Normal excretion of vasopressin and the effect of everyday activity. The urinary excretion of arginine vasopressin (AVP) was measured by bioassay in normal subjects at rest, on reduced physical activity and on routine everyday activity. The values obtained under rest conditions were all less than 10 mu/24 h with a mean less than 6.6 mu/24 h. Excretion of vasopressin increased with increasing activity, despite free access to water to mean values of 17 mu/24 h and 29 mu/24 h under conditions of reduced and routine every day activity respectively.


Acute effect of inorganic iodide after 131I therapy for hyperthyroidism. Patients treated with inorganic iodide weeks to years following 131I therapy for hyperthyroidism do not adapt to its antithyroid effect. To determine whether such adaptation occurs soon after 131I therapy, serum thyroxine (T4) and triiodothyronine (T3) concentrations were measured daily for 9-14 days following 131I therapy in seventeen hyperthyroid patients. Nine patients received 150 mg KI daily starting 48 h after 131I administration; eight received only 131I. Serum T4 and T3 concentrations did not change significantly in the patients who received only 131I. In the patients who received 131I and KI, serum T4 and T3 concentrations fell promptly, reaching nadir values 2-10 days after initiation of iodide, and then increased despite continuation of KI therapy. The mean maximal fall in serum T4 was 34% and in serum T3 42%. These results show that "escape" from the acute anti-thyroid effect of iodide occurs when it is given immediately after 131I therapy, thus limiting the utility of iodide as a therapeutic agent at this time.


Heredity of idiopathic haemochromatosis: a study of 106 families. More than 80% of the first degree relatives of 106 patients with iron overload - 97 with idiopathic haemochromatosis (I.H.) and nine with haemosiderosis secondary to alcohol induced liver disease (A.H. - were examined. Physical examination and measurement of plasma iron level and UIBC were done in all subjects; relatives who presented with some anomaly were submitted to a desferrioxamine test and, if the latter showed a high urinary iron output, to a liver biopsy. While absent in relatives of A.H. patients, iron overload was present in 78 out of 499 relatives of I.H. patients: 29 major and 49 minor forms. The major forms involved the sibships almost exclusively. The genetic analysis showed much evidence in favour of a recessive or rather intermediate form of inheritance, with heterozygous developing minor forms. However, other modes of transmission, especially polygenic (probably oligogenic), cannot be totally excluded. Data from recent studies showing a strong correlation between I.H. and certain HLA antigens do not conflict with the above conclusions.


No evidence for a correlation between behaviour and the size of the Y chromosome. Y chromosome variation has been studied in three groups of Norwegian males: 35 boys from an adolescent psychiatric hospital; 45 men from a hospital for hard-to-manage or dangerous, psychotic men; and 26 boys from two ordinary school classes. Y chromosomes with 1, 2, and 3 brightly fluorescing bands were found in all three groups. One boy carried a Y with no bands. The mean values of the Yf/Yq ratio were not significantly different in the three groups (Yf is the length of the distal, brightly fluorescing part of Yq). Two cases of XY/XYY mosaicism were found among the psychotic men. The study shows that the human species is polymorphic with regard to the size of the Y chromosome, i.e. the number of fluorescent bands in the long arm. No phenotypical manifestation of this polymorphism, particularly as regards behaviour, was found.


Unusual association of Saethre-Chotzen syndrome and congenital adrenal hyperplasia. This report describes and discusses the very rare occurrence of two heritable traits, the Saethre-Chotzen syndrome and congenital adrenal hyperplasia (21 hydroxylase deficiency, salt-losing type) in a female infant whose father presents the clinical manifestations of Saethre-Chotzen syndrome. Family study revealed no other instances of the recessively inherited adrenogenital syndrome. Other literature cases combining acrocephalosyndactyly and urogenital anomalies are discussed and compared.


Colton blood groups: indication of linkage with the Kidd (Jk) system as support for assignment to chromosome 7. A material of normal Danish families was tested for a number of genetic marker systems and analyzed for linkage. For the Colton-Kidd relationship the lod score was + 2.57. The Kidd system has earlier been tentatively assigned to chromosome 7 (Schokeir et al. 1973). The present data therefore permit a tentative assignment to chromosome 7 of the Colton system as well. The data also suggest that the discovery by Chapelle et al. (1975) of a conjunction of monosomy for chromosome 7 in the bone marrow of certain leukemia patients and absence of Colton antigen from the red cells may now be interpreted as being connected with location on chromosome 7 of the Colton system.


Prenatal diagnosis of dysplastic kidney disease. Sonolucent areas in the region of the kidneys were demonstrated by ultrasound in a 23-week-old fetus. These sonolucent areas persisted and enlarged during the pregnancy and the infant had the Potter phenotype and Potter type 2A dysplastic kidneys at birth. The use of prenatal sonographic evaluation of the fetal kidneys is discussed.


Purification and characterization of human liver-specific membrane lipoprotein (LSP). A liver-specific lipoprotein (LSP) which is present in 105,000 g supernatants of human liver has previously been shown to produce a lesion resembling chronic active hepatitis in rabbits immunized with human liver fractions containing this lipoprotein. In addition, it has been implicated as the principal target antigen involved in the liver cell cytotoxicity exhibited in vitro by lymphocytes from patients with chronic active hepatitis. The organ-specificity and species cross-reactivity of LSP is confirmed. Although very labile, is has been prepared in a stable form by gel filtration of Sepharose 6B in a Tris buffer containing 1 mm disodium EDTA. LSP is also stable in a borate buffer containing EDTA but is unstable in a number of other buffer systems tested. When prepared by this method it contains approximately 2% albumin as the only detectable contaminant. Gel filtration studies on the apoprotein of LSP revealed that it has an apparent mol. wt of between 4 X 10(6) and 20 X 10(6). SDA-polyacrylamide gel electrophoresis indicated that the lipoprotein may be composed of up to thirteen sub-units of different molecular sizes.


Complement in the induction of IgE antibody formation. The IgE antibody response of NIH mice to ovalbumin was suppressed by in vivo complement depletion with cobra factor. This observation extends to IgE the finding that complement participates in thymus-dependent antibody formation. Control mice producing IgI anti-ovalbumin antibody after boosting all developed marked peripheral eosinophilia, whereas mice in which the IgE antibody response had been suppressed by cobra factor did not. Administration of cobra factor itself had no effect on peripheral eosinophil levels.


Farmer's lung: immunological response to a group of extracellular enzymes of Micropolyspora faeni. An experimental and field study. Potent immunogenicity of certain extracellular 'chymotrypsin-like' enzymes of Micropolyspora faeni are demonstrated. One of them, Enzyme 1 seems particularly active in stimulating the formation of percipitins after intratracheal exposure in rabbits. Man or cattle exposed naturally to mouldy hay, either with or without clinical farmer's lung symptoms show a rather constant immunological reaction against Enzyme 1 and partly also against others of the same group. The detection of specific percipitins against these enzymes is not likely to improve the diagnostic value of the standard farmer's lung serology. Possible implications of these proteolytic enzymes in the pathogenesis of farmer's lung are discussed.


Immunosuppression by sex steroid hormones. The effect upon PHA- and PPD-stimulated lymphocytes. Progesterone, estradiol, testosterone, cortisol, and 11-desoxycortisol (compound S) were added to cultures of human lymphocytes stimulated with phytohaemagglutinin (PHA) and purified protein derivative (PPD). The immunosuppressive effect of cortisol was verified and the three sex-steroid hormones also were found to inhibit lymphocyte transformation although at concentrations higher than for cortisol. Compound S, a steroid of low biological potency, also had immunosuppressive activity. At concentrations (0-01-1-0 microng/ml), progesterone, oestrogen, testosterone, and Compound S augmented the transformation response to PPD but not to PHA. Marked variation from individual to individual in the suppressive effects of all the steroids were noted. The clinical implications of immunosuppression by the sex steroid hormones are discussed.


A human IgA myeloma protein interacting with staphylococcal alpha-toxin and protein A. High anti-staphylolysin activity was found in the serum from a patient with multiple myeloma. The activity was confined to the monoclonal IgA protein and was dependent on an intact Fc part of the molecule. An Fc-dependent interaction with protein A was also demonstrated. In addition, a part of the monoclonal IgA was found to be complexed with alpha2-macroglobulin. The results imply an unusual Fc-reactivity of the IgA protein.


An inhibitor of lymphocyte proliferation and lymphokine production released by unstimulated foetal monocytes. Supernatants obtained from 3-day cultures of cord blood monocytes inhibited normal lymphocyte activation by either PHA or in a two-way MLC. Both lymphocyte transformation and lymphokine production was significantly inhibited by these supernatants but not by those derived from adult mononuclear cell cultures. The inhibitory material produced by foetal monocytes was dialysable and was non-cytotoxic to target cells. It is postulated that this factor contributes to the depressed maternal cell-mediated immune response observed in pregnancy.


A radiomicroassay for cytotoxic antibody to human spermatozoa. Quantification by tritiated actinomycin d. A radiomicroassay for titration of spermocytotoxic antibody is described. The assay used [3H]AACTINOMYCIN D ([3H]Act D) to label damaged spermatozoa in a fashion analogous to penetration by vital dye. Optimal conditions for and some kinetics of the assay are presented. The assay is sensitive, reliable, simple to perform and uses only small amounts of serum and spermatozoa. Applied to sperm antibody positive human postvasectomy sera, the assay compared favourably in sensitivity eith vital dye microscopic observations and with parallel titration by the Isojima's immobilization tests.


Cellular immunity in newborn infants and children: stimulation of lymphocyte protein synthesis as a measure of immune competence. An assay based on the early stimulation of protein synthesis in lymphocytes has been used as an in vitro measure of cellular immune competence. 3H-labelled leucine incorporation into human peripheral lymphocytes (PBL) stimulated by the mitogens phytohaemagglutinin (PHA), wax bean agglutinin (WBA) and Concanavalin A (Con A) was measured after one day in culture. This assay offers a technical advantage over the analogous 3H-labelled thymidine incorporation assay, because of the short incubation time required and the absence of homologous serum in the assay system. Newborn infants and patients with Down's syndrome as a group had normal responses, whereas those suffering from recurrent infections demonstrated normal or hyper-reactive responses. Patients with lymphoproliferative disorders, ataxia telangiectasia, and some patients under steroid therapy had diminished immune proliferative reactions. These results are in agreement with most previously reported studies using other assay systems.


Deficienty of specific HLA antibodies in severe pregnancy pre-eclampsia/eclampsia. The paradox of the survival of the foetal allograft remains unresolved as does the aetiology of pre-eclampsia/eclampsia--the principle disease of pregnancy. In a prospective study of very severe cases of pre-eclampsia we have found significantly reduced antibody to paternal histocompatibility antigens. Lowered immune response to the foetal allograft may play a role in severe cases of pre-eclampsia.


Platelet activating factor, the trigger of haemostatic alterations in rat anaphylaxis. Platelet-activating factor (PAF) generated by an IgE-mediated reaction in the peritoneal cabity of rats was partially purified by adsorption to diatomaceous earth. It aggregated rat platelets and, as a consequence, activated Hageman factor in in vitro, as well as in vivo, conditions. The haemostatic alterations induced by PAF showed similarity to those observed in the early phase of rat anaphylaxis.


Epithelial cell proliferation in thymic hyperplasia induced by triiodothyronine. A significant hyperplasia of the thymus was induced in mice, treated with triiodothyronine during the first month of life. Stereological data showed that, in both treated and control mice, mononucleate epithelial cells were four times more numerous in the medulla that in the cortex. After triiodothyronine treatment, their absolute number in both cortex and medulla increased two-fold. The number of thymic epithelial cells could thus be regulated by thyroid hormones. The cortical volume in treated mice was also twice that of controls but medullar volume showed and increase of only fifty percent. Cortical epithelial cells increased at the same rate of the cortex volume by medullary epithelial cells grew more rapidly. In fact the medullary volume enlargement could be be explained mainly by the growth of the epithelium. Medullary lymphocytes did thus not preliferate in the same way as cortical lymphocytes after thyroid hormone administration. The recently described multinucleate epithelial cells were not modified in number and were thus insensitive to thyroid hormones.


Studies on the pathogenesis of experimental autoimmune renal tubulointerstitial disease in guinea-pigs. IV. failure to inhibit mononuclear cell accumulation with niridazole. Niridazole is a potent inhibitor of certain expressions of delayed-type hypersensitivity; however, its effect and specificity on other immunologically induced mononuclear cell infiltrates has not been determined. We therefore tested this drug in a model of auto-antibody-induced renal tubulointerstitial disease (RTD), which is characterized by the accumulation of lymphocytes and macrophages in the cortical interstitium. Niridazole-treated (100 mg/kg) and untreated guineapigs were injected with potent anti-tubular basement membrane serum from donors with RTD. Drug treatment was repeated 2-3 times during the course of 10 days. The characteristic renal lesions were found in both groups. However, a single dose of niridazole inhibited skin reactivity in tuberculin sensitive guinea-pigs for at least 8 days. These findings further support the contention that immunologic tissue injury in RTD does not involve mechanisms of delayed-type hypersensitivity.


Temporal correlation of lymphocyte blastogenesis, skin test responses and erythema during dermatophyte infections. The development of cellular hypersensitivity, as measured by lymphocyte blastogenic and skin tests assays, was correlated with intensification of lesion erythema in guinea-pigs infected with Trichophyton mentagrophytes. Development of lymphocyte blastogenic responses to trichophytin was assayed using forty infected animals and twenty controls; blastogenic conversion occurred between 9-11 days post spore application. The onset of cellular hypersensitivity was assayed in vivo in twenty infected guinea-pigs by skin testing at intervals after infection; positive responses occurred between 9-11 days post spore application which coincided with the time of blastogenic conversion. Clinical characteristics of lesions were followed in a group of twenty-four animals: lesions first appeared on day 7; erythema intensified until day 10; lesions reached maximum size by day 13; and alopecia began on day 17. Since cellular hypersensitivity (positive skin test and lymphocyte blastogenesis) develops at the same time as lesions reach maximum erythema, cellular hypersensitivity appears to be responsible for the intense inflammatory response associated with ringworm infections.


Autoantibodies against the inner aspect of erythrocyte membranes in NZB mice. Erythrocyte autoantibodies in NZB mice react by hemagglutination methods with exposed and hidden red cell antigens. The hidden antigens can be exposed by treatment with proteolytic enzymes. By indirect immunofluorescence one antibody population can be shown to react with modified red cells. In the present study the location of the corresponding autoantigen within the membrane was studied. Mechanical or hypotonic lysis of the red cells exposed the antigen. Proteolytic digestion known to expose other erythrocyte autoantigens had no effect. The autoantigen was exposed on 'inside out' erythrocyte membrane vesicles, but not on 'right-side out' vesicles, prepared from isolated erythrocyte ghosts. Frezzing and thawing as well as mechanical disintergration of red cells liberated antigenically active material as saline-insuluble fibrillar material. The observations indicate that the autoantigen studied is located at the inner aspect of the erythrocyte membrane and suggest that it is associated with fibril-forming structural components. The observed reactivity distinguishes the described antibodies from previously identified erythrocyte autoantibodies.


Hyper-responsiveness in NZB mice to the experimental induction of anti-red cell autoantibody. Strain differences in ease of induction of autoantibody production were observed when mice were injected with rat RBC. Responsiveness was not linked to the H-2 locus. NZB and (NZB X BALB/c)F1 mice were hyper-responsive both in terms of the induction of autoantibody and in the production of agglutinating antibody to rat RBC. C57BL/c and (C57BL X BALB/c)F1 were poor responders. Injection of the rat RBC in FCA converted a poor responder into a good responder. Adult thymectomy and ALS treatment did not significantly enhance autoantibody production.


Characterization of haemagglutinating factor produced by mouse spleen and lymph node in culture. Mouse spleen cells produce haemagglutinating activity in culture which is species specific but not strain specific. The activity is produced by all strains of mice tested including nude mice. It is produced in cultures of spleen and lymph node but not of peritoneal exudate cells. Production of the factor is not affected by macrophage depletion of the spleen. This activity is not antibody mediated.


Immunological reactivity of the lung. IV. Effect of cyclophosphamide on alveolar macrophage cytotoxic effector function. The effect of cyclophosphamide on the absolute numbers and function of alveolar macrophages following either in vitro or in vivo drug exposure was studied in the guinea-pig. Two separate regimens of in vivo cyclophosphamide administration (100 mg/kg/one dose or 20 mg/kg for 5 days) both of which produce identical decreases in each population of peripheral blood leucocytes 5 days after the initial injection did not produce anay change in alveolar macrophage numbers when compared to control values. Neither a brief exposure to CY in vitro nor a brief exposure in vivo (100 mg/kg/one dose) caused any change in cytotoxic effector function of alveolar macrophages using the PHA-induced and antibody-dependent cellular cytotoxicity assays against sheep erythrocyte targets. In contrast, the more prolonged in vivo exposure to CY (20 mg/kg for 5 days), produced a significant decrease in the killer cell function of these cells. Thus, this study demonstrates that different regimens of cyclophosphamide administration, although producing similar degrees of peripheral blood leucopenia can produce markedly different effects on the functional capabilities of alveolar macrophages without quantitatively decreasing the absolute numbers of these cells.


Disappearance of IgG2B autoantibodies associated with recovery from anaemia. Mice immunized with cross-reacting rat erythrocytes develop autoimmune haemolytic anaemia as indicated by haematological data and erythrocyte autoantibodies. With continued immunization the mice recover haematologically but remain Coombs' positive. Coombs' tests were performed using monospecific antisera to determine whether the recovery from anaemia was associated with a change in the class or subclass of the autoantibodies produced. In both splenectomized mice and in unsplenectomized mice the following subclass of erythrocyte autoantibodies were present: IgG1, IgG2A, IgG2B. IgA autoantibodies were not detected and IgM autoantibodies were only detected in splenectomized mice 1-3 weeks after the IgG autoantibodies had appeared. After six immunizations the frequency of IgG2B autoantibodies decreased and by the tenth immunization and thereon, IgG2B autoantibodies were not detected. It is proposed from these results that the anaemia is caused by IgG2B autoantibodies and the the sudden exacerbation in the anaemia that occurs in splenectomized mice is due to the production of IgM autoantibodies.


Guinea-pig nephrotoxic nephritis II. Autologous phase: complement activation without detectable injury. In the autologous phase of nephrotoxic induced by sheep antibody to glomerular basement membrane (GBM) in Dunkin-Hartley and C4 deficient strain guinea-pigs, less than 50% of animals developed proteinuria at the height of the autologous antibody response despite high anti-sheep immunolglobulin tetres and fixation of guinea-pig IgG and complement in the kidney. tonly two of thirty-sdven animals (5-4%) developed progressive. In a passive model of autologous phase injury using high titres rabbit antibody to sheep IgG, proteinuria failed to occur despite fixation of up to 95 microng rabbit antibody per kidney. Repeated injection of sheep nephrotoxic antibody (NTab) caused a persisting nephrotic syndrome but not the characteristic proliferative lesion of anti GBM diseases in other species.


Specific removal of antibody by extracorporeal circulation over antigen immobilized in collodion-charcoal. Studies were undertaken to determine whether BSA immobilized in collodion membranes adherent to activated charcoal particles, would be capable of specifically removing circulating BSA antibody in vitro and in vivo in an extracorporeal system in dogs. Up to 59-8 mg of BSA were retained in collodion membranes adherent to small particles. In vitro studies demonstrated that immobilized BSA could specifically reduce BSA binding activity from circulating antisera. For in vivo studies, an extracorporeal circulation system was established and arterial blood was circualted through a continuous flow celltrifuge in which plasma was separated from formed elements of the blood. Only plasma was circulated over the BSA collodion-charcoal immunoadsorbent. Anti-BSA and anti-HSA atibodies were passively infused into dogs and, after an equlibration period of 12 or 15 min, plasma was passed over the BSA collodion-charcoal immunoadsorben. Plasma exhibited a sharp reduction in BSA binding over the next 30-60 min with only slight reduction in anti-HSA binding the same period. Dogs, actively immunized to BSA and HSA, were also treated by extracorporeal plasma perfusion over BSA collodion-charcoal. A specific decline in BSA binding of sera, was again observed with minimal changes in HSA binding. A post-perfusion rebound of BSA binding was observed which reached pre-perfusion levels after 6-8 days. A second treatment during the rebound period also resulted in a specific decline in BSA binding with a similar pattern of antibody rebound. There were no significant changes in I-labelled BSA recorded on the charcoal before and after in vivo procedures and no signifcant alterations in haematocrit, serum sodium, potassium, calcium, magnesium or creatinine levels before and after the procedures. These data suggests that antigen-coated charcoal may specifically withdraw circulating antibodies in vivo with minimal release of the entrapped antigen and little alteration in the host's haematological and biochemical status.


Enhanced phagocytosis of immune complexes in pregnancy. Utilizing an in vitro immunofluorescence phagocytosis assay for the detection of circulating immune complexes sera from pregnant women, from women taking contraceptive agents and age-matched controls were tested for their effect on the phagocytosis of immune complexes by normal peripheral blood polymorphonuclear leucocytes (PMN). Immune complexes present in the serum of a patient with seropositive rheumatoid arthritis and heat-aggregated IgG (COHN fraction II) were used as substrate. A significant enhancement of the phagocytosis of immune complexes by PMN in the presence of increasing amounts of pregnancy serum was seen using rheumatoid arthritis serum as well as heat-aggregated IgG. Serum from patients taking contraceptive drugs and controls showed no effect on the phagocytosis of such complexes in vitro. These observations suggest that pregnancy serum contains factors which enhance the phagocytosis of immune complexes possibly resulting in an increased clearance of such complexes. The commonly seen improvement of rheumatic diseases in the course of pregnancy might at least partially be due to this mechanism.


Human antibody-dependent cell-mediated cytotoxicity against target cells infected with respiratory syncytial virus. A chromium release assay was established to study human antibody-dependent cell-mediated cytotoxicity (ADCC) of HEp 2 cells infected with respiratory syncytial (RS) virus. Human peripheral blood lymphocytes in the presence of specific antibody to RS virus caused in vitro lysis of RS virus infected target cells. ADCC was detected in sera of infants with RS virus infections and in specimens of colostrum. The ability of serum or colostrum to mediate the cytotoxic reaction appeared to be related to the level of specific IgG, or IgA antibody to RS virus, as detected by membrane fluorescence. Separation of effector cells by their glass adherence properties showed that the ability to produce cytotoxicity resided in non-adherent effector cells.


Development of immune response during typhoid fever in man. The development of both humoral and cell-mediated immune responses (CMIR) to antigens prepared from Salmonella typhi was investigated in patients suffering from typhoid fever. The antibodies were determined by the standard Widal test while the leucocyte migration test was used for CMIR. These immunological parameters were correlated with the duration of illness, the duration of chloramphenicol therapy and the severity of the illness. It was found that CMIR appeared after the first week of illness in uncomplicated cases of typhoid fever, where as it remained negative in the patients who had complications. The antibody titres were similar in the two groups. On further follow up of complicated cases, the clinical recovery coincided with the development of CMIR. It may be concluded that for recovery in typhoid fever CMIR is more important than antibodies.


Correlations between serum factor B and C3b inactivator levels in normal subjects and in patients with infections, nephrosis and hypocomplementaemic glomerulonephritis. In normal subjects, factor B and C3b inactivator (KAF) levels were linearly related (r = 0-71); factor B levels in subjects with low normal levels of KAF were significantly lower than in those with high normal levels of KAF. This relationship is postulated to be the result of modulation by the level of KAF of the availability of nascent, spontaneously formed, C3b, in turn responsible for a constant low-grade activation of the C3b feedback which determines in part the level of factor B. The correlation did not obtain in patients with infections; levels of KAF and, to a greater extent, factor B were elevated. In patients with glomerulonephritis and hypocomplementaemic because of in vivo classical pathway activation, KAF and factor B levels were also poorly correlated, presumably because many factors were influencing the levels of these proteins transcending the modulating effect of the concentration of KAF. On the other hand, in patients with nephrosis and with MPGN Type II, KAF and factor B levels were low but were directly correlated. In nephrosis the correlation may be the combined result of an equal rate of catabolism of these proteins and of modulation of factor B levels by the level of KAF as in normal subjects. In MPGN Type II, the correlation may reflect the fact, noted in in vitro studies, that with alternative pathway activation, the level of KAF influences the extent of factor B and C3 conversion to a greater extent than when complement is activated by the classical pathway.


Cell-mediated immune responses in patients with paracoccidioidomycosis. We tested the hypothesis that symptomatic infection with Paracoccidioides brasiliensis caused impaired host cellular immune responses. In a cross-sectional study in Colombia, the immune responses of thirty-six patients with paracoccidioidomycosis were compared with those of sixty normal individuals. Patients demonstrated increased skin sensitivity to paracoccidioidin (para) and histoplasmin, and reduced reactivity to candidin and dinitrochlorobenzene as compared to controls. The skin test response to tuberculin (PPD) was similar to that of controls. In vitro lymphocyte transformation (LT) and leucocyte migration responses to phytohaemagglutinin and PPD did not differ in patients and controls; these responses to PPD correlated with skin sensitivity in controls, but not in patients. LT and inhibition of leucocyte migration to para were seen in more patients than controls; the latter response correlated with skin sensitivity in controls only. Positive LT to para was associated with absence of antibodies to P. brasiliensis. Analysis of symptomatic patients suggests that the prevalence of para skin test positivity was lowest in patients with the longest duration of disease; this implies decrease in specific cell-mediated immunity with prolonged active infection. Analysis of clinically cured patients suggests that the prevalence of para skin sensitivity and LT to para and PPD increased with time elapsed since diagnosis; this implies development or restoration of immunocompetence upon clinical recovery. Results of a preliminary longitudinal study on the immunological responses of six patients with active paracoccidioidomycosis are compatible with the above observations.


Drugs used in the management of toxemia of pregnancy. Drugs used in the management of pregnancy-induced hypertension have been reviewed, and their value and adverse effects on both mother and fetus have been considered. Although magnesium and hydralazine remain the stalwarts of therapy, a number of other drugs have potential that may be realized in the future. Several new medications have promise in correcting the derangements of toxemia, but safety for the fetus has yet to be demonstrated. For the physician confronted with the complexities of old and new drugs in toxemia of pregnancy, the prayer of Lord Berkely may be just as appropriate in 1977 as it was dicades ago: From inability to let well enough alone, From too much zeal for the new, From too much contempt for what is old, From putting knowledge before wisdom and science before art, From making the cure of the disease more grievous than its endurnace, Good Lord, deliver us.


The value of noise-excluder shells in reducing overreferrals from a school audiometric screening program. Audiometric screening conducted in noisy environments can result in overreferrals to specialty clinics. A follow-up study, conducted to investigate referral rates as related to the type of headset used in screening programs, showed that noise-excluding shells reduced overreferrals without increasing underreferrals.


Hereditary aplasia cutis congenita and associated defects. Three instances in one family and a survey of reported cases. Hereditary aplasia cutis congenita (ACC) is a rare, dominantly inherited syndrome of scalp aplasia associated with defects of the underlying skull and absent distal phalanges of the feet. The scalp lesions are generally benign, but the increased risk of bleeding or meningitis may require skin grafting.


Gonococcal infections in young children. Studies on the social, familial, and clinical aspects of 11 instances. Of 43 youngsters with gonorrhea, 11 were under 10 years of age. These 11 had in common atypical clinical presentation, marital disharmony of the parents, crowded living conditions; some had been abused sexually. Management of gonorrhea in such young children may require a concerted effort by a team of medical, social, and legal personnel to meet the needs of this unique entity.


A study of the efficacy of the Feingold diet on hyperkinetic children. Some favorable personal observations. A study was conducted with 59 children, ages 6 to 14 years, heterogeneously grouped together under the diagnosis of the hyperkinetic, minimal brain dysfunction syndrome. Of 32 who were able to tolerate the Feingold salicylate-low and additive-free diet, 11 were markedly improved. A placebo effect could not definitely be ruled out, but the startling changes seen in patients who had been followed for years with other forms of therapy suggest strongly that this improvement was genuine.


Absorption and metabolism of lanatoside C. II. Fate after oral administration. The absorption, metabolism, and excretion of lanatoside C were studied in hospitalized subjects following oral administration of the tritiated drug. Previous reports of an unusual double peak in plasma levels of radioactivity were confirmed. Fifty plasma samples taken from 31 patients showed that an average of 74% of the radioactive material was digoxin and its metabolites. There was little or no lanatoside C in 36 of the 50 samples of plasma. Similar results were obtained for urine radioactivity. The results confirm that lanatoside C is converted to "digoxin" in the gut prior to absorption as previously proposed by us. "Digoxin" refers to digoxin and its breakdown products, namely, digoxigenin and its mono- and didigitoxosides. According to these proposals, the conversion to "digoxin"  takes place partly as a result of acid hydrolysis in the gut and partly by the action of bacteria in the intestine. The effects of concurrent administration of antacid therapy, anticholinergic therapy, and food on the fate of oral lanatoside C were separately studied. There were no significant differences between groups with respect to the amount of radioactive material absorbed or excreted, but there were marked qualitative differences in the plasma profiles. There was a statistically significant increase in the time to the first peak in plasma radioactivity in patients concurrently receiving either food or anticholinergic therapy and there was a significant decrease in the relative height of the first peak in patients treated concurrently with antacid.


Oral and intravenous propranolol during exercise. The intrinsic sinoatrial (SA) rate at rest and during exercise was measured in 5 normal male subjects after prolonged oral and acute intravenous administration of propranolol and atropine. At rest, the intrinsic SA rate was similar after both oral and intravenous propranolol. At the higher levels of power output on a cycle ergometer, cardiac rate was slower after oral than after intravenous propranolol. When the intravenous study was repeated with the use of an additional dose of propranolol, cardiac rate was lower at comparable levels of power output, but not as low as that after oral propanolol. Differences in responses were interpreted as reflecting varying degrees of beta blockade, the most complete being that after prolonged oral propranolol administration of 320 mg daily. The intravenous dose of propranolol usually used to obtain the "pharmacologically isolated heart" at rest is too small to induce full beta blockade in exercise.


Safety of single large oral doses of guanethidine. The cardiovascular effects of single 100-mg doses of guanethidine were assessed in hypertensive patients by measurement of arterial pressure, heart rate, and systolic time intervals. In the 3-hr period following a dose there was no evidence of an inotropic effect. Therefore, large doses of guanethidine as required for the guanethidine loading regimen would seem to be safe even in patients in whom inotropic effects of released catecholamines would be contraindicated.


Kinetics of hydralazine elimination.

Kinetics of hydralazine elimination. Hydralazine was given orally in single doses of 10, 25, and 50 mg to 2 slow-acetylating subjects, while 2 rapid-acetylating subjects also received 100- and 150-mg doses on different occasions. Administration of the 50-mg dose to the subjects who were slow acetylators and the 150-mg dose to those who were rapid acetylators caused a disproportionately large increase in the amount of unchanged drug appearing in the systemic circulation as judged from the increases in the ratios of areas under concentration-time curves (AUC) to dose. A modification of the gas-liquid chromatographic hydralazine assay allowed the simultaneous determination of hydralazine and its acetylated metabolite, 3-methyl-s-triazolo-3,4,a-phthalazine (MTP), in serum. It was found that the disproportionately large increases in the AUC/dose ratio of hydralazine upon intake of 50 or 150-mg doses by the slow and rapid-acetylating subjects, respectively, were paralleled by a decrease in the ratio AUCMTP/AUChydralazine during a 6-hr observation period. It is concluded that the acetylation of hydralazine in man is a capacity-limited process.


Disposition of pirprofen, a new anti-inflammatory drug. Plasma and urine concentrations of 2-(3-chloro-4[3-pyrrolinyl]phenyl) propionic acid, pirprofen, a new nonsteroidal anti-inflammatory compound, are described for normal male volunteers receiving one or more doses of the drug. Orally administered pirprofen is rapidly and almost completely absorbed from the gastrointestinal tract, resulting in maximum plasma levels in 1 to 2 hr. Mean peak levels are 23 microng/ml after an oral pirprofen dose of 200 mg; lower doses given proportionally lower levels. Administration 1 hr after a meal slightly delays the peak plasma level, but the extent of absorption is not affected significantly. Administration of pirprofen, 150 mg, 4 times daily, or 200 mg, 3 times daily, results in nearly identical plasma levels at steady-state. Pirprofen has an apparent elimination half-life of about 7 hr. The results obtained from a 200-mg pirprofen-14C dose indicate that excretion of the drug occurs primarily by the renal route in the form of metabolites and is essentially complete within 24 hr. In urine, less than 5% of the administered dose is accounted for as unchanged drug.


Interruption of the enterohepatic circulation of phenprocoumon by cholestyramine. The effect of cholestyramine (12 gm/day divided into 3 doses) on the pharmacokinetics and pharmacodynamics of a single intravenouse dose (30 mg) of phenprocoumon was studied in 6 normal subjects. Cholestyramine treatment led to an increase in the rate of elimination of phenprocoumon in all. Total clearance increased 1.5- to 2-fold. The total anticoagulant effect per dose was considerably reduced during treatment with cholestyramine. Binding studies in vitro showed that phenprocoumon is strongly bound to cholestyramine and that at a given cholestyramine concentration the percentage of phenprocoumon bound remained constant over a large concentration range of phenprocoumon. The results suggest that phenprocoumon undergoes extensive enterohepatic recycling in man which can be effectively interrupted by cholestyramine.


An approach to the radiological examination of the cervico-dorsal junction following injury. In 257 cases of cervical spinal cord injury the orthopaedic level of injury was found to be between C6 and T1 in 34%, emphasising the frequency of injury in the cervico-dorsal region. This is a difficult region of the spine to X-ray and different techniques to demonstrate this region have been assessed. An additional technique which has proved useful is described and a scheme is suggested for the adequate visualisation of the cervico-dorsal region.


Double contrast knee arthrography. Some new points of technique including the use of Dimer X. A short review of the development of techniques in knee arthrography is given, together with a full account of the author's technique, including the use of a specially designed pad and a frame to facilitate radiography and a new method to demonstrate the cruciate ligaments. Side effects in a group of patients examined using Dimer X as the positive contrast medium are compared with those in a group of patients who were examined using Urografin 60%. Comparason of the radiological advantages of Dimer X examinations with Urografin 60% examinations has been made. A possible method to distinguish normal from damaged or degenerate tissues is suggested. The author concludes that Dimer X is the positive contrast medium of choice at the present time.


Investigation of shoulder disability by arthrography. Fifty patients with pain and limitation of movement at the shoulder joint were investigated by arthrography. Normal findings using a double contrast technique are described. The main arthrographic patterns encountered were found in complete and incomplete tears of the rotator cuff, and capsulitis. Abnormalities of the bicipital tendon sheath were non-filling and leakage of contrast medium from the sheath. Extravasation of contrast medium from the bicipital tendon sheath and subscapularis bursa was considered to be due to over-distension of a joint with a reduced capacity. The accuracy of the procedure and the reasons for false negative arthrograms and surgical exploration are discussed.


The oil myelogram after operation for lumbar disc lesions. Post-operative myelograms in patients with renewed or persistant pain in the back or sciatica after lumbar disc surgery were reviewed in an attempt to differentiate between recurrent disc prolapse and other changes, particularly scarring and inflammation of the meninges. The most useful sign of recurrent disc prolapse was anterior indentation of the iophendylate (Myodil) column opposite a disc space. Inflammatory changes in the meninges were indicated by loculation of the subarachnoid space, matting or marked swelling of the nerve roots, irregularity of the theca, and by the absence of a posterior bulge of the subarachnoid space at the level of the operation. Waisting of the contrast medium column, non-filling of nerve root sheaths, complete myelographic block and posteriorly placed indentations were confirmatory evidence of the presence of disease, but not helpful in determining its nature.


Contrast medium extravasation from aneurysmal rupture during cerebral angiography. The radiographic demonstration of contrast medium extravasation from a rupturing intracranial aneurysm is rare. We have detected this occurrence a mere thrice in 15 years, a period in which angiography was routinely used for the investigation of subarchnoid haemorrhage. We have added these three cases to 14 others that were previously reported in the literature and summarised the total. There does not appear to be a common aetiological factor, though further experimental studies on intracaratid pressures distal to the site of injection seem to be warranted. Ventricular opacification during cerebral angiography occurred in five of the 17 cases: in our most recent case the contrast medium outlined intraventricular haematomata, a finding not hitherto reported in the literature and a feature of prognostic significance. Mortality in this series was extremely high and in excess of that usually found either with an aneurysmal re-bleed or an intracerebral haematoma or both. However, although a combination of these two lesions is notoriously hazardous, perhaps the added insult of the contrast medium extravasation is the cause for the inordinately high fatality rate. Only three of the 17 cases survived, two of whom had a significant residual neurological deficit.


A modified afterloading technique for small implants using iridium-192 wires for interstitial therapy. A new method is described for small iridium-192 wire implants upon the skin of the face. The method is a miniaturisation of a technique described previously (Paine, 1972), and has the advantage that is results in less scarring and therefore a better cosmetic end-result than in the case when the more conventional wide-bore tubing is employed. This new method produces similar clinical results in terms of tumour cure to other methods, and a degree of after-loading helps in radiation protection.


The significance of conjugated phenobutiodil (biliodyl) in the intestine in the absence of gallbladder opacification a preliminary assessment. Conjugated phenobutiodil (Biliodyl) in the small and large bowel can be recognised by its fine, homogeneous appearance. The findings in 41 patients undergoing oral cholecystography with subsequent clinical follow-up are reported. When the gallbladder fails to opacify on oral cholecystography, the presence of conjugated contrast medium in the intestine appears to provide reasonable evidence that the gallbladder is diseased.


The significance of an air oesophagogram visualised on conventional chest radiographs. Air may occasionally be seen outlining the entire oesophagus on conventional chest radiographs, this being referred to as an air oesophagogram. The reported causes of this radiological sign are reviewed. The chest radiographs of 24 cases of scleroderma with oesophageal involvement, and 29 cases of achalasia, have been studied. An air oesophagogram was seen in three cases (12.5%) of scleroderma and three cases (10%) of achalasia, without an oesophageal air fluid level and with air in the gastric fundus. An air oesophagogram has not been previously described in achalasia. The significance of this sign, which was found to occur in advanced scleroderma and in early achalasia, is discussed.


An evaluation of the double contrast barium meal (DCBM) against endoscopy. The diagnostic accuracy of the DCBM and of endoscopy were compared in 50 consecutive patients. Examinations were conducted in comparable circumstances, without any cross information. A percentage score method was evolved to allow a numerically more significant assessment. The potential accuracy of the DCBM was calculated to be 96% of that accorded to fibre-endoscopy.


The pulmonary manifestations of septic shock. Septic shock carries a high mortality. It is manifest haematologically by thromobocytopaenia and other coagulation disturbances. The radiological manifestations are various degrees of pulmonary oedema, usually affecting the lower zones, without evidence of pulmonary hypertension. Radiological signs are always preceded on accompanied by thrombocytopaenia.


The plain chest radiograph in infants with an isolated ventricular septal defect. The plain chest radiographic features of 43 infants with a ventricular septal defect are described. All were under 1 year of age, and cardiac catheter studies confirmed that they had an isolated ventricular septal defect (VSD), so that the RV pressure, size of the shunt and the pulmonary vascular resistance could be related to the radiographic appearances. The radiographs of a number of normal infants of similar age were available for comparison. Four patterns were seen in those with a VSD. In group 1 the radiograph appeared normal. In group 2 there was dilatation of the pulmonary artery and the proximal lung vessels, while in group 3 only the proximal lung vessels were dilated. In group 4 only some of the hilar and proximal lung vessles were dilated, so that the blood distribution appeared uneven.


Lymphography in alveolar soft part sarcoma. Alveolar soft part sarcoma is a rare tumour found in musculofasculofascial planes, most often in the lower limbs of young adults. The tumour shows a characteristic orderly cellular arrangement and the few mitoses belie the often rapid progress of the disease. Cytoplasmic crystals unique to this tumour may be demonstrated. The need for thorough investigation of the patient as an initial staging procedure and to provide a prognostic forecast is emphasised. Isotope scanning of the bones, brain and liver is indicated. Two cases are reported which demonstrate the value of lymphography. The nodal features found were: 1. Enlargement of a lymph node of normal interal architecture. 2. Almost complete nodal replacement by tumour. 3. Pseudolymphomatous appearances. Follow up films are required, after an interval, to show the progress of the disease or response to therapy.


Crossed renal ectopia: clinical and radiological findings in 22 cases. The clinical and radiological features of 22 patients with crossed ectopic kidneys are reported, including a case with unusual mobility of an unfused ectopic kidney. In some cases the anomaly was an incidental finding. However, complications were frequent and included seven hydronephrotic and three non-functioning kidneys, two of the latter were found to be obstructed by a calculus. Vesico-ureteral reflux was demonstrated in three of the five children in whom the examination was performed. Anomalous blood supply was present in all patients who underwent renal arteriography or surgery. Skeletal anomalies were present in 11 patients, one of whom had in addition coarctation of the aorta, and another atrial septal defect and anal atresia.


Urinoma.

Urinoma. A urinoma is a mass formed by encapsulated extravasated urine. It may follow closed renal injury, surgical operation or arise spontaneously in the presence of obstruction. The essential factors are continued renal function, rupture of the collecting system and distal obstruction. The extravasating urine is localised within the perirenal fascia and stimulates an intense fibrous reaction which forms a thick wall. Early diagnosis is important for successful treatment. The clinical features include malaise, vague abdominal pain, weight loss and a palpable mass. Plain films usually reveal a mass with loss of the retroperitoneal landmarks. High-dose excretion urography usually shows renal displacement, hydronephrosis and extravasation of contrast medium into the urinoma. Should renal function be inadequate for diagnosis, renal puncture, preceded by ultrasound examination, is the investigation of choice.


Functional and structural changes after disuse of human muscle. 1. Seven patients who had suffered unilateral leg fracture were studied after removal of immobilizing plaster casts. 2. Leg volume measured anthropometrically was reduced by 12% in the injured leg (5-68 +/- 1-05 litres) compared with the uninjured (6-43 +/- 0-87 litres). Associated with this loss was a similar reduction in the net maximum oxygen uptake achieved in one-leg cycling, from 1-89 +/- 0-21 1/min in the uninjured leg to 1-57 +/- 0-18 1/min in the injured. 3. Measured by a percutaneous needle biopsy technique, a reduction of 42% was found in the cross-sectional area of the muscle fibres sampled from the vastus lateralis of the injured compared with the uninjured leg. 4. Staining for myosin adenosine triphosphatase activity showed that both type I and II fibres were affected, being reduced respectively from 3410 to 1840 micronm2 and from 3810 to 2390 micronm2 cross-sectional area. 5. Possible reasons and implications are discussed for the discrepancy between the magnitude of the difference observed in the gross measurement of leg function (maximum oxygen uptake) and structure (leg volume) as compared with the cellular level (cross-sectional fibre area).


Failure of selected endocrine organ ablation to modify the natriuresis of blood volume expansion in the dog. 1. Selected organ-ablation experiments were performed in dogs in an attempt to identify the source of the natriuretic hormone postulated to participate in the natriuresis of blood volume expansion. 2. An isolated dog kidney perfused with blood from the femoral artery of deoxycorticosterone-loaded dogs subjected to acute volume expansion with equilibrated blood served as the bioassay system for the natriuretic factor. Four groups were studied after the following procedures: group I, no ablation; group II, thyroparathyroidectomy; group III, hypophysectomy; group IV, adrenalectomy. 3. In all groups, the administration of equilibrated blood promoted a significant increase in sodium chloride excretion in the isolated kidney. The natriuresis was unrelated to changes in glomerular filtration rate, renal blood flow, renal arterial pressure, plasma protein concentration or packed cell volume. In the absence of volume expansion, sodium chloride excretion in the isolated kidney did not change or decreased. 4. These results argue against the thyroid, parathyroid, adrenal and pituitary glands as the source of natriuretic hormone.


Suppression of plasma renin activity by intravenous infusion of antidiuretic hormone in man. 1. Ten patients on maintenance diuretic treatment received an intravenous infusion of antidiuretic hormone at a low rate for 1 hr. 2. A gradual reduction in mean plasma renin activity was observed and this was significant at 60 min. 3. There was a significant correlation between the initial value and the extent of the fall in plasma renin activity. There was no consistent change in blood pressure, heart rate and blood volume. 4. The results point to an intrarenal site of action of antidiuretic hormone.


Sodium restriction and inhibition of the renin-angiotensin system in renovascular hypertension in the rat. 1. In the early phase of hypertension produced by renal artery constriction with the opposite kidney intact, infusion of the angiotensin antagonist Sar1-Ala8-angiotensin II or bilateral nephrectomy lowered blood pressure. However, the extent of the fall was variable and some animals remained hypertensive after each procedure. 2. To assess whether sodium retention was the additional factor which maintained blood pressure when the renin-angiotensin system was suppressed, rats were maintained on a low-salt diet before and during the development of hypertension. The blood pressure-lowering effect of bilateral nephrectomy or antagonist infusion was not enhanced. 3. Infusion of antagonist or converting-enzyme inhibitor 6 h after bilateral nephrectomy had only a minor blood pressure-lowering action, indicating that, at this late stage after nephrectomy, the renin-angiotensin system makes only a very small contribution to blood pressure maintenance.


A new open-circuit method for estimating carbon dioxide tension in mixed venous blood. 1. A new open-circuit respiratory method was developed to estimate mixed venous PCO2 more rapidly and accurately than is possible with rebreathing techniques. 2. The subject breathes a mixture of CO2 in air from an open circuit. Carbon dioxide is added to the air flowing through the circuit at a rate such that the PCO2 in the inspired and expired gases (recorded continuously with a CO2 analyser) are almost identical. 3. Results from respiratory and cardiac patients showed that equilibrium occurred in less than 10 s. There was good agreement between the tensions of CO2 in the respiratory plateaux and in mixed venous and arterial blood withdrawn during equilibrium. 4. During exercise, the tensions of CO2 of the plateaux and arterial blood at equilibrium also showed good agreement. 5. It is suggested that the new method represents an improvement over rebreathing methods as equilibrium is achieved rapidly before the mixed venous tension rises from recirculation.


Muscle metabolism in patients with chronic obstructive lung disease and acute respiratory failure. 1. The concentration of metabolites in intercostal and quadriceps muscle, and pulmonary function, were studied in twelve patients with chronic obstructive lung disease and acute respiratory failure before, during and after standardized treatment at an intensive care unit. The findings were compared with those obtained in hospitalized patients of comparable age with non-pulmonary diseases. 2. On admission, when the patients had marked hypoxaemia, hypercapnia and acidosis, the concentrations of ATP and creatine phosphate were low in both intercostal and quadriceps muscle, particularly the latter. The lactate concentration was increased in relation to control values but glycogen did not differ significantly. 3. In response to therapy, the Pa,CO2 and the patient's acidosis decreased, the vital capacity increased and lung mechanics improved along with the clinical condition. At the same time there were significant increases in the concentrations of ATP, creatine phosphate and glycogen in intercostal and quadriceps muscles, to values similar to, and for glycogen in excess of, those found in control subjects. Lactate concentration fell significantly during treatment. 4. In view of the low initial muscle concentrations of ATP and creatine phosphate in the patients, it is suggested that dysfunction of the respiratory muscles may be an important component of respiratory failure. Moreover, the concentration of energy-rich compounds in muscle rose significantly as the patients responded to treatment, which emphasizes the importance of adequate nutritional therapy in this disorder.


Haemodynamic characteristics of low-renin hypertension. 1. Intra-arterial pressure, cardiac output, renal blood flow and glomerular filtration rate were measured in 19 patients with low-renin hypertension and in 30 patients with normal-renin hypertension. 2. Cardiac output and renal blood flow were significantly lower in low-renin hypertension. Total peripheral and renal vascular resistance were markedly higher in this group. 3. Plasma renin concentration correlated inversely with both total peripheral and renal vascular resistance as well as with age. Multiple regression analysis indicated that part of the relationship between renin and haemodynamic variables did not depend on age. Furthermore, plasma renin concentration did not decrease with age in a group of 40 normotensive control subjects of similar age to the hypertensive patients. 4. The results provide further confirmation that renin decreases as hypertension progresses.


Bronchial provocation in the study of sensations associated with disordered breathing. 1. Lung volumes, airway resistance and flow/volume curves were measured in ten asthmatic subjects at times when tightness in the chest was just sensed (threshold symptom). 2. These measurements when the threshold symptom was induced by methacholine inhalation were compared with those when a similar symptom occurred spontaneously, in the same subjects. 3. Values during the methacholine-induced thresholds were very similar to those observed when threshold symptoms developed spontaneously. 4. Controlled bronchial provocation mimics spontaneous asthma sufficiently well to allow this technique to be used in the study of sensations associated with breathing. This has some advantages over the already established models utilizing external hindrances to breathing.


Porphyrins in erythrocytes and blood plasma: preliminary studies with qualitative thin-layer chromatography. 1. A simple chromatographic method for the study of porphyrins in erythrocytes and blood plasma, requiring little technician time, is described. The findings in adults and neonates are presented as well as those from severely ill patients. 2. The regular occurrence of uro-, copro- and proto-porphyrin in erythrocytes is deomonstrable as well as sporadic occurrence of tri-, penta-, hexa- and hepta-carboxylic porphyrin. The method gives, however, irregular values for protoporphyrin, which seems to occur in a more labile form in some subjects than in others; this is especially the case in erythropoietic protoporphyria. 3. In blood plasma, uroporphyrin occurs regularly, and coproporphyrin less regularly. Protoporphyrin and penta- to hepta-carboxylic porphyrin are found only occasionally.


Intrarenal distribution of plasma flow in cirrhosis as measured by transit renography: relationship with plasma renin activity, and sodium and water excretion. 1. The intrarenal distribution of plasma flow was determined with a technique based on the analysis of the transit time of sodium o-[131I]- iodohippurate through the kidney in 43 patients with cirrhosis with near-normal total renal perfusion. 2. Twenty-five of the patients had an abnormal pattern of transit times, suggesting a redistribution of plasma flow from outer cortical to juxtamedullary nephrons. 3. Plasma renin activity ranged from below normal to six times normal and high values were found only in patients showing an abnormal pattern of transit times. The latter was also found to be related to sodium retention and a reduced renal capacity to excrete free water.


Plasma noradrenaline concentrations in experimental renovascular hypertension in the rat. 1. Plasma noradrenaline concentrations and dopamine beta-hydroxylase activity have been measured at various stages in the development of hypertension in the one-kidney Goldblatt rat (unilateral renal arterial constriction and contralateral nephrectomy). 2. Although plasma noradrenaline concentrations were significantly elevated from control values at 7, 14 and 28 days, plasma dopamine beta-hydroxylase activity was not significantly different from control values except at 24 h. 3. These findings suggest that peripheral sympathetic activity is increased in the one-kidney Goldblatt model of experimental hypertension but that plasma dopamine beta-hydroxylase activity is poor index of this increase. 4. Both the rise in blood pressure and the rise in plasma noradrenaline concentrations were prevented by pretreatment with intracisternal 6-hydroxydopamine, suggesting that the increased sympathetic activity is at least in part centrally mediated.


Protein metabolism in human neonates: nitrogen-balance studies, estimated obligatory losses of nitrogen and whole-body turnover of nitrogen. 1. Aspects of nitrogen metabolism in the human neonate were assessed in one full-term infant and six premature infants by means of nitrogen-balance measurements, estimates of obligatory nitrogen losses and determinations of whole-body nitrogen turnover. 2. Our data indicate that the mean protein requirement for maintenance is 1-1 g of protein day-1 kg-1 and that 3-8 g of protein day-1 kg-1 should be sufficient for adequate growth in healthy premature babies. 3. The mean obligatory urinary, faecal and total nitrogen losses were estimated to be 24, 106, 145 mg day-1 kg-1 respectively. These figures are compared with published values for older infants, and the possible metabolic basis for changes in nitrogen losses during growth and development is discussed. 4. Mean values for whole-body protein synthesis and breakdown were 26-3 +/- 7-0 and 23-8 +/- 7-4 g of protein day-1 kg-1 respectively. Dietary nitrogen intake accounted for 6--18% of the nitrogen flux through the metabolic pool; urea excretion accounted for 2% of the nitrogen flux. 5. The net protein gain, estimated from nitrogen-balanced data, accounted for 9-6% of total daily protein synthesis. 6. These results are discussed in relation to published estimates of whole-body protein synthesis and breakdown at various ages. Their possible significance in the assessment of a "maintenance" requirement for protein and amino acids during the period of rapid growth and development is also considered.


The effect of 25-hydroxy vitamin D3 in the osteomalacia of chronic renal failure. 1. Five patients with the osteomalacia of chronic renal failure were given 50--100 nmol of 25-hydroxy vitamin D3 intravenously per day for 24--28 days. 2. In all five patients, during administration of 25-hydroxy vitamin D3 there was a substantial rise in the plasma concentration of 25-hydroxy vitamin D from initially abnormally low values. 3. Significant improvement in bone mineralization, intestinal calcium absorption and muscle strength occurred in the three patients with the greatest rise in plasma 25-hydroxy vitamin D.


Human hepatic delta-aminolaevulinate synthase: requirement of an exogenous system for succinyl-coenzyme A generation to demonstrate increased activity in cirrhotic and anticonvulsant-treated subjects. 1. We have studied activity of delta-aminolaevulinate synthase in needle liver biopsy specimens obtained from 12 human cirrhotic subjects, five subjects who had ingested anticonvulsants and from control subjects. Liver iron concentrations and quantitative urinary excretions of porphyrins plus their precursors were also determined. 2. In liver homogenates from subjects of each group, addition of an exogenous system for generation of succinyl-coenzyme A (CoA), including succinic thiokinase, resulted in appreciable enhancement of activity beyond that obtained without this system. 3. Mean activities for delta-aminolaevulinate synthease were not significantly different among patient groups when assayed without the exogenous succinyl-CoA-generating system, but liver homogenates from cirrhotic patients and subjects ingesting anticonvulsants had significantly higher activities than control subjects in the presence of the succinyl-CoA-generating system. 4. Although mean liver iron concentration in the cirrhotic group was slightly higher than in control subjects, and in control subjects there was some correlation between liver iron concentration and activity of delta-aminolaevulinate synthase, variations in this activity could not be accounted for solely on the basis of chronic hepatic deposition. Nor were these variations  ascribable to differences among subjects in ingestion of ethanol before biopsy or severity of hepatic inflammation as judged biochemically and histologically. 5. Cirrhotic subjects excreted more uro- and copro-porphyrin than control subjects, whereas subjects ingesting anticonvulsants excreted more delta-aminolaevulinic acid and porphobilinogen than control subjects. However, these increases were small and not sufficient to account for all the increased delta-aminolaevulinic acid which potentially could have been formed by these subjects. 6. These considerations raise the possibilities that in vivo: (a) rate of human hepatic synthesis of delta-aminolaevulinic acid is modulated by the supply of succinyl-CoA; (b) the rate of hepatic synthesis of haem is increased in cirrhotic patients and subjects ingesting anticonvulsants; (c) other important routes exist for disposition of haem precursors in these subjects, besides utilization for haem synthesis.


Bone necrosis and urinary hydroxyproline excretion in rabbits. 1. Aseptic necrosis of bone is a serious chronic complication of deep-sea diving and compressed-air work. 2. The changes to the bone which occur in this condition take time to develop to the stage where they cause the radiographic signs of bone necrosis, and consequently there is a delay of some months between the causal incident and the first diagnosis by radiography. 3. As a possible method for the earlier detection of bone necrosis the 24 h urinary excretion of hydroxyproline was measured over a period before and after experimental production of bone necrosis in rabbits by the intra-arterial injection of glass microspheres. 4. Total hydroxyproline excretion rose significantly within a few days of the injection in those rabbits in which there was later shown to be historical evidence of bone necrosis. This rise occurred long before there was any radiographic changes. 5. It is suggested that measurements of urinary hydroxyproline might be used to give an early indication of bone necrosis in man.


Muscle-protein catabolism after injury in man, as measured by urinary excretion of 3-methylhistidine. 1. Urinary excretion of 3-methylhistidine, an index of the rate of muscle breakdown, has been measured during the first 7 days in patients after elective surgery or accidental injury. 2. There was no major difference between the mean daily excretion after skin grafting or total hip replacement, or in injured patients who were hyperketonaemic for the first 24 h after admission. 3. The group of injured patients who did not develop hyperketonaemia had a mean urinary 3-methylhistidine excretion which was twice that of the other groups. 4. It is concluded that increased breakdown of muscle protein makes a major contribution to the greater urinary nitrogen excretion in the normoketonaemic group of injured patients.


Proline and hydroxyproline excretion and vitamin C status in elderly human subjects. 1. Plasma and buffy-coat vitamin C, urinary proline, hydroxyproline, creatinine and total amino acid concentrations were meausred in 23 healthy elderly subjects at intervals of 3 months. 2. There was a strong positive correlation between plasma vitamin C and buffy-coat vititamin C. 3. There were not significant correlations between plasma or buffy-coat vitamin CPAMIN C. 3. There were not significant correlations between plasma or buffy-coat vitamin C and total urinary hydroxyproline, whether expressed on a creatinine basis or on a total amino acid basis. Similarly, no significant correlations could be detected involving the proline/hydroxyproline ratio in urine hydrolysates. 4. There was a significant negative correlation between plasma or buffy-coat vitamin C and total urinary proline, when expressed per unit of total urinary proline, when expressed per unit of total urinary proline, when expressed per unit of total amino acids in the hydrolysates. This correlation was not observed with unhydrolysed urine, and it appeared to reside in the diffusible fraction, part of whose proline could be liberated by prolidase digestion. In addition, in the man, there was some evidence for a positive correlation between plasma or buffy-coat vitamin C and the ratio of total urinary amino acids to creatinine. 5. These results support the view that poor vitamin C status in elderly humans may be associated with a defect in collagen proline hydroxylation, reflected by increased excretion of proline-rich, collagen-derived peptides. If this interpretation is correct, it indicates a potential defect in connective tissue repair, and could form the basis of a functional test for subclinical vitamin C deficiency.


Intrarenal role of angiotensin II in controlling sodium excretion during dehydration in dogs. 1. The intrarenal role of angiotensin II in controlling sodium excretion was examined in anaesthetized, dehydrated dogs by infusing the angiotensin II antagonist Sar1-Ile8-angiotensin II directly into the renal artery. Comparisons were made with dehydrated dogs receiving only sodium chloride solution intrarenally. 2. Intrarenal angiotensin II blockade resulted in significant increases in urinary sodium excretion and urine flow rate. 3. The results indicate that during the high-renin state of dehydration endogenous angiotensin II has intrarenal effects which lead to salt and water retention.


Intravenous Energine--a case report.

Intravenous Energine--a case report. The intravenous route has been used with increasing frequency as a means of abusing drugs as well as co-mercial products. However, to date, no information has been available regarding the toxic effects of Energine or the kerosine derivatives following their intravenous use. A patient is presented who survived 3-4 cc of intravenous Energine with very few systemic side effects. This report provides information which may be useful in providing a guide as to what may be expected after a relatively high intravenous dose of the kerosine derivatives.


Toxicologic data from documented drug-induced or drug-related fatal cases. Seventy-six fatal cases are presented in which the total dose of drug(s) ingested is known. Blood and liver concentrations for the various drugs are given, as well as the total recovery from the stomach contents.


A fatal ingestion of caffeine.

A fatal ingestion of caffeine. Tissue concentrations are given in a fatal case involving caffeine. Methods for the detection and quantitation of the drug are described. A brief review of reported caffeine fatalities is given.


An unusual case of nicotine poisoning.

An unusual case of nicotine poisoning. Acute nicotine poisoning by enema is an uncommon event. A review of the last 70 years of the English and Spanish medical literature has failed to reveal a case of nicotine poisoning by enema in an adult. The use of tobacco enemas in children to treat intestinal parasites has been reported as a cause of poisoning and death. We have recently treated an adult for acute nicotine poisoning from a tobacco enema. This unusual case allowed us to observe some of the complex pharmacologic responses of the body to nicotine.


Co-trimoxazole in chronic renal failure--a controlled experiment in Wistar rats. Co-trimoxazole failed to cause a deterioration in renal function, as measured by pre- and posttreatment plasma urea levels, in groups of Wistar rats with either normal renal function or surgically induced chronic renal failure. In addition tubular necrosis was not produced. Co-trimoxazole does not appear to be extremely toxic to the Wistar rat kidney.


Clonazepam overdose resulting in cyclic coma. Cyclic coma in a 4-year-old boy followed an ingestion of clonazepam, a new benzodiazepine, utilized in treatment of convulsive disorders. Alternation between coma and a hyperalert state occurred even after further gastrointestinal absorption had, presumably, been precluded. Laboratory identification by routine examination for benzodiazepines was unsuccessful.


Reversal by physostigmine of clozapine-induced delirium. Clozapine, a new antipsychotic drug without extrapyramidal side effects and with strong sedating potency, can produce acute symptoms of central anticholinergic toxicity. The authors report that physostigmine, a reversible anticholinesterase agent, which can pass the blood-brain barrier, was effective in reversing the clozapine-induced brain syndrome in two patients. Physostigmine also reduced one patient's tachycardia.


Acute digitoxin intoxication treated by intracardiac pacemaker: experience in sixty-eight patients. Out of 124 patients who had taken massive doses of digitoxin in attempted suicide, emergency endocardial pacing was performed in the 68 with the worst prognosis. The mortality (13%) in the 124 patients compared favorably with the mortality (20%) in a previous series of 70 similar patients none of whom were paced. Sixteen (23%) of the 68 paced patients died. The causes of death were: asystole (two); cardiogenic shock (two); septicemia (one); and ventricular fibrillation (eleven). Ventricular fibrillation occurred during introduction of the pacing catheter in two patients, as a result of electrode displacement in these patients, because of premature withdrawal of the catheter in one patient, and for no detectable reason, during normally proceeding pacing, in five patients. Endocardial pacing has a place in the emergency treatment of massive digitoxin poisoning. Its chief hazards are mechanical, and one of the commonest is electrode displacement.


Diagnosis, localization, and treatment of primary aldosteronism. PA should be suspected in any hypertensive patient with evidence of renin suppression and should be confirmed by demonstration of inappropriate and excessive aldosterone production. Preoperative differentiation of unilateral and bilateral forms of the syndrome should be pursued to identify those patients most likely to benefit from surgical intervention. In patients with apparent bilateral disease, specific medical therapy should be pursued.


A computer analysis of cardiac electrograms. Computer programs were constructed for the temporal analysis of 8 electrograms obtained from various regions of isolated dog hearts. The electrograms were recorded on photosensitive paper. A computer program written in the Fortran II language allowed an x-y digitizing table to be used to input the coordinates of each electrogram into a computer. Each electrode recording within a given cardiac cycle was digitized in this manner, and the temporal intervals between the 28 combinations of electrode pairs were calculated. The program also computed the heart rate and cardiac cycle length. Subroutine options permitted the grouping of data into experiment, record, and event numbers. All data were stored on a magnetic disk. A separate computer program written in the Fortran IV language performed basic statistical operations on each of the data files. The computer system described in the present report accurately and reliably processed over 10,000 cardiac cycles. Such a system can be used to analyze large amounts of data from sources other than electrograms. Temporal analysis of the standard electrocardiogram is offered as an example of the versatility of the programs.


An on-line method for the acquisition of medical information for computer processing as applied to radiotherapy. Based on a structured medical record, specially designed for patients with malignant disease, an on-line data capture system has been developed. This enables the collection of virtually any type of information contained in the patient's case notes. The structure of the record is described, with actual examples. The record is typed on a typewriter terminal linked to a mini-computer. Data is recorded as code + heading + value string. The headings are identified automatically, and an internal code generated, describing the type of information. Record keeping according to the principles described was introduced in clinical routine at the department in 1971. Data collection was implemented later that year, using an off-line magnetic tape encoder (IBM MT72). The system has been developed further and converted to a versatile on-line system. The data base, collected with these systems, now contains data on about 20,000 patients.


A computer program for calculating different kinds of intraclass correlation coefficients. A program for calculating different forms of intraclass correlation coefficients is described. Confidence limits as well as unbiased estimates are given for those kinds of coefficients, for which an exact sampling distribution is derivable. Additionally, coefficients based upon Krippendorff's model are computed so that error components responsible for the lack of perfect correlation can be specified.


A computer program for multiple decrement life table analyses. Life table analysis has traditionally been the tool of choice in analyzing distribution of "survival" times when a parametric form for the survival curve could not be reasonably assumed. Chiang, in two papers [1,2] formalized the theory of life table analyses in a Markov chain framework and derived maximum likelihood estimates of the relevant parameters for the analyses. He also discussed how the techniques could be generalized to consider competing risks and follow-up studies. Although various computer programs exist for doing different types of life table analysis [3] to date, there has not been a generally available, well documented computer program to carry out multiple decrement analyses, either by Chiang's or any other method. This paper describes such a program developed by Research Triangle Institute. A user's manual is available at printing costs which supplements the contents of this paper with a discussion of the formula used in the program listing.


Language processor generation with BNF inputs: methods and implementation. This paper describes an SLR (1) parser generator written in SAIL for the PDR-10. It accepts grammars defined in a BNF formalism and produces a SAIL program module which is the bottom-up parser produced from the grammar. This module may then be compiled and loaded with semantic routines to produce a language processor. The generator is written in SAIL with a heavy emphasis placed on the use of the LEAP facilities of SAIL for the manipulation of the data structures required for the generator.


Pitfalls of Swan-Ganz catheterization.

Pitfalls of Swan-Ganz catheterization. In 60 patients in whom Swan-Ganz catheters apparently had been positioned correctly, the balloon was visualized by inflation with radiopaque contrast medium. Sixteen were located peripherrally; in 15 of these 16, the balloon inflated eccentrically and in each of these instances, an accurate wedge pressure could not be obtained. One patient in this group had an episode of hemoptysis immediately prior to detection of the peripheral location and eccentric inflation of the balloon. The correct placement and safe use of the Swan-Ganz catheter demand that the catheter tip be located in a large pulmonary artery and that redundant loops of catheter be avoided to prevent subsequent peripheral migration. Identification of peripheral placement and eccentric inflation should be suspected if a pulmonary wedge pressure is obtained with a significantly smaller volume of air than the balloon capacity. The use of a continuous flush system will provide an additional alert by a steady rise in the pseudowedge pressure on attempted balloon inflation.


Tissue blood flow in brain, liver, renal cortex, and renal medulla in experimental hemorrhagic shock. Cerebral, hepatic, renal cortical, and medullary tissue blood flows of the dog during hemorrhagic shock were measured continuously using the thermoelectrical method. The effects of blood replacement, adrenergic alpha-stimulator and -blockade and hydrocortisone on the tissue blood flows were studied. After hemorrhage, cerebral blood flow was well maintained while renal cortical blood flow was poorly maintained. Following retransfusion, the blood flow returned rapidly to the brain and slowly to the renal cortex. Norepinephrine, phentolamine, and hydrocortisone were not effective in maintaining the organ blood flows in shock. However, when norepinephrine was given systemically and phentolamine administered to the renal artery simultaneously during shock, both cerebral and renal flows were well maintained. After the blood replacement and administration of alpha-blockade or hydrocortisone, all the measured blood flows returned to normal levels.


Westermark's sign in the diagnosis of pulmonary emboli in patients with the adult respiratory distress syndrome. Two patients with adult respiratory distress syndrome (ARDS) are described in which the development of localized areas of increased lucency on chest roentgenogram, Westermark's sign, aided in the rapid diagnosis of concurrent pulmonary emboli. Recognition of this radiological sign represents a noninvasive technique for diagnosing this complication.


Acute renal failure. Community hospital experience with hemodialysis as intensive care adjunct. A 3-year experience with 50 acute renal failure patients managed by hemodialysis in a 417-bed community hospital is reviewed. The 58% survival rate was better than that reported in other recent series. Possible reasons for our favorable mortality experience include: (1) Hemodialysis was performed within the ICU facility by the ICU staff. Continuity of total care was thereby maintained and hemodialysis problems, such as maintenance of circulating volume, were managed in the context of continued assessment of the patient's cardiopulmonary status. (2) In contrast to previous reports, the presence of sepsis did not influence recovery rates from acute renal failure. Early administration of specific antibiotics, mainly gentamicin, rapid drainage of abdominal abscesses, and early and frequent dialysis were all utilized in spetic patients and may have contributed to their high recovery rate. (3) The use of agressive dialysis may also have lessened other uremic complications, notably gastrointestinal bleeding. Our dialysis organization and procedures are described.


Educational objectives for house staff in the pediatric intensive care unit. The educational objectives in use in our Pediatric ICU are described. These have importance for educational programs in critical care medicine, in particular, where patient care needs can easily overwhelm educational needs. It is important not to overlook our role as teachers in the development of proper attitudes and of the more complex areas of thought; skills and rote memory should not be overstressed.


Suctioning of the left bronchial tree in critically ill patients. When suctioning patients with either a tracheostomy or endotracheal tube, the incidence of entry into the left main stem bronchus was recored at the time of routine AP chest examinations in an ICU. The success rate was 8% with an endotracheal tube and 25% when a tracheostomy tube was present; this was lower than has been reported by others. It could reflect the small size of the series or a more accurate picture.


Congenital lentiginosis.

Congenital lentiginosis. Because lentiginosis may be associated with multiple somatic anomalies (as in the "LEOPARD syndrome"), its recognition is important clinically. A case of lentiginosis detected in the neonatal period, without accompanying defects, is reported. The significance of histologic confirmation and the importance of searching for other abnormalities are discussed.


Effect of intramuscular triamcinolone acetonide on the human ovulatory cycle. The effect of intramuscular triamcinolone acetonide (TCA-A) on pituitary gonadotropins and ovarian hormones was studied in a normally menstruating woman. Serum levels of luteinizing hormone (LH) and follicle-stimulating hormone (FSH), as well estradiol 17-beta (E2) and progesterone (P), were determined daily in a normal "ovulatory" pretreatment cycle. A total of 160 mg of TCA-A was then administered in four injections over two and a half months. Daily serum levels of LH, FHS, E2, and P were again measured during a period beginning thirty days after the last injection of TCA-A. Cyclicity of all these hormones was absent after treatment. Both LH and FSH were suppressed in the first half of the post-treatment period when compared with the pretreatment ovulatory cycle. A potent corticosteroid such as TCA-A is apparently capable of producing anovulatory cycles in humans by disruption of cyclic pituitary gonadotropin secretion.


Systemic lupus erythematosus complicated by panniculitis, optic atrophy, and hemiplegia: report of a case. A case is presented of a patient with systemic lupus erythematosus who had three of its rarest complications--panniculitis, optic atrophy, and hemiplegia, the latter two occurring despite adequate corticosteroid therapy. There appears to be a missing link in this patient's immune mechanism, which faulted her complete response to corticosteroid therapy and led to the three complications.


Dermatitis artefacta.

Dermatitis artefacta. A case of dermatitis artefacta is reported. The lesions were shown to contain silver and were probably caused by a silver nitrate caustic stick. The patient never admitted to having produced these lesions.


A radiologic sign of epidermolytic hyperkeratosis. The radiologic finding of innumerable fine ridges in the outer soft tissues of a patient with severe generalized epidermolytic hyperkeratosis is presented as a sign of the disease. The radiodensity results from the density of keratin and low water content in the scales of epidermolytic hyperkeratosis.


Comparison of synemol cream and other topical corticosteroid creams using the vasoconstrictor bioassay. The human vasoconstrictor bioassay was used to assess the potency of open applications of Synemol cream (0.025%), Diprosone cream (0.05%), Aristocort-A cream (0.5%), and Valisone cream (0.1%). Intensity of vasoconstriction was determined eight, twenty-four, and thirty-two hours after application. Results obtained from the average intensity scores of the three determinations indicated that Synemol cream (0.025%) is actually a more active compound than are Diprosone cream (0.05%), Aristocort-A cream (0.5%), and Valisone cream (0.1%), and that its activity is longer acting.


Stability of centromere-center distances in normal human metaphases. Centromere-center distances were analyzed in 50 normal female and 100 normal male metaphases. Compared with the random distribution of all chromosomes, chromosome pair 6 had a significantly different distribution in both female and male metaphases. Moreover, a significant peripheral location of chromosome pairs 4 and 5 and a significant central location of chromosome pairs 13, 15, 21, and 22 were found in male metaphases. But no specific peripheral location could be assigned to the X or Y chromosomes. No inter- nor intraindividual differences or sex-dependent variation in centromere-center distances were observed. Variance analyses demonstrated consistent centromere-center distances in normal human metaphases obtained from individuals of the same age. The constancy of these chromosome distributions may correlate with chromosome duplication pattern, chromosome length, and chromosome structure.


Cytogenetic examination of pre-implantation blastocysts of ewes mated to rams heterozygous for the Massey I (t1) translocation. One hundred-and-two 13- to 18-day blastocysts were collected from 98 Scottish Blackface ewes mated to one of four New Zealand Romney rams heterozygous for the Massey I (t1) translocation. The karyotype of 75 blastocysts was established, of which 22 were 54,XY, 18 were 54,XX, 20 were 53,XY,t1, and 15 were 53,XX,t1. It is suggested that these results indicated that there was no increase in embryonic loss in ewes mated to rams heterozygous for the Massey I (t1) translocation and that the unbalanced secondary spermatocytes in heterozygous males probably did not mature to spermatozoa.


Nonrandom sex-chromosome association and constitutive heterochromatin in the brush-tailed possum, Trichosurus vulpecula (Marsupialia: Phalangeridae). Nonrandom associations between the short arms of the sex chromosomes of six Trichosurus vulpecula were studied in 455 cells from the spleen and bone marrow. The association occurs in both sexes and was found to be independent of age. There was, however, a significant difference in the degree of association between the two tissues studied. Regions of constitutive heterochromatin were found to be located in the short arms of the X and Y chromosomes by using a C-banding technique. Nucleolar organizers were detected in the middle of the long arm of the X chromosome and in the short arm of the Y chromosome by N-banding. These results indicate that the nonrandom association of the sex chromosomes may reflect an association between heterochromatin regions during interphase of the cell cycle.


Sex-chromosome ratios in cattle and their relationship to reproductive development in freemartins. Nineteen "female" Holstein-Friesian calves born co-twin with a bull were purchased shortly after birth. One subsequently was judged to be a normal female with 0% XY (100% XX) karyotypes in cultures of blood lymphocytes. However, one typical freemartin also had 0% XY (100% XX) Karyotypes in 300 cells when examined at three ages. Overall, 18 freemartins examined at 1, 24, and 52 weeks of age averaged 60.7%, 57.9%, and 55.5% XY cells, respectively (P greater than 0.05). No systematic relationship was found between the proportion of XY cells and the abnormalities of the reproductive organs, as judged by vaginal depth and clitoral development at 1, 24, and 52 weeks, and examination of the reproductive organs per rectum at 54 weeks of age. The clitoris of untreated freemartins and those treated with estrone or estradiol postnatally did not enlarge. Testosterone treatment caused enlargement. None of the hormones affected vaginal depth. These studies provide convincing evidence that the blood lymphocyte XX:XY karyotype ratio (1) is not related to the degree of masculinization and (2) is stabile in the postnatal freemartin. Thirdly, the freemartin reproductive organs do not respond to common sex-steroid hormones postnatally other than the clitoral response to testosterone.