Immunologic factors influencing the intra-tumor localization of ADCC effector cells. The role of cellular and humoral immunity in the localization of blood-borne, bone marrow-derived ADCC effector cells into the T1699 mammary adenocarcinoma was investigated. Administration of ALG before tumor inoculation caused total immunosuppression and resulted in minimal in situ inflammation. ALG treatment started at the time of tumor inoculation suppressed the delayed hypersensitivity response below a detectable level but permitted a significant antibody response. Under these circumstances, the localization of ADCC effector cells into the tumors appeared normal. Similarly, administration of ALG at later stages of tumor growth, where ALG acts as an anti-inflammatory agent, did not interfere with the normal infiltration of ADCC effector cells in situ, although the delayed hypersensitivity response was totally suppressed. When melphalan treatment was used to produce tumor-bearing mice with an intact delayed hypersensitivity response but devoid of a significant antibody response, the drug-treated animals were found to have high levels of ADCC effector cells in situ. These results demonstrate that although the in situ inflammatory reaction appears to be immunologically inflammatory reaction appears to be immunologically dependent, neither the delayed hypersensitivity nor the antibody response is solely responsible for the localization of ADCC effector cells in the T1699 mammary tumor.


In situ lymphoid cells of mouse mammary tumors. I. Development and evaluation of a method for the separation of lymphoid cells from mouse mammary tumors. A method of separating lymphoid cells from solid mouse mammary tumors was developed and evaluated. In this method the tumors are digested with 0.01% collagenase, 0.01% DNAase, and 0.025% trypsin in Dulbecco's PBS into suspensions of cells with a viability of 90%. The suspensions are fractionated on a continuous gradient of Ficoll in tissue culture medium. In model experiments this gradient was found to separate, cleanly, admixed cells of an established mammary tumor cell line and dissociated thymus glands. Recovery rates were 50% for the tumor cells and 80% for the thymocytes. The preparation of the cell suspensions and the gradient separation procedure are not harmful to the cells as indicated by trypan blue exclusion and the ability to grow in cell culture.


In situ lymphoid cells of mouse mammary tumors. II. The characterization of lymphoid cells separated from mouse mammary tumors. Lymphoid cells were isolated from mouse mammary tumors by isokinetic gradient centrifugation. theta-bearing and ALS-sensitive cells were always the largest subpopulations found in these tumors. In fractions 4 to 6 from the isokinetic gradient, theta-positive cells ranged from 8 to 46% in autochthonous tumors and 14 to 47% in passaged tumors, and ALS-positive cells ranged from 34 to 46% in autochthonous tumors and 14 to 100% in passaged tumors. SIg-positive cells were only found in occasional tumors and, where present, averaged 2% of the separated population. Fc receptor-bearing cells averaged 15% and phagocytic cells averaged 8% of the cells found in fractions 4 to 6 of the gradient. Occasional ALS-positive and one-third of the Fc receptor-bearing and phagocytic cells also separated in fractions 7 to 10 of the isokinetic gradient. Although the individual tumors were very variable in the proportions of the various lymphoid subpopulations that they contained, this variability was a stable characteristic for at least one passage generation.


In situ lymphoid cells of mouse mammary tumors. III. In vitro stimulation of tumor cell survival by lymphoid cells separated from mammary tumors. Lymphoid cells were isolated by isokinetic gradient centrifugation from mouse mammary tumors and evaluated for their ability to affect tumor cell survival with the microcytotoxicity assay. In all experiments stimulation of the growth or survival of tumor cells was seen. This stimulation was not seen with separated lymphoid cells treated with anti-lymphocyte serum and complement. The lymphoid cells separated from tumors were more stimulatory than were lymph node cells; even toxic to the tumor cells, the separated tumor-associated lymphoid cells were markedly stimulatory. The gradient procedure had no effect on the activity of sensitized lymph node cells, but it did separate cytotoxicity and stimulation into different fractions.


Macrophage-mediated in vitro sensitization of lymphocytes. II. The detection of neo-antigens on transformed lymphocytes and passages of normal fibroblasts. Unprimed lymphocytes were sensitized in vitro by incubating them with syngeneic macrophages that had been fed with viral or cellular antigens. The sensitized lymphocytes were tested for their cytotoxic activity against virus-infected and noninfected fibroblasts. The antigenic preparations used for priming the macrophages were either tumor cell-free extracts or supernatants from virus productive cells. Cell-free extracts from the productive RadLV-induced lymphoma cells or the nonproductive radiation-induced lymphoma cells were immunogenic when presented to lymphocytes by macrophages. In contrast, cell-free extracts from normal thymocytes were much less immunogenic, suggesting that the presence of viral associated antigens (VAA) can selectively be detected on lymphoma cells by this assay. Fibroblastic cell lines but not primary fibroblasts were also susceptible to the cytotoxic lymphocytes induced by RadLV-fed macrophages. Primary fibroblasts became susceptible to the sensitized lymphocytes either after infection with the corresponding virus, or if not infected, after several passages in vitro, suggesting that neo-antigens cross-reacting with viral antigens appear during sub-culturing of fibroblasts in vitro. This system makes it possible to detect VAA either as immunogens when presented to lymphocytes by macrophages, or as targets for cytotoxic lymphocytes.


Structure and function of immunoglobulin domains. VII. Studies on the structural requirements of human immunoglobulin G for granulocyte binding. The ability of various fragments of human myeloma IgG1 to inhibit rosette formation between human anti-D-coated human red blood cells and human polymorphonuclear leukocytes has been investigated. Although IgG and Fc showed a dose-dependent inhibition of rosettes and Fc showed a dose-dependent inhibition of rosettes at equimolar concentrations, neither of the fragments corresponding to the Cgamma2 and Cgamma3 homology regions obtained by acid-tryptic cleavage of Fc was able to inhibit rosette formation. The pepsin fragment of Fc, pFc', which represents the complete Cgamma3 domain, was also unable to prevent rosette formation. Reduction and alkylation of IgG or Fc markedly diminished cytophilic activity as measured by this system. These data indicate that the site in human IgG1 bound by granulocytes is dependent on the full quaternary structure of Fc, a requirement in marked contrast to that noted for binding by macrophages and monocytes.


Cellular immunity to solubilized tumor antigens of a methylcholanthrene-induced sarcoma with a migration inhibition assay. BALB/c mice immunized with Nonidet P-40 (NP-40) crude solubilized (CS) extracts of a syngenetic methylcholanthrene-induced BALB/c sarcoma (Meth A) were challenged with viable Meth A cells to determine the ability of the solubilized preparations to induce transplantation rejection. Animals resisting such challenge were then used in agarose microdroplet macrophage migration inhibition (MMI) and tumor cell neutralization (Winn) assays to evaluate the antigenic specificity of these CS extracts. Spleen cells from those animals that rejected Meth A after immunization with the NP-40-solubilized preparations effectively neutralized the tumor-producing capacity of Meth A tumor cells as determined in Winn assays. MMI assays were quite sensitive and detected migration inhibition of peritoneal exudate (PE) cells from immunized mice with extract concentrations as low as picogram quantities. Specificity studies demonstrated that Meth A expressed no antigenic cross-reactivity with similarly prepared extracts of an unrelated SV40-induced sarcoma (mKSA), nor with a mineral oil-induced plasmacytoma (ADJ-PC5) of BALB/c mice. Inhibition of PE cell migration was mediated by culture supernatants (presumably migration inhibition factor [MIF]) generated from a mixture of immune spleen cells and mitomycin C (MMC)-treated Meth A cells as assayed in an indirect MMI test.


Use of [75Se]selenomethionine in immunoglobulin biosynthetic studies. The gamma-emitting amino acid analog, [75Se]selenomethionine, has been used as a biosynthetic label for immunoglobulins secreted by plasmacytomas in tissue culture. The secreted products are structurally intact with respect to their antibody combining sites and their class and allotype antigenic specificities. A component of [75Se]selenomethionine preparations was found to bind to fetal calf serum proteins, in a manner releasable by mercaptoethanol, but not by sodium dodecyl sulfate (SDS) and urea. Methods for circumventing the problems caused by this binding are described.


A simple and convenient method for producing anti-activated lymphocyte alloantisera which does not require prior absorption. A BALB/c B cell lymphoma, 2PK-3, was found to be activation lymphocyte alloantigen (Ala-1)-positive by virtue of its ability to absorb out the cytotoxic anti-Ala-1.1-like antibody activity of an antiserum against activated BALB/c (Ala-1.1) lymphocytes. Injection of 2PK-3 cells from the spleens or ascites of lymphomatous BALB/c mice into H-2d compatible DBA/2 mice led to the rapid development of an antiserum with properties identical to anti-Ala-1.1 alloantisera. Thus, it did not significantly kill normal spleen cells from any one of 7 different strains tested, but killed over 85% of Con A- or LPS-stimulated spleen cells of 4 Ala-1.1 positive strains; activated lymphocytes of Ala-1.2 were not affected. Furthermore, these properties were seen with unabsorbed antisera. The results indicate that the Ala-1 phenotype may, in some cases, be retained on neoplastic lymphocytes and that such cells, being rapidly and easily obtained in vivo in large quantities, can serve as a convenient source of immunogen for the development of anti-Ala-1 alloantisera in certain donor-recipient combinations.


Studies on the microcytotoxicity test. II. The uptake of amino acids ([3H]leucine or [75Se]methionine) but not nucleosides ([3H]thymidine or [125I]IUdR) or 51CrO24-provides a direct and quantitative measure of target cell survival in the presence of lymphoid cells. We have studied the suitability of various commonly used radioactive materials for the direct post-labeling of adherent rat target cells in long-term cytotoxicity tests. The use of nucleosides at high concentration avoids the necessity of adding fluorodeoxyuridine to enhance nucleoside uptake by target cells, and reduces the degree of non-specific inhibition of nucleoside uptake caused by products released from effector lymphoid cells. However, when [125I]iododeoxyuridine was used for labelling, such inhibition was not completely avoided even at very high nucleoside concentration, necessitating the washing of target cells prior to labelling. Similarly, without prewashing, the uptake of 51CrO24-ions frequently failed to correlate well with the numbers of surviving target cells as assessed by cell counting. On the other hand, radiolabelled amino acids, when present at semi-saturating concentrations, were taken up quantitatively by target cells under all conditions tested. Furthermore, in comparison to [125I]iododeoxyuridine, radioactive amino acids showed little if any toxicity to target cells. The use of the gamma-emitting amino acid analogue, [75Se]selenomethionine, is particularly recommended.


Rabbit IgM: its isolation in high yield by a convenient procedure using serum from trypanosome-infected animals. Rabbit sera contain little IgM. This is a major obstacle for its isolation. However, levels of IgM up to 10 mg/ml are found in rabbits infected with living trypanosomes. A simple procedure, involving gel filtration, standing in the cold, and agarose block electrophoresis is described which allows the isolation of IgM from these sera in 60% yield, with a purity of better than 90%.


Separation of cells by affinity chromatography on SpA-sepharose 6MB. A cell separation technique was designed which was based on the reaction of protein A of Staphylococcus aureus (SpA) with the Fc regions of IgG antibodies. SpA covalently linked to Sepharose 6MB is able to fix antibody-bearing cells, while non-fixed cells are removed by washing. The fixed cells can be released by dog IgG or by mechanical treatment. As an example of the use of the technique, Ig-bearing cells were isolated from mouse spleen cells treated with rabbit IgG anti-mouse Ig antibody; the purity of the Ig-bearing lymphocytes so isolated was better than 90%. The viability and the ability of the cells to shed the antibodies from their surface were not significantly impaired by the fractionation method. The technique can be generally applied to cell separation providing IgG antibodies against specific surface markers are available.


Comparison of three methods used for the measurement of the avidity of antibody to DNA. Three methods for determining the avidity of antibodies to single-stranded DNA (ssDNA) have been compared. None of the 3 methods was totally satisfactory but for theoretical and practical reasons the measurement of avidity by determination of dissociation rate is considered the most appropriate.


Spectrophotometric determination of lymphocyte mediated sheep red blood cell hemolysis in vitro. An assay has been developed in which the degree of in vitro spleen cell-mediated sheep red blood cell (SRBC) hemolysis is quantitated spectrophotometrically (QHS). Immune mouse spleen cells, SRBC and guinea pig complement were incubated at 37 degrees C for 1 h in buffer, centrifuged, and the supernatant solutions read at 413 nm. The greatest degree of cell-mediated SRBC hemolysis was observed in day +5 harvested spleens following a day 0, 5% SRBC i.p. injection. In the assay system, it was found that a stimulator SRBC dose of 0.2% resulted in maximal stimulation with little non-specific hemolysis. This assay is presented as an alternative to the well established plaque forming and rosette assays.


Chemiluminescence-linked immunoassay.

Chemiluminescence-linked immunoassay. Covalent complexes of a chemiluminescent compound (a luminol derivative), protein and a steroidal hapten have been used as a labelled antigen in a way analogous to the radioactive label in radioimmunoassay. The antibody-bound complex emits light when treated with hydrogen peroxide and copper acetate at high pH. The chemiluminescent complex bound to antibody can be displaced by free steroid to produce a standard curve in a way analogous to radioimmunoassay.


Radioimmunoassay of murine leukemia virus p30 using Staphylococcus aureus as immunoadsorbent. A competition radioimmunoassay for murine leukemia virus p30 has been developed. Serial dilutions of the unknown in wells of microtiter plates are incubated with 125I-labeled p30 and goat antiserum specific for p30. Bound p30 is then removed by an immunoadsorbent specific for goat immunoglobulin, prepared from S. aureus. An internal standard of 51Cr is used to correct for volumetric errors, the amount of the labeled p30 precipitated being calculated from the 125I/51 Cr ratio of the supernatant. The assay is rapid, being completed within 2 h, precise, having a coefficient of variation less than 1%, and sensitive, being capable of detecting p30 concentrations as low as 2 ng/ml in a volume of 0.02 ml. It has been used to measure p30 levels in a series of MCA-induced fibrosarcomas of BALB/c mice.


Classical and alloimmune anaphylactic degranulation of isolated single mast cells. Viable mast cells, directly isolated by micromanipulation from a mouse peritoneal cell suspension, were deposited on the bottom of microtiter-plate wells and submitted to histamine release. Conventional antigen-induced anaphylactic degranulation as well as direct allogeneic anaphylactic degranulation were strongly inhibited when these mast cells were settled on normal tissue culture plastic surfaces. Nevertheless, normal degranulation could be recovered by pretreatment of the experimental surface with a multipositive charged molecule (poly-L-lysine). Under these conditions, we demonstrate that the degranulation of one isolated mast cell is possible and consequently, as regards the direct allogeneic anaphylactic degranulation, confirm the "self-triggering mechanism" in which the recognition of histocompatibility antigens on the membrane of the mast cell itself is the trigger to the secretory response. The technique of monocellular degranulation described in this paper provides a new tool which leads us to think that the problem of detection of anaphylactic antibody-secreting cells can be solved.


Studies on the membrane glycoprotein defect of En(a-) erythrocytes. III. N-terminal amino acids of sialoglycoproteins from normal and En(a-) red cells. Sodium dodecylsulphate polyacrylamide gel electrophoretic methods and quantitative analyses of the N-terminal amino acids were applied to the sialoglycoprotein mixture and glycoprotein fractions from normal erythrocyte membranes, as well as preparations from red cells of individuals belonging to the English and Finnish En(a-) families. The data confirm the observation by alternative methods that SS cells exhibit a higher Ss glycoprotein content than ss erythrocytes. The results of end-group analyses suggest that the N-terminal amino acids serine and leucine represent the structures differentiating the MN and the 'M' and 'N' antigens on the MN and Ss glycoproteins respectively. Data from peptide sequence analyses confirm that the glycine/glutamic acid polymorphism at the fifth position of the MN glycoprotein's peptide chain is closely or absolutely linked with the serine/leucine polymorphism at its N-terminal position. As normal (EnaEna) red cells exhibiting 'M' antigenic properties have not been detected, the hypothesis is proposed that the Ss glycoprotein of English En(a-) erythrocytes possesses an MN-Ss hybrid polypeptide chain analogous to those of the delta-beta Lepore haemoglobins.


Lack of specificity of the limulus lysate test in the diagnosis of pyogenic arthritis. The diagnosis of pyogenic arthritis may be difficult to confirm since culture results are sometimes negative. This study attempted to evaluate the utility of the limulus lysate assay for the early detection of pyogenic arthritis due to gram-negative organisms. Seven-one specimens of synovial fluid from 46 patients were evaluated for reactivity in the limulus test, pyrogenic responses in rabbits, total white blood cell count, total neutrophil count, total red blood cell count, and protein and glucose concentrations. All patients with culture-proven septic arthritis or presumptive septic arthritis had joint fluid specimens that yielded a positive result in the limulus assay (12 patients). However, 52.9% of patients (18 of 34) who had a nonseptic cause for their joint effusion also had a joint fluid specimen that was positive in the limulus test. A positive limulus test result showed a significant correlation with an elevated total white blood cell count (P less than 0.0005), an elevated absolute neutrophil count (P less than 0.0005), and a decreased concentration of glucose (P less than 0.005) in synovial fluid, and the production of fever in rabbits after injection of synovial fluid (P less than 0.05). Thus, this study suggests that a positive result in the limulus test on joint fluid is nonspecific for a septic process, but a negative result would be evidence against it.


Serologic typing of Staphylococcus epidermidis biotype 4. Three hundred sixty-five isolates of Staphylococcus epidermidis (coagulase-negative) obtained over a 12-month period from 10 selected wards at New York University Medical Center-Goldwater Memorial Hospital, Roosevelt Island, N.Y., were typed serologically by slide agglutination. The isolates were first biotyped by the Baird-Parker scheme and then subtyped as proteinase-positive or proteinase-negative so that the selection of strains for immunologic study was based on biochemical and enzymatic factors rather than on random choice. The biotyping scheme of Baird-Parker and the differentiation between proteolytic and nonproteolytic strains were of limited in initial categorization of isolates of S. epidermidis. Antisera to proteinase-positive and proteinase-negative S. epidermidis biotypes 1 and 4 were absorbed with different permutations of homologous and heterologous thermostable (TS) and thermolabile (TL) antigens, and four distinct TL and two distinct TS antigenic groups, representing five different serotype patterns (i.e., A1-2, B1-2, C-D1, C-D1-2, and E1), were detected. The TL antigens also appeared to be more widespread and were shared more frequently by strains of S. epidermidis than were TS antigens, but the use of both TS and TL antigens provided a better serologic system than use of either TS or TL antigens alone.


Conditions for bacille Calmette-Guérin-induced resistance to infection with Schistosoma mansoni in mice. Intravenous administration of a lyphilized preparation of bacille Calmette-Guérin (BCG-Tice) into mice significantly protected these animals from infection with Schistosoma mansoni. The protective effect depended on the dose of BCG and required the administration of at least 2 X 10(7) viable organisms. The route of administration of BCG was also crucial, as only intravenous inoculation produced significant protection. The BCG-induced resistance was found to last for eight weeks. Significant inflammation of the lungs was observed in mice receiving either viable or heat-killed BCG; however, protection followed only the administration of viable bacilli. Expression of BCG-induced protection was dependent on the presence of significant numbers of viable organisms and may have been associated with pulmonary inflammation at the time of passage of the schistosomula through the lungs.


Clinical pharmacology of tobramycin in children. The pharmacokinetics of tobramycin were evaluated in 50 pediatric patients (two to 18 years of age) with malignancies and normal renal function. Patients receiving either 240 or 300 mg/m2 per 24 hr (8 or 10 mg/kg per 24 hr) divided into doses given every 4 hr had peak serum concentrations (mean +/- standard error) of 3.10 +/- 0.23 microgram/ml and 4.23 +/- 0.25 microgram/ml, respectively, at the end of a 1-hr infusion. Serum concentrations at 4 hr were 0.82 +/- 0.15 and 1.05 +/- 0.15 microgram/ml, respectively. The half-life of the drug was 96.6 min and was inversely correlated with age of the patients. The total clearance rate of tobramycin was 164 +/- 15 mg/min per 1.73 m2 and was directly correlated with age. The mean volume of distribution was 0.42 +/- 0.038 liter/kg and was inversely correlated with age. No accumulation of tobramycin was noted, and no side effects occurred. If therapeutic serum concentrations of tobramycin are to be achieved and maintained in children, the currently recommended dose and frequency of administration should be changed to 300 mg/m2 per 24 hr given in divided doses every 4 hr.


Influence of transplacentally acquired antibody on neonatal susceptibility to canine distemper virus in gnotobiotic dogs. In utero acquistion of protective levels of neutralizing antibody to canine distemper virus (CDV) was observed in four litters of colostrum-deprived gnotobiotic and specific-pathogen-free puppies. Pregnant bitches with high antibody titers passively transferred antibody to these pups transplacentally in average titers of 1:7 to 1:16 per litter. Maternally derived antibody protected neonatal pups from otherwise fatal infection with virulent CDV. Protection was associated with a transient lymphopenia and viremia and temporary suppression of lymphocyte responses to phytohemagglutinin-P.


Treatment of cutaneous Herpesvirus hominis type 2 infection with 8-methoxypsoralen and long-wave ultraviolet light in guinea pigs. Treatment of cutaneous Herpesvirus hominis type 2 infection in albino guinea pigs with 8-methoxypsoralen plus long-wave ultraviolet light was evaluated by clinical assessment and quantitative viral cultures. There was a statistically significant difference between the treated animals and the controls in relation to vesicular development, rate of healing, and viral titers. The treatment was effective after the appearance of lesions, when viral multiplication has already begun.


Effect ob broad-spectrum antibiotics on in vitro synthesis of DNA in the rabbit colon. Rabbit colonic mucosa was cultured in vitro in the presence of broad-spectrum antibiotics. DNA synthesis, as determined by [3H]thymidine incorporation into DNA, was inhibited by clindamycin (32%) and tetracycline (28%). Penicillin G, ampicillin, and metronidazole had no effect. When bile acids were added to the incubation at a concentration of 10 mM, the more lipophilic drug, lincomycin, inhibited DNA synthesis by 38% (cholic acid) and by 23% (chenic acid). Bile acids alone did not alter thymidine incorporation. Inhibition by clindamycin demonstrated a gradual dose-response curve, with inhibition first noted at about 20 microgram of antibiotic/ml and maximal inhibition at 1,000 microgram/ml. The more biologically active metabolite of clindamycin, N-demethylclindamycin, inhibited DNA synthesis at concentrations of as low as 10 microgram/ml. The inhibition was reversible, and the drugs did not affect thymidine uptake, thymidine pool concentrations, or protein or mucopolysaccharide synthesis at concentrations of up to 300 microgram/ml. These data demonstrate a direct but reversible toxic action on mammalian colonic mucosa by certain antibiotics implicated in the production of pseudomembranous colitis and are consistent with the hypothesis that such a toxic action may be one factor in the pathogenesis of antibiotic-associated colitis.


Immunization with a human diploid cell strain of rabies virus vaccine: two-year results. Antibody responses following primary vaccination with 1.0 ml of intramuscularly (im) or 0.1 ml of intradermally (id) administered human diploid cell rabies virus vaccine were observered for two years. Three primary doses of vaccine were given to 77 volunteers on days 0, 28, and 56. An antibody response was detected in all vacinees after a single dose; at one month, the response in the group that received vaccine id was identical to that in the group that was given vaccine im, although only 1/10th of the dose of vaccine was used. After the second and third doses, the antibody responses were higher with the primary im regimen; this difference was significant at two, three, and 12 months when the geometric mean titers of antibody were twofold higher for im than for id vaccination. The antibody responses to a booster dose of vaccine administered to randomly grouped volunteers by the subcutaneous or id route at six, 12, or 24 months were similar irrespective of the method of primary immunization but were greater with increasing intervals between primary and booster doses.


Synergistic nephrotoxicity of amphotericin B and cortisone acetate in mice. Striking mortality in mice receiving amphotericin B and cortisone acetate concomitantly prompted studies to characterize the toxic interaction of these two drugs further. Adult female CD-1 mice received daily injections of cortisone acetate (0--50 mg/kg subcutaneously) and/or amphotericin B (0--12.5 mg/kg intraperitoneally) in a checkerboard combination dosage pattern for 30 days. Dosages of amphotericin B and cortisone acetate that produced little or no mortality individually produced significant (P less than 0.005) mortality in combination. Light and electron microscopic studies of sections of brain, heart, lung, adrenal gland, liver, and kidney revealed only renal lesions. These appeared within six days, were dose-related in severity, and were not produced by either drug alone. The lesions consisted of focal swelling of proximal, distal, and collecting tubular cells which progressed to necrosis and intraluminal cast formation. These findings may be relevant to the development of nephrotoxicity in patients treated simultaneously with amphotericin B and corticosteroids.


Development of in vitro correlates of cell-mediated immunity to respiratory syncytial virus infection in humans. Groups of infants and children with infections due to respiratory syncytial virus (RSV) were tested at the onset of illness and one, two, and five months later for the presence of RSV-specific cell-mediated immunity, as determined by in vitro lymphocyte transformation (LTF) activity, and for complement-fixing (CF) antibody. An LTF response specific for RSV was observed in 65 % of patients, and the response was largely associated with E-rosette-forming thymus-derived (T) lymphocytes. A significant cell-mediated immune response was observed in 78% of patients six months of age or younger, whereas only 46% of patients older than six months exhibited such responses. The difference between the mean stimulation index of the maximal LTF response in the two age groups was statistically significant (P less than 0.05). On the other hand, a fourfold or greater rise in titers of CF antibody was observed in only 22% of patients six months of age or younger, whereas significant rises in antibody activity were observed in 50% of subjects older than six months. In view of the fact that RSV infection is most severe in the young infant, these observations raise the possibility that cell-mediated hypersensitivity reactions may be related to the pathogenesis of RSV infection of infants.


Increased urinary riboflavin excretion resulting from boric acid ingestion. The urinary excretion of riboflavin (vitamin B2) was determined in 14 patients, both children and adults, after the ingestion of boric acid. These patients reported to the New York City Poison Control Center during a 2 1/2 year period. Riboflavin was determined by a modification of a previously described method which is based upon competitive protein binding. Boric acid ingestion was associated with greatly increased urinary riboflavin excretion in approximately two thirds of the patients. Most of the riboflavin appeared to be excreted within the first 24 hr after ingestion of boric acid. These data provide evidence of a previously unrecognized hazard of boric acid ingestion in patients.


Effect of inflammation on erythroid precursors (BFU-E and CFU-E) in bone marrow and spleen of mice. Inflammation, induced in mice by a single intramuscular injection of turpentine, caused a long lasting reduction in the number of morphologically unrecognizable CFU-E in the bone marrow. This resulted in marked decreases in marrow erythroblasts and their iron incorporation into heme. The effect is attributed to blood-borne mediators of inflammation which either caused an emigration of progenitors of CFU-E from the marrow or inhibited their proliferation, possibly as the result of increases in marrow myelopoiesis. CFU-S as well as erythroid and myeloid precursors were markedly increased in the spleen during the inflammatory reaction.


The action of halofenate on platelet shape change and prostaglandin synthesis. HAL, a congener of clofibrate, has previously been shown to inhibit epinephrine- and ADP-induced platelet aggregation and 14C-serotonin release. We further investigated the site of action of HAL by examining platelet shape change, MDA production as a measure of prostaglandin synthesis, and platelet aggregation and MDA production induced by SA. At the usual maximal therapeutic concentration of HAL (0.96 mM), this drug did not affect the velocity of platelet shape change as measured by a spectrophotometric method. However, at a higher concentration (3.12 mM), HAL significantly inhibited shape change (p less than 0.01). When epinephrine was used to initiate aggregation of PRP, HAL (0.96 mM) was found to inhibit MDA production over a wide range of epinephrine concentrations (p less than 0.01). This was not due to a direct inhibition of prostaglandin formation, since HAL had no effect on SA-induced platelet aggregation or MDA production. Aspirin (4 mM), on the other hand, produced a marked inhibition of MDA production and of platelet aggregation after stimulation with SA. We conclude that HAL works to inhibit some step in the platelet reaction prior to the appearance of free arachidonic acid.


Factors influencing the release of procoagulant-tissue factor activity from leukocytes. Leukocytes stimulated with endotoxin generate a procoagulant (tissue factor) activity. Part of this procoagulant activity is released rapidly into the surrounding milieu, with maximum release occurring within 30 min incubation. Optimal release of procoagulant activity requires the presence of Ca ions in a concentration of 2.5 mM, a pH of 7-8, and a temperature of 37 degrees C. The released procoagulant activity is TFa as determined by the two-stage assay and the ability of an antibody to tissue factor to neutralize the procoagulant activity. The release of TFa is not parallel to LDH release. Release of TFa is inhibited by vinblastine and cytochalasin B.


Human plasma prekallikrein (Fletcher factor) clotting activity and antigen in health and disease. Human plasma prekallikrein (Fletcher factor) clotting activity and antigen levels have been examined in various clinical conditions. Prekallikrein antigen was measured by a newly developed, specific, and sensitive radioimmunoassay. The assay had no demonstrable cross-reactivity with human urinary kallikrein nor, in the species tested, animal plasma prekallikrein. This assay was able to measure plasma kallikrein after its biological functions had been inactivated by plasma inhibitors. Normal human pooled plasma contained approximately 50 microgram/ml prekallikrein. Quantitative measurement of plasma prekallikrein was possible for concentrations as low as 0.3% of that of normal pooled plasma. A good correlation (correlation coefficient = 0.71) existed between titers of plasma prekallikrein measured by Fletcher factor clotting assays and radioimmunoassays among 40 normal subjects. Both prekallikrein clotting activity and antigen were significantly reduced in plasmas of patients with advanced hepatic cirrhosis or DIC. Prekallikrein activity and antigen were mildly decreased in plasmas or serums of patients with chronic renal failure and nephrotic syndrome but were normal in those of patients under treatment with warfarin or suffering from SLE, rheumatoid arthritis, sarcoidosis, or HANE. Human cord serum contained a lower titer of prekallikrein antigen than adult serum. Strenuous physical exercise did not significantly change plasma prekallikrein levels.


Osmotic treatment of cochleopathies other than Menière's disease. The effect of osmotic treatment on cases with fluctuating sensorineural hearing loss other than Menière's disease is described in this paper. Complete normalization of the hearing threshold has been obtained in eight patients suffering from cochlear hydrops (one case), sensorineural concussion deafness (five cases), temporary noise threshold shift (one case), sudden deafness (two cases). Relief of tinnitus has been observed in a case of post-stapedectomy deafness. The audiometric pattern of end organ disease in a case of cohlear otosclerosis showed a change into a classical otosclerosis audiograph after glycerol administration. The action of osmotic drugs on the inner ear is though to be twofold, i.e. reabsorbing hydrops and normalizing rheological alterations. Therefore, an osmotic treatment is indicated for menieric and non-menieric hydrops and for microcirculatory impairment of the labyrinth. On the basis of these statements the glycerol test for the diagnosis of Menière's disease is called into doubt as not being absolutely specific.


Simple nasal polyps and allergic manifestations. A series of 74 consecutive patients with simple nasal polyps were interviewed with regards to features of allergy. Skin testing with a variety of antigenic extracts and estimations of peripheral blood immunoglobulins including total serum IgE were also carried out. The simple tests performed in this study have not been able to delineate a specific subgroup of atopic patients with nasal polyps. Positive skin testing with house dust mite extract may form the basis of a clinical evaluation of hyposensitization.


Diagnosis of acute corrosive lesions of the oesophagus. Early diagnosis of acute corrosive lesions of the oesophagus enables adequate treatment to be given to the patient and prevents unnecessary treatment of uninjured individuals. In an analysis of 64 patients of varying ages subjected to oesophagoscopy during a 10-year period for suspected corrosive lesions of the oesophagus caused by alkali, acids and other corrosive substances, it was found that neither clinical signs, laboratory investigations nor X-ray examination gives sufficient information about whether the patient has a corrosive lesion of the oesophagus or not. Oesophagoscopy establishes the diagnosis. Patients suspected of having corrosive lesions of the oesphagus should therefore be subjected to oesophagoscopy as soon as their condition permits.


Primary malignant haemangiopericytoma of the larynx (a case report with autopsy). This is a report of an exceptional case of haemangiopericytoma of the larynx, which occurred in a 50-year-old male patient. Histological examination of biopsy fragments allowed us to make the correct diagnosis, later confirmed at autopsy. From a comprehensive review of the world literature on haemangiopericytomas, it appears that cases of indisputable well-documented laryngeal occurrence of the neoplasm amount to two only, including the present case. The morphological pattern, histogenesis, biological behaviour and therapy of the tumour, as well as differential diagnosis from other lesions, are discussed.


Chondrosarcoma of the larynx.

Chondrosarcoma of the larynx. We report one case of chondrosarcoma of the larynx, which is considered to be rather uncommon. Clinical signs and symptoms have been noted, as well as some suggestions on the aetiology, incidence and site of cartliaginous tumours of the larynx.


Interfacial oxidation of alpha-tocopherol and the surface properties of its oxidation products. dl-alpha-Tocopherol spread on an acidic subphase as a gaseous monolayer was oxidized slowly to a derivative that was identified by thin-layer chromatography as alpha-tocopherylquinone. The derivative generated the same II-A isotherm as alpha-tocopherylquinone. When the subphase contained gold chloride, alpha-tocopherol was oxidized rapidly and quantitatively to alpha-tocopherylquinone. dl-alpha-Tocopherol spread on a basic subphase as a gaseous monolayer was oxidized slowly to a mixture that contained alpha-tocopherol, a quinone, and a nonpolar derivative. The mixture generated a II-A isotherm with an inflection point below the equilibrium spreading pressure of either alpha-tocopherol or alpha-tocopherylquinone. When potassium ferricyanide was added to the alkaline subphase, alpha-tocopherol was oxidized rapidly to a mixture that contained both the nonpolar derivative (major product) and the quinone (minor product). The nonpolar derivative was isolated by thin-layer chromatography and identified as the spirodienone ether by ultraviolet, infrared, and chemical ionization mass spectra. The spirodienone ether had a low equilibrium spreading pressure that explained the inflection point in the II-A isotherm generated by alpha-tocopherol on an alkaline subphase. Surface area data showed that dl-alpha-tocopherol formed immiscible films with stearyl alcohol and miscible films with oleyl alcohol. II-A isotherms showed that alpha-tocopherol in both immiscible and miscible mixtures was oxidized rapidly on an alkaline potassium ferricyanide subphase to the spirodienone ether. Collapse pressure data showed that the spirodienone ether formed an immiscible film with stearyl alcohol and a miscible film with oleyl alcohol. Interfacial oxidation experiments showed that alpha-tocopherol is oxidized either to tocopherylquinone (acidic subphase) or to the spirodienone ether (alkaline subphase). The natural occurrence of both tocopherylquinone and the spirodienone ether suggests that several types of oxidant stress are found in biological systems. One type of oxidant stress may involve the peroxy radical generating tocopherylquinone; a second type may involve hydroxyl radical-hydroxide ion generating the spirodienone ether.


Studies on serum lipids, insulin, and glucagon and on muscle triglyceride in rats adapted to high-fat and high-carbohydrate diets. A comparisonwas made of lipid circulation, storage, and mobilization in rats adapted to lard or glucose diets. In the morning, lard-fed rats had higher blood triglyceride (TG) and free fatty acid (FFA) levels. In the evening TG was higher, but FFA was significantly lower in the lard vs. the glucose group. Fasting did not produce the characteristic increase in blood FFA in the lard-fed rats but was associated with a severe drop in their serum TG. Circulating glucose and insulin were not affected, while glucagon levels were increased by lard feeding. Nicotinic acid decreased fasting FFA levels to a greater extent in the glucose-fed rats. It was concluded that lard feeding depresses mobilization of fat from adipose tissue; on the other hand, it was found to increase storage and utilization of muscle TG. Fat feeding increased diaphragm TG concentrations threefold, as well as the number and size of intracellular fat droplets at the light and electron microscopic levels. Fasting decreased diaphragm TG in both groups, but the amount lost was greater in the fat-fed rats. Also, in vitro basal isoproterenol-stimulated (1 microgram/ml) FFA release by the incubated diaphragm was higher in the lard-fed group.


Lipid synthesis in isolated intestinal cells. Since the small intestine contributes significantly to serum cholesterol and very low density lipoprotein levels, acute regulation of lipid synthesis was investigated in isolated rat intestinal cells incubated in Krebs-Ringer bicarbonate buffer with 5 mM glucose and [14c]acetate or 3H2O. Incorporation of [14c]acetate into cellular lipids was 6- to 8-fold greater in crypt than in villus cells. In both cell types the distribution of 14C among the various lipid classes was as follows: 52.5% in triglycerides, diglycerides, and monoglycerides; 22.3% in cholesterol; 8.3% in cholesteryl esters; 1.9% in fatty acids; and 15.0% in phospholidpids. In contrast, the medium lipids contained significantly higher amounts of tri-, di- and monoglycerides (61.1%) and lower amounts of cholesteryl esters (2.3%) and phospholipids (11.9%). After saponification, 2/3 of the recovered 3H2O was in fatty acids and 1/3 in cholesterol. Ethanol (10 mM) tripled 3H2O incorporation into cellular lipids but had no effect on [14c]acetate incorporation. Epinephrine and norepinephrine (10 micron), glucagon (10 micron), dibutyryl cyclic AMP (1MM), dexamethasone (1 mM and 1 micron), and cholera toxin (1 microgram/ml) did not affect [14c]acetate incorporation. We concluded that ehtanol stimulates intestinal lipid synthesis; however, in sharp contrast to their inhibition of lipid synthesis in hepatocytes and adipocytes, catecholamines, glucagon, and dibutyryl cyclic AMP do not inhibit lipid synthesis in intestinal cells.


Radioimmunoassay of ursodeoxycholic acid in serum. A sensitivie and specific radioimmunoassay for the measurement of serum ursodeoxycholic acid has been developed. Ursodeoxycholic acid bound to bovine serum albumin was used as an antigen, and antiserum to this antigen was raised in the rabbit. [11, 12-3h2]Ursodeoxycholic acid was used as the radioactive tracer, and the radioimmunoassay was carried out by the method of Simmonds et al. (1973. Gastroenterology. 65: 705-711). The percentage of bound radioactivity decreased linearly with a logarithmic increase in unlabeled ursodeoxycholic acid from 10 to 200 pmol. The antiserum showed extremely high specificity for ursodeoxycholic acid (free and conjugated), and the values determined by radioimmunoassay indicated a close correlation with those found by gas-liquid chromatography. In normal Japanese subjects, a small amount of ursodeoxycholic acid in serum was detected, and the level was detected, and the level was 0.15 +/- 0.11 nmol/ml. This convenient radioimmunoassay will provide useful information about the metabolism of ursodeoxycholic acid in man.


Cholesterol absorption and steroid excretion in cholesterol-fed guinea pigs. Cholesterol absorption was studied in groups of guinea pigs fed diets containing 0, 0.1%, or 1% cholesterol. A similar proportion of tracer cholesterol was absorbed regardless of the cholesterol content of the diet. Furthermore, the proportion of tracer cholesterol absorbed by individual animals did not change when the cholesterol-free diet was changed to one containing 1% cholesterol. Cholesterol absorption was also measured in hyporesponding guinea pigs. These guinea pigs had been fed 1% cholesterol-containing diets for nearly a year with minimal pathological effects. These hyporesponders had a decreased intestinal transit time, which enabled them to decrease the fractional absorption of cholesterol below the levels seen in the controls, and to absorb less cholesterol/kg body weight than the hyperresponders. Excretion of total and of neutral steroids was measured in guinea pigs fed 0 or 1% cholesterol-containing diets. The 1% cholesterol-fed guinea pigs increased the excretion of steroids 3-fold over control levels. However, they absorbed more dietary cholesterol than they excreted in any form. It seems, therefore, that a major cause of the cholesterol pool expansion in the guinea pig is its inability to limit absorption of dietary cholesterol in conjunction with its inability to sufficiently increase excretion of steroids.


Rapid increase in hepatic HMG CoA reductase activity and in vivo cholesterol synthesis after Triton WR 1339 injection. Triton WR 1339, injected intravenously into rats, caused a 12% decrease in hepatic cholesterol within 30 minutes and a 34% decrease after 2 hours. An early and progressive increase in plasma cholesterol and triglycerides was also confirmed. Although hepatic HMG Coa reductase activity was unchanged after 30 minutes, it had increased seven-fold after 105 minutes. In vivo cholesterol synthesis measured by determining incorporation of intraperitoneally-injected 3H2O into cholesterol also showed an early increase, suggesting that the enzyme was rate controlling for cholesterogenesis under conditions of rapid stimulation. These findings strongly suggest that Triton WR 1339 stimulates hepatic cholesterogenesis by depleting hepatic cholesterol and trapping it in the blood compartment. The rapidity with which the drug acts supports the hypothesis that hepatocellular flux of cholesterol or its derivatized product could mediate the diurnal and hormonally induced fluctuations of cholesterogenesis.


Turnover of phospholipid linoleic and arachidonic acids in human platelets from plasma lecithins. Incubation of platelet-rich plasma with high density lipoproteins labeled either with 1-acyl-2[1-14c]-arachidonoyl-sn-glycero-3-phosphocholine or 1-acyl-2-[1-14c]linoleoyl-sn-glycero-3-phosphocholine showed the existence of a pool of phosphatidylcholine in platelets, which rapidly exchanges with the phosphatidylcholine in plasma. The labeled linoleic and arachidonic acids from the respective labeled phosphatidylcholines were found in the other glycerophospholipids. These transacylation processes were much more active with the arachidonoyl-labeled phosphatidylcholine than with linoleoyl-labeled phosphatidylcholine. Arachidonic acid was mainly found in the phosphatidylinositol.


Determination of conjugated bile acids in human bile and duodenal fluid by reverse-phase high-performance liquid chromatography. A simple mehtod using reverse-phase liquid chromatography is presented for resolution and quantitation of the major conjugated bile acids of man, including the glycine and taurine conjugates of the dihydroxy bile acids, chenodeoxycholic and deoxycholic acid. Using modern, high-performance chromatographic equipment, analysis time is less than 30 minutes. The quantitative range of the method, with detection by refractive index, is 0.05 to 0.1 mumol of bile acid and the limit of detection for an injection sample is 0.01 mumol. This provides a sensitivity sufficient for analysis of dilute duodenal and gallbladder bile with minimal sample preparation.


A multi-locus continuous-time selection model. A continuous time selection model is formulated for a diploid monoecious population with multiple alleles at each of an arbitrary number of loci, incorporating differential fertility and mortality as well as arbitrary mating and age structure. The model is simplified in the case of age-independence and for the case of a stable age distribution. The age-independent model is examined in detail for the special case of multiple alleles at each of two loci. This model is analyzed under the assumptions of random mating and additive fertilities, with close attention given to the behavior of the system with respect to Hardy-Weinberg proportions and linkage equilibrium.


Prediction of the functional refractory period of the atrioventricular node. Based on the new description of AV-nodal conductivity from our laboratory, we developed an equation which describes AV-nodal conduction time in the dog heart at all coupling intervals. This allows us to predict the functional refractory period (FRP) of the AV-node based on the AV-nodal conduction times of only five extra stimuli having relatively long coupling intervals. The equation predicted the FRP within acceptable limits when compared to values obtained by the classical technique in which the full range of extrasystolic intervals must be tested. Changes in FRP after the administration of antiarrhythmic drugs (lidocaine and quinidine) or due to changes in heart rate were predicted accurately. The ease and accuracy of the present method could allow determination of FRP in a short time.


Ventricular extrastimulation in the mitral valve prolapse syndrome. Evidence for ventricular reentry. Fourteen patients with mitral valve prolapse and essentially normal coronary arteries were evaluated for ventricular arrhythmias, utilizing programmed ventricular extrastimulation. Three were symptomatic with ventricular tachyarrhythmias. Application of appropriately timed ventricular extrasystoles initiated the tachyarrhythmias in these three patients. The remaining eleven mitral prolapse patients were apparently free of tachycardias. Repetitive ectopic beats were not induced by extrastimulation in these eleven patients. The initiation of ventricular tachyarrhythmias by extrastimulation suggests a reentrant mechanism for the ventricular ectopy of mitral valve prolapse.


Effects of the volume conductor on the apparent orientation of a known cardiac dipole. The surface electrocardiogram (EKG) is dependent on two major factors: the cardiac generator and the volume conductor. This investigation assessed the effects of the volume conductor in man on the apparent orientation of a simulated cardiac dipole. The apparent orientation of the dipole was calculated from measured surface potentials from about 60 locations on the body of five patients with implanted cardiac pacemakers. The real orientation of the dipole (an implanted pacemaker) was determined radiographically. The effects of both inhomogeneity and boundary characteristics of the volume conductor on the apparent orientation of the dipole were assessed using a new inverse algorithm. The difference between the orientation of the real and the calculated dipoles averaged 30 degrees (range 15 degrees--40 degrees) when the torso was assumed to be an infinite-homogeneous volume conductor. When the configuration of the torso was accounted for, however, the difference between the orientation of the real and calculated dipoles was reduced to 9 degrees (range 5 degrees--13 degrees). Thus, by taking into account the geometry of the torso and neglecting the inhomogeneities in the volume conductor, it is possible to calculate the orientation of a dipole in the cardiac region with an accuracy of about 9 degrees. It is reasonable to assume that the orientation of real activation wave fronts from localized areas of the heart could be calculated with a similar degree of accuracy.


Effects of electrode area on electrocardiographic voltages. Effects of two different sizes of chest electrodes--100 and 750 mm2 area--on x and z Frank leads were determined using electrocardiographic data from 25 subjects. In most cases, differences in Rx and Rz were below 50 uV, but in nine cases (36%) differences exceeded this value for either Rx or Rz or both. In six cases, differences exceeded 100 uV. For an additional 20 subjects, standard precordial leads were recorded using the same two electrode sizes. QRS amplitudes were significantly affected for V4 but not for V1 or V6. Variability caused by electrode size is greater than that caused by beat-to-beat variation and is comparable to that found in day-to-day variation. Interchangeability of data among ECG recording laboratories can be significantly improved by standardizing electrode size for precordial electrodes.


The surface electrocardiogram in complete intra-his heart block. In some cases, the surface ECG may be useful in predicting that the level of heart block is intra-His rather than supra-His. In five patients with third degree heart block the level of block was documented to be within the His bundle. In all five, the surface ECG showed an escape rhythm with QRS complexes of less than 0.10s. duration. The initial QRS forces were abnormal in that "septal" q waves were not present in leads 1 and V6. Two of the five patients had occasional conducted beats with normal "septal" q waves. Thus, heart block associated with an escape rhythm of narrow QRS morphology but abnormal septal depolarization may indicate that the level of the block is intra-His rather than supra-His.


Studies of acute myocardial infarction with intermittent bundle branch and hemiblock. Two cases of transient hemiblock occurring during the course of acute myocardial infarction are reported. The transient manifestation permits the accurate evaluation of the diagnostic features of the hemiblocks as modified by acute infarction. One case reflects the development of left bundle branch block due to bilateral post-divisional block which inter alia permits the study of left bundle branch block in the presence of acute myocardial infarction.


Theoretical analysis of T-wave polarity based on a model of cardiac electrical activity. The effect of the gradient of transmembrane action potential duration through the ventricular wall on T-wave polarity and QRS-T angle was investigated using a mathematical model of the electrical activity of the heart which incorporates the characteristic electrophysiological properties of the left ventricular wall. Two models, a rectangular solid model and a concave model, were constructed to simulate a part of the left ventricular wall. The ventricular gradient was defined as a linear decrease (beta msec/cm) of the action potential duration from the endocardium to epicardium. The theoretically-obtained relationship between the QRS-T angle and the ventricular gradient revealed that the transmural gradient (beta) was 10--40 msec/cm when the QRS-T angle was within the normal range. The positive T wave was obtained at the observation point which would correspond to the precordial lead when the transmural gradient was more than 30 msec/cm. The amplitude of the simulated T-wave increased with the ventricular gradient. Thus, our mathematical models can provide the quantitative relationship between the transmural ventricular gradient and T-wave polarity and are compatible with further simulation study for various pathological conditions.


Two-to-one A-V block with four-to-three A-V nodal wenckebach, a form of spontaneous multilevel block. Electrophysiologic studies in one patient with spontaneous 2:1 atrioventricular block and variable PR intervals revealed two sites of conduction block. Typical 4:3 A-V nodal Wenckebach was present in addition to Mobitz type II infra-His block. The HV of conducted complexes was 120 msec and the shortest recorded AH interval was 250 msec. When 2:1 A-V block with fixed PR interval was present, only 2:1 Mobitz type II infra His-block was present. The mechanism of this example of spontaneous multilevel A-V block is discussed and compared to other previously reported cases.


A case of sick sinus syndrome in primary systemic amyloidosis. A case of sick sinus syndrome due to primary systemic amyloidosis which involved mainly the heart and lungs is presented. The electrocardiogram showed various changes; low voltage, bradyarrhythmia with junctional escape beats, paroxysmal atrial tachyarrhythmia that terminates abruptly with subsequent long asystole, junctional rhythm from different origins and complete right bundle branch block which appeared at shorter and longer diastolic intervals. Histological examination showed an extensive amyloid infiltration in the upper parts of the conduction system, with major damage in the sinus node and also elsewhere in the heart. The patient died despite pacemaker implantation.


Multiform accelerated idioventricular rhythm in acute myocardial infarction. The presence of accelerated idioventricular rhythm (AIVR) in its multiform variant in two patients with acute myocardial infarction is described. No difference was noted in the clinical evolution of this arrhythmia and the more commonly observed unifocal AIVR.


A note on the application of Morse theory to the study of the potential extrema of body surface potential maps. The entire body may be approximated with a closed surface having the homotopy type of a sphere. The Morse inequalities then yield certain relationships between the local potential extrema and the saddle points appearing on body surface potential maps (BSPMs). In particular, a list of possible extremal configurations is presented.


Demand pacemaker slowing: a simple bedside technique. We present a simple noninvasive bedside technique to slow gradually any R-wave inhibited ventricular demand pacemaker up to one-half its original rate for indefinite periods of time. Gradual pacemaker slowing allows accurate diagnostic observations and therapeutic interventions in pacemaker-induced arrhythmias and may possibly be used in the management of unstable angina in patients with ventricular demand pacemakers.


Response of antidiuretic hormone to acute exposure to mild and severe hypoxia in man. Eight men, 19-35 years of age, breathed 20.9% (normal oxygen), 13.9% (mild hypoxia) or 11.1% (severe hypoxia) oxygen in nitrogen gas mixtures during three 20 min periods, which were separated by 1 h recovery periods. The order in which the gas mixtures were breathed was random. The partial pressure of oxygen decreased from a mean of 93.5 during exposure to normal oxygen to 53.9 and 36.7 mmHg during mild and severe hypoxia respectively. There were corresponding decreases in haemoglobin saturation. The partial pressure of carbon dioxide was lower and the pH higher during severe hypoxia than during exposure to normal oxygen. There were no changes in the plasma osmolality or in the concentrations of sodium or potassium in the plasma. There was a tendency for both the renin activity and the concentration of aldosterone in the plasma to decrease progressively as the percentage of oxygen breathed decreased. Unlike severe hypoxia, mild hypoxia suppressed the concentration of antidiuretic hormone (ADH) in the plasma of all subjects by about 59%; during severe hypoxia the reduction was not significant, being only about 33%. These data are consistent with the suggestion that the effect of hypoxia on the release of ADH is dependent on the level of hypoxia.


Steroidogenesis in preovulatory follicles of patients given human menopausal and chorionic gonadotrophins as judged by the radioimmunoassay of steroids in follicular fluid. The administration of human menopausal gonadotrophin (HMG) followed by human chorionic gonadotrophin (HCG) stimulated the development of various numbers of follicles in patients treated for infertility. Graafian follicles from these patients were aspirated 32-33 h after the injection of HCG and the levels of steroids in the follicular fluid and matching serum samples were measured by radioimmunoassay. The follicles could not be grouped into two distinct clusters as found in patients given HCG during the menstrual cycle but a broad classification of follicles into four groups was indicated from the dendrogram. Two of the groups were similar to the ovulatory and non-ovulatory groups found previously, whereas the other two groups of follicles were more intermediate in nature. The use of a discriminant analysis showed that these two groups had clearly been stimulated by the HMG and HCG, although they were not yet fully ovulatory. Our data indicate that the number of developing follicles is considerably increased by treatment with HMG and HCG but there is asynchrony in follicular development because the pattern of steroid synthesis differs in many follicles. The effects of this asynchronous development on oocyte maturation and disorders of the luteal phase are discussed.


Steroidogenesis by cultured granulosa cells aspirated from human follicles using pregnenolone and androgens as precursors. Human granulosa cells from Graafian follicles aspirated 3-4 h before the expected time of ovulation were incubated with various steroid substrates, including pregnenolone, androstenedione, testosterone and dehydroepiandrosterone (DHA). Steroid production after 3 and 10 h of incubation was determined by radioimmunoassay. Progesterone and 17alpha-hydroxyprogesterone were the major products of granulosa cells in control short-term cultures with endogenous substrates. The addition of pregnenolone increased the synthesis of progesterone and 17alpha-hydroxyprogesterone compared with the controls, although the response varied considerably between paired short-term cultures. Little or no oestradiol-17beta was produced from endogenous precursors or short-term cultures to which pregnenolone had been added; one follicle, however, produced similar amounts of oestradiol-17beta in the control cultures and after incubation with pregnenolone. When granulosa cells were cultured with various amounts of androstenedione, DHA or testosterone, large amounts of oestradiol-17beta were produced, especially in short-term cultures in which larger amounts of substrate were added. Progesterone production continued and progesterone was synthesized more rapidly or in greater amounts in some short-term test cultures than in the controls. The results indicate that human granulosa cells are one source of oestradiol-17beta during the preovulatory phase. The data support the two-cell theory for oestradiol synthesis, for granulosa cells do not appear to undertake steroid conversion via the 5-unsaturated pathway, but aromatize androgens known to be produced by thecal cells. It is also suggested that either androgens or oestradiol-17beta stimulate progesterone production by granulosa cells, at least in vitro.


Development and characterization of a homologous radioimmunoassay for bovine follicle-stimulating hormone. A radioimmunoassay for bovine FSH has been developed using a rabbit antiserum against highly purified bovine FSH (160 X NIH-FSH-S1) and a 125I-labelled tracer of the same preparation. The sensitivity was 0.25 ng/ml for purified bovine FSH or 25 ng/ml with reference to a crude bovine FSH (NIH-FSH-B1) standard. Purified bovine LH and TSH showed cross-reactivities of less than 1%, while their subunits and other purified protein hormones showed no significant inhibition at concentrations up to 100 ng/ml. Ovine FSH cross-reacted significantly but in a non-parallel manner; human and rat FSH cross-reacted only slightly. The concentrations of FSH (means +/- S.E.M.) in the sera of cows (n = 12), cows at oestrus (4), bulls (7) and steers (9) were measured as 25.4 +/- 4.7, 58.4 +/- 12.6, 45.7 +/- 9.5 and 120.2 +/- 36.0 ng/ml respectively. The FSH content of bovine pituitary glands varied greatly between individuals, from 2 to 25 microgram/mg tissue. The inhibition curves of pituitary and serum FSH were parallel to that of the bovine FSH standard.


Effect of low calcium and low phosphorus diets on the intestinal absorption of phosphate in intact and parathyroidectomized pigs. The intestinal absorption of phosphate has been studied in conscious pigs, each prepared with a Thiry-Vella loop of jejunum. The feeding of diets low in either calcium or phosphorus caused a significant increase in the efficiency of absorption of phosphate from the solution used to perfuse the jejunal loop in both intact and parathyroidectomized (PTX) pigs. An intravenous infusion of parathyroid hormone (0.22 u. kg-1 h-1) into a PTX pig also enhanced the absorption of phosphate. The increase in the absorption of phosphate when the low phosphorus diet was fed was not caused by an increase in the concentration gradient of phosphate ions between the jejunal lumen and blood. It is concluded that the intestinal absorption of phosphate shows similar changes to those of calcium when diets low in calcium or phosphorus are fed and that parathyroid hormone, although capable of stimulating the absorption of phosphate, is not essential for this adaptation. These effects are probably brought about by changes in the renal production and mucosal uptake of 1,25-dihydroxycholecalciferol, the active metabolite of vitamin D3.


Photoperiodic regulation of copulatory behaviour in the male hamster. The influence of daylength on copulatory behaviour was assessed by comparing male hamsters exposed to long or short photoperiods (14 or 2 h light/24 h). Copulation declined in animals transferred from long to short days; 13 out of 14 hamsters ceased to ejaculate within 9 weeks and many no longer intromitted in tests with sexually receptive female hamsters. The decline in copulation in hamsters experiencing short days was associated with atrophy of the gonads and flank glands. Behavioural changes in these animals were far more gradual than those observed in hamsters after surgical castration. There was significantly more mating behaviour in tests during the subjective night of the hamsters than during their subjective day. Exogenous testosterone was more effective in restoring copulation in castrated hamsters exposed to long days than in castrated animals experiencing short days. This suggests that in short days the substrate for copulatory behaviour is relatively refractory to androgens. Photoperiodically mediated changes in behaviour, physiology and morphology may each contribute directly to the reproductive quiescence presumed to occur in the field during the short days of autumn and winter.


Macroscopic identification and steroidogenic function of atretic follicles in sheep. The degree of translucency, vascularization of the follicle wall and the integrity of the membrana granulosa, as seen under a stereoscopic microscope, were used to distinguish between non-atretic and atretic isolated follicles. Subsequent histological evaluation showed that both non-atretic and severely atretic follicles could be correctly identified with over 95% accuracy. The concentrations of steroids were measured in both follicular tissue and fluid. The total steroid content of large (3.1-6.0 mm diameter) non-atretic follicles in vivo (115 pmol/follicle) exceeded that of large atretic follicles (54 pmol) and also that of small (2.0-3.0 mm diameter) non-atretic and atretic follicles (6 pmol). Oestrogen accounted for 80%, testosterone 13% and progesterone 7% of the total steroid content in large non-atretic follicles, whereas testosterone accounted for 75% of the steroid content in the other three categories of follicles. A similar pattern is observed when the concentrations of steroids are expressed on the basis of follicular weight. Total oestrogen secretion, as measured by the output of steroid into the culture medium in 24 h, was 937 pmol for large non-atretic, 31 pmol for large atretic, 65 pmol for small non-atretic and 4 pmol for small atretic follicles. In terms of steroid production (pmol/mg tissue), the four follicular categories were equally efficient. However, the type of steroid produced depended on the category of follicle and corresponded to its steroid content.


Effects of oestrogen and/or pituitary grafts on nucleic acid synthesis in the mammary glands of lactating mice. The mammary gland synthesizes little DNA during lactation in mice. The effects of daily injections of oestradiol benzoate (OB) between days 9 and 11 of lactation, and/or grafting with three isologous anterior pituitary glands on day 1, on the growth of the litter and the development and function of mammary glands were studied on day 12 of lactation in C3H/He mice. The level of prolactin in the plasma of mice with pituitary grafts was raised, but mammary gland function was not affected. The synthesis and content of mammary gland RNA was depressed after injection of 0.5 microgram OB/day; at a dose of 10 microgram/day, OB also depressed litter growth and mammary DNA content, but increased the synthesis of DNA and the level of prolactin in the plasma. Pituitary grafting enhanced the effect of 10 microgram OB/day on DNA synthesis. These findings suggest that one of the causes of the low level of DNA synthesis in the mammary gland during lactation in mice is a low level of oestrogen in the circulation.


Labelling of the thyroid cell surface with 125I. The surface membrane proteins of cultured porcine thyroid cells have been labelled with 125I by the lactoperoxidase method. Evidence that the labelling was restricted to the cell surface was supported by the high viability of the cells in suspension, the high proportion of labelled material in the particulate fraction after homogenization and electron-microscopic autoradiographic studies. The labelled proteins were analysed by electrophoresis on polyacrylamide gels containing sodium dodecyl sulphate and this indicated the presence of ten major labelled protein bands with approximate molecular weights of 175 000, 155 000, 135 000, 88 000, 80 000, 52 300, 39 000, 30 000, 21 000 and 14 300. Comparison of the electrophoretic patterns obtained with cultured human and porcine thyroid cells suggested that there were species differences in the proportions of lower-molecular-weight proteins.


Concentrations of prostaglandins F2alpha and E2 in the endometrium throughout the human menstrual cycle, after the administration of clomiphene or an oestrogen-progestogen pill and in early pregnancy. The concentrations of prostaglandins F2alpha (PGF) and E2 (PGE) were measured by gas chromatography-mass spectrometry in endometrial tissue obtained from 45 normal women at various stages of the menstrual cycle. During the proliferative stages, the concentration of PGF in the endometrium was correlated with the concentration of oestradiol in the plasma. The concentration of PGF during the mid-secretory stage (mean, 2.047, range, 0.549-4.344 microgram/g fresh endometrial tissue) was significantly higher than the concentrations during the late proliferative and late secretory stages. The endometrial concentration of PGE did not show a cyclic variation. The concentrations of PGF and PGE in samples of endometrium collected after the administration of clomiphene were significantly lower than the concentrations observed in endometrial tissue obtained from normally menstruating women in the mid-proliferative period. The administration of an oestrogen-progestogen pill resulted in higher endometrial concentrations of PGE than were measured in the mid-secretory phase. The concentrations of PGF and PGE in decidual tissue (conceptual age 3-10 weeks) were lower than those measured at any stage of the normal menstrual cycle. During the human menstrual cycle, high levels of oestradiol and progesterone are related to high endometrial levels of PGF but not PGE. The presence of a conceptus apparently blocks the effect of high concentrations of ovarian steroids on the synthesis or catabolism of prostaglandins.


Effects of subcutaneous implants of progesterone on the induction and duration of sexual receptivity in ovariectomized rats. Ovariectomized rats, pre-implanted with elastomer capsules containing oestradiol, became sexually receptive after exposure to progesterone (implanted in elastomer capsules) for 4-6 h. Implantation of progesterone capsules facilitated receptivity in oestradiol-implanted rats independently of both previous exposure to progesterone implants and the presence of progesterone at the time of implantation. The duration of sexual receptivity in ovariectomized rats implanted with oestradiol and progesterone capsules was dependent upon the length of both the oestradiol and progesterone capsules, but the decline in sexual behaviour of receptive rats was independent of the continued presence of either oestradiol or progesterone. Repeated implantation of progesterone capsules at 6 hourly intervals prevented the decline of sexual receptivity.


A daily rhythm in the behavioural sensitivity of the female rat to oestradiol. Ovariectomized rats were implanted with oestradiol-filled elastomer capsules which were removed at various times after implantation. Sexual receptivity was tested after implantation of a progesterone-filled elastomer capsule 42 h after the onset of treatment with oestradiol. Exposure to oestradiol for about 32 h was required for induction of receptivity. Intact rats with regular 4 day oestrous cycles, and exposed to oestradiol-filled elastomer capsules for 6 h, showed sexual receptivity 24 h after the onset of oestradiol treatment. The behavioural effects of oestradiol in both ovariectomized and intact rats depended on when during the light-darkness (LD) cycle stimulation with oestradiol occurred; maximum effects were seen only if the oestradiol capsules were implanted at 16.00 h (4 h after lights off in the 12 h L : 12 h D cycle). The behavioural effect of progesterone implants, however, did not depend on the phase of the LD cycle. The LD-dependent rhythm in oestradiol sensitivity was eliminated by lesions in the suprachiasmatic nuclei of the hypothalamus.


Construction of equal-hue discriminability scales for the pigeon. Equal-hue discriminability steps for the pigeon are shown as tabular entries that can be summed or interpolated to produce sequences of equal discriminability steps of various step size. Equal-hue discriminability sequences can be constructed where the number of stimuli and spectral range are specified, or where an interval in one spectral region is to be equated to an interval in another spectral region.


Effects of alcohol on the storage and retrieval processes of heavy social drinkers. Two experiments investigated the effects of intoxication, expectation of intoxication, and state dependency on learning and relearning in male heavy social drinkers. In both studies, subjects participated in two daily sessions. On Day 1, intoxicated and sober subjects were presented with word lists for immediate free recall, followed by total free recall of all words. On Day 2, with or without a change in drug state, subjects were given a second total recall test, the same lists for immediate recall, and a third total recall test. In Experiment 1, 10 subjects served in each of four groups formed by crossing expectation with reception of alcohol on Day 1; all subjects were sober on Day 2. In Experiment 2, 12 subjects served in each of four groups formed by crossing drug state on Day 1 with drug state on Day 2 (sober-sober, sober-intoxicated, intoxicated-intoxicated, intoxicated-sober), and all expected alcohol. In both studies, intoxication produced a performance deficit, but retention loss on Day 2 was the same for change- and constant-state subjects. Expectation had no effect on performance. Results are discussed in terms of an alcohol-induced storage deficiency rather than a retrieval deficit.


Letter identification as a function of type of perceptual limitation and type of attribute. It is argued that the distribution of errors in letter identification depends on two factors: (a) whether the set of letters is defined by features that exist or do not exist or by dimensions that exist at some positive value, and (b) whether errors are produced by process limitation in which the letter patterns are distorted or by state limitation in which there is inadequate energy. A specific hypothesis tested was that error distributions reflect the attribute structure under both types of limitation if dimensions define the letter set, but only under a process limitation if features define the letter set. Under a state limitation, feature set errors are primarily produced by a loss of features, so that a letter with more features is called a letter with fewer features more often than conversely. An experiment completely validated the hypothesis under test. In addition, the relative discriminabilities of two dimensions defining a dimension set of letters was reversed from state to process limitation. Thus the attribute structure derived from error distributions is not invariant across types of perceptual limitation, nor are distances between letter pairs always symmetric.


Perception and masking of wholes and parts. These exerpiments show that the effects of masking on reports of target lines depend on the context in which the target lines appear. Subjects viewed brief presentations of target lines either alone or in drawings of three-dimensional objects, and each target display was preceded and followed by one of several different mask stimuli. There were two main findings: (a) A mask containing a haphazard array of lines interfered more with single lines than it did with lines in objects. (b) A mask containing drawings of the object displays interfered more with lines in objects than did either of two control masks containing relatively flat, less coherent patterns. In a control condition, the object mask interfered slightly less with reports of single lines than either of the control masks did. The discussion considers how the effects obtained here bear on models of the processing of wholistic stimuli and their component parts.


Geometric and semantic similarity in visual masking. Semantic and geometric or physical similarity were manipulated separately in a backward-masking situation. When the target was a word to be read aloud, formal similarity between the letters of target and mask facilitated target recognition, as did associative similarity. Masking a target word by its own anagram also facilitated whole word report. In contrast, formal similarity was inhibitory rather than facilitatory of report when the target was spelled letter-by-letter, rather than read whole. This was true even for the same target words whose whole report was facilitated by formal similarity. A model to account for this reversal in the broader context of the neural substrate of reading is advanced. It is proposed that letter and word processing are fundamentally different in that letters are recognized by hierarchical feature analysis while words are stored and recognized wholistically by diffuse and redundant networks. Implications of the results for the study of reading are discussed.


Age differences in peripheral perceptual processing: a monoptic backward masking investigation. Peripheral processes in vision were investigated in two experiments involving monoptic backward masking with random noise. For young and old subjects, peripheral processing time (represented by stimulus onset asynchrony of target and mask) was characterized as a power function of target energy. Although processing time for both age groups showed a similar rate of decline with increasing target energy, old subjects processed targets more slowly at all energy levels. Results were independent of education, sex, and criterion differences between young and old. Target duration was related to critical interstimulus interval, such that stimulus onset asynchrony between target and mask was approximately constant for a given target energy within each age group. Evidence suggests that peripheral processing begins with target onset and that processing time is best characterized by a power function relating stimulus onset asynchrony of target and mask to target energy.


Studies of visual synthesis: integration of fragments into forms. On each of a series of trials, subjects indicated whether two sequential visual forms were the same or different. The first form was presented on some trials as a whole within a square frame and on others in fragments--with its perimeter distributed over two or three frames. The subject was instructed to visualize the first form as a whole in any case, and study time (ST) for the form was recorded. The same/different reaction time (RT) for the second, test, form (always presented in one frame) was also recorded. Experiment 1 revealed that variables affecting ST had little effect on RT and indicated that subjects can process fragments of forms in parallel. Experiment 2 demonstrated that the representation encoded from fragments differed from one generated from long-term memory. Whereas the first experiments used wholes as test stimuli, in Experiments 3 and 4 on some trials, fragments were used. In Experiment 3, RT was facilitated when a test fragment coincided with an intact fragment of the first stimulus. This indicated that first stimuli were not encoded as complete wholes. In Experiment 4, irregular forms were used as stimuli, and the RT data departed from predictions of the parallel model. Taken as a whole, the results place constraints on the codes produced by constructive processes acting to synthesize fragments into wholes.


Picture processing during recognition.

Picture processing during recognition. This study investigated the processing of information during picture recognition. The subjects studied a single target picture and then were given a series of same-different recognition trials during which eye fixations were monitored. Distractors for the test trials were systematic transformations of the target picture. The results indicated that during recognition, information is encoded from a wide area and utilized both to direct additional eye fixations and to reach response decisions. The data also suggested that some of the processes involved in picture recognition are active simultaneously.


On the plasticity of visual-proprioceptive bias effects. Recent research has suggested that attentional factors play a role in determining the direction of intermodality adaptation. The present work explored the role of such factors in the visual/proprioceptive dominance, or bias, paradigm. In a preliminary experiment, an instructional approach was used and proved totally ineffective in shifting dominance. In Experiments 1 and 2, an active pointing approach was used, in which the subject was caused to concentrate on one modality or the other by having him localize a large number of unconflicted targets in that modality. This approach was successful in changing the normal dominance relation. Such an altered dominance relation may indeed be a necessary part of the shifting of normal adaptation patterns.


Application of signal detection theory to error detection in ballistic motor skills. Signal detection procedures were used to measure subjects' ability to detect errors in performance as they tried to hit a target in a ballistic motor task, since current methods were found to have several important shortcomings. Two tasks were used; one involved moving a slide 24.1 cm in 150 msec (temporal target), and the other involved rolling a ball at a visible target (spatial target). Subjects in both tasks were poor at detecting errors. Variability in the perceptual processes, measured by signal detection proceudres, was found to be about twice as much as that in the motor processes, measured by calculating variable error. This finding was inconsistent with a strictly closed-loop model of motor skills. Signal detection theory was also able to fill a gap in present theories of motor learning by explaining why some of the subjects in this experiment were able to detect errors better in the absence of knowledge of results.


Group therapy in family medicine: part 1. Group psychotherapy may often be the treatment of choice for patients whose somatic symptoms are a reflection of interpersonal difficulties which are not of sufficient magnitude to warrant referral to a mental health professional. This type of treatment can be offered in the context of family practice, with benefit to both patient and physician. The physician may function as co-therapist with a more experienced group leader; it is essential, also, that competent supervision be available. Such a group was established in a family practice center; it met for 20 weekly sessions. Patient improvement ranged from minimal to considerable; in addition, the frequency of visits to the Center for essentially non-medical reasons decreased considerably, with the greatest decrease in such visits occurring 6 to 15 months after termination of group treatment. This is the first part in a four-part series dealing with group therapy in family medicine.


Termination and transfer of patients in family practice. Once established, each physician-patient relationship faces termination. In this paper attention is given to various effects of that separation on both patient and family physician. Examples are given to show the importance of the management of termination in the ongoing care and health of the individual patient as well as for the emotional well-being of the family physician. This paper places its major focus upon the characteristics and coping behaviors of the patient and the physician. Suggestions are given to help reduce the transfer reaction and stress so that adjustment is more therapeutic.


Immunization status of patients in a residency-based family practice. Immunization studies in the United States have revealed that about 35 percent of children are not adequately immunized. This family practice residency desired to evaluate its immunization patterns, particularly since it was involved in the education of physicians. All of the charts of those patients from birth to 14 years of age were reviewed from July 1, 1974, when the residency accepted its first residents until April 1, 1977, when this evaluation was completed. The results revealed two patterns. First, the older the patient the less likely that his/her immunizations were up to date. Secondly, the older the patient the more likely that there were no immunization records. The evaluation resulted in the initiation of many improvements in patient and staff education which, it is hoped, will enable the desired goal of having the immunization up-to-date percentages raised to 95 percent within two years.


Instructor plays patient: an alternative to the case presentation method. This article describes a teaching technique which provides an alternative to the usual case presentation for teaching small groups. In this method the instructor plays a patient, an intern, and a laboratory technician, while a group of students play the role of physicians. Students have the opportunity to deal with a combination of medical and psychosocial problems, demonstrate their ability to interact with patients, and discover that in the total clinical process a correct diagnosis is only one step toward solving the patient's problem. This technique allows the instructor to teach material not found in standard texts, assess students' problem solving efforts, and observe student interaction. Other advantages of this method are that it involves a group of students in "live" interaction with a patient and various members of the healthcare team. The instructor can also observe the thought processes of students during their interaction around a case paralleling what one typically faces in a clinical setting.


Cooperation between an academic subspecialty department and a community-based family medicine department: a developmental model. While new, community-based family practice residency programs desperately need support from sister departments in academic centers, a variety of problems frequently prevents such cooperation. At the University of Wisconsin, Madison, the Department of Human Oncology, which is University Hospital-based, has worked to develop an appropriate educational program in oncology, together with and for the Department of Family Medicine and Practice, which is community-based. This paper, relating how and why these two departments have cooperated in this project, is presented to assist other departments in similar situations.


A new advanced studies program for faculty development in primary care. To meet the growing demand for more innovative teaching in primary care medicine and simultaneously to improve the overall quality of family practice, McGill University and The Montreal General Hospital, with the cooperation of the McGill School of Nursing, have inaugurated a faculty development center offering a program for advanced studies in primary care medicine and nursing. This program is offered to physicians and nurses who are already members of, or plan to join, a university faculty to teach primary care medicine. The program is diverse and interdisciplinary. Advanced courses are offered in teaching methods, investigative principles, biomedical communication, and management. In addition, each student Fellow participates in academic activities in fields of education, clinical practice, research, and community health care. All Fellows and faculty of the center rotate periodically to several satellite community-based teaching practice units in urban and rural areas of Quebec and to a region of northern New Brunswick. This activity enriches the medical manpower of the various regions, and the urgan physicians acquire an increased awareness of the particular problems and challenges of practicing medicine where full hospital and laboratory services are not always available.


Physicians' responses to patients: a study of factors involved in the office interview. The emotional responses of a physician are an important determinant for the outcome of each patient encounter. This study examines how physician, patient, and problem characteristics influence the emotions of the physician. In a family medical center, 559 office visits were recorded by 13 residents and 3 staff physicians on an encounter sheet. The emotions studied were anxiety, frustration, interest, and comfort in dealing with problem and note of feelings at the end of the encounter. The physicians reported more anxiety and frustration, less interest and comfort, and a less satisfactory note at the end of the interview when they were junior residents, when they were dealing with psychosocial problems, or when seeing lower social-class patients. Age and sex of patients and time of day of interview were not important in determining the physicians' responses. In a situation involving junior residents dealing with psychosocial problems, awareness of the anxiety and frustration present should enable the teacher of family medicine to become more effective.


Physician preference for criteria mapping in medical care evaluation. This study was designed to determine which of three quality assessment methods most validly identifies deficient care. Process criteria were developed to assess outpatient care for urinary tract infection using each of three methods: a limited "list" of seven criteria, an extensive "list" of 40 criteria, and a criteria map (CM) which uses branching logic to identify applicable criteria according to the specific needs of each case. Defining deficiency as compliance with less than 60 percent of criteria, the extensive list found all 66 cases deficient; the limited list, 27 (41.0 percent); and the CM system, 15 (22.7 percent). After excluding the extensive list because of its nondiscrimination, 23 discrepancies in rating remained between the limited list and the CM. Ten physicians unaware of the results reviewed all 23 cases. In 12 of these 23 cases, at least seven of the ten physicians preferred the rating of one method over another; the CM assessment was preferred in 11 of the 12 cases (P less than .01). Criteria maps, providing a patient-specific approach, offer a more valid assessment of medical care than either the extensive or limited list.


Medical evaluation for outpatient dental procedures. Family physicians are often consulted to evaluate medically a patient for various dental procedures. The majority of the referrals are for diseases of the cardiovascular system. General guidelines have been established at the University of Maryland Family Health Center for the evaluation of these patients. These guidelines pertain to the use of local anesthetics and prophylaxis for endocarditis, as well as to the evaluation of patients with cardiac disease, hypertension, pulmonary disease, endocrine disease, neurological disease, hepatic disease, pregnancy, and anticoagulant therapy.


The psychological effects of sudden infant death syndrome on surviving family members. It has been estimated that 7,000 to 10,000 deaths each year may be attributed to Sudden Infant Death Syndrome (SIDS). Although some clinicians have published their personal observations regarding the psychological effects of SIDS on surviving family members, a literature search failed to reveal more thorough studies of the aftermath of SIDS. This study reports the responses to a 13-page questionnaire of 32 parents who had experienced SIDS. Several major findings were observed: (1) SIDS is the most severe crisis these parents had ever experienced, taking their families an average of 8.3 months to regain the level of family organization they had held prior to the death, and taking individual parents an average of 15.9 months to regain the level of personal happiness they had held prior to the death; (2) a majority of parents suffered personal guilt, and numerous other psychological and/or physiological difficulties; (3) relationships with other family members were affected in various ways in the vast majority of cases; and (4) 60 percent of parents who had experienced SIDS in this particular population could not be found for participation in the study; all of these parents had, within 2 1/2 years of the death, moved from their home towns. Implications for crisis prevention and intervention are outlined.


Major side effects of antipsychotic drugs. Since the introduction of phenothiazines into clinical practice in 1952, over 250 million people have received these drugs for the treatment of psychotic states. In addition to the phenothiazines, five other classes of neuroleptic medications are now in use: butyrophenones, thioxanthenes, dihydroindolones, diphenylbutylpiperidines, and dibenzoxazepines. Besides their use in the treatment of psychosis, these drugs have been used in the treatment of anxiety, depression, nausea, alcoholic withdrawal, and pain, and are often administered in combination with other medications. Through the use of these drugs, many psychotic patients have been able to move back into the community, and the family physician is coming into contact with more patients on maintenance dosages of neuroleptics. He/she may wish to prescribe these drugs or may, in the treatment of a medical problem, need to prescribe other medication to an individual already receiving neuroleptics. It is important, therefore, for the family physician to be aware of the side effects of these drugs and of complications which can arise when neuroleptics are given in combination with other families of drugs.


Syndromes of vertebrobasilar insufficiency and their possible surgical treatment. Occlusive disease of the vertebrobasilar system may cause a variety of syndromes depending on the artery or arteries involved and the available collateral circulation. Based on the clinical picture and the angiographic findings, some of the patients may benefit from a gross reconstructive surgical procedure in the vertebral or carotid arteries. When these arteries are not correctable by gross surgical techniques, an occipital artery-posterior inferior cerebellular artery microanastomosis may also prove beneficial. An early clinical diagnosis of the brain-stem and occipital lobes ischemia and angiographic studies of the cerebral arteries are of prime importance and the key to the surgical management of these patient.


Major helminthic diseases of North America: a review. Disease producing worms are worldwide in distribution. The worms of significance in North America are the nematodes and the cestodes. Diagnosis is rarely made on clinical grounds alone because the clinical presentation of infection varies widely. Examination of stool for ova is usually the definitive diagnostic step. Follow-up stool examination several weeks after treatment is mandatory. The clinical findings pertaining to each type of worm and the recommended treatment are delineated.


Suicide assessment: a clinical model.

Suicide assessment: a clinical model. One of the most critical and ill-defined areas of the physican's practice is the evaluation of suicidal intent, particularly of the patient who has made no previous such attempts. Making the problem more complex is the attitude of the physician toward the self-destroyer, as determined by his/her upbringing and training. This article first confronts the issue of how the attitude of the physician can and does affect the potentially suicidal patient. Secondly, a conceptual model for a suicide evaluation is presented. This model has been designed for flexibility and practicality in order to help ensure that a complete evaluation can be done within the requirements and necessities of the practicing physician.


Group therapy in family medicine. Part 2: establishing the group. This paper is the second in a four-part series and describes some of the prerequisites necessary for the establishment of a therapy group in family medicine. In setting up a group, it is necessary to have group leadsers, a supervisor, patients, a suitable room, and time set aside for the purpose. Referral sources and criteria for referral are presented, as well as a description of patient characteristics. Factors leading to referral are discussed, and contraindications for referral considered.