Effect of dimethylmyleran on cell-mediated immunity to a tumor allograft.

C57BL/6 mice (H-2b) were inoculated on day 0 with killed Moloney lymphoma cells (LSTRA) of BALB/c origin (H-2d), and their spleen cells were tested for reactivity against LSTRA by the 51Cr-release cytotoxicity assay. Cytotoxic reactivity of cells from ice not treated with drug was maximal by day 6 and disappeared by day 10. Cells from mice given dimethylmyleran (DDM) (12 or 16 mg/kg) on day -1 showed higher levels of cytotoxicity, whereas DMM administered on day +1 had little effect. The effect of DMM on the secondary response was tested and compared with that of cyclophosphamide (CY), 180 mg/kg. Cytotoxicity of cells from mice immunized on days 0 and 10 was maximal on day 15 and then declined. CY administered on day 11 prevented the development of any cytotoxicity and, when given on day 14 in the presence of a detectably strong secondary cytotoxic response, abolished the established response. In contrast, DMM given on day 11 delayed the onset and moderately decreased the peaks of secondary reactivity but had no effect when administered on day 14. These results showed that DMM enhanced a primary response, interfered somewhat with the development of a secondary response, and had no effect on an established secondary cell-mediated response to a tumor allograft. DMM thus was one of the rare agents with antitumor activity and little immunosuppressive action.


Further observations on the inhibition of tumor growth by Corynebacterium parvum with cyclophosphamide. I. Variation in administration of both agents.

Studies from this laboratory have indicated that the administration of cyclophosphamide (CY) and Corynebacterium parvum (CP) over a prolonged time to C3H mice with established measurable tumors resulted in complete arrest of tumor growth as well as partial and complete regressions in many instances. The present investigations on optimal dosage, route, frequency, and sequence of administration of CY and CP in the model system were performed to obtain information that could be useful in the design of chemotherapeutic and immunotherapeutic regimens for the treatment of human tumors. Findings have suggested the need for administration of CP in more than one instance. Although a single dose of CP in combination with weekly injections of CY had a significantly prolonged inhibitory effect, weekly doses of CP and CY were more effective. We also concluded that the time between doses of an immunostimulating agent (I-I interval) as well as between administration of chemotherapy (C-C interval) may be critical for an optimal result. In this model system, C-C and I-I intervals of 7 days inhibited tumor growth most effectively. The time between administration of chemotherapy and immunotherapy (C-I interval) has been considered critical. Whereas slightly better results were achieved in these studies when the immunotherapy was administered 4 days after the CY or when the C-I interval was +4 days, almost equally good results were obtained when both agents were given on the same day, which signified that the C-I interval may not be as critical as other investigators have reported. The present findings confirmed and extended our prior observations and indicated that the iv and ip routes of administration were superior to the im and sc routes in our model. The observed tumor growth inhibition was a result of both chemotherapeutic and immunotherapeutic modalities; also, the inhibitory properties of the regimen were more related to the chemotherapeutic component. Finally, almost identical tumor growth inhibition was observed when CP obtained from two different laboratories was used in conjunction with CY.


Activation in vitro of mouse macrophages by syngeneic, allogeneic, or xenogeneic lymphocyte supernatants.

Macrophages from normal C57BL/6 mice, those with a subcutaneous B16 melanoma, and mice immunized against the tumor were examined for in vitro cytotoxicity to B16 tumor cells. Macrophages were treated by incubation with supernatants from B16 cells grown either in unmixed cultures or in cultures containing syngeneic, normal, or sensitized allogeneic (A mouse), or xenogeneic (rat) lymphocytes. The various treated and untreated macrophages were then cultured for 5 days with viable B16 cells prelabeled with 125I-5-iodo-2'-deoxyuridine; the cultures were terminated, and the extent of destruction of the B16 target cells was determined from the amounts of radioactivity remaining in adherent tumor cells. Of the untreated macrophages, only those from immunized mice were cytotoxic to the tumor cells; macrophages from normal and tumor-bearing mice became cytotoxic by incubation with supernatants from cultures containing lymphocytes from immunized syngeneic mice, sensitized allogeneic mice, or sensitized rats; and macrophages incubated with supernatants from cultures containing normal nonsensitized allogeneic or xenogeneic lymphocytes showed no cytotoxicity. Thes results suggested that macrophages from tumor-bearing animals are potentially cytotoxic to their syngeneic tumors and can be activated by mediators released from sensitized syngeneic, allogeneic, and/or xenogeneic lymphocytes in vitro.


Neoplastic and life-span effects of chronic exposure to tritium. II. Rats exposed in utero.

A study was conducted to determine the effects on neoplasia incidence and life-span of exposure in utero to a major environmental radionuclide. Sprague-Dawley rats were continuously exposed to tritiated water (HTO) from conception through birth in doses of 0, 1, 10, 50, and 100 muCi HTO/ml body water. HTO administration was terminated at birth. Calculated cumulative doses during gestation were approximately 0, 6.6, 66, 330, and 660 rads of total body irradiation. Under these exposure conditions, the two highest doses resulted in sterile offspring. Animals surviving through 30 days postnatally were defined as the study population and observed until their deaths. Intrauterine exposures to doses up to 66 rads had no significant effects on either sex with respect to life-span, overall neoplasia incidence, incidence rate, or onset of mammary fibroadenomas. Females exposed to 330 or 660 rads were sterile and had lower incidence rates of mammary fibroadenomass than did controls; at 660 rads females had a lower incidence of overall neoplasia and reduced mean life-spans. Sterile male offspring had reduced mean longevity after irradiation at 660 rads. Regardless of dose group, females had significantly higher incidences of neoplasia and longer life-spans than males.


Stimulation of erythropoietic differentiation in BALB/c mice infected with Rauscher leukemia virus.

The function of phenylhydrazine (PHZ) hemolysis in ameliorating the anemia induced in mice by a slow-acting strain of Rauscher leukemia virus (RLV-A) was described. After cessation of treatment with PHZ, mid-stage RLV-A-infected, anemic mice responded with massive reticulocytoses and a rebound in hematocrit above control levels. RLV-infected mice, subjected to PHZ-induced hemolysis or phlebotomy, produced high levels of plasma erythropoietin (Ep); this suggested that Ep mediated the PHZ-induced differentiation. In addition, administration of exogenous Ep induced a wave of erythroid maturation in RLV-infected anemic mice, which indicated that virus-infected erythroid precursors could still respond to the hormone governing normal differentiation.


Neoplastic transformation of fetal rat brain cells in culture after exposure to ethylnitrosourea in vivo.

A single, transplacental pulse of N-ethyl-N-nitrosourea (ENU; 75 mug/g body wt) to the fetal (18th day of gestation) BD IX rat led to death with malignant tumors of the central and peripheral nervous system after a median time of approximately 195 days. In contrast to untreated control cells, dissociated brain cells transferred to long-term cell culture 20-90 hours after the ENU pulse became tumorigenic after approximately 200 days, as assayed by reimplantation into baby BD IX rats. This was preceded by a characteristic sequence of phenotypic alterations (termed "stages I-IV"). During early primary culture (stage I), both ENU and control cultures exhibited stationary glia-like cells on a growing layer of epithelioid (possibly glia precursors) and few fibroblast-like cells. Stage II (approximately 10th-40th day) was characterized by a constant proportion of glia-like cells in the ENU cultures and by their disappearance in the controls. During stage III (approximately 40th-100th day), slowly proliferating glia-like cells in the ENU cultures formed "piled-up" foci. They could then be removed from the underlying cell layer and cultured separately. Transition to stage IV (approximately 100th-200th day) was marked by proliferation of morphologically altered cells, which subsequently acquired the capacity of form colonies in semisolid agar and finally became tumorigenic (stage V). This system may represent a model for the study of malignant transformation.


Metronidazole: effect on radiosensitivity of tumor and normal tissues in mice.

Local control of a mammary carcinoma in air-breathing C3H mice was enhanced by giving metronidazole before radiotherapy; When 0.5-1.0 mg metronidazole/g body weight was given ip 10 minutes before irradiation, the dose required for local control of 50% of the tumors (TCD50) was reduced by a factor of 1.37-1.38. The TCD50 was reduced by a factor of 1.48-1.50 when tumors were irradiated 30-60 minutes after 1.0 mg/g. Metronidazole alone, at a dose of 1.0 mg/g, only slightly inhibited tumor growth. The acute skin response of the leg, as determined by the radiation dose required to produce complete moist desquamation in 50% of the animals (DD50), was enhanced by a factor of 1.26 when mice were irradiated 10 minutes after a dose of 1.0 mg metronidazole/g. Clonogenic cells in the jejunal epithelium were not sensitized after metronidazole administration in either air-breathing mice or those irradiated in O2 30 pounds per square inch, but the drug appeared to exert a slight protective effect at higher doses of radiation.


Nonimmunogenic sarcomas induced by 3-methylcholanthrene treatment of murine fibroblasts in diffusion chambers.

A 30-mug dose of 3-methylcholanthrene (MCA) was applied for 1 week to normal BALB/c fibroblasts in cell-impermeable diffusion chambers (DC) in the peritoneal cavities of BALB/c micemtwo groups of DC cultures, in which the carcinogen was given during weeks 1 and 5 of cultivation, respectively, were compared for the frequency of malignant transformation and for the immunogenicity of the resulting neoplasms. The cells from each DC were transplanted sc into immunodepressed semisyngeneic mice for assay of their tumorigenicity. Although tumor yield was similar in the 2 groups (25 and 22%, respectively), there was clear difference in immunogenicity; 10 of 16 sarcomas from fibroblasts treated during week 1 of culture were nonimmunogenic, whereas 8 of 9 tumors from the older cultures were immunogenic (P less than 0.02). A kinetic study of normal fibroblasts in DC revealed that cells proliferated rapidly, with a peak at day 4 after seeding, then grew progressively more slowly and ceased to replicate between 14 and 28 days of culture. Thus there was a notable difference at the moment of MCA application in the growth phase of the target cell population of the first as compared with the fifth week of culture, possible related to the different expression of tumor-associated transplantation antigens in the resulting neoplasms.


Metabolism of dimethylnitrosamine to mutagenic intermediates by kidney microsomal enzymes and correlation with reported host susceptibility to kidney tumors.

Purified kidney microsomal enzymes from C3H/HeJ and Ha/1CR mice exhibited an unusually high capacity to generate mutagenic metabolites from dimethylnitrosamine (DMNA) when compared with similar enzyme preparations from BALB/cJ and RF/J mice. These results suggested that the DMNA-activating enzymes involved in mutagen formation were either present at higher levels or were more active in the kidneys of C3H/HeJ and Ha/ICR mice than in those of the other two strains. This strain difference correlated with the established susceptibility of these four strains to the neoplastic activity of DMNA.


Tumor growth: suppression in mice by submanidibular gland extirpation.

Transplanted A-10 breast adenocarcinomas grew more slowly in young-adult male A/HeJ mice from which the submandibular glands had been extirpated than in sham-operated or unoperated control mice of the same strain. The mitotic index was lower in tumors from experimental animals than in those from controls. Vascularization about the tumor margins was also less prominent. The C1300 neuroblastoma grew more slowly in sialoadenectomized mice than in controls. Modulation of tumor growth by factors of salivary gland origin may have been responsible for these effects.


Carcinogenic effect of 2,2'-dimethyldipropylnitrosamine in Syrian hamsters.

Oxidation at the beta carbon occurred in metabolism of di-n-propylnitrosamine (DPN), previously shown to be carcinogenic for animals. When 2,2'-dimethyldipropylnitrosamine (DMDPN) was injected sc once a week for life into male and female Syrian hamsters at levels of 500, 250, 125, and 62.5 mg/kg body weight, it induced neoplasms in the nasal cavities, larynx, trachea, and stem bronchi. Since the presence of a methyl group on the beta carbon suggested that DMDPN could not undergo beta oxidation, the carcinogenicity of DPN for these portions of the respiratory tract was probably unrelated to beta oxidation, though earlier experiments had indicated the possibility of this mechanism. Because DMDPN failed to induce neoplasms in other organs, the carcinogenicity of DPN or its beta metabolites for the lungs, liver, pancreas, and kidneys was not explained by this experiment.


Topologic forms of mitochondrial DNA in AKR mice.

Circular dimer forms of mitochondrial DNA were found in leukemic and preleukemic AKR mice but not in nonleukemic animals. There was a positive correlation between the presence of circular dimers and progression of the disease, the leukemic mice having the greatest evidence of circular dimers. This finding suggested that the occurrence of early subcellular changes is an important cellular modification in the leukemogenic process.


The dependence of successful immunotherapy on adequate tumor burden as shown by the treatment of AKR leukemia with poly A-poly U.

The therapeutic efficacy of polyadenlyic-polyuridylic acid (poly A-poly U) on the transplantable AKR leukemia varied with the dose of tumor cells implanted. The greater the number of AKR tumor cells injected into 8-week-old AKR mice free of clinical evidence of cancer, the greater the effect of poly A-poly U in mediating host immunologic control of the tumor. Poly A-poly U was either ineffective or could enhance tumor growth when smaller doses of tumor cells were transferred. The efficacy of an immune adjuvant depended on a tumor burden affording optimum host responsiveness. This does not necessarily arise in the host bearing minimal tumor burden.


Tumor suppression by a lymphokine released into the circulation of mice with delayed hypersensitivity.

Lymphokines such as migration inhibitory factor and type II interferon were released into the circulation of tuberculin-sensitive mice after iv injection of old tuberculin. Daily administration of such sera into the tumor sites of mice given implants of sarcoma MC-36 markedly suppressed tumor growth.


Conversion of nitrosobenzene to N-phenylacetohydroxamic acid by yeast pyruvate decarboxylase.

In the presence of yeast enzyme concentrate or purified yeast pyruvate decarboxylase, nitrosobenzene was converted in part to N-phenylacetohydroxamic acid. This transformation had to be catalyzed by the enzyme, since the incubation of nitrosobenzene with the cofactor of pyruvate decarboxylase did not produce the hydroxamic acid. Similar incubations conducted with phenylhydroxylamine did not yield any detectable amounts of N-phenylacetohydroxamic acid.


Prognosis in Kaposi's sarcoma.

We studied and followed up 112 African patients with Kaposi's sarcoma for at least 3 years or until death to determine what features of the disease at presentation most accurately predicted the prognosis. The clinical pattern of disease at presentation was most important. All patients with generalized disease died of their disease; the only deaths among those with nodular disease were due to intercurrent illness. The 3-year survuval rate among patients with locally aggressive lesions with 64%. We could obtain greater refinement of prognosis by noting the response to a dinitrochlorobenzene challenge, the presence of nodal involvement, and the histologic pattern of the tumor. The age and sex of the patient influenced the pattern of disease likely to be found, but the prognosis for a given clinical pattern was the same in both sexes and at different ages.


Differentiation of melanocytes in cultures of primary malignant melanoma indicated by 5-S-cysteinyldopa formation.

The dedifferentiation of cultured primary human malignant melanocytes was not accompanied by disappearance of 5-S-cysteinyldopa formation. The addition of conditioned medium from undifferentiated fibroblast-like cells brought about the reappearance of pigmented melanocytes and the increase of the metabolite in the cells and culture medium. The presence of 5-S-cysteinyldopa in cultured cells indicated the melanocytic origin of undifferentiated cells, and the increase of this metabolite was characteristic of differentiation.


Feline oncornavirus-associated cell membrane antigen. V. Humoral immune response to virus and cell membrane antigens in cats inoculated with Gardner-Arnstein feline sarcoma virus.

Tumor growth responses in 5- to 6-week-old kittens inoculated with the Gardner-Arnstein strain of feline sarcoma virus exhibited three distinct pattern: 1) complete tumor regression or no detectable tumor growth in approximately one-third of 43 inoculated kittens, 2) rapid tumor progression which led to debilitation and death within 16.2 +/- 4.2 weeks following infection in an additional one-third, and 3) slow tumor growth or temporary regressions in the remaining third. The feline oncornavirus-associated cell membrane antigen (FOCMA) antibody response was closely correlated with tumor progression; rapid progressors had the lowest antibody titers, whereas those in the "no tumor or permanent regression" categories had the highest titers. These results agreed with those previously observed with another virus strain, the Snyder-Theilen feline sarcoma virus. Cats in the intermediate categories of tumor growth also had intermediate levels of FOCMA antibody. The presence of virus-neutralizing (VN) activity was not always correlated with anti-FOCMA activity. Animals in the rapid-progressor category, compared to the regressors or slow progressors, were more likely to have detectable VN antibody during early periods. Conversely, animals in the regressor group or group with no tumors were more likely to show an early rise in detectable anti-FOCMA activity than animals in either of the progressor groups.


Cell proliferation and atrophic gastritis in explanted canine gastric mucosa.

We produced experimental atrophic gastritis in 7 mongrel dogs by explanting a full-thickness wedge of vascularized mucosa from the gastric greater curvature onto the abdominal wall. Autoradiography of mucosal specimens was done after the iv injection of triated thymidine. The labeling index, S-phase duration, and cell cycle time were measured in normal and explanted fundic mucosa. The spatial distribution histograms of the labeled cells showed an enlarged are of proliferation. As in human atrophic gastritis, proliferation was shifted toward the mucosal surface. Significantly higher labeling indices were observed in the atrophic mucosa. Shortening of the S-phase  duration and the cell cycle time was indicated by the curves of the labeled mitoses. Proliferative activity was significantly accelerated in this experimental model of atrophic gastritis.


Inhibitory effect of sodium ascorbate on ethylurea and sodium nitrite carcinogensis and negative findings in progeny after intestinal inoculation of precursors into pregnant hamsters.

To assess their carcinogenic effects, the ethylnitrosourea (ENU) precursors, ethylurea and sodium nitrite, [were administered to pregnant hamsters as a single intragastic] dose on day 15 of gestation, or introduced into the cecum on day 14. Since sodium ascorbate (NaASC) inhibits the biosynthesis of nitrosamides, identical doses of the precursors were given concomitantly with NaASC. Progeny of mothers treater intragastrically developed significant incidences of neurogenic tumors of the peripheral nervous system, with a predominance in females. The concurrent administration of NaASC with ENU precursors prevented carcinogenic effects in the progency, whereas the simultaneous inoculation of the precursors into the cecum produced no carcinogenic effects in the offspring.


Mucosal damage induced by various gastric carcinogens in the glandular stomach of the rat.

The process of erosion formation in the glandular stomach of the rat given single and multiple intragastric doses of 100 mg N-methyl-N'-nitro-N-nitrosoguanidine (MNNG)/kg body weight, was studied histologically, histochemically, and ultramicroscopically and compared with erosion induced by other gastric carcinogens and erosion-forming chemicals. The acute effect of several nongastric carcinogens on the glandular mucosa was also studied. The earliest degenerative transformation, fatty change, was found in the surface mucous cells within 1 hour a one-pulse intragastric dose of 100 mg MNNG/kg body weight; the change gradually progressed into deeper glandular cells and after three successive doses, erosion was complete in every rat. Ultrastructurally, four main glandular cells showed essentially similar degenerative alterations. Fatty change was also induced by other gastric caricnogens such as 4-nitroquinoline-1-oxide, methylnitrosocyanamide, methylnitrosourea, N-2-fluorenylacetamide, and iodacetamide, a noncarcinogenic alkylating agent. Mucosal damage induced by acetylsalicylic acid and thermal burn did not show fatty change. Nongastric carcinogens failed to induce mucosal damage. The relationship of the carcinogen-induced fatty change and mucosal damage to carcinogenesis was discussed.


Mchanisms of antitumor action of Corynebacterium parvum: nonspecific tumor cell destruction at site of immunologically mediated sensitivity reaction to C. parvum.

Mice immunized in the footpad with Corynebacterium parvum developed a systemic mechanism with a potential for destroying syngeneic tumor cells. The development of this mechanism of antitumor action depended on the generation of a state of systemic sensitivity to C. parvum antigens, which allowed an immunologically mediated inflammatory response to be focused at the site of a tumor cell challenge or in the bed of an established tumor. This resulted in complete inhibition of growth of the former regression of the latter. This nonspecific mechanism of tumor cell destruction could be utilized only during a relatively short period when mice were responding maximally to the organism. This corresponded to a period during which there was maximum cell division in the lymph node draining the site of immunization with C. parvum, maximum systemic macrophage activation, and maximum sensitivity to eliciting injections of the organism. The potential for destroying tumor cells could be transferred to normal recipients with lymph node cells from C. parvum-immunized donors, which indicated the distinct possibility that antitumor action was based on the cell-mediated response to C. parvum antigens. That the destruction of tumor cells at the site of a C. parvum sensitivity reaction was associated with a massive influx of mono-nuclear cells provided further support for this possibility.


Autoradiographic evidence for the association of DNA with intracytoplasmic A-particle inclusions in situ.

Mice with subcutaneous transplants of a Leydig cell tumor were given tritiated thymidine sc proximal to the tumor mass. The labeled tissue was collected and samples for autoradiography were taken. Nuclei and intracytoplasmic. A particle(s) (CAP) were purified from the remainder of the tumor pool. The distribution of radioisotopic grains over electron microscopic autoradiography was semiquantitated and analyzed. Granin were found over CAP inclusions in situ. Comparison of the relative frequency of CAP-associated grains to nuclear grains by probability on a planar area basis revealed a higher frequency of thymidine incorporation into these structures. Isolation and comparison of the DNA(s) associated with CAP and nuclei showed a higher specific activity for CAP-associated DNA than for nuclear DNA, which was in good agreement with the autoradiographic analysis. The DNA associated with the purified CAP possessed a significantly higher buoyant density  in CsCl than did the nuclear DNA. These reslult implied that this DNA was present in CAP inclusions in situ.


Spontaneous tumors in ACI/N rats.

One hundred ninety-five spontaneous tumors, developing in 55 male and 209 female ACI/N rats in 169 weeks, were studied. The incidence was 56% (31/55) in males and 52% (108/209) in females; their average survival time was 113 and 108 weeks, respectively. These neoplasms were found in all organ systems except those of the sensory and locomotor systems. In the males, interstitial cell tumors of the testis (45.5%, 25/55) were most frequent, followed by those in the adrenal (16.4%, 9/55) and pituitary glands (5.5%, 3/55), skin (5.5%, 3/55), and urinary bladder (3.6%, 2/55). In female rats, tumors of the pituitary gland (21.1%, 44/209), uterus (12.9%, 27/209), mammary gland (11.1%, 23/209), adrenal gland (5.7%, 12/209), urinary bladder (4.8%, 10/209), thymus and lymph nodes (4.3%, 9/209), subcutaneous tissues (1.4%, 3/209), heart (1.4%, 3/209), vagina (1.0%, 2/209), and salivary gland (1.0%, 2/209) were detected. In addition, tumors of the glandular stomach, small intestine, spleen, trachea, lacrymal gland, ovary, brain, kidney, thyroid, and bone marrow were detected in 1 female each, and those of the small intestine, spleen, lung, and peritoneum in 1 male rat each. Only 6 adenocarcinomas of the uterus, 3 lymphatic leukemias, 1 cortical carcinoma, and 1 mesothelioma of 195 tumors observed in the present studies metastasized to remote organs.


Mode of action of immunosuppressive substances in sera of tumor-bearing mice.

Sera from mice with transplanted 3-methylcholanthrene (MCA)-induced tumors inhibited the proliferative response of normal mouse lymphocytes to mitogens and allogeneic cells. The sera were not toxic to these cells and did not inhibit mitogen responses by an increased binding of mitogen to serum components. The sera could have prevented the initiation of the proliferative response or could have inhibited cells already proliferating. The uptake of 3H-uridine, an event preceding DNA synthesis, was also suppressed. The sera had no effect on proliferation of a normal tissue culture line or an allogeneic tumor cell line induced by MCA. However, sera from tumor-bearing mice slowed growth of the autochthonous tumor cells and allogeneic lymphoma cells but did not completely block their proliferation. Exposure of lymphoid cells to the sera for a period as brief as 1 hour markedly decreased the ability of cells to respond subsequently to mitogens, and washing of the cells did not restore that ability. The inhibitory activity of the sera was only partially removed by absorption with lymphoid cells or cell lines.


Growth of human normal and neoplastic mammary tissues in the cleared mammary fat pad of the nude mouse.

Dysplastic and malignant human breast tissues were grown successfully in the cleared mammary fat pads (CFP) of nude mice. The mammary fat pads were cleared while the mice were in a germfree isolator. Prepared mice were removed fron the germfree enviornment to facilitate transplantation of the human mammary tissue  into their CFP and subsequently were maintained in sterile laminar flow racks.


In vitro growth promotion of rat leukemia L5222 cells in the presence of 2-mercaptoethanol.

Propagation of the transplantable acute rat leukemia L5222 in vitro was highly dependent on the reducing agent 2-mercaptoethanol (2-Me). Maximum growth promotion was obtained in the simultaneous presence of 1.25-2.5 x 10-4m 2-Me and 30% fetal bovine serum in enriched tissue culture medium NCTC 135. A short exposure to the reducing agent insured growth of the leukemia cells for 5 days, but extended culture necessitated constant presence of the thiol. After 2-8 days of culture, inoculation of the cell suspension produced widespread leukemia in inbred BD IX rats.


Colon carcinoma of highly inbred rats.

Colon carcinoma in related WF rats was found in several colonies. The tumors were noted in generations 12-15. Usually, the lesions were detected in 6-month-old animals. However, in later generations, the tumors seemed to occur earlier.


Schistosomiasis: its significance in a changing human ecology.

Schistosomiasis is a man-made disease. Evaluation of the current status of schistosomiasis requires knowledge of the intensity of infection, a measure now dependent on quantitative egg counts and applied to data only on a limited scale. The determinants of intensity of infection are as yet ill-defined. Morbidity and mortality associated with schistosomiasis are difficult to assess in indigenous populations saddled with a multiplicity of diseases. However, the problem of schistosomiasis and its deleterious consequences will rapidly worsen as an expanding population creates new aquatic habitats favorable for the snail intermediate hosts and as people have increased contact with infected water. Moreover, the number of children is increasing fastest in the developing regions of the world. Children and young adolescents are the age groups primarily responsible for the transmission of schistosomiasis. We are in an era when a predominantly young population will increasingly contaminate a finite environment.


Clinically available antischistosomal drugs.

The indications, the contraindications, and the characteristics of the antimonial and nonantimonial drugs clinically available for the treatment of human schistosomiasis are outlined. Of the antimonial compounds, antimony potassium tartrate or antimony sodium tartrate, both given by the intravenous route, are effective against Schistosoma japonicum, S. mansoni, and S. hematobium, but the production of severe side effects limits their use outside the treatment of individuals. Sodium antimonyl gluconate is less effective against S. mansoni and S. hemotobium and is also given intravenously. Of those antimonial compounds given intramuscularly, antimony dimercaptosuccinate is the most effective against all three common human schistosomes. Four available nonmetallic schistosomicides are considered. Niridazole, orally administered, is effective against all three common species of schistosome infecting man, but activity is maximal against S. hematobium. Many minor side effects have been described, but the major and most important side effects, neuropsychiatric symptoms and signs, are fortunately rare. Lucanthone hydrochloride, of moderate efficiency when given orally for S. hematobium or S. mansoni infections, is probably best used as a suppressant in small doses. Troublesome gastrointestinal toxicity limits its therapeutic use. Metrifonate, a cholinesterase-inhibiting organophosphorus compound, is effective only against S. hematobium. Clinical tolerance is very good. Hycanthone mesylate is highly effective against S. mansoni and S. hematobium but ineffective against S. japonicum. It is given as a single intramuscular dose. Many contraindications to its use exist, and acute hepatotoxicity has occurred infrequently. Its association with mutagenicity in certain experimental test systems has stimulated numerous ongoing studies to clarify the implications of its use in humans.


Evaluation of schistosomicides against experimentally established Schistosoma mansoni infections in mice and hamsters.

The procedures employed at the Sterling Winthrop Research Institute for the maintenance of Schistosoma mansoni, method of infection, and measurement of efficacy are discussed. Data are presented illustrating the activities of a number of known antischistosomal agents in mice and hamsters against a Puerto Rican strain of the parasite with a well-documented origin.


Additional statistical evaluation and pharmacological considerations of hycanthone methanesulfonate-induced dominant lethality.

Investigations of the mutagenicity of hycanthone methanesulfonate (HCT) in mammals have led to varied results. To avoid ambiguous interpretation of significant results previously reported in two dominant-lethal studies of HCT a nested analysis of variance was performed on the number of corpora lutea per pregnant female, the number of implantations per pregnant female, average preimplantation losses, the number of dead implants per pregnant female, and the number of live implants. The analysis showed that variability among males and females was not responsible for the reported significant effects and consequently established the validity of the previous studies. Based on a comparison of the mammalian mutagenicity work performed utilizing hycanthone, pharmacokinetic factors are thought to be responsible for the differences seen; consideration of these factors in the future may lead to fewer false-negative results in mammalian systems.


Results of tests for possible transmitted genetic effects of hycanthone in mammals.

Extensive tests to detect transmitted genetic effects of hycanthone in mammals have been made to provide the most pertinent information for estimating a possible mutagenic hazard of this compound. The tests include dominant lethal studies in males and females, X chromosome loss study in offspring of treated females, and a search for deficiencies and gene mutations in the offspring of treated males whose germ cells were exposed in spermatogonial and postspermatogonial stages. In most tests, no genetic effect of hycanthone was observed even at dosages much higher than the clinical level. In the few cases where the results are possibly or definitely positive, there is none where the magnitude of the effect estimated, with maximizing assumptions, at the clinical level reaches as high as 10% of the spontaneous mutation rate or 10% of the frequency in controls.


A study of chromosomes of lymphocytes from patients treated with hycanthone.

The frequency of cells presenting chromosome abnormalities was determined in patients with schistosomiasis before and after treatment with a single dose of 2.5 mg/kg body weight of hycanthone methanosulfonate. No significant effect of the drug was detected with this therapeutic dose.


Evaluation of the teratogenic activity of hycanthone in mice and rabbits.

Hycanthone has been tested for embryotoxic activity in mice and rabbits. Treatment of mice on days 6-11 of gestation produced little embryotoxicity at a dose of 12.5 mg/kg, but produced teratogenic effects at 25 mg/kg and induced almost complete intrauterine death at 50 mg/kg. Single injections on various days of gestation demonstrated that the mouse conceptus is most sensitive to hycanthone-induced teratogenesis on gestation days 6 and 7, at which time a high incidence of exencephaly and skeletal malformations was found. Hycanthone (50 mg/kg) given to pregnant mice on day 7 of gestation depressed DNA synthesis in embryonic tissue, an effect which was evident 30 minutes after drug treatment and which lasted at least 3 hours. Following a single injection of [3H-U]hycanthone into 7-day pregnant mice, radioactivity was rapidly cleared from the maternal plasma, having a half-life of 1-2 hours; higher levels of radioactivity were attained in the embryonic vesicles than in maternal plasma at all time intervals tested. Hycanthone also had embryotoxic activity in rabbits. A dose of 25 mg/kg increased the incidence of intrauterine death, and at 50 mg/kg both embryolethal and teratogenic effects were noted.


Transformation of cell cultures as a parameter for detecting the potential carcinogenicity of antischistosomal drugs.

Several antischistosomal drugs and their metabolites were found to transform rat embryo cell cultures persistently infected with the Rauscher leukemia virus. The transformed cells produced fibrosarcomas when implanted into newborn rats. Cell cultures treated with either virus or chemical alone were not transformed nor were they invasive in rats. The advantages of early screening of developmental drugs in cell culture systems are discussed.


Dissociation of mutagenic and other toxic properties from schistosomicides.

Structural alterations of two schistosomicides (hycanthone and niridazole) can bring about very marked reductions in mutagenic activity without decreasing antischistosomal potency. Therefore, these two effects are not necessarily associated with each other, providing opportunities for the design and development of safer schistosomicidal drugs.


Long-term toxicity of antischistosomal drugs: summary and perspectives.

In addition to the papers presented at the workshop, there were also discussion periods following the presentations and concluding the whole workshop. The various parts in the present section represent summaries of the different discussions that took place at the end of the workshop, except for the first part, which reports on drugs currently used in the treatment of schistosomiasis and makes recommendations for developing new and better drugs. The other parts in this section present the discussions and recommendations dealing with these areas: epidemiology, infected animal studies, in vitro and in vivo test correlations, and benefit vs. risk correlation. The author of each paper served as a rapporteur for these discussion sessions.


[Vesico-renal reflux in adults (author's transl)].

This article is based on an analysis of 88 cases of vesico-renal reflux, 43 primary and 45 secundary ones. The author consider successively the clinical, bacteriological, radiological and endoscopical facts and their relations to the different types of reflux. They emphasize the frequency and the gravity of the primary reflux in adults and its probable connection with the genesis of the non-obstructive pyelonephrities and the unilateral renal atrophies. Its noxioness is primarily connected with the infection. The secundary reflux, however, even infected, is relatively well tolerated in adults. In case of primary vesico-renal reflux the therapeutical conduct has to be extremely well suited. A surgical correction should only be considered if the kidney has satisfactorily maintained its fonction and if the tonicity of the excreting ways is still good enough. In case of secundary reflux, the therapeutical conduct depends first of all on the etiology. In the group of primary reflux 11 patients derived benefit from ureteral reimplantation; whereas in the group of secundary reflux only 5 patients were submitted to an operation. The method applied was that of Paquin.


[Long-term results of conservative surgery for bilateral renal tuberculosis (author's transl)].

Long term results of conservative surgery for bilateral renal tuberculosis treated medically should be examined periodically (clinically, bacteriologically and radiologically) in order to detect early any possible changes in the renal or ureteric lesions, since surgery is sometimes of great benefit in particular in the case of a single kidney. Conservative and reparative operations are essential procedures which must be adapted to each individual case after careful study and only when covered by adequate treatment.


[Neo-bladder made from the rectum in surgical cure of uro-genital malformations (author's transl)].

The authors give a critical account of the results of artificial bladder construction using the rectum in complex genito-urinary malformations, such as, extrophic bladder, failure of correction of epispadias, and discuss 12 personal cases of which 6 out of 10 had been followed up for between 10 and 15 years. One important recommendation: in adults where the shincter system is normal, according to our experience, there is little trouble with urinary or fecal incontinence. In children, it is still necessary to develop a procedure which might permit one to express, numerically, the conclusions of the electrical examination and the volume above which resistance begins to break down. In small boys, after formation of the new bladder, one should attempt to restore micturition by the natural route, by reconstruction of the neck of the bladder, ileoplasty and reimplantation of the ureters in situ.


Protein synthesis in BHK-21 cells infected with semliki forest virus.

[3H]leucine-labeled proteins synthesized in BHK-21 cells infected with Semliki Forest virus were fractionated by polyacrylamide gel electrophoresis (PAGE). Cellular and virus-specific proteins were identified by difference analysis of the PAGE profiles. The specific activity of intracellular [3H-A1leucine was determined. Two alterations of protein synthesis, which develop with different time courses, were discerned. (i) In infected cultures an inhibition of overall protein synthesis to about 25% of the protein synthesis in mock-infected cultures develops between about 1 and 4 h postinfection (p.i.). (ii) The relative amount of virus-specific polypeptides versus cellular polypeptides increases after infection. About 80% of the proteins synthesized at 4 h p.i. are cellular proteins. Since significant amounts of nontranslocating robosomes in polyribosomes were not detected up to 7 h p.i., the inhibition of protein synthesis is not caused by inactivation of about 75% of all polyribosomes but by a decreased protein synthetic activity of the majority of polyribosomes. Indirect evidence indicates that an inhibition of elongation and/or release of protein synthesis develops in infected cells, which is sufficient to account for the observed inhibition of protein synthesis. Inhibition of over-all protein synthesis developed when virus-specific RNA began to accumulate at the maximal rate. This relationship was observed during virus multiplication at 37, 30, and 25 C. A possible mechanism by which synthesis of virus-specific RNA in the cytoplasm could inhibit cellular protein synthesis is discussed. Indirect evidence and analysis of polyribosomal RNA show that the increased synthesis of virus-specific protein is brought about by a substitution of cellular by viral mRNA in the polyribosomes.


Viral RNA synthesis and levels of DNA-dependent RNA polymerases during replication of adenovirus 2.

The rates of RNA synthesis in cultured human KB cells infected by adenovirus 2 were estimated by measuring the endogenous RNA polymerase activities in isolated nuclei. The fungal toxin alpha-amanitin was used to determine the relative and absolute levels of RNA polymerases I, II, and III in nuclei isolated during the course of infection. Whereas the level of endogenous RNA polymerase I activity in nuclei from infected cells remained constant relative to the level in nuclei from mock-infected cells, the endogenous RNA polymerase II and III activities each increased about 10-fold. These increases in endogenous RNA polymerase activities were accompanied by concomitant increases in the rates of synthesis in isolated nuclei of viral mRNA precursor, which was quantitated by electrophoretic analysis on polyacrylamide gels. The cellular RNA polymerase levels were measured with exogenous templates after solubilization and chromatographic resolution of the enzymes on DEAE-Sephadex, using procedures in which no losses of activity were apparent. In contrast to the endogenous RNA polymerase activities in isolated nuclei, the cellular levels of the solubilized class I, II, and III RNA polymerases remained constant throughout the course of the infection. Furthermore, no differences were detected in the chromatographic properties of the RNA polymerases obtained from infected or control mock-infected cells. These observations suggest that the increases in endogenous RNA polymerase activities in isolated nuclei are not due to variations in the cellular concentrations of the enzymes. Instead, it is likely that the increased endogenous enzyme activities result from either the large amounts of viral DNA template available as a consequence of viral replication of from replication or from functional modifications of the RNA polymerases or from a combination of these effects.


DNA-minus temperature-sensitive mutants of adenovirus type 5 help adenovirus-associated virus replication.

Efficient potentiation of adenovirus-associated viruses (AAV) replication occurs in coinfections with either of two DNA-minus temperature-sensitive mutants of adenovirus type 5 (Ad5), ts125 and ts149. The helper activity of these mutants does not result from leakiness. At the nonpermissive termperature (39.5 C) there was little or no detectable adenovirus DNA synthesis, and only a relatively low level of adenovirus transcription was observed. However, the synthesis of AAV DNA and RNA and the yield of infectious AAV were comparable in amounts to those found when wild-type Ad5 was the helper. Furthermore, an apparent lag in the initiation of AAV transcription after the onset of AAV DNA synthesis was seen in coinfections with both wild type or ts125. These findings strongly suggest that the adenovirus factor(s) required for AAV multiplication is produced early in the adenovirus DNA replication, this requirement does not include all factors directly needed for adenovirus DNA synthesis.


Restriction enzyme digests of rapidly renaturing fragments of vaccinia virus DNA.

Vaccinia virus DNA fragments that have been denatured by alkali and then neutralized contain a fraction that rapidly reforms duplex structures. The fraction is enriched by fractionating on hydroxyapatite columns and serves as as substrate for digestion by two restriction endonucleases isolated from Hemophilus parainfluenzae, Hpa I and HPa II. The patterns obtained by gel electrophoresis of the digested fragments show the presence of three major bands after Hpa I digestion and four major bands after Hpa II digestion. The DNA that is isolated from some of these bands quickly reforms duplex regions after alkaline denaturation. The size of the DNA segments in the major bands has been estimated to be in the range of 0.44 X 10(6) to 3.2 X 10(6) daltons. The fragments which rapidly reform duplex chains after denaturation are sensitive to single-strand-specific nucleases. These results are consistent with a model of vaccinia virus DNA which has a covalent link connecting complementary chains.


Rapid purification of 70S RNA from media of cells producing RNA tumor viruses.

Media from cells producing RNA tumor viruses, when treated with sodium dodecyl sulfate and polyvinyl sulfate, yield 70S RNA as the major species binding oligo(dT)-cellulose. The procedure described for purifying 70S RNA requires no special equipment and is suitable for rapidly processing large quantities of media or for purifying RNA from commercially avialable virus, with a 5- to 10-fold higher yield than was obtained using existing methods.


Molecular weights of DNA from bacteriophages T5, T5st(O), BF23, and BF23st(4).

The DNA molecular weights were determined by calibrated electron microscopy. The results (in units of 10(6)) are: for T5, 77.4 +/- 2.4 T5st(O), 72.4 +/- 1.9; BF23, 76.7 +/- 2.3; and BF23st(4), 71.4 +/- 1.7.


Comparison of RNA polymerase associated with Newcastle disease virus and a temperature-sensitive mutant of Newcastle disease virus isolated from persistently infected L cells.

An in vitro comparison was made of the RNA polymerase activity associated with Newcastle disease virus (NDVo) and three clones of the temperature-sensitive mutant (NDVpi) isolated from persistently infected L cells. Less polymerase activity was associated with the NDVpi clones. Also, compared to NDVo, an increase in incubation temperature from 32 to 37 or 42 C resulted in a marked decrease in polymerase activity for the temperature-sensitive mutants which coincided with their inability to replicate at 42 C.


Unit activity in somatosensory area II (SII) and tooth pulp stimulation in a cat.

Within and near the rostral half of the anterior ectosylvian gyrus of an unanesthetized chronic cat, properties of units which responded to stimulation of the ipsilateral upper canine tooth pulp were studied. In total 75 responsive units were recorded by 192 microelectrode penetrations. Discharge patterns of these units to pulp stimulation were classified into 3 types: single spike response (4 units), short burst response (66 units) and prolonged response continuing up to several hundred msec (4 units). Spontaneous activities of one exceptional unit were depressed for 200-300 msec after pulp stimulation. These units were scattered in the explored cortical area, indicating that the SII somatotopically organized area may also receive nociceptive inputs. Most of these units responded to some modalities of mechanical stimuli applied to various parts of the body surface including face and head. This result suggests that they may correspond to the neurons unspecific with regard to modality and place observed in the anesthetized cat. Few units activated by pulp stimulation were encountered in the rostral portion of the anterior ectosylvian gyrus, where MELZACK and HAUGEN (1957) recorded the evoked potential by pulp stimulation. Five tooth pulp-sensitive units which were excited only by pin pricks and/or firm pressure were encountered on the dorsal bank of the anterior ectosylvian sulcus, the non-somatotopically organized area of SII.


A method of analysis of the pulmonary gas exchange system.

This method of system analysis is based on O2 and CO2 concentration curves obtained simultaneously from expired air during constant flow expiration. First, theoretical equations for alveolar O2 and CO2 curves were derived by using a simple gas exchange model. By substituting them with the measured data on alveolar gas concentrations and volume, such parameters as O2 uptake VO2, pulmonary blood flow Q and venous PCO2 were estimated. Expired air was continuously analyzed by means of a glow discharge gas analyzer and the alveolar gas volume was measured immediately after the gas analysis using a body plethysmograph. The estimated Q value showed a dispersion of about 14% average standard deviation in each subject, but other parameters showed no large variation. The average Q values of several measurements, however, corresponded with those obtained by an acetylene inhalation method. The VO2 also corresponded well with that measured by spirometry. This coinciding data seemed to reveal that the model was reasonable for the analysis. CO2 output, by virtue of the Haldane effect, was examined through the analyses in both normoxia and hypoxia in 9 normal subjects. No significant effect was observed.


Inhibition of hypoglossal motoneurons by stimulation of the jaw-opening muscle afferents.

The synaptic linkage of jaw-opening muscle afferents with the retractive and the protrusive motoneurons (R-Mns and P-Mns) in the hypoglossal motor nucleus was explored in anesthetized cats. It was found that stimulation of low-threshold afferents arising in the jaw-opening muscles (m. mylohyoideus and m. digastricus) evoked IPSPs in both R-Mns and P-Mns with about 10 to 15 msec latencies. By injecting Cl ions into R-Mns or P-Mns, the hyperpolarizing postsynaptic potentials evoked by jaw-opening muscle afferent impulses were reversed to depolarizing potentials. The lingual-IPSPs of hypoglossal motoneurons were concluded to be dependent on increase of Cl conductance. Stimulation of low threshold lingual afferents evoked a reflex discharge in the retractive nerve fibers with a 6.0 msec latency and in the protrusive nerve fibers with a 5.5 msec latency. Inhibition of the linguohypoglossal reflex by stimulation of the jaw-opening muscle afferents was completely removed by an intravenous injection of strychnine (0.1 mg/kg) or picrotoxin (6 mg/kg). It is concluded that the low threshold afferents arising in the jaw-opening muscles are connected to both R-Mns and P-Mns and P-Mns through inhibitory synapses via a polysynaptic pathway.


Thermal influence on palmar sweating and mental influence on generalized sweating in man.

Sweat rates on the forearm and on the palm were simultaneously recorded by resistance hygrometry and the mode of sweating in these areas in response to thermal and non-thermal stimuli were compared with each other. In Series A, periodic infrared irradiation (1 min on, 1 min off) was done to the back of the trunk, and reflex responses in sweat rate were recorded on both test areas. A high correlation was noted between the mean changes in the palmar sweat rate and those in the forearm one during the irradiation cycle in a majority of cases. However the magnitude of the sweat response was much less on the palm than on the forearm. These observations reveal that the central mechanism of palmar sweating may be affected to some extent by the thermoregulatory mechanism. Series B was concerned with the pattern of response in forearm sweating to various non-thermal stimuli. Careful observations showed that the forearm sweating responded diversely to various mental stimuli, unlike the palmar sweating whose response was always an increase. Mental arithmetic, mental testing and physical exercise caused an immediate increase in the palmar sweating but often elicited a transient decrease in the forearm sweating, whereas pain, noise, and emotional stimuli consistently provoked an increase of sweating on the forearm as well as on the palm. These observations suggest that the activities of higher centers, presumably involving neocortex and limbic cortex, exert various influences on the central mechanisms of palmar and generalized sweating.


Protein synthesis in mouse brain during development of acute morphine tolerance.

In order to observe the effects of morphine on protein metabolism in mouse brain, experimental procedures were carried out over a 7 hr period of infusion. When the analgesia reached a peak, namely around 2 hr after the start of infusion, the in vivo incorporation of radioactive leucine into protein estimated by the dual label technique was uniformally depressed in all the examined subcellular fractions of both brain and liver. After tolerance developed, however, the incorporation of leucine increased to a much higher level than the control in brain subcellular fractions and the increase was masked by naloxone. In contrast, the incorporation into a TCA soluble fraction of the brain S2, separated by Gray and Whittaker's method, was more than doubled even after 4 hr infusion. While the in vitro incorporation rate of the mitochondrial fraction significantly fluctuated during development of tolerance with naloxone that of the synaptosomal fraction did not fluctuate. The observed coincidence in the time course of development of tolerance and changes in the brain protein synthesis indicates a possible relationship between the phenomena, though the causal nature of the relationship could not be elucidated.


Effect of diltiazem on electrical and mechanical activity of isolated cardiac ventricular muscle of guinea pig.

Diltiazem, a new 1,5-benzothiazepine derivative, antagonized calcium ion and thus caused a reduction in the contractile force of isolated papillary muscle. The antagonistic ratio of diltiazem to calcium ion was estimated to be approx. 1: 100. A lower concentration of diltiazem (2.2 x 10(-6) M) decreased the contractile force without affecting significantly the intracellularly recorded resting and action potentials. When the concentration of the compound was increased to 2.2 x 10(-5) M, only the maximum rate of rise of the action potential was reduced, while the other parameters of the action potential were also affected at 1.1 x 10(-4) M diltiazem. There was no significant change in the resting potential. Under conditions where the contractile force almost disappeared (1.1 x 10(-4) M), the membrane excitability was retained. It is concluded that diltiazem is an excitation-contraction  uncoupler in the cardiac muscle cell and that the compound may exhibit its negative inotropic action by reducing in some way the intracellular concentration of free calcium ion available for the contractile mechanism.


Effects of S-8527 (1, 1-bis (4'-(1"-carboxy-1"-methylpropoxy) phenyl) cyclohexane), a new hypolipidemic compound, on platelet aggregation, adhesiveness and blood coagulation in rats.

Effects of S-8527 (1,1-bis[4'-(1"-carboxy-1"-methylpropoxy) phenyl] cyclohexane) on platelet aggregation, adhesiveness and blood coagulation were examined in rats. In animals maintained on a semisynthetic diet containing sucrose (62%) as the only carbohydrate source, platelet adhesiveness increased as compared with that in rats fed a normal chow pellet. Under these experimental conditions, oral dose of S-8527 (30-300 mg/kg) for 14 days decreased platelet adhesiveness and ADP-induced platelet aggregation, but did not decrease collagen-induced platelet aggregation. S-8527 also showed a slight but significant increase of R value of thrombelastograph. In rats which were fed a normal chow pellet oral dose of S-8527 for 14 days did not significantly affect the several tests of platelet function and blood coagulation. These results suggest that S-8527 normalizes the platelet function in a hyper-adhesive state, but does not affect the platelet function in a normal state.


Coronary vasodilatation and adrenergic receptors in the dog heart and coronary.

The question of whether the coronary blood vessels contain an intrinsic adrenergic mechanism for vasodilatation of physiological significance has been examined in the canine heart-lung preparation with a donor by studying the response of the coronary vessels to epinephrine, norepinephrine, isoproterenol and salbutamol in combination with practolol. To differentiate the vasodilatation mediated through adrenoceptors in the coronary vessels from that resulting from an increase in the myocardial O2 consumption, a special method of analysis was developed based on the linear relation between the coronary flow and the myocardial O2 consumption. It was found that all four compounds produced an increase in the coronary flow attributable to an increased myocardial O2 consumption. Epinephrine and norepinephrine produced a decrease in the coronary flow after practolol which completely abolished the increase in the myocardial O2 consumption as well as the positive inotropic and chronotropic effects produced by these compounds, while isoproterenol and salbutamol produced an increase. These results indicate that adrenergic beta-receptor exists in the coronary subserving a vasodilatation. However, the vasodilatation through this mechanism is of minor importance under physiological conditions and becomes completely masked in the presence of an overwhelmingly strong vasodilatation consequent to an increase in the myocardial O2 consumption.


Comparison of the effects of norepinephrine and acetylcholine between intraarterial and extravascular administration to the isolated, blood-perfused canine atrium.

Effects of acetylcholine (ACh) and norepinephrine on atrial contractility and pacemaker activity were investigated in isolated and blood-perfused canine atrium preparations whith a support dog which were suspended in the blood-filled bath kept at 37 degrees C. The drug was given in two forms of administration, i.e., intraarterial injection into the cannulated sinus node artery or direct administration into the bath. ACh administered into the bath produced a significant decrease in the developed tension from a concentration of 10(-5) g/ml and norepinephrine produced a significant increase in the developed tension from 3 X 10(-6) g/ml. An injection via the sinus node artery resulted in 300 and 100 times greater response to ACh and norepinephrine, respectively, in the tension development. In atrial pacemaker activity, ACh given into the bath did not produce a dose-related decrease while norepinephrine produced a dose-related increase frequently accompanied by an irregularity of rhythmicity.


Modifications of responses to adrenergic drugs in arterial strip by treatment in vivo with ephedrine and reserpine.

The aim of the present experiment was to investigate effects of ephedrine and reserpine, administered in vivo, on responses of dog isolated arterial strips to adrenergic drugs, and to study a possible mechanism involved in the reversal of blood pressure responses to dopamine. Dose-dependent contractile responses to adrenaline (A), dopamine (DA) and ephedrine (ED) were depressed in the femoral strips isolated from the ED-treated dogs as compared with those isolated from the untreated dogs. Those to noradrenaline (NA) were potentiated in low concentration and in hibited in high concentration, though those to tyramine (TY) were not altered. Relaxing and contractile responses to isoprenaline (IP) were inhibited. DA did not induce a relaxing effect but a contractile one even in the strips brought to a state of moderate tone with ED or phelypressin. In the strips isolated from the reserpine-treated dogs, contractile responses were to some extent potentiated by NA, A and DA, and significantly by ED, while those to TY were inhibited. Relaxing responses to IP were reduced and contractile responses potentiated. In the strips extirpated from the reserpine and ED-treated dogs, contractile responses to NA and A were potentiated in low concentration and tended to be potentiated in high concentration whereas those to DA and ED were not affected. Dose-dependent relaxing effects of DA in the dog renal and mesenteric strips contracted previously by KCl after phenoxybenzamine were attenuated by treatment with ephedrine in vivo. The results suggested that the dopamine reversal in the blood pressure may be mainly due to actions other than its peripheral effect on the blood vessels.


Cyanotic congenital heart disease: Surgical techniques and pitfalls.

A review is presented of the currently employed approaches and techniques for the treatment of several forms of cyanotic congenital heart disease. Emphasis is placed on unusual associated defects which require special approaches for management. The question of definitive repair in infancy, as opposed to early palliation and later repair, is particularly pertinent to these conditions. It is evident that considerable progress has been made during the thirty-year evolution of surgery for congenital heart disease, but there are many advances yet to be made.


Histological characteristics and postoperative course of gastric carcinoma.

The histological features of gastric carcinoma in patients survived more than 5 years after the resection were reviewed. In general prognosis and length of survival were related clearly to the degree of malignancy of cancer. Duration of the remission was also reciprocaly related. Certain type of carcinoma simplex or undifferentiated carcinoma was associated with unexpectedly more favorable prognosis. Paradoxical relation was also demonstrated between degree of atypism in adenocarcinoma papillare with introversive pseudopapillary pattern and its prognosis.


Prophylactic administrations of aspirin for the prevention of thrombo-embolic complications in postoperative reactive thrombocytosis.

Hyperfunctioning platelets in the thrombocytotic patients after major surgery were satisfactorily controlled by a small dose of aspirin ingestion. Since aspirin is well documented as a potent inhibitor of platelet aggregation, a small dose of prophylactic administration of aspirin appeared to be a legitimate approach to a possible life-threatening thrombo-embolic complication after surgery, particularly when the platelets are excessively produced and hyperfunctioning.


Occurrence of pulmonary insufficiency in abdominal trauma.

The alteration of pulmonary function in 35 patients with abdominal trauma admitted to the Trauma ICU of Oska University Hospital were studied. A fall of PaO2 reaching the lowest level on the third post-traumatic day, incomplete recovery even on the seventh posttraumatic day and of longer duration was remarkable in comparison to those seen after elective abdominal surgery. Thirty two patients recovered without need of particular respiratory control but remaining three died with progressive decrease of PaO2 in spite of the intensive respiratory care. The hypoxia seen in the fatal cases was irresponsive to the administration of 100 per cent O2 with mechanical ventilation. Therefore, increase in intrapulmonary shunt was likely to be responsible for their fatal course.


Acute gangrenous colitis proximal to obstructive cancer of the sigmoid colon.

Two cases of massive gangrenous inflammation of the colon proximal to obstructive carcinomatous lesions, the so-called obstructive colitis, are reported. Because of the rarity of this condition, the etiological factors responsible for this entity are not yet clear. The detailed pathological and microbiological studies at the time of operation are essential to their further clarification.


Mild beta-thalassemia in black subjects.

In two American black families with beta-thalassemia, globin chain synthesis was investigated in vitro. The resultant alpha/beta and alpha/non-alpha labelling ratios were expressed in terms of both specific activity and total counts. In one family, two brothers with clinical presentations compatible with thalassemia intermedia had apparently each inherited two different beta-thalassemia alleles. Thus, they are compound heterozygotes. Their alpha/beta (or alpha/non-alpha) ratios were in the same range as those found in Caucasian subjects with severe Cooley's anemia. In addition, alpha/beta ratios in heterozygotes in this study were the same as those found in Caucasian heterozygotes. A difference in degree of chain imbalance measured by our present method cannot explain the relative lack of severe clinical manifestations of beta-thalassemia in blacks. Further family studies are indicated to discover other genetic or environmental factors modifying the effects of beta-thalassemia.


Early diagnosis of ischemic necrosis of the femoral head.

Intraosseous pressure in the intertrochanteric region, and response to a five mililiter saline load injected intraosseously were measured in twenty-four hips in twenty patients with ischemic necrosis of the femoral head and nine hips in seven controls. All hips in which subsequent biopsy proved ischemic necrosis of the femoral head showed either intraosseous pressure greater than 30 mmHg, a hypertensive response to the saline load, or both. All controls measure less than 30 mmHg intraosseous pressure and no significant pressure rise to the saline injection. Intramedullary venography in ischemic necrosis of the femoral head revealed poor filling of extraosseous veins, diaphyseal reflux and delayed clearance of dye. These changes were present in all stages of ischemic necrosis of the femoral head including the pre-radiologic stage and constitute the basis for early detection.


[Relationship between lipid and carbohydrate metabolism and hyperinsulinemia in coronary arteriosclerosis].

The disorders in the carbohydrates metabolism were studied along with the level of insulinemia in patients with coronary atherosclerosis, and the interrelationship between the pathological shifts in the lipid and carbohydrates metabolism were clarified. The study was conducted in 45 persons: 31 patients with coronary atherosclerosis and 14 normals. The indices of the lipid (cholestrol, triglycerides, NEFA, lipoproteids) and carbohydrates metabolism (blood sugar immunoreactive insulin) were analysed on an empty stomach and after glucose provocation. Twenty of the 31 patients demonstrated hyperinsulinemia, 25--an altered tolerance of carbohydrates. The authors believe that in atherosclerosis hyperinsulinemia develops against the background of pre-existing disorders in the lipid metabolism, and correlates with the degree of the increase in atherogenic lipoproteids.


[Comparison of electrocardiographic data with morphological picture of atrial infarct].

The electrocardiographic changes were studied in autopsyproven fresh atrial infarction and compared with the morphological pattern of the lesion. The infarction was found to localize predominantly in the posterior wall of the right atrium. The morphological pattern of atrial infarction was similar to the changes developing in focal lesions of the left ventricular myocardium. The electrocardiographic pattern was characterized by the development of various rhythm and conductivity disorders, PQ (S-TP) segment shift, longer duration of the P wave, changes in its morphology, increase in the Macrus index. The electrocardiographic signs were demonstrated most comprehensively in cases of transmural lesions and with approximately the same rate on the 1st, 2nd, and 3rd day of the lesion.


[Meso-telesystolic sounds in children].

Many years of observations over 80 children with meso-telesystolic clicks have brought evidence that these clicks usually come in combination with late systolic murmur and specific alterations in the posterio-phrenic portion of the left ventricle myocardium. The prevalent view today is that at the root of this interrelated triad lies a single intracardiac pathogenetic mechanism triggered by various causative factors. The pathology in question is met with in children of different age and may appear as a consequence of congenital maldevelopment, of an overt or cubclinical inflammation and also of a fibrotic process in the subvalvular region of the posterio-phrenic portion of the left ventricle. Clinical observations point also to the etiological part played by the rheumatic heart disease in the development of the said changes. It is on rare occasions only that the systolic click is of an extracardiac origin, being caused by pleuropericardiac adhesions. The meso-telesystolic click and late systolic murmur, being an expression  of a mild and moderate mitral insufficiency, have a favourable prognosis.


[Treatment of circulatory insufficiency in patients with ischemic heart disease with digoxin and determination of its concentration in the blood serum by radioisotope method].

The radioisotope method with Rb86 was used for determining in vitro the serum concentration of Digoxin. The study was conducted in 57 patients with cardiac insufficiency in the acute period of myocardial infarction and with post infarction cardiosclerosis. The mean values of Digoxin concentration depending on the daily maintenance dose were obtained. The direct correlation between the amount of the drug taken and the content of the drug in the blood serum was proved. Digoxin intoxication was found to develop in cases of its content exceeding the mean level for the given dosage (4 patients), however, in 2 patients signs of intoxication developed with a low concentration of Digoxin. The causes favouring the development of intoxication are discussed.


[Use of gutimine for treatment of chronic coronary insufficiency].

The therapeutic effect of an antihypoxic drug--Gutimine--was studied in 30 patients with chronic coronary insufficiency. The effect of gutimine on the adaptation for physical exercises connected with motor hypoxy in 5 normal individuals was used as control. The treatment with Gutimine resulted in a clear subjective improvement (less frequent and less intense anginal attacks) in 2/3 of the patients with chronic coronary insufficiency. Objective signs of improvement (positive ECG shifts, phases of the left ventricular systole and hemodynamics; increased tolerance of physical exercises) after Gutimine therapy were noted only in 4 patients who had a comparatively mild course of their disease and less distinct sclerotic changes in the myocardium. When Gutimine was used in normals, significant improvement of their capacity for work was noted, as well as an improvement of their cardiovascular functions and gas exchange parameters during "extreme" exercises. The positive effect of Gutimine was more distinct after 1-2 weeks of its administration. Side effects were absent.


[Comparative characteristics of the effect of curanthil on blood vessels of different organs].

In experiments on dogs conducted by means of resistography Curanthil (Dipyridamol) was shown to produce a consistent fall in the resistance to the blood flow in the cardiac vessels due to their active depressor reaction. Besides, Curanthil helps a distinct fall in the resistance of the vessels of the small intestine, sceletal muscles and, to a lower degree, of the brain. These data do not support those of a selective coronary-dilating action of this drug. The reaction of the renal vessels to Curanthil was not uniform and was predominantly of a pressor nature.


[Contractile function and the effectiveness of oxygen utilization by the heart during adaptation to hypoxia].

Experiments on isolated functioning hearts of rats established that under equal filling pressure the hearts of the animals who are adapted to the periodic effect of hypoxy develop a higher force and rate of contractions; ultimately, the contractile function of such hearts, as calculated per unit of myocardial mass and unit of time, appears to be increased by 1/3. Oxygen consumption by the hearts of adapted animals does not much differ from the control values, and consequently, the efficiency of oxygen utilization increases approximately by 1/3. A considerable increase of adrenoreactivity of the hearts of adapted animals is also noted. The obtained data are discussed proceeding from the assumption that an increased power of the potassium pump in the sarcoplasmatic reticulum of the myocardium of adapted animals may influence the coupling of oxydation with phosphorillation in the mytochondria.


[Histoxic hypoxia as one of the causes of ventricular fibrillation and decreased myocardial contractility].

Long-lasting infusions of adrenalin were demonstrated to result in histotoxic hypoxy of the myocardium and its decreased contractility. After a preliminary ligation of several branches of the coronary arteries such situations often caused ventricular fibrillation. The restoration of the myocardial contractility and of the oxydation processes was achieved by the administration of Unithiol, Methionin, Cystein and Succimere. The latter often produce an unusual effect--arrest of ventricular fibrillation and restoration of a normal cardiac rhythm without electric defibrillation. The beneficial effect of these drugs is attributed by the authors to the presence of thiol groups in their structure.


[Stimulation of protein synthesis in damaged cardiac muscle with RNA preparations].

Local injuries of the myocardium in rats induced by means of diathermocoagulation, as judged by the inclusion of C14-labelled aminoacids, stimulate the reparative biosynthesis of proteins in the injured and intact zones of the myocardium. Intraperitoneal administrations of a polymer RNA preparation from the cattle liver (6 mg/100 g of body weight) enhance the biosynthesis of proteins in the injured and intact zones of the myocardium 1.5--2--fold. The enzymatic hydrolyzate of RNA produces a less distinct stimulating effect. The authors believe that the RNA preparations may find their place in clinical stimulation of the reparative processes in the injured myocardium.


[Content of sugar and immunoreactive insulin in the blood of patients with myocardial infarct].

The content of sugar in the blood and that of immunoreactive insulin was determined in myocardial infarction cases on the 1st, 7th and 30th day. On the 30th day the carbohydrates tolerance test was conducted, and the content of immunoreactive insulin was determined after a glucose provocation. The assessment of glycemia and of the content of immunoreactive insulin was made in accordance with the type of the sugar curve. Hyperglycemia during the acute period of myocardial infarction was detected in 1/3 of the patients, a decrease of carbohydrates tolerance--2/3. Transient hyperglycemia was observed in persons in whom the glycemic and insulinemic curves resembled those in diabetes mellitus. The patients of this group displayed the same symptoms as those with diabetes mellitus. The dynamics of the content of the immunoreactive insulin from day to day of the disease differed in patients with transient hyperglycemia from those with normoglycemia.


Surface areas of brush border and lateral cell walls in the rabbit proximal nephron.

A morphometric technique is used to estimate the absolute and relative surface areas of the brush border microvilli and cell walls bordering lateral intercellular spaces. In isolated, perfused proximal tubule from rabbit, the luminal and lateral surfaces are equal in area. For proximal convoluted tubules (PCT) each surface is 4.1 +/- 0.3 mu2/mu3 of epithelial cell volume or approximately 2.9 X 10(6) mu2/mm of tubule length. In proximal straight tubules (PST) the areas are 2.6 +/- 0.2 mu2/mu3 or 1.2 X 10(6) mu2/mm. Brush border enlarges the apical cell surface 36-fold in PCT and 15-fold in PST. The luminal and lateral cell surfaces each are approximately 20-fold (in PCT) and 10-fold (in PST) greater than the areas of the basal cell surface and tubule basement membrane. These data may be important in the context of an intercellular transport model.


Growth in experimental renal failure: role of calorie and amino acid intake.

In order to evaluate the role of calorie and protein intake in growth impairment due to chronic renal failure (CRF), a subtotal nephrectomy was performed in weanling Wistar rats. A two-thirds reduction of renal function was obtained, which induced a marked growth retardation. Growth retardation was identical in nephrectomized and in pair-fed controls, and thus appeared to be entirely due to a deficient food intake. Using low protein diets, administration of a supplement with small amounts of essential amino acids (EAA) resulted in accelerated growth associated with a higher calorie intake, a better utilization of ingested calories for growth and a greater fall of blood urea nitrogen concentration.


Effects of furosemide on low-dose mercuric chloride acute renal failure in the rat.

The use of potent diuretics in acute renal failure remains controversial. Both beneficial and detrimental effects have been reported. In the present study, the effects of both low and high doses of furosemide administered in the developmental and established stages of mercuric chloride-induced acute renal failure were evaluated. Both low and high doses of furosemide produced a significant diuresis when given early in the course of experimental acute renal failure. Despite this diuresis, furosemide did not modify the development of the acute renal failure. Continued administration of a low dose of furosemide had no effect on renal function; however, prolonged administration of high doses of furosemide resulted in significantly lower creatinine clearances 48 hr after induction of acute renal failure. This detrimental effect was due to sodium depletion by the diuretic since it was prevented by continuous replacement of urinary sodium losses. In the absence of sodium depletion, high doses of furosemide produced a significant diuresis, both in the developmental and established phases of acute renal failure, but it had no effect on the degree of renal functional impairment.


Transepithelial potential difference profile of the distal tubule of the rat kidney.

In a recent micropuncture study electrodes with relatively large tips (3 to 5 mu O.D.) and, hence, low tip resistances were used to measure the transepithelial potential difference (PD) across the proximal tubule of the rat kidney. The present study reexamines the PD of the distal tubule of the rat kidney using such electrodes. In contrast to previous studies where a negative PD has been uniformly found in the distal tubule, the transtubular PD was found to be positively oriented (+3.7 mv) when particular efforts were made to puncture the earliest accessible segments. In accord with previous observations, the PD of the late segment was consistently negative (mean, -19.6 mv). Morphologic examination of the epithelium at the site of puncture suggests that in the very early distal tubule where positive potentials are recorded, the epithelium is characteristic of the distal convoluted tubule. By contrast, in the latter part of the distal tubule, where negative potentials are recorded, the epithelium displays the morphologic characteristics of the cortical collecting duct. The results of these studies suggest that the net transport properties of the distal tubule, that is the region of the nephron beginning just beyond the macula densa and extending to the first junction with another renal tubule, are a composite of activities of at least two types of epithelium.


[Some clinical aspects concerning diplopia after retinal detachment surgery with cryopexy and episcleral silastic sponge (author's transl)].

The aetiology of diplopia following retinal detachment surgery after the Lincoff-Custodis method is examined. Of 140 patients operated, 16 (i.e. 11.4%) developed diplopia. The authors believe that this diplopia is due to a fixation of the eyeball at the point of the silastic sponge placement. As responsible factors, which depend on the manner of sponge fixation and the size of the sponge, they regard: Alteration of the bulb curvature, shortening of the Tenon's capsule placed over the sponge, and changes in the conditions of muscular action.


[Mechanical factors contributing to the cause of retinal detachment (author's transl)].

There is no doubt that besides the anatomical changes in vitreous and retinal structures mechanical factors are involved in producing retinal detachment. Especially vertical accelerations can produce fast movements of the vitreous, which also can induce the retina. To investigate the effect of various external movements upon the eye a number of experiments were made: 31 variations of movements with and without different vehicles at different speeds have been investigated. As direct measurements of acceleration of the eye are not possible at present, the upper verges of the orbitae were chosen as measuring point. Additionally accelerations were measured nearest to the place of the entrance of vibration to the body in order to examine the transmissibility of vibration to the orbita. The transduced signal of the accelerometer was recorded on a tape. When measuring in vehicles or riding, radiotelemetry of the signal was used. The statistical analysis of the results was performed. Typical frequencies were found in which the amplitude of the induced acceleration even is enlargen on its way through the body to the orbita. The significance of the different results for producing dangerous mechanical stress to the eye is discussed.


[Block-excision of intraocular processes. II. Epithelial ingrowth into the anterior segment of the eye (author's transl)].

Extensive posttraumatic epithelial ingrowth was completely removed by block-excision of 10 to 11 nm diameter from 3 eyes. The cyst is excised together with adjacent cornea, sclera, iris and ciliary body as a single "block". Thus direct manipulation of the delicate wall of the intact cyst is avoided, the invading epithelium is totally eradicated and a recurrence impossible. The defect of the globe extending up to 6 mm beyond the limbus is covered by a tectonic corneal graft. This procedure was derived from a clinicopathologic study of 35 epithelial ingrowths among 1300 enucleations between 1966-1974. Attempts of excision confined to cornea and iris always have been incomplete. 25 enucleated globes with epithelial ingrowth revealed an attached retina in 16 eyes indicating probably useful visual acuity in case of early complete "block-excision".


[Visual training of partial blinds due to organic lesions (author's transl)].

The immanent sense of optic orientation in space is related to the unchangeable line of principal visual direction and its collaterals. Therefore in patients with loss of central vision due to organic lesion the orientation in space is impaired as well. as a result of a vicious circle of indistinct vision, eccentric fixation and suppresion of foveal perception. By a systematic training the normal sense of direction may be restored and thereby relatively good orientation and by reactivation of the suppressed macular perceptions some reading ability may be regained. Based on experience during 15 years the special diagnostic, the training course and the results of the method are reported and the possibility of rehabilitation of patients with to a high degree impaired central vision due to organic lesions is shown.


[Angiographic diagnosis of hemangiomas in the orbital region (author's transl)].

The polymorphus hemangiomas-especially those of the cavernous type in the orbital region, the face, the scalp or the rhinopharynx are not demonstrable neither by arterial nor venous angiography. If direct puncture of the angioma is possible, the injection of radioopaque medium shows a characteristic picture. The smooth limitation, partial septation and the delayed outflow of contrast medium are important criterions for the differential diagnosis. Moreover the delimitation of the hemangioma from the surrounding tissue is possible and the best surgical access can be selected. If the expanding process is situated in the orbit, and has reached a certain size, the venography of the orbit indicates the extent and localization of the orbital mass.


[Differential diagnosis of bitemporal paracentral visual fields defects in "low-tension glaucoma" and tumors of the pituitary gland (author's transl)].

A 46-year-old patient shows paracentral scotomas in the oblique meridians of the visual fields. Additionally there exists pathologically cupped, atrophical disks which lead to the tentative diagnosis of "low-tension glaucoma". As the scotomas are bitemporally located a tumor near the chiasm must be the cause for these field defects. During the operation a chromophobe adenoma of the pituitary gland was found in the patient. We pointed out that even arcuate scotomas which cross the vertical meridian of the visual field can be caused by an intra- or parasellar tumor. As Hoyt has shown in his investigations in animals one could suppose that these scotomas can be developed from direct compression of the chiasm.


[Problems of intraocular pressure in scuba diving (author's transl)].

The reactions of intraocular pressure (i. o. p.), pulse rate, and blood pressure were studied on 30 scuba divers in a pressure tank. Under excess pressures of 2 and 4 atm the i.o.p. showed an average fall of 2-3 mm Hg. The pulse rate fell in average by 4-5/min, while the blood pressure only showed minor changes. In the authors' opinion a well compensated chronic simple glaucoma with intact discs and fields does not exclude fitness for scuba diving.


[Clinical problems of different forms of heterochromie(author's transl)].

The causes of hypo- and hyperchromic heterochromia were analysed in 94 patients. The hypochromic forms were the commonest, especially the Fuchs-Herrenschwandt heterochromia, and heterochromia simplex. Also after degenerative diseases and accidents appears almost exclusively hypochromic heterochromia. Causes of hyperchromic heterochromia (siderosis, melanosis, wart-iris) were in the minority. Finally a heterogenous group of pseudoheterochromiae were more closely examined. This group seemed to be mainly hypochromic but in 2 rare cases the pseudoheterochromia was cuased by a brown dystrophy of the repeatedly inflamed cornea, probably associated with repeated fluorescien-staining of large corneal erosions.


[Monitoring the progress of lens opacities in cases of senile cataract by retro-illumination photography (author's transl)].

A follow-up study of lens opacities, utilizing retro-illumination photography with the fundus camera is described. After giving technical details, results are discussed and possible errors pointed out. If evaluation by planimetry or other devices is not possible, a useful procedure is the evaluation of simultaneous projected slides by a group of ophthalmologists not directly involved in the trial. This is demonstrated by testing the effect of 1-hydroxy-pyrido-(3,2alpha)-5-phenoxazone-3-carboxylic acid on the progress of senile cataract in a total of 48 eyes. Together with slit image photography of Brown (2, 3) the method of retro-illumination photography of the lens presented in this paper is a definite improvement in demonstrating the temporal course of cataract development.


[Practical experiences with the pilocarpine-test for the early diagnosis of glaucoma (author's transl)].

The Pilocarpin-test according to Hollwich proved to be useful expecially for older patients where the carrying out of a functional test can be difficult also for myopes with suspected glaucoma.


[The control of postoperative inflammation with fluorometholon (author's transl)].

Control of postoperative inflammation is essential in corneal surgery. Frequently this control must be extended for long periods of time. The long-term use of steroids such as prednisolone or dexamethasone is therefore limited because of the risk of inducing a rise in intraocular pressure. Personal experience in almost 400 surgical procedures indicates that fluorometholone has the ability to suppress inflammation without inducing significant increases in intraocular pressure. Fluorometholone should therefore be considered as the steroid of choice for the control of postoperative inflammation.


[Persistent iridoplegia and filamentary keratitis complications following cataract extraction (author's transl)].

In a series of 3,222 cataract operations where enzymatic zonulolysis with Alphachymotrypsin was employed, the authors describe two complications which are thought to be due to the effects of the enzyme. They are the persistent iridoplegia in 18 cases (0.05) and the filamentary keratitis in 34 patients (1.05%). The clinical picture of an acute enzymatic intraocular pressure increase and the appearance of a persistent iridoplegia are discussed. Furthermore, these complications are brought together in tables and associated with other which are also thought to be caused by Chymotrypsin.


[Fitting of contact lenses in children and juveniles with progressive myopia (author's transl)].

More than 200 children and juveniles till 15 years who got contact lenses because of myopia progressiva, were continuously controlled more than 3 years before and after the fitting. In the majority of the cases a favorable influence on the progression of myopia could be observed.


[Results with automatic refraction (author's transl)].

Hundred eyes of young patients with an average age of 25 years were measured with two refraction methods: 1. subjectiv refraction and 2. automatic refraction with the "Dioptron". The results of refraction and visual acuity before and after cycloplegia were compared. As for the spherical aquivalents we found a very good correlation between both methods (r - 0,98). The "Dioptron" printed out stronger cylindric powers as were found with the subjectiv refraction. Furthermore it could be shown that the stronger the cylindric power the smaller the axial deviation between subjectiv and automatic refraction. We believe that the automatic refraction with "Dioptron" is a good screening method, which cannot replace fine subjective adjustments, but complements them by serving as a good starting point for the refractive procedure.


[The psychosomatic factors in ophthalmology (author's transl)].

The importance of the psychosomatic factors is gradually increasing in the ophthalmological practice. In cases with hysterical symptoms they cause amaurosis and changes of refraction. Emotional factors lead to strabism and photophoby. Anxiety conditions and stress effect lead to glaucoma. In a short review the principles of psychosomatic treatment are dealt with.


[Diagnosis of Vogt-Koyanagi-Harada-syndrome (uveoencephalitis) (author's transl)].

Some aspects of the diagnosis, therapy and prognosis of VHK-syndrome are described from the long term observations of two cases in our clinic. The most important point in differential diagnosis is the presence of proved meningo-encephalitis. Systemic immunosuppressive therapy did probably not modify the course of the disease. The functional results in our patients were good.


[Maculopathia solaris after ingestion of LSD (author's transl)].

Report on a case of maculopathia solaris in a 25-year-old white male following an ingestion of LSD. Within a period of 7 months there was an amelioration of the visual acuity from 0.4 respectively 0.6 to 1.0 in both eyes.


[Vibration, a new way of cutting in ophthalmic surgery (author's transl)].

Rapid movement (vibration) of a movable scissor blade against a stationary blade at alternating current frequency (50 Hz) provides considerable improvement of cutting power and decreases distortion and crushing of the tissue. The article describes vibrational scissors for cataract surgery.


[Retinal detachment, caused by hyperaemia of the choroid? Remarks on the supposed relationship between retinal detachment and "indirect trauma" (author's transl)].

It was recently stressed by Scheerer that retinal detachment in a highly myopic eye may be caused by hyperaemia of the choroid, presumably occuring during heavy physical labour which is performed by a non-trained person. Clinical studies have shown, however, that choroidal detachment, resulting from either hemorrhagic, or serous accumulation of fluid during operative procedures or during postoperative periods, is not followed by retinal detachment. Also experimental occlusion of large choroidal vessels, associated with hyperaemia in the choroidal vasculature, does not lead to retinal changes inducing the separation of the neuroretina from the pigment epithelium layer. Thus, it is concluded that choroidal hyperaemia, possibly occuring during heavy physical labour, has no relationship to the development of a retinal detachment in a "disposed" eye.


[Cataract surgery and trabeculectomy at the same time (author's transl)].

It is not unusual to observe in the same eye a chronic glaucoma and a cataract. Surgery may be indicated for one of these diseases separately or for both of them. For simultaneous operation on glaucoma and cataract several attitudes could be discussed: a) cataract surgery and medical treatment of glaucoma, b) glaucoma surgery at first and then cataract surgery, c) cataract and glaucoma surgery at the same time. Since trabeculectomy is used for glaucoma surgery, the author performs the combined method, i.e. the simultaneous lens extraction and the operation of glaucoma through trabeculectomy. The advantages of trabec-lectomy over the other techniques for glaucoma surgery indicated that trabeculectomy over the other techniques for glaucoma surgery indicated that trabeculectomy is the best technique to be used in association with intracapsular cataract extraction. Our material consists of 65 patients, amongst which there are 11 patients with diabetes. 91 eyes have been operated upon during the last 2 years. Most of the postoperative complications, i.e. hyphaema, vitreous haemorrhage and prolapse, pupillary block, postoperatve rise of i.o. pressure are not severe and have no influence in the desired fall of i.o. pressure. It may be pointed out that a permanent regulation of i.o. pressure often occurs only 3 months postoperatively. Finally it can be said that the trabeculectomy associated with intracapsular cataract extraction appeared to be the best operation in case of glaucoma and cataract, provided that on the one hand the vascular status of these patients is controlled and on the other hand the operation microscope is exclusively used in surgery of the trabeculum.


[Indications and results of operative exposure of traumatically damaged optic nerves (author's transl)].

The indications for operative treatment of traumatically damaged optic nerves are given and the results from microsurgical transethmoid approaches are communicated. This operation method has such a low risk, that it can be also used on patients with recent head injuries. The early diagnosis of traumatic optic nerve damage and the earliest possible exposure of the nerve with pressure relief of the traumatised optic nerves are important for possible success. The development of microsurgery of the orbit, the possibility of a low-risk anaesthetic, the use of modern post-operative therapy and observation make older treatments such as waiting for spontaneous return of vision out of date. During the operation undiagnosed dural tears and other secondary damage are often found, which can be repaired at the same time. This is a further argument for a broadly-based indication to operation.


[The influence of pilocarpine upon the aqueous humour dynamics using ocusert with continuous delivery rate (author's transl)].

Sustained drug release systems could be especially useful in glaucoma treatment. Continuous delivery could be advantageous for maintaining an efficient tissue drug level. The aim of our investigations therefore was not only to control intraocular tension after having applied ocusert, but also to study aqueous humour dynamics by means of tonography. Conventional pilocarpine application and the new sustained drug release system were compared.


[Late results of cataract surgery after oculopression (author's transl)].

By the hypotonisation of the eyeball with an oculopressor the loss of vitreous during the cataract extraction can be almost always avoided. The anatomic and functional results are discussed from 65 cases examined at follow-up. The further supervision should not be neglected as also recommended in cases of cataract extractions without previous oculopression.