Combined modality therapy of Ewing's sarcoma. Since 1964, 66 consecutive patients with Ewing's sarcoma have been treated at the National Cancer Institute with local irradiation of the primary site combined with adjuvant regimens of progressively more intensive systemic chemotherapy. Actuarial survival rates for the total series show a 56% 2-year and 35% 5-year survival. The 43 patients without clinically detectable metastases at diagnosis have 64% 2-year and 52% 5-year survival rates. The current protocol, alternating high-dose pulses of adriamycin and cyclophosphamide-vincristine, is providing improved disease-free survival as compared to previous protocols, and indicates further progress toward the ultimate goal of complete tumor eradication. In addition to the problems of diagnostic accuracy in evaluating treatment results, other major factors influencing prognosis include initial metastatic disease, site of the primary tumor, age at diagnosis, and presence of systemic symptoms. At least these, and probably others, must be taken into account in developing randomized prospective trials for determination of optimal adjuvant therapy.


How do you know you've done any better?

How do you know you've done any better? Three points are made in this paper. It is found that concurrent controlled randomized trials are most useful (especially Phase II trials) in speeding up the introduction of better treatments for cancer patients. A scheme of continuing comparative trials, proposed by Theodore Colton, which require no statistical significance tests, is strongly recommended. The "historical-controls" approach of Gehan and Freireich is examined and is largely rejected because it appears to be unworkable. It is urged that patient characteristics that are associated with good response be determined, for the process of giving each patient the optimal treatment for him. This is referred to as "the epidemiology of treatment." Two examples of how early uncontrolled results are misleading in evaluating potential cancer treatments are given.


Activity of 6-methyl-8-substituted ergolines against the 7,12-dimethylbenz(a)anthracene-induced mammary carcinoma. The ability of a series of 8-beta-carboxamido ergolines, 8-formamido ergolines, and 8-methyl ergolines to cause regressions of established dimethylbenz[a]anthracene-induced mammary carcinomas was compared to some ergot alkaloids. Although most of the ergoline derivatives depressed serum prolactin concentrations in rats, only a few had pronounced effects against the dimethylbenz[a]anthracene-induced mammary carcinoma in rats. Some derivatives from each of the three groups of substituted ergolines gave comparable activities against the dimethylbenz[a]anthracene-induced mammary carcinoma.


Inhibition of renal tubular transport of methotrexate by probenecid. The mechanism of excretion of methotrexate (MTX) has been investigated in the monkey. Under steady-state conditions of varied plasma levels of MTX, it was determined that MTX was excreted by renal tubular transport as well as by glomerular filtration. The maximum rate of renal tubular transport of MTX (81 mug/min) was attained at plasma levels of MTX from 6 to 8 mug/ml. Correspondingly, the rate of clearance of MTX from plasma was shown to diminish from a value that was 3-fold greater than the glomerular filtration rate at plasma levels of MTX from 6 to 32 mug/ml. Pretreatment of animals with probenecid (700 mg/sq m) totally inhibited renal tubular transport of MTX when MTX was administered in doses from 1.8 to 621 mg/sq m. Following inhibition of renal tubular transport of MTX by probenecid, steady-state plasma levels of MTX in animals pretreated with probenecid (700 mg/sq m) was reduced by a factor of 2.6 from values determined in non-probenecid-pretreated control animals receiving similar varied doses of MTX (1.8 P to greater than 600 mg/sq m). The mode of i.v. injection of MTX was seen to effect the concentration of MTX in plasma. Initial loading followed by continuous sustaining infusion of MTX provided stable and higher levels of MTX in plasma than was determined in controls or in experimental animals pretreated with probenecid and receiving identical doses of MTX by single bolus injection.


Identification, subcellular localization, and estrogen regulation of peroxidase in 7,12-dimethylbenz(a)anthracene-induced rat mammary tumors. An estrogen-induced, intensely staining peroxidase 3,3-diaminobenzidine-positive reaction product is found to be characteristic of hormone-dependent, 7,12-dimenthylbenz(a)anthracene-induced mammary tumors of the rat. This product is demonstrated in thick sections of such tumors from intact or estrogen-treated castrate rats but is not seen in tumors that are in regression due to castration or estrogen deprivation. It is, furthermore, absent from tumors whose growth is unaffected by castration. The subcellular localization of this enzyme activity is restricted mainly to the nuclear envelope and cisternae of the granular endoplasmic reticulum in addition to secretory granules. This provides the first evidence for a criterion that would allow differentiation of hormone-dependent and hormone-independent mammary cancer on histological sections and, as such, may have considerable potential as an aid in the classification of human breast cancer.


Extraction of a factor from Ehrlich ascites tumor cells that increases the activity of the fetal isozyme of pyruvate kinase in mouse liver. Isoelectrofocusing studies of mouse tissue extracts show mice to have a pyruvate kinase isozyme pattern very similar to that of the rat. Moreover, electrofocusing or kinetic assays conducted on liver extracts from normal mice and from mice bearing Ehrlich ascites tumors show that the latter have a higher proportion of the fetal K-isozyme of pyruvate kinase. Serial injection of the supernatant remaining after centrifugation of homogenized tumor cells at 100,000 x g, or of the phenolic extracts from the latter, produced a similar shift in the liver isozyme pattern involves both a decrease in L-isozyme activity and an increase in K-isozyme activity. However, only the increase in activity of the K-isozyme appears to be a specific response to injection of the extracts. The presence of a specific factor in these extracts was confirmed by the observation that similar extracts prepared from normal adult tissues did not increase activity of the K-isozyme. On the other hand, phenolic extracts from fetal mice did increase K-isozyme activity as did injections of serum from tumor-bearing mice or of the cell-free ascites fluid. Evidence is presented supporting the concept that the factor is proteinaceous in a nature, and that it acts by deprepressing synthesis of the K-isozyme.


Clinical and immunological significance of human melanoma cytotoxic antibody. The activity of a complement-dependent cytotoxic antibody in the sera of 21 melanoma patients was investigated using a microcytotoxicity assay. Heat-inactivated sera were caused to react against mechanically dispersed fresh tumor cells in the presence of exogenous blood group AB complement. Cytotoxicity was evaluated relative to pooled normal sera as a control. Sera were cytotoxic against autochthonous tumor cells in 9 of 10 patients with localized or regional melanoma and in 1 of 11 patients with disseminated metastases. Cytotoxicity of sera was unrelated to size of tumor burden. Six of 7 antibody-positive sera (autochthonous system) were noncytotoxic to between 2 and 7 different allogeneic melanoma tumor cell preparations. Immunological reactivity of the cytotoxic antibody-positive and -negative groups was similar with respect to their capacity to be sensitized to dinitrochlorobenzene, produce positive skin tests to microbial antigens, and produce antibodies to typhoid vaccination; serum immunoglobulins were comparable. These results support the reported findings of the presence of cytotoxic antibody in the sera of melanoma patients without disseminated metastases.


Importance of physical properties of benzo(a)pyrene-ferric oxide mixtures in lung tumor induction. Three mixtures of benzo(alpha)(a)pyrene (BP) and ferric oxide with different physical properties were given intratracheally to Syrian golden hamsters for an examination of their neoplastic potential. Hamsters treated with a preparation containing large aggregates of BP and ferric oxide resulting from nucleation of BP on the particles showed an earlier onset and higher incidence of respiratory tract tumors than animals given a mixture containing smaller aggregates prepared by hand-grinding. The greatest number of tumors were present in the trachea and the predominant type was the squamous carcinoma. A third preparation in which the carcinogen was not attached to the ferric oxide showed a low tumor incidence similar to that present after intratracheal intubation of BP in gelatin without a carrier particle. For this model system of respiratory carcinogenesis, the physical attachment of BP and the carrier dust is necessary for a high tumor yield.


Biological behavior of malignant melanoma cells correlated to their survival in vivo. Successive B16 melanoma tumor lines were selected for their ability to form pulmonary tumor nodules. This was accomplished by injecting tumor cells i.v. into syngeneic C57BL/6 mice and 2 to 3 weeks later collecting the secondary tumor growths and placing them into tissue culture. These tumor cells were then injected i.v. into new syngeneic mice and the process was repeated several times. With each successive tumor line the number of experimental lung tumor nodules was significantly increased. The B16 lines were found to be stable in their metastatic properties even after many subculturings in vitro. These studies demonstrated that tumor cells that succeed in forming pulmonary tumor colonies also had increased invasive properties into normal tissues when implanted s.c. In addition, the tumor cell lines were prelabeled in vitro with [125-I]-5-iodo-2'-deoxyuridine and suspensions of labeled cells were injected i.v. into normal syngeneic hosts. Animals were killed at intervals afterwards, and the lungs and blood were processed and monitored for radioactivity. At any time interval, the lungs of mice treated by injections of cells of high metastatic yield contained more tumor cells. The differences in tumor cell numbers in the lungs were most pronounced immediately following i.v. injection. These results suggest that an increased initial arrest of highly metastatic cells in a capillary bed may be a major factor in their increased survival. Low numbers of normal lymphocytes or lymphocytes from syngeneic mice immunized to the B16 melanoma, when mixed in vitro with the tumor cells, lead to the formation of multitumor cell-lymphocyte clumps. The degree of clumping was related to both the type of the metastatic tumor line and/or the syngeneic lymphocyte. These results support the hypothesis that the survival of invasive and/or circulating malignant tumor cells is not a random phenomenon; rather it appears that malignant cells possess unique qualities which allow for their survival.


Metabolism and selective effects of 1-beta-D-arabinofuranosylcytosine in L1210 and Host tissues in vivo. The selectivity of action of 1-beta-D-arabinofuranosylcytosine (ara-C) against leukemic cells was studied in vivo. Dynamic state tissue levels of ara-C and of its mono-, di-, and triphosphate (ara-CTP) were measured in L1210 leukemic cells and in C57BL x DBA/2 F1 host tissues at different times after various doses of the agent. The levels were correlated with inhibition of thymidine incorporation into DNA and with cytocidal effects as measured by loss of isotopically prelabeled DNA. ara-CTP levels, but not those of the mono- and diphosphates of ara-C, were higher in leukemic cells and in host cell renewal systems than in other host tissues. DNA synthesis was equally inhibited by similar levels of ara-CTP in ascitic L1210 cells, in leukemic infiltrates in liver, and in small intestine. However, L1210 cells accumulated higher levels of ara-CTP for longer periods than did small intestine, and correspondingly the inhibition of DNA synthesis was greater and more prolonged in leukemic cells. ara-C caused greater losses of prelabeled DNA in ascites cells and in infiltrated liver than in host small intestine. It appears that the differential net tissue level of ara-CTP and its duration are the determinants of chemotherapeutic efficacy of ara-C against L1210 leukemia. ara-C was the predominant nucleoside present in hydrolysates of ara-CTP fractions. By contrast, 1-beta-D-arabinofuranosyluracil predominated in hydrolysates of monophosphate nucleotide fractions from ascites cells, liver, small intestine, and blood. Monophosphate nucleotide was also present in ascites fluid and plasma.


Effects of cigarette smoking on aryl hydrocarbon hydroxylase activity in lungs and tissues of inbred mice. Inbred strains of mice have been classified as aromatic hydrocarbon responsive or nonresponsive depending upon whether the parenteral administration of these substances increases hepatic aryl hydrocarbon hydroxylase (AHH) activity. Aromatic hydrocarbon responsiveness is controlled by genes at a small number of loci. Using 3-methylcholanthrene as inducing agent, strains A/J, C3H/HeJ, and C57BL/6J have been classified as responsive, whereas strains AKR/J, DBA/2J, and SWR/J are nonresponsive. Inhalation of cigarette smoke by both hepatic responsive and nonresponsive mice induces AHH activity in lung, but not in liver, stomach, small intestine, or kidney. The responsive strains have significantly higher levels of basal and induced AHH in the lung than do the hepatic nonresponsive strains. However, because of the especially low basal activity of AHH in lungs of hepatic nonresponsive strains, the ratio of AHH activity in animals treated with cigarette smoke to that in untreated animals is higher in nonresponsive than in responsive strains. AHH activity in lungs is fully induced within 6 to 12 hr after smoke inhalation and remains at the same level whether animals are treated 1 day or daily for 4 week;. AHH in lung returns to basal levels within 5 days after cessation of smoking.


Specific and nonspecific stimulation of resistance to the growth and metastasis of the line 1 lung carcinoma. The effects of specific dead tumor cell immunization and nonspecific immunostimulation with Corynebacterium parvum on the s.c. growth of the line 1 carcinoma in syngeneic BALB/c mice have been studied. Injection of heavily irradiated line ) carcinoma cells did not inhibit the transplantability or growth of the line 1 carcinoma, and in certain cases these treatments actually prolonged the period of rapid growth. This latter observation was traced to a mild inhibition of metastatic spread, which itself can slow the s.c. tumor growth. Treatment of the mice with 0.25 mg of C. parvum 7 days prior to transplant of the tumor had no effect on its growth by itself; but in combination with i.v.-injected tumor cells, which themselves had no effect on tumor growth, a 45% inhibition of tumor growth was induced. These data demonstrate that, in the weekly immunogenic line 1 carcinoma system, inhibition of s.c. transplants requires not only exposure to tumor antigens but also stimulation of the immunological reactivity.


The effect of nephrectomy on the incidence of breast carcinoma in irradiated parabiosed rats. The incidence of carsinoma the breast in parabiosed female NEDH rats is 2.5%. When one member of such a pair is irradiated, the incidence rises to 11% in the irradiated partner and 10% in the nonirradiated partner. If in such a pair of rats one kidney is removed from each partner, the incidence of breast carcinoma rises fivefold in the nonirradiated partner. The factors involved in such an increase probably have to do with alteration in retention, interchange, and feedback of the pituitary and ovarian hormones.


A role for the macrophage in in vivo and in vitro resistance to murine bladder tumor cell growth. Studies were performed to determine the role of macrophages in inhibition of growth of the same tumor cell type both in vitro and in vivo. Bladder transitional epithelium tumor cells were injected s.c. into Toxoplasma-infected mice, previously shown to contain activated macrophages, and into uninfected controls. The subsequent growth of a solid tumor was significantly less in the Toxoplasma-infected animals. Bladder tumor cells from the same cell line were grown in vitro either alone or in the presence of peritoneal lymphocytes and/or macrophages from oxoplasma-infected and control, uninfected mice. [3H]Thymidine incorporation by the tumor cells was inhibited only in the presence of macrophages from the Toxoplasma-infected animals. Lymphocytes alone did not appear to be cytotoxic under the conditions used. Moreover, lymphocytes from Toxoplasma-infected mice did not convey cytotoxicity to macrophages from control animals under the experimental conditions used.


Suggestive evidence for in vivo binding of specific antitumor antibodies of human melanomas. Antibodies eluted from homogenates of human melanoma cells reacted against melanoma cells reacted against melanoma antigens in a complement fixation test. Before elution, sonically treated homogenate did not react significantly against autologous serum but, following elution, antigenic activity increased markedly (up to 32-fold). Eluate of one melanoma reacted with the sonically treated residue of other melanomas but not with similarly prepared residues of sarcoma, carcinomas, or normal tissues. Melanoma eluates comtained more IgG than IgA. Traces of IgM were found in two melanoma eluates. Eluates of normal tissues (lung, kidney, and muscle) were devoid of serum proteins and did not react with the soncially treated melanoma residues. These results support the hypothesis that antitumor antibodies are bound to melanoma cells in vivo and that these antigens are cross-reactive.


Intercalative binding of ellipticine to DNA. Ellipticine (NSC 71795), a plant alkaloid with antitumor activity, is a weakly basic polycyclic molecule with dimensions similar to those of proflavin. Like proflavin, ellipticine exhibits hypocromic and bathochromic changes in absorption spectrum in the presence of DNA. It binds preferentially to helical DNA by intercalation, but the strength of binding is substantially greater than that of proflavin. The evidence for intercalation is based on effects on the sedimentation and viscosity of sheared DNA fragments, removal and reversal of the supercoiling of closed circular DNA, and electric dichroism measurements. The sedimentation and viscosity changes are quantitatively similar to those produced by proflavin. The unwinding angle on binding to supercoiled DNA is estimated to be 7.9 degrees, similar to that of proflavin. Electric dichroism shows the plane of the bound ellipticine molecule to be oriented parallel (plus or minus 7 degrees) to the plane of the bases in helical DNA. Ellipticine differs from proflavin in that it is uncharged at neutral pH and becomes protonated under mildly acid conditions. This feature may influence the intracellular distribution of the drug. Ellipticine bound to DNA is probably in its protonated form.


Sputum cytology among frequent users of pressurized spray cans. Sputum samples were collected from a group of private patients who had no respiratory symptoms but who frequently used aerosols generated by pressurized cans, and from two groups of controls. Atypical metaplastic changes in exfoliated cells were compared between the groups. An excess of moderate and marked atypical metaplastic cells was found among the frequent aerosol users. This association, which suggests that some aerosol preparations either alter the flora of the bronchial tree or contain carcinogenic agents, strongly suggests that additional studies be done on aerosol can ingredients, and that these sprays be used in a manner to minimize inhalation of the resultant aerosol, except for medical preparations where proper control is exercised.


Lymphatic obstruction in carcinomatous ascites. The i.p. inoculation of C3H mice with 5 times 10-6 cells of a transplantable ovarian carcinoma invariably evokes accumulation of large amounts of ascitic fluid. Histological and pharmacotherapeutic studies indicate that obstruction to peritoneal lymphatic drainage is a key factor in the formation of carcinomatous ascites in this model. In the early stages of ascites formation, an intense inflammatory reaction appears to occlude the condusts that connect the peritoneal cavity to the subdiaphragmatic lymphatic plexus. This inflammatory reaction, elicited by the presence of tumor cells within the peritoneal cavity, can be inhibited with high-dose systemic corticosteroid therapy. Ascitic fluid accumulation in animals so treated is markedly retarded. Tumor cells do not gain access to lymphatic capillaries draining the peritoneal cavity until ascitic fluid accumulation is massive. Systemic anticoagulation with heparin or sodium warfarin does not prevent lodgment of tumor cells within these lymphatic capillaries, nor does it alter the pattern of ascitic fluid accumulation. Various considerations suggest that excess production of ascitic fluid is not a likely pathogenetic factor in murine carcinomatous ascites.


Ultrastructural evidence for destruction in the halo nevus. Nine halo nevi in various stages of regression were examined by electron microscopy for fine structural evidence of an immunological mechanism of tumor cell destruction and halo formation. Early regressing lesions (Stage I) showed nevus cells associated with infiltrating lymphocytes, monocytes, and plasma cells, but without nevus cell destruction. In later lesions (Stages II and III), vacuolar cytolysis was commonly observed in nevus cells. In Stage III lesions, portions of nevus cells are found within macrophages. The electron microscopic findings of lymphocyte, monocyte, and plasma cell infiltration of the tumor followed by vacuolar cytolysis support the concept of an immune reaction in regressing halo nevi.


Mucous metaplasia and gap junctions in the vitamin A acid-treated skin tumor, keratoacanthoma. Desmosomes are the usual cell junctions found in normal rabbit epithelium as well as in the untreated keratoacanthoma. This study reports the finding of a second cell junction, the gap junction, when epithelium, normal or tumorous, is subjected to topical applications of vitamin A acid. The gap junction forms early in mucous metaplasia (after 2 days of application of vitamin A acid) and appears before the gross appearance of mucus. The presence of the gap junction occurs when there is an increase in the rough-surfaced endoplasmic reticulum and Golgi cisternae and vesicles. It is possible that the early appearance of the gap junction facilitates and mediates the mucous metaplasia. This suggestion is strengthened by the fact that the gap junction, once present in the mucus-producing tumor, is sparse when the tumor reverts back to the dry, keratotic condition upon cessation of vitamin A acid applications.


Studies on mammalian ribonucleotide reductase inhibition by pyridoxal phosphate and the dialdehyde derivatives of adenosine, adenosine 5'-monophosphate, and adenosine 5'-triphosphate. Ribonucleotide reductase activity in a partially purified enzyme preparation from Ehrilich tumor cells was inhibited by the dialdehyde derivatives of adenosine, 5-adenylic acid, and adenosine 5-triphosphate (prepared by the periodate oxidation of adenosine 5-adenylic acid, and adenosine 5-triphosphate). The borohydride-reduced derivative of periodate-oxidized adenosine was not inhibitory to the ribonucleotide reductase activity, showing that the aldehyde moiety was important in the inhibitory interactions of these compounds. This suggested the formation of a Schiff base between the dialdehyde derivative and an amino group (presumably, the epsilon-amino group of lysine). Pyridoxal phosphate, which is known to inhibit enzymes that have lysyl residues in the catalytic or allosteric sites, was an inhibitor of ribonucleotide reductase. Pyridoxal, pyridoxamine phosphate, pyridoxamine, and pyridoxine were not inhibitors. Borohydride reduction of the enzyme in the presence of pyridoxal phosphate produced a protein fraction that had little reductase activity remaining. The inhibition by pyridoxal phosphate was not influenced by increasing the substrate concentration (cytidine 5-diphosphate or adenosine 5-diphosphate), but was diminished by increasing the ratio of allosteric effector to pyridoxal phosphate concentrations, suggesting an interaction of pyridoxal phosphate at the regulatory site of ribonucleotide reductase. The addition of adenosine 5-triphosphate to the pyridoxal phosphate-enzyme mixture, which was subsequently treated with borohydride, partially prevented the inhibition by pyridoxal phosphate. Heat treatment of the ribonucleotide reductase enzyme preparation in the presence of pyridoxal phosphate protected the enzyme against loss of cytidine 5-diphosphate and adenosine 5-diphosphate reductase activities.


Possible interactions between the urea cycle and synthesis of pyrimidines and polyamines in regenerating liver. Ornithine levels rise progressively in the liver of partially hepatectomized rats, probably as a consequence of the increased flow of metabolites through the urea cycle. Ammonia and urea concentrations in the blood and liber of partially hepatectomized animals are not significantly different from those of sham-operated rats. However, in regenerating livers, the ability to remove ammonia from the blood is close to its maximal limit. Ammonia overload leads to the production of large amounts of orotic acid and causes a marked elevation of hepatic ornithine decarboxylase activity. Among the pyrimidine precursors dihydroorotic acid injections increase the activity of the enzyme while orotic acid is without effect. A peak of labeled material that corresponds to dihydroorotic acid was identified by partition chromatography of acid-soluble extracts of livers of partially hepatectomized rats previously given injections of [14-C2 bicarbonate. The labeling of dihydroorotic acid from [14-C] bicarbibate is increased in the liver of rats given injections of ornithine. Despite the difficulties involved in studies of ornithine decarbozylase activity in vivo, our results suggest that mutual interactions between urea, pyrimidine, and polyamine synthesis take place during liver regeneration.


Apparent cellular ingress of albumin in Walker 256 tumor and rat muscle. Tissue albumin distribution was measured in Walker 256 tumor and skeletal muscle in vivo in 36 rats. Vascular, extravascular-extracellular, and total tissue water spaces were determined for each tissue sample by isotopic techniques. Tissue interstitial and lymph albumin values were calculated from thoracic duct albumin concentrations, and vascular albumin was determined from serum albumin levels. Total tissue albumin was measured by dilution. These data demonstrate a third tissue albumin pool that equilibrates in 3 days compared to the rapid equilibration (2 hr) of vascular and extracellular-extravascular spaces. The pool is present in both muscle and tumor but appears to equilibrate more rapidly in tumor tissue. This finding suggests that cellular ingress of albumin occurs in vivo, which may explain increased albumin catabolism in tumor-bearing hosts.


The role of serum factors in the acceleration by Freund's complete adjuvant of the growth of transplanted murine leukemic cells. Attempted nonspecific immunotherapy led to acceleration rather than retardation of tumor growth. Mice given injections of Freund's adjuvant were more susceptible to transplanted syngeneic Gross virus-induced leukemic cells when Freund's complete adjuvant was administered i.p. 0 to 7 days before or 1 day after tumor; thereafter, the adjuvant had no effect. Two serum-mediated phenomeana were demonstrated in vitro: (a) sera from mice immunized with Freund's complete adjuvant and tumor facilitated killing of tumor cells by peritoneal exudate cells from nonimmune mice; (b) sera from all mice with progressive tumor blocked the cytotoxicity of a xenogeneic tumor-specific serum. Certain sera produced both effects. However, sera that either blocked or facilitated tumor killing in vitro had no effect on the growth in vivo of transplanted tumor cells.


The carcinogenicity of fluorenylhydroxamic acids and N-acetoxy-N-fluorenylacetamides for the rat as related to the reactivity of the esters toward nucleophiles. In extension of previous work indicating that the carcinogenicity of isomeric fluorenylhydroxamic acids depends on the point of attachment of the nitrogen atom on the fluorene system, the carcinogenicities of N-hydroxy-3-fluorenylacetamide and of N-hydroxy-4-fluorenylacetamide were evaluated in male and female Sprague-Dawley rats by several routes of administration and were compared with the carcinogenicity of N-hydroxy-2-fluorenylacetamide. The earlier observation that N-hydroxy-3-fluorenylacetamide is a specific mamary carcinogen was confirmed. N-Hydroxy-4-fluorenylacetamide was only marginally carcinogenic. Neither isomer gave tumors at the site after i.m. administration of the compounds into the hind leg of the rat. A comparison of the carcinogenicity of the isomers indicated the following order of activity: N-Hydroxy-2-fluorenylacetamide greater than N-hydroxy-3-fluorenylacetamide greater than N-hydroxy-4-fluorenylacetamide. Because of the current concept that arylhydroxamic acids are further acitvated to electrophilic reactants capable of interacting covalently with cellular nucleophiles and because esters of N-hydroxy-2-fluorenylacetamide give rise to an electrophilic reactant, the acetate esters of N-hydroxy-3-fluorenylacetamide and N-hydroxy-4-fluorenylacetamide were prepared and tested for their carcinogenicity in male and female Spaguw-Dawley rats by i.p. and i.m. administration. The order of carcinogenicity of the isomeric esters followed that of the parent hydroxamic acids (N-acetoxy-2-fluorenylacetamide greater than N-acetoxy-3-fluorenylacetamide greater than N-acetoxy-4-fluorenylacetamide). In order to correlate the carcinogeniciyt of the isomeric esters with their reactivity toward nucleophiles, the esters were reacted with methionine, transfer RNA, and the nucleosides, guanosine and adenosine. Under identical conditions, the reactivity of N-acetoxy-2-fluorenylacetamide towards methionine was at least tenfold greater than that of N-acetoxy-4-fluorenylacetamide. In addition to  o-methylthio-2-fluorenylacemide, a new adduct, o-methylsulfoxo-2-fluorenylacetamide, was isolated from the reaction of N-acetoxy-2-fluorenylacetamide with methionine. Reaction of N-acetoxy-4-fluorenylacetamide and 1-methylthio-4-fluorenylacetamide. N-Acetoxy-3-fluorenylacetamide did not react with methionine. Continued.


[Expediture during intensification of working processes in the hospital]. The intensification of working processes in hospitals is reflected also in indicators of expenditure which characterize the consumption expressed in financial terms. The intensity of operation may be reflected to a certain extent also in the operational costs per unit of capacity or performance, although from the expenditure alone it is not possible to draw unequivocal conclusions on the degree of intensity. When evaluating the economic results of hospitals information on the influence of changes as regards the use of bed capacity is useful, as well as information on changes in the length of the diagnostic and therapeutic operations performed by the common diagnostic and therapeutic complement of the hospital with policlinic and the influence of newly established units of intensive care on indicators of operational costs. The present article attempts to indicate the trend and force of action of these changes on the example of a type two hospital possessing all departments (district hospital).


[Mortality due to cardiovascular diseases in relation to age and sex. Comparison  of routine statistics with results of a special epidemiological survey]. The author presents an account of results of routine statistics and a special epidemiological survey where Prqgue, the Central Bohemian region and CSSR were compared. Existing possibilities as regards the diagnosis of a difficult group of cardiovascular diseases was tested. Careful processing of these causes of death revealed that routine statistics are as regards details of different groups of cardiovascular diseases somewhat inaccurate; despite this they give a fairly correct idea of the mortality from this group of diseases. The results of the investigation confirmed again that cardiovascular diseases are at present not only a very serious health issue but also a social problem.


[Analysis of mortality in the Zilina district]. From death certificates assemble in the Zilina district in three years (1968-1970) the authors prepared and coded questionnaires with 29 criteria. In the present article they submit some results obtained by automatic computing and biometric evaluation of these data. In the introduction they draw attention to and explain the rising trend of mortality in the Zilina district as well as in the Slovak Socialist Republic. Significant differences were revealed in the marital status of men and women with a predominance of married man and widows. The investigated variations of the number of deceased per day or week is not statistically significant; they were significant only in the course of the year with the maximum of deaths in March and the minimum in August. The specific mortality by decades revealed that men have from birth throughout life a higher death rate than women. As regards causes of death according to the 17 classes of the International Classification four classes dominate similarly an in the entire Slovak Socialist Republic, i. e. cardiovascular diseases 40.8%, tumours 17.8%, respiratory diseases 17.2% and accidents 7.5% all diagnoses. The order of diseases is the same for men and women only in the five most numerous classes and even there is a significant difference in the mortality level in three. Trichotomic classification of communities throws some light on the problem of causes of death of the rural and urban population. The last doctor attending the patient before death was in 48,3% the health community doctor, in 39,1% the hospital, in 8,9% (accidents and acute attacks) nobody whereby the percentage structure of men and women differs significantly also in this indicator. Finally the authors draw attention to the fact that the number of post mortem examinations (31,8%) is highest, as compared with the Central Slovak region (19,9%), the Slovak Socialist Republic (21,1%), the Czech Socialist Republic (29,8%) and the CSSR (27,6%).


[Results in the management of transfusion preparations in the West Bohemian Region during 1973]. The authors present an analysis of the use of transfusion preparations in 1973 in the West Bohemian region, where satisfactory results were obtained due to the cooperation of the regional commission for expedient pharmacotherapy, specialists of different branches, heads of blood transfusion departments and doctors working in these departments. A more objective approach to indications for transfusion is manifested by a reduced administration of whole blood (by 15%), reduced administration of locally produced plasma (by11%), increased administration of erythrocyte mass (by 21%) and special transfusion preparations (by 35%) and thus a reduction of expenditure on blood per bed per day in all district institutes of national health in the West Bohemian region.


[Drug therapy in homes for retired persons]. The authors analyzed the prescriptions in an old age pensioners home in Rokytnice near Prerov (240 people) in 1966-1972 and the assembled results were compared with drug expenditure in an old age pensioners home in Radkova Lhota (102 people) in 1972). Almost half the people in these homes suffer from at least three diseases which must be considered during drug pprscription; the great moribidity explains the almost fivefold expenditure on drugs per head, as compared with ambulatory care. Prescription of psychopharmaceutical preparations, antibiotics, analgetics and bronchodilatating drugs corresponds to the principles of expedient pharmacotherapy. More attention must be devoted to the dosage of cardiotonics. Geriatric drugs and vitamins, specially ascorbic acid are prescribed little.


Androgen binding proteins in the anterior pituitary, hypothalamus, preoptic area and brain cortex of the rat. The cytosol fractions of the anterior pituitary, hypothalamus, preoptic area and brain cortex of castrated male rats have been found to possess specific androgen binding proteins. The physicochemical characteristics of these binding proteins appear to be very similar. Thus, they were excluded by Sephadex G-100 gel and had a sedimentation coefficient of 6-7S by sucrose gradient centrifugation. The protein nature of the androgen binding components was supported by the fact that protease, but not DNase and RNase eliminated the binding of androgens. In addition, the elimination of the binding by 1 mM p-chloro-mereuriphenylsulfonate (PCMPS) and by heat treatment at 45 C for 30 min indicate that free sulfhydryl groups are necessary for androgen binding and that the proteins are thermolabile. Testosterone, 5alpha-dihydrotestosterone and the antiandrogen Cyproterone acetate were found to possess a much higher affinity than 17beta-estradiol and cortisol for the binding components. Dissociation studies revealed that [3H]testosterone is not easily displaced by unlabeled androgens. In the anterior pituitary, hypothalamus and preoptic area testosterone accounted for the major part of the radioactive material in the total tissue homogenates and also for the greater part of the bound radioactivity 15 min after in vivo administration of [3H]testosterone. [3H]17beta-estradiol accounted for less than 3% of the bound radioactivity under these conditions. If binding of a steroid sex hormone by specific proteins is a prerequisite for the hormonal action, the present study indicates the potential for a direct effect of androgens on the target cells of the anterior pituitary and of the central nervous system


Sympathetic innervation of the thyroid: variation with species and with age. Fluorescence histochemistry was used to study the sympathetic innervation of the thyroids from adult individuals of six different species; mouse, rat, hamster, dog, sheep, and pig. In addition, thyroids from very young rats and from very old mice were examined. Generally, thyroidal sympathetic, adrenergic nerve terminals were found not only as a network around vessels, but also as single terminals between, and sometimes around, follicles. Interfollicular terminals were numerous in thethyroids of adult mice, sheep and hamsters, but they were few in the thyroids of adult rats and dogs, and even fewer in the porcine thyroid. In contrast to the findings in thyroids from adult mice and rats, several interfollicular terminals were found in thyroids from very young rats while very few such terminals were detected in the thyroids from very old mice. The observations suggest that there is a pronounced interspecies variation in the number of thyroidal interfollicular sympathetic nerve terminals and that, at least in the rat and the mouse, there is also a variation with age. Since, in mice, sympathetic activation appears to induce thyroid hormone secretion by a direct action of norepinephrine released from intrathyroidal sympathetic fibers, the recorded variations are presumed to have functional importance.


Mechanism of the effects of hypothalamic deafferentation on prolactin secretion in the rat. Male rats with complete hypothalamic deafferentation had consistently lower serums prolactin concentrations than controls when the blood samples were obtained under other anesthesia. However, when rats were decapitated, both groups had similar low prolactin levels. Posterolateral deafferentation was as effective as complete deafferentation in preventing the stress-induced prolactin release, whereas anterior frontal deafferentation had only a small effect, L-Dopa (100 mg/kg body wt, ip) decreased prolactin titers in both control and deafferented animals, whereas reserpine (1 mg/kg body wt, ip) had the opposite effect. Since both drugs inhibited prolactin release from pituitaries in vitro, the decrease of prolactin levels following L-dopa in vivo might have been caused not only by stimulation of PIF release but also at least partly by the direct effect of the drug on the pituitary. However, the increase of serum prolactin following reserpine was in all probability caused by inhibition of PIF secretion. Electrolytic lesions in the median eminence of deafferented rats caused an elevation of serum prolactin which was more marked in female than in male rats. On the contrary, deafferentation in the females affected prolactin levels less than in males. It is concluded that hypothalamic deafferentation prevents ether-induced release of prolactin and that the "low" levels of the deafferented animals are probably due to a tonic release of prolactin-inhibiting factor (PIF) from the isolated island. It is though that this continuous release of PIF might be maintained by persisting autonomous activity of the adrenergic, presumably dopaminergic, neurons contained in the isolated island.


Episodic secretion of renin.

Episodic secretion of renin. Renin is secreted episodically in the absence of overt stimulation in the pentobarital-anesthetized, saline-loaded cat. Ninety min postlaparotomy, arterial and renal venous plasma renin concentrations (PRC) were determined at 15-min intervals for a 2 hr period. The pattern of renin secretion consisted of significant secretory peaks and periods in which little or no renin was secreted. In only a few instances could renin secretion be attributed to a preceding arterial blood pressure drop. The secretory episodes were also dissociated from flow.


Effect of splanchnic nerve stimulation on glucagon and insulin output in the dog. In order to study the role of the sympathetic nerves in the regulation of glucagon and insulin secretion, the distal stump of the left splanchnic nerve was electrically stimulated at the diaphragmatic level in the anesthetized dog under bilateral ligation of the adrenal veins. During stimulation, plasma glucose concentration rose rapidly, and pancreatic vein plasma concentration of glucagon increased along with pancreatic vein blood flow, indicating a greater output of glucagon. Insulin output in pancreatic vein plasma was slowly elevated despite continued stimulation. Pretreatment with propranolol resulted in a decline of the basal output of both glucagon and insulin and in their marked initial fall at the onset of the stimulus. However, glucagon output still showed a vigorous increase during neural stimulation whereas insulin output remained totally suppressed, but showed a rebound rise after cessation of stimulation. Pretreatment with phentolamine evoked an enhancement in both basal output of insulin and its response to splanchnic stimulation, but did not exert any marked effect on glucagon output. Pretreatment with atropine inhibited the basal output of glucagon and insulin, but the response of insulin output to splanchnic stimulation was not suppressed, thus excluding the possibility that activation of aberrant parasympathetic nerve fibers located in the splanchnic nerve would be responsible for the delayed increase in insulin  release. The present results indicate that glucagon secretion may be regulated by different receptor mechanisms from those involved in insulin release following sympathetic activation.


Sequential patterns of circulating LH and FSH in female sheep during the early postnatal period: effect of gonadectomy. To determine the basis for the marked daily variability in circulating luteinizing hormone (LH) in the female lamb shortly after birth and to determine whether circulating follicle-stimulating hormone (FSH) exhibits similar variability during this period of life, serum levels of both gonadotropins were monitored frequently (20-min intervals) over a 3- or 6-hr period each week for the first 9 weeks of life. Similar measurements of circulating LH and FSH were made in lambs ovariectomized at 2 weeks of age to assess whether the ovary influences the secretion of these gonadotropins. Pulsatile release of LH, but not FSH, was observed in both groups of lambs. Although mean concentrations of circulating FSH in intact female lambs were similar to basal levels of the cyclic adult, mean concentrations of serum LH were much higher. Because of the discontinuous release of LH in intact lambs after 4-5 weeks of age, patterns of LH were often indistinguishable from those of the long-term ovariectomized adult. At 9 weeks of age the frequency of episodic LH release in intact lambs ranged from 0.33-1.1 pulses/hr. Castration at 2 weeks of age produced a concomitant, but delayed, rise in mean serum LH and FSH beginning 4-5 weeks later. By 9 weeks of age serum LH, but not FSH, had attained levels comparable to those of the castrated adult, and the mean frequency of LH release (about hourly) was similar for both groups. The results indicate that by 9 weeks of age the ovary of the lamb influences the secretion of LH and FSH. Because in the 9-week-old intact female lamb episodic release of LH occurs producing high (castrate) levels of this gonadotropin while circulating concentrations of FSH remain stable and within basal levels of the adult cycling female, it is suggested that acute concomitant release of LH and FSH  does not occur at this age and that separate negative feedback loops for the control of LH and FSH secretion may exist during early postnatal life.


The metabolism and binding properties of 3H-aldosterone in plasma and its sex dependence in adrenalectomized rats. The rates of clearance of plasma 3-H radioactivitivity following intravenous injection of 3-H aldosterone was demonstrated to be sex-dependent in adrenalectomized rats. The perchantage plasma radioactivity which is CH-2CL-2extractable is greater in female than in male rats from 5 min to 90 min postinjection; however the quantities of CH2-CL2-extractable label are not significantly different until 60 min postinjection. The quantities of nonextractable, water-soluble metabolites of adosterone (NEPD), which are markedly greater in the plasma of males, reach peak levels 30 min after injections of aldosterone, during the latent period of the hormone.N females, these polar metabolites (NEPD)are rapidly cleared from the blood. The quantities of 3-H-radioactivity associated with the plasma binding proteins are similar in both males and females. The unbound levels of aldosterone and its metabolities are significantly greater in the plasma of males. These findings indicate that the sex hormones may influence not only the metabolism of aldosterone in rats, but also the plasma levels of unmetabolized aldosterone and its metabolites.


The effects of dexamethasone on the peripheral plasma concentrations of androstenedione, testosterone and cortisol in the pregnant rhesus monkey. The concentrations of androstenedione, testosterone and cortisol have been measured in the maternal peripheral plasma of normal pregnant rhesus monkeys (Macaca mulatta), and in rhesus monkeys treated daily with dexamethasone during late pregnancy. During the last 30 days of pregnancy, the mean plasma concentrations of androstenedione, testosterone and cortisol were about 1400-2000 pg/m1375-425pg/ml and 300-400 ng/ml, respectively. None of these steroids increased significantly before parturition. As there was no rise in maternal androgens in late pregnancy when plasma estrogens increase sharply, it suggested that his elevation of plasma estrogens is related to an increase of fetal precursors Dexamethasone treatment resulted in 90% suppression of plasma cortisol and 40%-60% suppression of androstendione and testosterone. As the suppression of maternal androgens was of lesser magnitude than the decline of plasma estrogens, and as the androgens did not continue to fall with continuing dexamethasone treatment as did the estrogens, these findings also suggest that the decline in plasma estrogens is related in large part to suppression and atrophy of the fetal adrenals.


Growth hormone-dependent serum stimulation of DNA synthesis in chick embryo fibroblasts in culture. We have investigated the role of GH in the serum requirement for the multiplication of chick embryo fibroblasts (CEF-S) in culture . Serum from hypophysectomized (hypox.) rats is much less effective than normal serum in stimulating the incorporation of (3H-methyl]thymidine into DNA. More importantly, bovine GH(bGH) treatment of the hypox. rat restores 60% or more of the activity in the 3H-thymidine incorporation assay. Bovine GH is inactive when tested directly in the assay. Mixing experiments show that the decreased activity of hypox. serum is not due to the presence of an inhibitor in the hypox. serum. The GH is dependent factor is nondialysable and stable to Boiling at pH5.5. boiling the normal, hypox. and bGH treating hypox. rat sera results not only in enhancement of the activity but also a more linear dose response curve in the 3H-thymidine incorporation assay. The thesis because measurements of cell numbers show the CEFs multiply less well in boiled normal rat serum and bGH treatment of the hypox. rat restores approximately half of the multiplication stimulating activity of normal boiled rat serum. CEFs in culture may provide a satisfactory in vitro system for  the study of the mechanism of action of the growth hormone dependent anabolic factors found in serum.


Changes in plasma calcitonin and calcium during the migration of salmon. The levels of immunoassayable calcitonin and of calcium were measured in the preblood of sockeye salmon during their migration from sea water to fresh water to spawn. Plasma calcitonin was higher in the females than in the males during all stages of migration  as was plasma calcium except during spawning. In both sexes calcium decreased progressively throughout migration. In the male, calcitonin decreased as the fish arrived in fresh water but increased again at the spawning. These observations suggest that calcitonin may play an important role in the reproductive cycle of fish.


Effects of acute stress on serum LH and prolactin in intact, castrate and dexamethasone-treated male rats. The effects of handling, ether vapor anesthesia and blood sampling on serum LH and prolactin were determined in intact, castrate and dexamethasone-treated male rats. Cage removal and transport to an adjacent room increased LH and prolactin levels by 10 and 15 min after the initial animal disturbance. Intact male rats subjected to repeated ether anesthesia and blood sampling showed a more rapid increase in serum LH and prolactin than the preceding rats, since serum LH and prolactin was increased by 4, 8 and 15 min after initial cage disturbance. In a group of rats subjected to serial blood sampling over a longer time interval, both prolactin and LH levels remained higher than 90 min after initial animal handling. At 90 minutes after a single blood sampling, blood prolactin concentration remained higher than in controls. Serum LH levels returned to control levels 90 min after the stress of a single blood sampling. Although serum prolactin was increased in the castrate group subjected to serial anesthesia and blood sampling, LH concentrations were reduced under the same conditions. Injection of 5 and 50 mug of dexamethasone/100 g body wt for 8 days markedly reduced adrenocortical responsiveness to the stress of serial anesthesia and blood sampling at 1, 4, 8 and 15 min after initial rat disturbance. The 50 mug dexamethasone treatment reduced the stress-stimulated increase in serum prolactin at all blood sampling intervals. The dexamethasone-treated groups also showed smaller increases in serum LH at 8 and 15 min after first animal handling than the control rats. These results indicate that serum LH and prolactin concentrations are consistently increased by acute stress in intact male rats, the duration of the stress stimulation of LH and prolactin is at least 90 min under the conditions of this study, serum LH levels of castrate male rats are decreased by acute stress and dexamethasone administration lowers stress stimulation of LH and prolactin release.


Preparation of sperm-free seminal plasma from human semen. Whole human semen was centrifuged at various centrifugal forces to obtain sperm-free seminal plasma. Most samples of seminal plasma collected after centrifguation of up to 10,000 g were contaminated with spermatozoa. Centrifugation at 40,000 g yielded sperm-free seminal plasma in two thirds of the samples centrifuged. Filtration of whole semen with Millipore filters (pore size 0.45 mu) removed all spermatozoa.


Micropuncture and microanalytic studies of the rat testis and epididymis. Micropuncture techniques developed for the study of renal physiology have been adapted for investigation of the male reproductive tract. Ultramicro specimens were obtained in vivo from the tubules of the rat testis and epididymis. These samples were analyzed for sperm morphology and concentration. The new methods developed to conduct these studies are discussed in detail. The mean in vivo spermatocrits were 0.411 plus and minus 0.029, 0.355 plus and minus 0.019, and 0;731 plus and minus 0.028 in the seminiferous tubule, caput epididymidis, and caudal spermatocrit was significantly higher than the spermatocrit in the caput or seminiferous tubule. The percentages of abnormal spermatozoa in the caput and cauda were 5.5% plus and minus .7% and 4.3% plus and minus .6%, respectively.


Development of reversible vas deferens occlusive device: IV. Rigid prosthetic devices. Different types of rigid, reversible, vas deferens occlusive devices were developed and evaluated in 14 unilaterally vasectomized dogs. All prosthetic devices had molded silicone rubber bodies, and rigid inflow and outflow tubes. Various techniques for the removal of the vas luminal epithelium, and for the preparation of porous ceramic and etched stainless steel surfaces to encourage tissue ingrowth into the prosthetic device end tubues were attempted. The devices differed in their methods of achieving occlusion. One device used a "rotary stem valve" which had a C-section rotating mechanism; the others used the "shuttle stem valve" which possessed an occlusive element that moved transverse to the axis of flow in the device, thus occluding the device when the stem was depressed. The rotarystem valve was implanted by means of a longitudinal incision. The remaining 13 shuttle stem devices were placed in the vas using either a longitudinal or a transverse implantation. Inno case was sperm transport through the prosthetic devices obtained for more than a few ejaculations.


Development of reversible vas deferens occlusive device: V. Flexible prosthetic devices. In contrast to the results with rigid-ended prosthetic devices implanted in the vas deferens of the dog, effective sperm transport was obtained for prolonged periods of time with flexible-ended (all soft) devices. Such transport could be halted by device occlusion with clips or shuttle stem valves. Opening the devices resulted once again in the passage of spermatozoa, indicating that these devices may be potentially useful as reversible male contraceptives. More research is necessary to determine the cause of an overall decrease in sperm output after device implantations and to evaluate any adverse side effects of such devices. Dacron velour-covered suture rings on the devices permitted effective tissue ingrowth and prevented leakage or recanalization.


Prevalence of circulating HL-A lymphocytotoxic antibodies in men after vasectomy. Thirty-two men undergoing vasectomy were studied for one year to determine presence of HL-A antibodies after surgery. Blood samples were taken prior to vasectomy and at three, six, nine, and 12 months following surgery. Twenty-six men showed no increase in antibody activity during the study when their sera were matched against a 25-member typed lymphocyte donor panel. Sera of two men showed a definite increase in positive reactions, six to 12 months after surgery. The sera of four men showed slight increases in reactivity between three and 12 months after vasectomy. The serum of one man showed a single positive reaction against his own lymphocytes three months after surgery, but no positive reactivity against the lymphocyte donor panel. These studies suggest that HL-A antibodies are not regularly formed as a result of standard vasectomy procedures, but that further long-term evaluation of vasectomized patients may be needed to make definite conclusions.


In vitro action of progestogens on sperm migration in human cervical mucus;. The presence of progestogens in the cervical mucus suppresses and arrests sperm penetration. Using the Kremer technique, the effects of in vitro released progesterone, d-norgestrel, and cyproterone acetate were studied by inserting silicone rubber threads bearing the respective compounds into capillary tubes containing cervical mucus. Control tubes were fitted with nonmedicated silicone rubber threads. After 24 hours of incubation, the sperm migration test was carried out to evaluate penetration depth, qualitative motility, and proportion of motile forms. Progesterone produced the greatest alterations. Migration was arrested within 30 minutes, the distance reached was consistently less than 2 cm, and sperm were completely immobile at 24 hours. D-norgestrel also exhibited a distinct spermiostatic effect, but it was not as intense as that of progesterone. Cyproterone acetate was practically effective during the first 120 minutes and produced alterations only in the qualitative and proportional motility.


The effect of combination and low dose progestogen oral contraceptives on serum lipids. Fasting serum triglyceride, free fatty acid, phospholipid, and cholesterol levels were determined in women who were taking either combination or low dose progestogen oral contraceptives. The contraceptives used were: ethynodiol diacetate and ethynyl estradiol; norgestrel and ethynyl estradiol; norgestrel; and megestrol acetate. Serum lipids significantly increased in women taking combination pills. They significantly decreased in patients taking norgestrel, while they remained almost unchanged in patients taking megestrol acetate. This decrease varied with the type of progestogen used in continuous low dosage therapy. The confusion when interpreting the results from different reports on the effects of oral contraceptives on serum lipids will be reduced if proper attention is given to the types of steroid used.


Effects of danazol on the pituitary-gonadal axis in male gerbils and mice. Danazol administration caused lesions in the seminiferous tubules of gerbils and mice. The seminiferous epithelium became systematically depleted of spermatogonia, spermatocytes, spermatids, and finally spermatozoa. Danazol administration did not cause damage to the epididymal cells but was followed by a significant increase (p smaller than 0.01) in the diameter of the Leydig cell nuclei. The growth of androgen-dependent organs was reversibly suppressed after treatment. Resumption of normal gonadal function in the mouse occurred 32 days after discontinuation of medication. Danazol brought about transient changes resembling those of bilateral gonadectomy in the anterior lobe of the hypophysis. Inhibition of endogenous gonadotropins occurred, reflected in the increased basophilic cell percentage.


Prostaglandin F2-alpha for induction of midterm abortion: a comparative study. The action of prostaglandin F2alpha (PGF2-alpha) to induce midterm abortion in rabbits, rats, hamsters, and mice using different methods and routes of administration was studied. Administration of PGF-alpha in a Silastic-PVP implant was more effective than was the parenteral injection at the same dose levels. The efficacy of PGF2alpha was optimum when deposited locally in the uterine lumen as a Silastic-PVP implant, a condition comparable to a continuous intra-amniotic or extra-amniotic administration of PGF2alpha in women. It is possible that the insertion of a Silastic-PVP implant into the uterine lumen results in a continuous PGF2alpha release and a high local PGF2alpha concentration which minimizes such factors as dilution and the short half life displayed in the general circulation. PGF2alpha contained in a Silastic-PVP implant and inserted into the uterine lumen may effectively induce abortion with a comparatively lower dose than that necessary for parenteral routes of administration.


Radioimmunoassay of rhesus monkey chorionic gonadotropin. A radioimmunoassay for rhesus monkey chorionic gonadotropin (mCG) employing an antiovine LH antiserum, 125I or 131I-ovine LH tracer, and mCG for standards was developed. Radioimmunoassay of serum levels of mCG during pregnancy indicated that mCG began increasing as early as day 12 after mating, reached a peak by day 25, and declined to nondetectable levels around day 35. The assay procedure was adapted for use as a rapid method for pregnancy diagnosis; the results were available as early as 12 hours after collection of serum samples. The method is capable of detecting a few pregnancies by day 12 and all pregnancies by day 17. Routine use of this method provided accurate pregnancy diagnosis four days earlier than was possible with the mouse uterine weight bioassay method previously used in this laboratory.


Halfway houses for the mentally ill and alcoholics: a 1973 survey. A survey of halfway houses made in October 1973 identified 209 facilities primarily for psychiatric patients and 597 for alcoholics. The facilities for alcoholics average fewer employees than the psychiatric halfway houses, and proportionately more of them are recovered patients. The alcoholism facilities serve older clients, most of them males. Patients admitted to psychiatric halfway houses are more likely to enter from a hospital than from the community, and they have longer stays than the alcoholic patients. The largest percentage of both groups return to independent living; 15 per cent of the psychiatric patients are readmitted to hospitals.


Gathering naturalistic, objective data on the behavior of schizophrenic patients. A behavioral observation system, consisting of 12 behavior categories and an apparatus for recording them, was designed as a tool for gathering objective, naturalistic data on the ongoing behavior of hospitalized schizophrenics. After the system was tested and evaluated, it was used to draw behavioral profiles of 62 schizophrenics on two psychiatric wards of a Veterans Administration hospital. The results indicate the labeled schizophrenic is typified by a lack of adaptive behavior, a blankness, and a failure to get involved with his environment.


A study of hospitalized paranoid schizophrenics with grandiose symptomatology. Twenty-one paranoid schizophrenics who were being treated in a therapeutic community were divided into groups with grandiose and nongrandiose symptomatology, based on ratings on the Inpatient Multidimensional Psychiatric Scale. The nine nongrandiose patients showed significantly greater improvement during hospitalization. A follow-up of five nongrandiose and nine grandiose patients one year after discharge revealed a trend toward greater improvement by the nongrandiose group. The authors feel that a patient's grandiosity creates a barrier that keeps the therapist and the members of the therapeutic community at a distance and makes him less accessible to therapeutic intervention. The field dependence of patients was also rated, but was of no prognostic significance.


Catatonia: diagnosis and management.

Catatonia: diagnosis and management. The number of cases of catatonic schizophrenia has decreased in the past 50 years, but a few patients with the syndrome are still seen. The author describes the excited and withdrawn types of catatonia, reviews some organic and psychiatric conditions that resemble them, and gives suggestions for making the differential diagnosis. He discusses the use of the barbiturate interview, ECT, and phenothiazines in treatment, using case examples.


Using community psychiatry methods in private practice. Two cases that incorporate community resources into psychiatric-medical treatment plans for private patients illustrate the use of community psychiatry concepts in a private office. In both cases the private practitioner formed treatment teams with representatives of other community agencies to help the patients return and adapt to the community. Two problems that arise in the author's continuing work with community resources are the time it takes to implement clinical decisions through an agency and the agency staff's feeling of territoriality.


The Catholic hospital: options for survival. The traditional mission of the Church and its ministry to the sick through the Catholic hospital is being called into question by the confluence of a series of internal and external forces. This questioning occurs simultaneous to the modern world's growing need for the unique contributions of Catholic hospitals. Constructive, careful, and intensive reexamination of assumptions about Catholic hospitals is in order--reexamination by the religious orders who operate the hospitals, by the ecclesiastic authorities who must ultimately approve them, and by the Catholic laity who support them. Each must examine these key questions: What is unique about the Catholic hospital? Is it needed in the modern world? Is that uniqueness indissolubly linked to operation by religious orders? How would an alternate model of the Catholic hospital system be designed? This article has attempted to prove that the Catholic hospital is indeed unique as a religious, Christian, and Catholic institution; that this uniqueness is especially pertinent to some of the major problems of the sick in the modern world; that in essence this uniqueness is not contingent upon operation by religious orders; and that new relationsh?IPS are possible between the laity, the religious congregations, and the ecclesiastic authority which will maintain the Catholicity of the hospital of the future, despite the actions of erosive forces which seem to threaten it today. The Catholic hospital remains one of the most visible and effective witnesses to the Christian message and the Mystical Body. We who constitute it are called upon to reexamine how its mission to the sick can be expanded, not contracted. Expansion requires new forms which promise as much for the future as the older forms have accomplished in the past. In assessing Christ's own healing mission, Romano Guardini pointedly emphasized that Christ was more than "the great philanthropist." Today the sick need such individuals more acutely and more profoundly than ever before. Therein lies the mission--and the obligation--of the Catholic hospital, which must continue into the future whatever new forms of organization exigencies may dictate. By concentrating on its essential features, the Catholic hospital can protect itself against dissolution and an inauthentic existence--alternatives which are neither Christian nor Catholic.


Prognostic factors in colon carcinoma: correlation of serum carcinoembryonic antigen level and tumor histopathology. The results of histopathologic study and the preoperative circulating carcinoembryonic antigen levels were correlated with each other and with the postoperative clinical course in 45 surgically treated patients with cancer of the colon. Histopathologic evaluation of the tumor included the depth of bowel wall involvement according to the Dukes classification, the histologic differentiation of cells on the basis of Broders' grades of malignancy, evidence of lymphocyte and plasma cell infiltration within and surrounding the primary tumor, and evidence of blood vessel, lymphatic, and perineural invasion. All these parameters, including the serum carcinoembryonic antigen level, had prognostic value. Low serum carcinoembryonic antigen levels in patients with colonic cancer suggested tumor localized within the bowel wall; the highest values were found in patients with tumors that had spread beyond the bowel wall. An inverse correlation was noted between the degree of tumor differentiation and carcinoembryonic antigen levels in the same patient. Carcinoembryonic antigen levels tended to be elevated when blood vessel, lymphatic, and perineural invasion was present. An inverse correlation was also noted between the preoperative carcinoembryonic antigen level and the degree of lymphocyte and plasma cell infiltration in the primary tumor. Round cell infiltration was interpreted as an indication of the host's immune response against the tumor. Thus, on the basis of clinical follow-up of the patients it is concluded that all morphologic parameters evaluated have prognostic value, that preoperative serum carcinoembryonic antigen levels have prognostic value, that all prognostic parameters correlate with each other appropriately, and that the combined parameters are more reliable than any single one alone.


Immunosuppression and toxoplasmic encephalitis: clinical and experimental aspects. Encephalitis developing after prolonged antineoplastic therapy in two patients with Hodgkin's disease and in one with multiple myeloma was found at autopsy to be caused by toxoplasmosis. To better understand the pathogenesis of the brain lesions, ranging from microscopic foci to some having a diameter of 6 cm. and characterized by proliferation of the organisms at the margins of expanding necrosis, an animal model was studied. Similar lesions were produced in hamsters by inducing relapse of chronic latent toxoplasmosis through administration of cortisone, cyclophosphamide, or whole body irradiation, but toxic doses of nitrogen mustard and urethane did not precipitate relapse. Notably, relapsing toxoplasmosis generally involves the brain exclusively, suggesting a special susceptibility related to immune mechanisms. The roles of cells and of antibodies in immune surveillance against this chronic infection in otherwise normal hosts are considered. In man the suppression of cellular immunities by certain antineoplastic agents would seem to be decisive in causing relapse of toxoplasmosis, rather than the replacement of immunologically active cells by neoplasm. Because the infection can be controlled with sulfadiazine and pyrimethamine, a high index of suspicion is essential to detect incipient cerebral toxoplasmosis. serial serologic testing is helpful by demonstrating titer elevations; however, poor antibody production or transferred antibody may be misleading clinically when single tests are evaluated. Similarly, a poor inflammatory cell response can make it difficult for the histopathologist to detect small lesions in these patients.


A preliminary report on the supraoptic nucleus and control of intraocular pressure. Four animals received unilateral optic nerve sections which ablated that eye's rise in intraocular pressure in response to water drinking. Bilateral supraoptic nucleus lesions in two animals resulted in ablation of the other eye's response to water drinking. Both animals showed histopathologic proof of the lesion site. Two animals received sham operations for the supraoptic nucleus lesions with no change in their differential response to water drinking. This report gives preliminary evidence of the hypothesis of a supraoptic nuclear control mechanism of intraocular pressure.


Morphology of the breakdown of the blood-aqueous barrier in the ciliary processes of the rabbit eye after prostaglandin E2. Protaglandin E2, administered topically to the rabbit eye, causes disruption of  the blood-aqueous barrier resulting in a large increase in the protein content of the aqueous humor. The route of plasma proteins into the aqueous humor was studied with the electron microscope, using horseradish peroxidase as a protein tracer. The tracer penetrated the tight junctions of the nonpigmented layer of the ciliary epithelium, filling the lateral intercellular clefts and staining the internal limiting membrane. These morphological studies confirm the prior physiologic demonstration that, in response to prostaglandin, plasma proteins enter the posterior chamber via the intercellular clefts of the nonpigmented epithelium.


Pattern of ocular response to topical and systemic prostaglandin. Changes in both intraocular pressure and total outflow facility were determined after short- and long-term infusion and topical application of prostaglandin E1 and E2. The intraocular pressure with both routes of administration increased within 15 minutes by 10 to 15 mm. Hg; long-term infusion caused the intraocular pressure to be elevated for a longer time, although a fall in intraocualr pressure occurred despite continued infusion. Total outflow facility did not increase until 30 minutes after initiation of treatment and thereafter increased further with time, irrespective of the route of drug application. The initial increase in intraocular pressure is suggested to be the result of vascular changes, namely an increase in the leakiness of the iris vessels and the capillary pressure of the ciliary body vessels caused by the vasodilatory actions of prostaglandins.


The long-acting Ocusert-pilocarpine system in the management of glaucoma. The Ocusert-pilocarpine devides with seven days' therapeutic duration were compared with pilocarpine eye drops for efficacy and ocular tolerance in the management of glaucoma in 16 patients. Magnitude of pressure reduction with release rates of 20 mcg. and 40 mcg. of pilocarpine per hour were as effective in the treatment of glaucoma as 2 per cent and 4 per cent pilocarpine eye drops, respectively. Ocular tolerance and retention in the human eyes were good. There were no appreciable side effects other than the occasional sudden leakage phenomenon encountered. Further refinement of the Ocusert-pilocarpine device to reduce the incidence of leakage would not only ensure precision in the rate of drug release, but would also expand its clinical application.


Ocular findings and corticosteroid responsiveness in parents of children with primary infantile glaucoma. Aqueous humor dynamics, visual fields, optic discs, anterior chamber angles, and topical cortidosteroid responsiveness were studied in twenty parents of children having primary congenital glaucoma. The findings indicate that parents of children with primary congenital glaucoma resemble the general population with respect to the parameters tested, and do not resemble close relatives of patients with primary open-angle glaucoma.


Water drinking and outflow facility.

Water drinking and outflow facility. In a series of patients with ocular hypertension, the effect of water drinking upon pressure and outflow facility was determined by impression (Schiotz) tonometry and tonography. The statistical facility-depressing effect of water drinking revealed by numerous earlier studies was confirmed, but found to be too small to be readily demonstrable in the individual eye. The water-drinking test in patients with primary ocular hypertension presents a situation in which tonography adds little to the information provided by tonometry.


Chorioretinal diffusion processes following pigment epithelial degeneration. We studied the effect of sodium iodate-induced pigment epithelial degeneration on chorioretinal diffusion processes. Rabbits received two intravenous injections of sodium iodate at the retinotoxic dose of 22.5 mg. per kilogram over a six- to eight-hour period. Combined horseradish peroxidase tracing technique and electron microscopy were used to compare diffusion processes over a five-week period. Ultrastructural examination of retina twenty-four hours after iodate administration revealed pigment epithelial degeneration, accompanied by disruption of junctional complexes (zonulae occludentes). Peroxidase molecules were found in areas of greater cytoplasmic degeneration and in intercellular spaces up to the level of the external limiting membrane. Ultrastructural observations at later stages revealed similar findings except in the case of Muller cells, 20 per cent of which showed cytoplasmic degeneration and peroxidase uptake. The diffusion barrier was not re-established as the replacement cells did not rebuild zonulae occludentes.


A new form of hereditary retinal degeneration in Wag/Rij rats. A spontaneous, hereditable, bilateral retinal degeneration affecting all adult animals in a closed, imbred colony of Wag/Rij rats has been discovered. The disorder is characterized by early onset and a slow progressive course. Early lesions are detected by one month in retinas which are otherwise fully developed. Destruction of the photoreceptor layer proceeds as more and more cells degenerate. Degeneration appears to begin in the photoreceptor cell body and only secondarily affects the outer segment. Futhermore, phagocytic activity of pigment epithelium remains intact until late in the disease. Endstage lesions include retinal disorganization, proliferation and vascularization of pigment epithelium, and migration of pigment epithilial cells into the retina. The temporal and structural characteristics of this retinopathy indicate it may serve as a useful model for study of retinitis pigmentosa in man.


Aphakic macular edema: incidence and pathogenesis. In a prospective study, the incidence of cystoid macular edema for two groups of patients was found at six weeks following surgery. The first group who underwent cataract extraction had a 50 per cent incidence. The second group who underwent elective glaucoma surgery had no patient with cystoid macular endema. At six weeks, 16 per cent of those patients who had originally developed cystoid edema, had a visual acuity of 6/12 or less, with no other cause for the poor visual result. The two major differences between these two groups of patients were the actual cataract extraction, and the presence of postoperative vitreous inflammation. No factors were noted to cause persistence of the aphakic macular edema although the technique of cataract extraction and vascular disease were implicated.


Experimentally determined optical properties of goldfish cones and rods. The optical properties of goldfish photoreceptors were evaluated using the special microscope-microspectrophotometer divice. Mode patterns transmitted were identified for both natural and reverse path illumination. Photomechanical changes with adaptive state could be identified. Complex mode interactive phenomena and cross-coupling of energy were observed. These are related to the fact that there are double cones and apposition or near apposition of neighboring receptors  in this species. The directionality of individual cones and rods was quantified by making use of the principle of reversibility of light path. Radiation patterns were recorded and analyzed on a computer controlled microdensitometer. Individual cones and rods were shown to exhibit marked directionality. Light collection properites of cones were strikingly evident.


Ultrasonic transmission holography of the eye. Ocular ultrasonic transmission holography of the eye using equipment capable of real-time imaging has not previously been described. A method using pulsed ultrasound focused on an air/liquid interface is used to demonstate normal ocular structures including lens, optic nerve, and sclera. Intraocular foreign bodies imaged include radiopaque and nonradiopaque materials. A limit of resolution of at lease 1 mm. is demonstrated.


Contrast sensitivity in meridional amblyopia. Contrast (modulation) sensitivities for gratings of various spatial frequencies and orientations have been determined for meridional amblyopes. The entire contrast sensitivity function is reduced for gratings oriented in the amblyopic meridian. Therefore, neural elements that process a broad range of spatial frequencies are affected by meridional amblyopia.


Accommodative effects of aceclidine in the treatment of glaucoma. In 18 patients, 2% pilocarpine, 2% pilocarpine plus tropicamide 10:1, and 2% aceclidine were tested with respect to the degree of spasm of accommodation induced by these drugs. Aceclidine had the least effect on accommodation, making it the recommended drug for use in patients with glaucoma and considerable remaining accommodation, i.e., most patients under the age of 50 years.


Unsuccessful eccentric perilimbal suction after filtering surgery. Eccentric suction was applied over the surgical site in 47 eyes thought to have unsuccessful external filtering procedures. Referrals for suction were made either because the postoperative intraocular pressure was uncontrolled or because blebs were becoming progressively flatter. Patients had an average of seven such treatment sessions. No discernible benefit from eccentric suction in failing filtering surgery was noted one year postoperatively.


Primary spheroidal degeneration of the cornea in Labrador and northern Newfoundland. The reported prevalence and severity of primary spheroidal degeneration in Labrador and nothern Newfoundland is based on a survey of 929 patients. The degeneration is associated with man in outdoor occupations and with pinguecula, but not with glaucoma. Ultraviolet radiation is a probable causative factor and prophylaxis using appropriately filtering glass a possibilty.


Massive eye relief project in India.

Massive eye relief project in India. In India, nearly 1.5% of the population is blind due to cataracts, most of them mature. The facilities available for eye operations are not adequate to restore sight to all these people, so eye camps are conducted all over India. A massive eye camp project begun in June 1972 fixed a goal of 100,000 cataract operations a year in the eye camps. About 50,000 cataract operations were done in that period. Most of the people who receive operations are poor and they are provided with free surgery, medicine, food, and glasses. This project will continue until enough eye hospitals are built to accommodate all the patients in our locality. The other states in India are planning similar programs.


A portable monocular indirect ophthalmoscopic technique. A simple, inexpensive, and portable method of monocular indirect ophthalmoscopy is used as the physician's examining eye is aligned in the axis of the patient's eye, a flashlight is held against the examiner's malar area beneath the dominant eye, and the beam of the flashlight is directed to the patient's eye. A plus 30 lens is then interposed 1 or 2 inches in front of the patient's eye and the fundus viewed.


Leber's miliary aneurysms associated with telangiectasia of the nasal mucosa. A 20-year-old woman, treated with cryopexy and xenon- and argon-laser photocoagulation for Leber's miliary aneurysms in her right eye, suffered from repeated epistaxis. She underwent an endoscopy that showed an unusual number of telangiectatic veins. Laboratory results and routine physical and neurologic examinations showed normal values. Dematologic examination revealed no signs of hereditary hemorrhagic telangiectasis (Osler's disease). Nevertheless, it seems reasonable to assume that the combination of microvascular disturbances in one eye and in the nasal mucous membrane is not a coincidental finding.


Angiographic appearance of the normal equine foot and alterations in chronic laminitis. The angiographic appearance of the normal equine foot was compared with the appearance of equine feet affected with chronic laminitis. The normal foot was characterized by complete filling of the terminal arch, 8 to 10 main branches between 0.1 and 0.2 cm in diameter, a symmetrical netlike vascular pattern in the corium of the hoof, and numerous fine vessels in the corium of the coronary band. The feet affected with chronic laminitis were characterized by poor filling of the terminal arch, larger and less numerous primary branches, an irregular vascular pattern in the corium of the hoof, areas of the corium of the hoof that were apparently avascular, and irregular, tortuous vessels in the corium of the coronary band.


Best's vitelliform macular dystrophy.

Best's vitelliform macular dystrophy. A patient with Best's vitelliform macular dystrophy in his right eye had an intact vitelliform disk and drusen of the optic papilla. Although the foveola elevated by a few tenths of a millimeter, resolution was only slightly affected and the retinal receptors remained remarkably well-aligned, suggesting that mechanisms subserving receptor alignment still functioned. Hue discrimination and visual acuity were only slightly affected and the electroretinogram and visually evoked response showed essentially normal values. The vitelliform disk in the left eye ruptured by direct, blunt trauma. This same eye later developed subretinal macular neovascularization, as its visual acuity reduced, retinal sensitivity decreased, receptor orientation showed abnormalities, and hue discrimination became less efficient; the electroretinogram and visually evoked response remained normal.


Delayed diagnosis of pituitary tumors.

Delayed diagnosis of pituitary tumors. Of 38 patients with presumed or proven pituitary adenomas, 24 first presented with ocular complaints. Of these, ten patients had a physician-caused delay in the formulation of the correct diagnosis. Reasons for the physician-caused delay in diagnosis include inadequate history evaluation, failure to perform adequate testing, provide follow-up examination, and recognize typical signs of pituitary adenomas.


Superior oblique tendon sheath syndrome of Brown. Twenty-four patients with true superior oblique tendon sheath syndrome (Brown's syndrome) were extensively examined surgically. Since a tight or short anterior sheath of the superior oblique tendon was not present in any of our cases, we are not able to support the theory that this form of the syndrome is due to a congenital anomaly of the anterior sheath. The superior oblique tendon was taut and shortened in only two cases; in all the others it was limp, even in attempts to elevate the eye passively in adduction. Thus the majority of cases of constant congenital Brown's syndrome remain unexplained with no obvious abnormality found at surgery in any of the six extraocular muscles. However, our surgical findings did suggest that a restrictive band posterior and inferior to the globe was responsible for the limited elevation in adduction.


Late glaucoma after interstitial keratitis. In a systematic study of 45 patients who had syphilitic interstitial keratitis early in life and, many years later, were discovered to have glaucoma, there was evidence of two different but equally common mechanisms. In one group of patients, a deep-chamber type of glaucoma was superimposed on old inflammatory changes, was characteristically refractory to medical treatment, but did well with filtering surgery. The other group of patients had reversible angle-closure glaucoma associated with anatomically small anterior segments, and typically responded well to iridectomy. The late, refractory, deep-chamber type of glaucoma may involve endothelialization and formation of glass membrane in the angle, as seen in one excised eye. Occurrence of the shallow-chamber, reversible angle-closure type of glaucoma after interstitial keratitis may be coincidental, since no other evidence supports the idea that small anterior segments might be particularly prevalent among patients who have had congenital syphilis or interstitial keratitis.


In vitro corticosteroid: correlation response with primary open-angle glaucoma and ocular corticosteroid sensitivity. The transformation of human peripheral blood lymphocytes can be inhibited by corticosteroid compounds. In an in vitro study of 100 patients with primary open-angle glaucoma and various degrees of ocular pressure responsiveness to corticosteroid testing, varying degrees of sensitivity to corticosteroid compounds existed systemically in the circulating lymphocyte. A high correlation exists between the level of corticosteroid sensitivity in the lymphocyte and in the eye. In vitro cellular systems may be useful in evaluating the molecular basis of the variability in corticosteroid response, and in understanding the pathogenesis of corticosteroid-induced ocular hypertension and primary open-angle glaucoma.


Chemical sympathectomy with 6-hydroxydopamine in the treatment of primary open-angle glaucoma. Chemical sympathectomy with 6-hydroxydopamine combined with subsequent topical epinephrine therapy was evaluated with regard to intraocular pressure effects in primary open-angle glaucoma. After chemical sympathectomy intraocular pressure was maintained below 20 mm Hg  with 1.0% epinephrine three times daily in 29 of 36 eyes of 25 patients for two to 29 weeks. Chemical sympathectomy combined with epinephrine therapy was most effective in patients whose intraocular pressure had been well controlled with pilocarpine and epinephrine and was less effective in patients whose intraocular pressure had not been controllable with maximum medical therapy prior to the administration of 6-hydroxydopamine. The results of this study suggest that chemical sympathectomy combined with topical epinephrine therapy has considerable clinical value in the medical management of primary open-angle glaucoma.


Enhanced carotid sinus baroreflex responses in dogs with chronic A-V block. Effects of carotid sinus pressure on arterial pressure, atrial rate, and ventricular rate were examined in anesthetized normal dogs and in dogs with chronic complete A-V block. Change in arterial pressure per mmHg change in sinus pressure was 0.8 plus or minus 0.2 mmHg for controls but increased (P is less than 0.001) to 1.6 plus or minus 0.1 mmHg in A-V blocked dogs. Arterial pressure was 140-145 mmHg at low sinus pressure in both groups, but at high sinus pressure arterial pressure was significantly lower in A-V blocked dogs (44 plus or minus 4 mmHg) than in controls (92 plus or minus 8 mmHg). These differences were virtually abolished after vagotomy. Heart rate increased in normal dogs as sinus pressure was increased before vagotomy, but decreased after vagotomy. In blocked dogs atrial and ventricular rates decreased at high sinus pressure either before or after vagotomy. The results show that reflex circulatory responses to changes in carotid sinus pressure are enhanced in dogs with A-V block. This enhancement may involve attenuation of buffering influences exerted from other baroreceptors whose afferents are in the vagus nerves.


Effect of preinspiratory lung volume on closing volume determination by nitrogen method. The effect of preinspiratory lung volume on the N2 closing volume (CV) was studied in simulated CV determination in a lung model. The model analysis supports our hypothesis that inspiration of O2 initiated at the "closing capacity" (CC = CV ;V) will improve the resolution of the inflection point between phases III and IV. It further indicates that if the inflection point is located by extrapolating the terminal portion of phase IV, then the original N2 method could underestimate CV systematically as much as 5% VC because of the relatively small initial rise in N2 concentration. Conversely, the CV obtained by the modified method should be closer to the value obtained by the "bolus method." In practice, the modification can be done simply by adding a dead space (DS) with its capacity equal to CV (600-700 ml in male adults). The theoretical lung model analysis was confirmed by the experimental study, which showed that CV with DS was consistently larger than CV without DS (a mean difference of 4.7% VC).


Acceleration time series resulting from repetitive extension-flexion of the hand. Power, or variance, spectra of acceleration records obtained from normal subjects during extension-flexion oscillations of a hand at frequencies between 0.5-5.0 Hz generally contained two or three frequency bands. Partial separation of these oscillations in the time domain was obtained using the method of digital filtering (smoothing). In general, the peak frequency of the lowest frequency band occurred at, or nearly at, the frequency that the subject attempted to maintain during a 16-s digitization period. Consideration of absolute frequencies and the effect of mass on frequency indicated that one of the higher frequency bands was the result of normal hand tremor. For low frequencies of voluntary oscillation (0.5-1.25 Hz), a second, higher frequency band occurred with a peak frequency (3.0-4.25 Hz) within the range (3-6 Hz) usually reported for abnormal hand tremor. For voluntary oscillation frequencies above about 1.5 Hz, this second, higher frequency oscillation generally occurred at twice the frequency of the voluntary oscillation.


Additive effects of acetylcholine released by vagal nerve stimulation on atrial rate. In reserpinized dogs, the decrease in atrial rate (AR) as a function of the frequency of stimulation (supramaximal strength) of a single vagal nerve can be described satisfactorily by a rectangular hyperbola (RH). If the RH of one vagal nerve has been determined and if one point of the RH of the other vagal nerve is known, then the latter RH can be determined. Both RHs being known and assuming that the acetylcholine released by the right and left vagal nerves is additive, the slowing of AR by simultaneous stimulation of both nerves can be predicted. A minor systematic deviation from the predicted AR during simultaneous stimulation is usually found, which could be accounted for by a time dependent decrease of the effect of vagal nerve stimulation. The results are qualitatively similar during norepinephrine infusion. We propose that, although the vagal innervation may vary from pacemaker cell to pacemaker cell, the ratio of the activities of the two vagal nerves is constant throughout the sinoatrial node.


De novo biosynthesis of plasminogen in the anephric rat. Two major forms of plasminogen exist in the plasma of many different species. Each form is present in normal amounts in anephric patients and each form is synthesized de novo in bilaterally nephrectomized rats. Although the rate of synthesis of each form of plasminogen is lower than normal immediately after nephrectomy, the rate of plasma protein synthesis is also apparently lower than normal in these cases. This is thought to reflect the fact that the nephrectomized rat is in a state of circulatory distress immediately after kidney ligation. It is concluded that the kidney is not responsible for de novo biosynthesis of plasminogen. This point has been the subject of some confusion.


Effect of muscle constriction on flow-limiting collapse of isolated canine trachea. Before and after trachealis muscle contraction, induced by application of acetylcholine, the relationship of changing pressures to flow through excised canine tracheas was examined in a mechanical model simulating isovolume pressure-flow relationships in vivo. At the same time, the change in cross-sectional lumen area at a point in the downstream third of the trachea was measured using slit-lamp transillumination and cinematographic measurements. Trachealis muscle contraction reduced the uncompressed lumen area but inhibited dynamic collapse as driving pressures increased. As a result, following contraction, the initial slope of the tracheal pressure-flow (TPF) curve changed, indicating increase in resistance at low flows, but higher flows were achieved at higher driving pressures. Results suggest that smooth muscle tone of large airways may affect maximum expiratory flow (Vmax) and explain apparent discrepancies between in vivo measurements of resistance and Vmax. The magnitude of the Bernoulli effect contributing to airway narrowing was demonstrated by measurements of lateral airway pressures well in excess of driving pressure.


Maximum permissible weight to be carried on the head by a male worker from eastern India. Six healthy adult male Indian workers whose physical characteristics resembled those of the average worker from eastern India, were required to carry compact loads of 20, 30, 40, and 50 kg at a speed of 5 km/h on separate days. From observations on energy expenditures, of peak pulse rates, and of the patterns of recovery pulse rates, it was decided that for the average eastern Indian male worker the permissible weight of a compact load for manual carriage on a hard, level terrain should not ordinarily be more than 30 kg.


Hypoxic ventilatory depression in dogs.

Hypoxic ventilatory depression in dogs. It is well known that hypoxia, acting mainly through peripheral chemoreceptors, is an important ventilatory stimulus. It is also known that under certain circumstances hypoxia can lead to ventilatory depression, perhaps through its effect on the central nervous system. This study, utilizing dogs, was carried out to determine the degree of hypoxia required to produce ventilatory depression and to study the effects of chloralose anesthesia, variations in blood carbon dioxide tension, and peripheral chemoreceptor denervation on hypoxic ventilatory depression. In the awake, intact dog, ventilatory depression did not occur until the Pao2 = 18.6 plus or minus 0.8 mmHg (SEM). This value was not significantly different from that observed in chloralose anesthetized dogs, Pao2 = 18.7 plus or minus 0.43 mmHg. Hyper- and hypocapnia had no significant effect on the Pao2 at which ventilatory depression occurred. Denervation of either aortic or carotid chemoreceptors produced a very small change in the Pao2 of ventilatory depression, increasing it from 18.6 plus or minus 0.58 to 20.8 plus or minus 0.93 mmHg. Denervation of both aortic and carotid chemoreceptors produced a further small increase (Pao2 = 21.8 plus or minus 0.76 mm Hg). In peripheral chemoreceptor-denervated animals, hypoxia produced no significant change in ventilation until the ventilatory depression point was reached. These studies indicate that in the dog hypoxic ventilatory depression occurs only during severe hypoxia and ventilatory depression occurs only during severe hypoxia and is uninfluenced by chloralose anesthesia, hyper- or hypocapnia, and only slightly affected by chemoreceptor denervation.