the corresponding hormone-producing pancreatic endocrine cells, against enteroglucagon and somatostatin cells outside the pancreas, and against V.I.P.-containing autonomic nerves throughout the body. The finding of iatrogenic autoimmunity and naturally occurring hormones in large numbers of insulin-dependent diabetics raises important questions about long-term treatment.


Fetal damage despite low-phenylalanine diet after conception in a phenylketonuric woman. A woman with phenylketonuria gave birth to an infant with a cardiac defect and microcephaly despite introduction of a low-phenylalanine diet 5 weeks after conception (3 weeks after the first missed period). In maternal phenylketonuria fetal damage leading to reduced brain growth and cardiac malformations probably occurs within a few weeks of conception.


Antibodies against Chlamydia of lymphogranuloma-venereum type in Crohn's disease. Antibodies against Chlamydia of lymphogranuloma-venereum type were detected by the micro-immunofluorescence technique in 38 (69%) of 55 patients with Crohn's disease. Weak positive reactions were seen in only 2 or 21 patients with other gastrointestinal disorders and 1 of 50 healthy blood-donors.


Improved renal allograft survival after blood transfusion: a nonspecific, erythrocyte-mediated immunoregulatory process? Phagocytosis of altered red blood cells in vitro by mononuclear phagocytic cells is followed by profound depression of bystander lymphocytes' responses to antigen. Rapid endocytosis of transfused erythrocytes in vivo may transiently impair mononuclear phagocytic cell function, resulting in immunological unresponsiveness as observed in vitro. Transplantation at this time would be predicted to benefit from this attenuation of recipient immunocompetence, resulting in improved graft survival.


Comparison of places and policies for terminal care. Patients receiving different types of adequate care for fatal neoplasms were compared by an assessment of their mood and opinions. 78% had spoken of dying, and, although 56% had some unhappiness and anxiety, many were not distressed. Most aspects of care were approved of with no consistant difference in ratings between acute hospital wards and a Foundation Home. Patients were least depressed and anxious at a hospice and preferred the more frank communication available there. Inpatients were slightly less troubled than outpatients who nevertheless praised this management.


Assessment of inactivated influenza-A vaccine after three outbreaks of influenza A at Christ's Hospital. The boys of Christ's Hospital experienced outbreaks of influenza A in 1972 (A/England/42/72), in 1974 (A/Port Chalmers), and in 1976 (A/Victoria). In each outbreak, the protective effect of inactivated influenza-A vaccine was limited to those boys, not already immune, who were vaccinated for the first time with the most up-to-date strain. Revaccination with the same strain did not increase the degree of protection, and revaccination with a later strain did not afford protection against subsequent challenge. The cummulative attack-rate in the three outbreaks was similar in all groups irrespective of vaccination history. These observations suggest that annual revaccination with inactivated influenza-A vaccine confers no long-term advantage.


Anaerobic subareolar breast abscess.

Anaerobic subareolar breast abscess. 15 non-puerperal women with breast abscess were seen during one year. In 8, anaerobes were cultured from pus obtained from the abscess, in 6, Staphylococcus aureus was grown, and in 1 the pus was sterile on culture. All 7 breast abscesses in puerperal women seen during the same period were staphylococcal. The anaerobic abscesses were all subareolar; they were recurrent in 4 patients and were associated with retracted nipples in 7. The anaerobes isolated were those found as normal commensals in the oropharynx and vagina but did not include the colonic commensal Bacteroides fragilis. Squamous metaplasia with keratin plugging of the breast ducts was identified histologically in the 2 non-puerperal patients in whom duct excision was performed. Surgical treatment of the underlying duct abnormality is important in the management of recurrent non-puerperal subareolar breast abscess.


Increased levels of a nerve-growth-factor cross-reacting protein in "central" neurofibromatosis. Nerve-growth factor (N.G.F.) from serum was assayed in 9 affected individuals from three kindreds with the trait "central neurofibromatosis". The hallmark of this disease is bilateral acoustic neuromas. Antigenic activity, as measured by radioimmunoassay, was significantly elevated. However, functional activity for N.G.F.; as measured by radioreceptor assay, was normal or low. This indicates that the central form of neurofibromatosis is characterised by high circulating N.G.F. levels which show low to normal function. These changes in N.G.F. differ from those in peripheral neurofibromatosis and suggest that the two hereditary conditions involve different alterations in N.G.F. synthesis and/or regulation.


Monoclonal characteristics of organising arterial thrombi: Significance in the origin and growth of human atherosclerotic plaques. The clonal characteristics of 26 arterial thrombi at different stages of organisation were determined using the X-linked enzyme, glucose-6-phosphate dehydrogenase (G.-6-P.D.), as a clonal marker in 13 women heterozygous for electrophoretically separable G.-6-P.D. isoenzymes. A gradation of increasing monoclonality was observed with increasing organisation of the thrombi, such that only 21% of poorly organised (red) thrombi displayed monoclonal characteristics similar to those of atherosclerotic plaques, whereas 78% of moderately organised (pink) thrombi and 91% of well-organised (white) thrombi showed such characteristics. These results provide objective evidence for the role of thrombosis in the formation of human atherosclerotic plaques.


[Nonsurgical therapy of hyperthyroidism (author's transl)]. Special procedures are: (1) Short-term treatment with steroid hormones; (2) antithyroid substances; (3) radioactive iodine; (4) operation. The first two methods are complementary to the definitive procedures of isotope and surgical therapy. The indications conform to the age of the patient and the size of the goiter. The treatment of choice in 60% of all cases is radioactive iodine; 20-25% are treated with antithyroid substances only for several years. The remaining cases, complicated by goiters of size II and more, should be handled surgically. Discussion based on personal experience with 3580 cases over 20 years).


[Basedow-Graves' disease: operative treatment (author's transl)]. For hyperthyroidism of Basedow's or Graves' type, surgery is the treatment of choice for large goiter, particularly in the presence of mechanical irritation, for cases of unsuccessful conservative medical treatment, or for cases where 131I-irradiation is contraindicated. The operative risk is less than 1%. Adequate preoperative antithyroid medication is obligatory because surgery should be carried out under euthyroid conditions.


[The place of surgery in the modern treatment of cancer (author's transl)]. Cancer is now the second most frequent cause of death in the Federal Republic of Germany. According to medical estimates, surgery is the primary treatment for 80-90% of all tumors, and it is curative in 30-40% with or without concomitant radiotherapy. Chemotherapy is potentially curative in about 7%, immunotherapy in only +/- 0%. After a general discussion of radical and palliative operative techniques, the place of surgery in prophylactic indications, in recurrences, and in metastases is dealt with. Special problems occur in various organ tumors (thyroid, breast, esophagus, stomach, colon, and Wilms' tumors). In Heidelberg, an interdisciplinary oncologic group has been in existence since 1966; this group forms the basis of a tumor center, consisting of the two academic clinics and the German Cancer Research Center. Whether a speciality in surgical oncology is also needed in Germany is a question for further consideration.


[Principles of radical treatment of soft tissue tumors (author's transl)]. Malignancy should always be suspected for any soft tissue tumor. Thus, histologic examination of the totally excised growth is mandatory. Amputation is indicated as a curative measure for recurrencies and lesions that cannot be excised locally. It is also indicated for palliation in cases with ulceration, impaired function, and distant metastases. Adjuvant radio- and chemotherapy, based on the type of tumor, is outlined. The importance of cooperation between surgeon, pathologist, radiologist, and chemotherapist and of a central soft tissue tumor register is emphasized.


Identification of cytoplasmic laminar bodies in neurons of the cat lateral geniculate nucleus by phase contrast microscopy. It is demonstrated that cytoplasmic laminar bodies (CLBs) can be identified in Nissl stained celloidin sections by means of phase contrast microscopy. Provided that the refractive index of the mounting medium is in the range of 1.56 to 1.65, CLBs appear as bright holes in the cytoplasm.


Reticulation, polychromasia and stippling of erythrocytes. The morphology of the immature erythrocyte (reticulocyte, polychromatic erythrocyte, stippled erythrocyte) is described. Literature on reticulation, polychromasia and stippling is reviewed with special consideration of the inter-relationship of these phenomena, their chemical basis and the role of preparative techniques in their production. Techniques of reticulocyte staining are summarised and common stains discussed. The effect of dye batch variations on the reticulocyte count is considered. Techniques and stains for polychromatic and stippled cells are described with emphasis on methods which may be used to increase the relative frequency of each cell type.


Nature of antigenic determinant of serovar-specific antigen of Leptospira interrogans serovar hebdomadis. The nondialyzable delipidized serovar-specific main antigen (NDTM antigen) of Leptospira interrogans serovar hebdomadis strain Hebdomadis (a variant which can grow in a synthetic medium) showed a strong inhibition of the complement fixation between the serovar-specific main (TM) antigen of this strain and the homologous antiserum. The inhibitory effect of the NDTM antigen was completely lost by treating the antigen with proteolytic enzymes, and the fractions of TM antigen containing amino sugar, neutral sugars, and lipids did not show any inhibition of complement fixation, indicating that the antigenic determinant of this strain is related to proteins. NDTM antigen contained more hydrophilic amino acids than hydrophobic amino acids, whereas TM antigen contained more hydrophobic amino acids than hydrophilic amino acids. The amino acid compositions of NDTM antigens of hebdomadis strain Hebdomadis (variant) and kremastos strain Kyoto, which belonged to the same serogroup, were considerably similar. Difference was found in the amounts of methionine, arginine, lysine and glutamine acid.


Serological studies on the major histocompatibility complex of new inbred strains of the guinea pig. New inbred strains of guinea pigs, JY 1, JY 2, JY 3, JY 6, JY 9 and JY 10 have been established in this Institute. Serologic studies of guinea pig leukocyte antigens (GPLA antigens) were carried out in order to examine their major histocompatibility complex (GPLA complex). Antisera specific for Ia antigens were raised by cross-immunization of NIH strain 2 (NIH 2) and NIH strain 13 (NIH 13) guinea pigs, well known inbred guinea pigs. The sera identified four distinct Ia specificities, which were designated as Ia.2a, Ia2b, Ia.13a and Ia.13b. Six antigenic specificities different from the above Ia specificities were identified by sera obtained by appropriate immunization of the inbred guinea pigs and were designated as P.1, P.2, P.3, P.4, P.5 and P.6. Antigenic specificities of GPLA antigens recognized in inbred guinea pigs were : NIH 2 (Ia.2a, Ia.2b, P.1, P.2, P.O, P.4), NIH 13 (Ia.13a, Ia.13b, P.1, P.2, P.3, P.4), JY 1 (Ia.13a, Ia.13b, P.5), JY 2 (Ia.2b, Ia.13b, P.3, P.4, P.6), JY 3 (Ia.13a, Ia.13b, P.2, P.4, P.5), JY 6 (Ia.2b, Ia.13b, P.3, P.6), JY 9 (Ia.13a, Ia.13b, P.4, P.5), JY 10 (Ia.13a, Ia.13b, P.2, P.3, P.4, P.6), JY 9 (Ia.13a, Ia.13b, P.4, P.5), JY 10 (Ia.13a, Ia.13b, P.2, P.3, P.4, P.6). The correspondence of these specificities to those already reported was discussed and the P.2 or P.4 was considered to be an additional specificity of GPLA antigens that have not been reported yet. As the new inbred strains of guinea pigs were thus found to possess characteristic GPLA complex, which differ from each other and from those of NIH 2 and NIH 13 strain, they should be useful for studies of roles of the major histocompatibility complex in the immune system.


An evaluation of the effectiveness of audio cassettes for CME. Medical teachers and practising doctors were surveyed by questionnaire and given pre- and post-tests to determine the efficiency and effectiveness of Practical Reviews in Cancer Management, a cassette tape programme of continuing medical education (CME). Doctors indicated a high degree of satisfaction with this approach; in particular the idea of keeping abreast of the current literature while commuting in their cars was appealing. The programme's effectiveness was measured by pre- and post-tests, and the data were analysed by the non-directional t-test for dependent groups. These tests indicated a significant (P less than 0.001) increase in knowledge from the pre- to post-tests.


An introduction to sexuality in the medical curriculum. An educational procedure is described for increasing comfort and clinical objectiveness when interviewing patients with sexual problems. It is based on the viewing of sexually explicit films interspersed with small group discussions. Judging from questionnaires completed by 329 students in four British medical schools, most felt that the procedure had benefited them both personally and professionally, and that it provided a good foundation for a course in human sexuality.


[Longterm therapy with i.v.-gamma-globulin in children (author's transl)]. gamma-Globulin for treatment should be injected by the intravenous route whenever possible. An unsplit molecule would be of great advantage in this context but there is the problem of antigenicity. One possibility to attain a good tolerance for i.v.-gamma-globin is to treat the molecule with beta-propiolactone. The acute tolerance and the efficacy of this preparation are proven. We wanted to find out if the modification of the immunoglobulin by beta-propiolactone would induce new antigene properties, which could lead to antibody production after repeated injections. There were no antibodies to be found neither in vivo nor in vitro in 6 children, which received 8--166 injections of this preparation.


Molecular mechanisms involved in the production of chromosomal aberrations. I. Utilization of Neurospora endonuclease for the study of aberration production in G2 stage of the cell cycle. Chinese hamster ovary cells (CHO) were X-irradiated in G2 stage of the cell cycle and immediately treated, in the presence of inactivated Sendai virus, with Neurospora endonuclease (E.C. 3.1.4.), an enzyme which is specific for cleaving single-stranded DNA. With this treatment, the frequencies of all types of chromosome aberrations increased when compared to X-irradiated controls. These results are interpreted as due to the conversion of some of the X-ray induced single-stranded DNA breaks into double-strand breaks by this enzyme. Similar enhancement due to this enzyme was found following treatment with methyl methanesulfonate (MMS) and bleomycin, but not following UV and mitomycin C. Addition of Micrococcus endonuclease and Neurospora endonuclease to the cells did not alter the frequencies of aberrations induced by UV. The introduction of enzymes with specific DNA-repair function offers possibilities to probe into the molecular events involved in the formation of structural chromosome aberrations induced by different classes of physical and chemical mutagens.


[Pregnancy associated alpha2-glycoprotein (alpha2-PAG) in the serum of patients with gynecologic carcinomas]. alpha2-PAG is a high-molecular, carbohydrate-containing glycoprotein. It occurs in traces in normal human serum. The variations in serum levels of this protein were studied during treatment of 32 gynecological cancer patients in the course of 2 years. The periodic alpha2-PAG determinations were done with an electro-immuno-assay. A correspondence between alpha2-PAG serum levels and the clinical course could be found in 60%. In 5 of 13 patients who did not respond to therapy alpha2-PAG levels rose, additional 4 had unchanged high levels, whereas 13 of 17 patients had significantly decreased levels on successful treatment. The relevance of periodic alpha2-PAG determinations is discussed.


[Diagnosis and therapy of malignant testicular neoplasms]. For successful treatment of even advanced testicular tumors an accurate histological classification and clinical staging is necessary. The pathohistomorphological classification can be completed by the so-called tumor markers such as alpha-fetoprotein and beta-humanchoriongonadotropin (beta-HCG). These markers are especially valuable in the follow-up of the patient and in the control of the therapeutical effectivity. By optimal diagnosis and therapy seminomas in stage I and II are in 70% to 100%, teratomas in 40% to 80% curable; in the more advanced stages in 30 to 40% a two years relapse-free time can be obtained.


[Prognosis of cardia carcinoma].

[Prognosis of cardia carcinoma]. Based on a material of 223 patients treated for cardia carcinoma the surgical problems and the results after palliative, radical and enlarged resection are discussed. In the early stage without nodular involvement (I) in 72% of the radically operated patients a 5-years and 10-years cure could be obtained, in relation to all patients observed the success, however, is only 10% for 5-years and 8% for 10-years cure. This is caused by the fact that stage I was found in only 10% of the patients admitted to our hospital. The need for a close observation programm for clearly defined high risk groups must be pointed out and the possibilities of a special postoperative adjunct therapy should be fully used.


[Value of transurethral laser therapy in the treatment of bladder carcinoma]. A new method has been developed allowing the introduction of the argon laser beam into the water-filled bladder using normal operation cystoscopes. The energy is applicated to the bladder by means of a light conductor which is placed into the bladder through the working channel of an operation cystoscope. Treating large tumors of the bladder we laser the resection bed after electroresection (TUR). The sole use of laser therapy on large tumors of the bladder is not to be recommended because of the uncertainty of their total destruction. On the other hand, the sole laser coagulation of small relapses of tumor up to the size of raspberries restricted to the mucous membrane seems to be more effective than electroresection. The advantage of laser treatment is the absence of electric power flow through the tissue which avoids muscle convulsions of the bladder and electric power leakage. Besides of this, laser therapy being painless allows treatment without anesthesia. So far 68 patients with tumors of the bladder have been treated by transurethral laser therapy combined with electroresection (TUR). The aim of transurethral laser therapy is the reduction of recidivity of bladder tumors.


[Chemotherapy of gastrointestinal tumors (review of the literature)]. There exist no common recommendations for palliative therapy of gastrointestinal cancer. Fluorouracil has been used for a long time, remission rates reported range from 0% to 80%. In larger series they figure about 20% but without prolongation of survival in responders. Although this drug is used for 20 years optimal dose and timing is still unknown. By combination of fluorouracil with other drugs remission rates were improved and in responders survival was prolonged (mitomycin C and/or adriamycin in gastric cancer, methyl-CCNU in colorectal cancer). The results of adjuvant chemotherapy of gastrointestinal cancer are contradictory, the routine usage is not recommendable. Adjuvant as well as palliative chemotherapy must be improved by controlled clinical trials.


Cell surface antigens containing beta2-microglobulin as the common subunit. beta2-Microglobulin, which was first discovered in various biological fluids, has been shown to be the common subunit of the human HLA-A,B,C antigens. In the mouse beta2-microglobulin is associated with H-2K, D and L antigens and with TL and Qa-2 antigens, beta2-microglobulin and the heavy HLA antigen chains are similar in structure to the immunoglobulins and it is suggested that the two types of molecules have had an interrelated evolution. Data are also presented which suggest that the structural similarity between transplantation antigens and immunoglobulins may be paralleled by a functional similarity as well.


[Study of lymphocyte membrane antigens and receptors with antibodies to beta2-microglobulin (author's transl)]. Anti-beta 2 microglobulin sera (beta2m AS) rendered specific after extensive absorptions were obtained following immunization of rabbits with highly purified beta2m prepared from urine of tubular proteinuria. beta2m AS were cytotoxic upon addition of selected rabbit complement for human T and B lymphocytes. Partial inhibition of sheep red blood cells receptor recognition on T lymphocytes (E rosettes) and C3 component recognition on B lymphocytes (EAC rosettes) was obtained only with high concentrations of Fab'2 anti-beta2m, eliminating a direct association of beta2m and those receptors. Fab'2 anti-beta2 induced very little inhibition of Fc portion receptor recognition (EA rosettes), but they had no effect on lysis of targets covered with IgG anti-targets (ADCC), a function mediated through that receptor. Anti-beta2m antibodies in excess inhibited antigen-induced proliferation (PPD) and the mixed lymphocyte reaction (MLR) performed in AB serum and fetal calf serum containing media ; whereas a potentiation of the response occurred in the presence of an antigen excess (beta2m) brought by the culture medium (AB serum) suggesting involvement of immune complexes. Pretreatment of responding cells with beta2m AS did block unilateral MLR ; conversely, treatement of stimulating cells had no effect. Independent migration of T cell membrane antigens (HTLA) and beta2m upon addition of suitable ligands, as well as the lack of inhibition by Fab'2 anti-beta2m of complement dependent lysis with IgG anti-HTLA, excluded possible association of HTLA and beta2m.


Total joint replacement in bunion surgery. A preliminary report is given for total joint replacement arthroplasty utilizing a silicone-polyester prosthesis, in selected cases of destroyed metatarsophalangeal joints of the great toe. Fifty-three prostheses were implanted over a period from March 1971 to March 1977, with a minimum follow-up of one year. Overall results were good from the standpoint of pain relief and cosmetic correction, in severely destroyed and deformed joints. The essential aspects for successful prosthetic arthroplasty include proper seating of the prosthesis and complete realignment of the first ray, paralleling the adjacent metatarsals. On the basis of these preliminary results, it is concluded that there is a place for total joint prosthetic replacement in the surgical reconstruction of the painful, destroyed metatarsophalangeal joint of the great toe.


The serum level and urinary excretion of beta2-microglobulin in health and renal disease. In healthy subjects with normal renal function beta2-microglobulin (beta2m) is constantly produced in the body. It is eliminated almost exclusively by the kidneys, predominantly by glomerular filtration but possibly also by some direct uptake from the blood. After glomerular filtration more than 99,9% of excreted protein is reabsorbed in the kidney tubules where it is catabolized. The main factor, influencing on the serum level of beta2m is the GFR. Determination of S-beta2m appears to be more effective than analysis of S-creatinine for the detection of a slightly reduced GFR. A relatively high S-beta2m, in comparison with the GFR, may be seen in e.g. malignant proliferative disorders and SLE. This indicates an increased production of the protein. An entirely free passage over the glomerular membranes is not likely for beta2m in healthy subjects but the sieving coefficient might approach 1,0 in renal disease. The increased glomerular elimination of the protein could then possibly be counterbalanced by an increased synthesis, which should explain the pronounced relationship at a log/log scale between S-beta2m and the GFR. An increased excretion of beta2m in the urine is a sensitive indicator of proximal tubular dysfunction in many clinical conditions. In marked renal insufficiency there is, however, an obligatory 100-1 000-fold increase of the normal excretion, not related to the kind of renal disorder. In studies of the protein precautions are necessary to avoid degradation of the protein, in urine with a low pH.


[Alteration of beta2-microglobulin metabolism in terminal chronic renal insufficiency (author's transl)]. In 63 patients with chronic renal insufficiency treated with intermittent dialysis plasma beta2m concentrations were shown to be stable and increased 8 to 60 times over normal values. The excretion of beta2m is achieved either through residual diuresis (up to 150 mg/24 h) or by filtration through high permeability membranes of the dialyser. In the absence of extra-renal catabolism of beta2m it is suggested that the rate of beta2m synthesis differs markedly among patients. beta2m it self does not to seem to contribute to the toxic manifestations of chronic renal insufficiency.


[Plasma concentrations and urinary excretion of beta2 microglobulin after renal transplantation (author's transl)]. beta2-Microglobulin (beta2m)levels were measured daily after transplantation in 44 recipients of renal allograft. beta2m was measured by radioimmunoassay. After transplantation, serum beta2m becomes inferior to 4 micrograms/ml within 4 days whereas urinary beta2m decreases down to 0,5 microgram/ml within 6 days. A correlation between serum creatinine and serumbeta2m is presented and a few dissociations between the 2 values are discussed. Picks of urinary beta2m concentrations were observed either before (22/30 cases) or concomitant (16/30 cases) with rejection episodes. However, a few patients presented massive urinary excretion of beta2m without development of a typical rejection. This study allows to define two types of renal alterations after transplantation : one associated with renal insufficiency and elevated serum beta2m, the other with proximal tubular dysfonction resulting in massive (up to 700 mg/24 h) urinary excretion of beta2m.


[beta2-Microglobulin in renal transplanted patients (author's transl)]. Plasma beta2m has been measured frequently during long term follow-up of kidney transplanted outpatients. The ratio of beta2m/log creatinine was abnormally high in 15 patients of this series bearing a symptomatic hepatitis independently of any modification of immunodepressive drug administration schedule (azathioprine and corticoids). The true effect of azathioprine could not be isolated whereas corticotherapy modified clearly the beta2m/creatinine ratio : increase of dosage for rejection resulted in a fall of the ratio whereas fast reduction increased the ratio acting essentially on circulating beta2m level (12 cases). The beta2m/creatinine ratio was normal or occasionally diminished in the 22 patients having an uneventful clinical course. Six patients showed mixed effects of hepatitis and variation of corticoid dosage and 7 cases were too much intricated to permit a good analysis of the data.


beta2-Microglobulin in Balkan endemic nephropathy. The results of low molecular weight (LMW) proteinuria test in urines of patients and suspect subjects in an endemic area of Balkan endemic nephropathy (BEN) in Yugoslavia are reported. An accordance between the positive LMW test and the clinical diagnosis of BEN has been found in more than 70%. The authors claim that LMW immunodiffusion test is a very useful procedure for detecting BEN and a great aid in the epidemiological work in the endemic field. The results of determining beta2-microglobuline (beta2m) in serums and urines by radioimmunoassay technique as well as counting of clearances of endogenous creatinine in healthy persons, "endangered" subjects in endemic area, and BEN patients without azotemia, with azotemia and uremia are reported. The group of 17 patients suffering of BEN without azotemia having slightly or more markedly lowered creatinine clearances showed higher serum and much higher urinary concentration of beta2m which are not in proportion with creatinine clearance. The results are interpreted so far as a consequence of the predominant tubular lesion in BEN. In groups of patients with azotemia and uremia no differences in beta2m handling have been found. The report has a preliminary character and requires further study.


Serum beta2-microglobulin in cadmium exposed workers. In cadmium exposed workers with renal tubular dysfunction the determination of beta2m in urine is an important diagnostic test. Cadmium exposure's influence on serum beta2m levels and its relationship to urinary excretion of beta2m were studied in 24 cadmium exposed workers with normal serum creatinine levels (less than 10 mg/l)) and no obvious tubular dysfunction. With increasing blood levels of cadmium beta2m was found to increase in serum. There was no concomitant increase in the urinary excretion of beta2m. Serum beta2m was not dependent on serum creatinine within the range studied. The results suggest that for evaluating renal glomerular function in cadmium exposed workers, it might be better to use the serum creatinine level, creatinine clearance or inulin clearance since beta2m might give some false positive results.


[beta2-Microglobulin and experimental nephropathies in macacus monkey (author's transl)]. In the monkey, the action of four renal toxics : lead acetate, sodium maleate, cadmium chloride and sodium chromate was compared. Tubulopathies were obtained only with cadmium chloride and sodium chromate with in the best cases about 16 mg/l of beta2-microglobulin (beta2m) in the urine. Monkey and human beta2m have the same molecular weight and are antigenically similar. However, they differed in electrophoretic mobility, the monkey beta2m being slightly more cathodic.


Urinary excretion of beta2-microglobulin and other proteins in workers exposed to cadmium, lead or mercury. For the range of exposure to heavy metals sustained by the different groups of workers, a significant increase in the urinary excretion of low and/or high molecular weight proteins was found in the workers exposed to cadmium or to lead + cadmium, but no in those exposed to lead only and those exposed to mercury. Our observations suggest that the classical "tubular" proteinuria induced by cadmium has two not necessarily concomitant components : a "tubular type" component with increased excretion of low molecular weight proteins and a "glomerular type" component with increased excretion of high molecular weight proteins.


[Determination of beta2-microglobulin in workers expposed to cadmium dust (author's transl)]. In a factory where workers are exposed to inhalation of small cadmium oxide particles we have determined beta2microglobulin (beta2m) in serum and urine and at the same time cadmium in corresponding samples and also in the atmosphere of the workshop. The rise in urinary beta2m generally detected seems to be dependent upon two parameters : 1) the number of years spent in the factory ; and 2) the atmospheric Cadmium concentration.


[beta2-Microglobulin in cancer patients (author's transl)]. Cancerembryonic antigen (CEA) and beta2-microglobulin (beta2m) have been measured in cancer patients and patients with benign diseases. Of 168 patients with intestinal cancer, almost 90% had increasing concentrations of either CEA or beta2m or both. In 29 patients at different stages of pancreatic cancer there was a high incidence of increased values in the more severe cases. In 60 patients with histologically classified colorectal cancer the TNomegaMomega group of 19 patients had 47% and 42% of elevated beta2m and CEA respectively. A significant correlation of beta2m or CEA to extension of disease was noted. In benign intestinal disease like cirrhosis and pancreatitis both beta2m and CEA is commonly elevated. Of 26 breast cancer patients, seven had elevated CEA and five had elevated beta2m values before treatment. In the patients with extraganglionary metastasis almost 90% had high beta2m or CEA or both. Of 40 patients with uterine cancer, 26 were found to have increased values of beta2m or CEA or both. Finally, 140 colorectal cancer patients, 62 patients with breast cancer and 10 patients with uterine cancer have been followed longitudinally.


[Comparative study of carcino-embryonic antigen and beta2-microglobulin. Methodological study and clinical interpretation (author's transl)]. beta2m was determined by radioimmunoassay in 43 serums from healthy blood donors. Serum concentrations varied from 0.67 to 1.9 mg/l with a mean of 1.29 mg/l. Reproductibility and sensitivity of the method were evaluated. 66 patients with advanced neoplasia were studied. Serum beta2m was greater than 2 mg/l in 70% of the cases and carcinoembryonic antigen (CEA) in 54%. In 26 documented cases with tumor progression and 14 with regression, associated variations of CEA were formed more frequent and of greater magnitude than those of beta2m.


beta2-Microglobulin in lymphoproliferative disorders with special reference to gammapathies. Plasma beta2-microglobulin ratio were calculated taking into account serum creatinine levels and were found to be elevated in a variety of lymphoproliferative disorders. Degree of elevation appeared to be proportional to the tumour mass.


[beta2-Microglobulin and monoclonal gammapathies (author's transl)]. 145 Determinations of beta2-microglobulin (beta2m) have been realized in 111 patients with a monoclonal gammapathy. The level of beta2m is significantly higher (p = 0,0001) in the group with monoclonal gammapathy (M = 4,75 mg/l +/- 5,62) than in normal subjects (M 1,38 mg/l +/- 0,38). In a group with monoclonal gammapathy with renal failure, the level of beta2m is higher (M = 7,07 mg/l +/- 7,76) than in a group with renal failure alone (M = 3,45 mg/l +/- 1,91). The difference is significant (p = 0,005). The level of beta2m is higher in IgA monoclonal gammapathies (M = 5,61 mg/l) than in IgG (M = 4,18 mg/l) or IgM (M = 4,37 mg/l) gammapathies, but the differences of the means between the three groups are not significant. The assay of beta-2m does not allow to distinguish myeloma (M = 3,18 mg/l +/- 1,83) from benign monoclonal gammapathy (M = 3,22 mg/l +/- 1,32) and is not useful when the diagnosis is difficult.