Stimulating effect of neutral proteases on cells in vitro. Some results concerning the stimulatory effect of proteases on lymphocytes and other cells such as Hela cells and fibroblasts are evaluated. Preliminary evidence indicates that such stimulating factors are indeed released from cells during phagocytosis and can be inhibited by aprotinin. The potential role of such proteases in inflammation is discussed.


Generation of a vasoactive peptide by a neutral protease of human neutrophil leukocytes. Neutrophil leukocyte lysosomes contain a neutral protease capable of cleaving a peptide from kininogen. The protease has a molecular weight of about 27,000-28,000, as determined by SDS-disc gel electrophoresis and gel filtration in the presence of guanidine-HCl. Its S-value is 2.7 and the pI 10.0-11.8. Although homogeneous by some criteria (sucrose density gradient ultracentrifugation, gel filtration in Sephadex G-75, SDS-disc gel electrophoresis, immunoelectrophoresis), the protease is heterogeneous by other criteria (cation exchange chromatography, cationic disc gel electrophoresis and isoelectric focusing). The heterogeneity is attributable to charge isomerism. The enzyme is inhibited by DFP and a number of chloromethyl ketone inhibitors. It is also inhibited by the plasma protease inhibitors alpha1-antitrypsin, alpha2-macroglobulin and antithrombin III. The generated peptide has chemical and pharmacological properties similar to the undecapeptide methionyl-lysyl-bradykinin, but probably contains one or two additional amino acids.


Activity of anti-inflammatory drugs on an experimental model of osteoarthritis. Osteoarthritis was induced in the rabbit by a single intra-articular injection of 0.1 ml of a 1% solution of papain. Degeneration of the cartilage was studied 3 hours, 1, 3 and 8 days after the injection by transmission electron microscopy (TEM) and quantified by measuring the fixed charge density (FCD) and 35S incorporation into glycosaminoglycans. TEM observations of chondrocytes revealed a close correlation between the development of this experimental degenerative joint disease and human osteoarthritis. The administration of CH3-prednisolone (0.1 mg/kg on the 2nd and 5th days, i.a.), of indomethacin (1 mg/kg per day X 7, i.v.), and of catalase (50,000 IU/kg per day X 7, i.m.) modified the biochemical parameters measured 8 days after the papain injection. The corticoid potentiated the action of papain (fall in GAG content and synthesis). None of the non-steroid anti-inflammatory drugs modified the FCD. On the other hand, the increase of 35S incorporation was low after indomethacin and very high after acetylsalicylic acid. Catalase brought about an almost complete recovery of GAG content, together with an important increase in 35S incorporation. This arthropathy could be widely used in experimental pharmacology as a selective test and as a means of studying the mechanism of action of osteoarthritic drugs.


Ambivalent role of copper in inflammatory disorders. Soluble copper (Cu) preparations are both acute/chronic irritants and effective anti-inflammatory agents in rats. Copper is a prevalent component in several folk remedies for arthritis. Patients with rheumatoid arthritis and ankylosing spondylitis are reported to have higher-than-normal levels of serum copper, mainly associated with albumin. The anti-arthritis drug, D-penicillamine (Pn), efficiently strips Cu from some of its (pharmacologically inert) storage forms, e.g. Cu-albumin, Cu-polynucleotides yielding low M.W. Cu-Pn complexes, which show anti-inflammatory activity (ca. 5 X phenylbutazone) in rats irritated with carrageenan, oleyl alcohol, sodium urate and adjuvants. Under certain conditions Pn also blocks the amine-oxidase activity of caeruloplasmin, a circulating copper protein which is elevated in inflamed animals (an 'acute phase reactant'). Drugs, nutritional factors and the disease process may all possibly affect the movement of copper in vivo between inert reversible pharmacoactive reversible toxic forms.


Effect of some purified plasma proteins on collagen biosynthesis in vitro. The haptoglobin-hemoglobin complex activates the incorporation of 14C-proline into the collagen hydroxyproline of rat or human dermis slices incubated in vitro. The same complex decreases the incorporation of proline into the structural glycoproteins of the connective tissue. None of the other plasma proteins studied had any effect.


Studies of chemotaxis of lymphocytes.

Studies of chemotaxis of lymphocytes. Lymphoblasts migrate into filters towards chemoattractants in vitro. Human lymphoblasts maintained in continuous culture and mouse lymphoblasts from unsensitized lymph nodes show chemotactic responses and migrate towards the same chemotactic factors as neutrophils and macrophages, namely activated plasma, casein, denatured serum albumin, oxazolone. On the other hand, mouse lymphoblasts from oxazolone-sensitized lymph nodes show considerable random migration and chemokinesis but not chemotaxis. The migration of lymphoblasts to these agents appears not to be antigen-specific. These migratory properties of lymphoblasts are probably relevant to their migration into inflammatory sites in vivo.


The migration of lymphocytes across vascular endothelium. According to Morris and his colleagues the migration of lymphocytes from the blood into inflammatory sites is a morphologically similar process to the large scale migration of lymphocytes into the paracortex of lymph-nodes which occurs under normal conditions. Little is known of the nature of the selective interaction between lymphocytes and specialized endothelial cells although several investigators have tested the migratory properties of lymphocytes which have been treated in vitro with enzymes or lectins and injected i.v. Such results are difficult to interpret because decreased lymph-node localization may be secondary to increased localization elsewhere. To overcome these difficulties the mesenteric lymph-node chain of the rat was perfused at 37 degrees C for 30-60 minutes with rat serum at 0.33 ml/min. When labelled lymphocytes were added to the perfusate the uptake of cells into the lymph-nodes was 2.13 +/- 0.63% of the number of which had passed through the preparation and this fraction was independent of the concentration in the perfusate over a wide range. No release of lymphocytes from the isolated node into the perfusate could be detected. Neuraminidase treated lymphocytes localized in the perfused lymph-node at least as well as did untreated lymphocytes in contrast to their deficient lymph-node localization following i.v. injection into intact recipients as originally found by Gesner. Other evidence has been found that the primary effect of neuraminidase treatment is to increase hepatic localization. Large lymphocytes migrate into the isolated node more readily than do small lymphocytes which is also in contrast to results in intact recipients. The migration of lymphocytes treated with trypsin or concanavalin A has also been studied.


Opsonizing activities of IgG, IgM antibodies and the C3b inactivator-cleaved third component of complement in macrophage phagocytosis. Phagocytosis of SRBC by guinea-pig peritoneal macrophages is enhanced by opsonizing IgG antibody alone. IgM antibody requires the presence of bound C3. Treatment of C3b coated SRBC with purified C3b inactivator (yielding EAIgM C1423d) does not reduce attachment to, and phagocytosis by, peritoneal macrophages. This finding suggests the existence of a C3d receptor on peritoneal macrophages. EC43b intermediates which have been produced by removing IgM antibody by mercaptoethanol treatment and by subsequent removal of C1 and C2, are phagocytosed despite the absence of IgM antibody. Furthermore, treatment of EC43b with C3b inactivator does not change phagocytosis. Thus, IgM antibody does not appear to be a necessary prerequisite for the stimulation of phagocytosis, C3b or C3d alone being sufficient.


Contractile events during inflammation.

Contractile events during inflammation. Contractile events during wound healing. During granulation tissue contraction, fibroblasts develop characteristics typical of smooth muscle; (1) they contain an extensive cytoplasmic fibrillar system, (2) they show immunofluorescent labeling of anti-actin antibodies, (3) there are cell and cell to stroma attachments, (4) strips of granulation tissue, when tested pharmacologically in vitro, behave similarly to smooth muscle. These data support the view that under certain conditions, fibroblasts can differentiate into a cell type structurally and functionally similar to smooth muscle and this cell, the 'myofibroblast', plays an important role in connective tissue contraction. During epithelialization, epidermal cells develop an extensive cytoplasmic contractile apparatus which has morphological and immunological characteristics similar to those of myofibroblasts. Such apparatus disappears as soon as epithelialization is completed. It is proposed that such a contractile apparatus plays a role in cell motility enabeling individual cells to rearrange themselves in an appropriate pattern. In conclusion, significant amounts of contractile proteins may be synthetized by fibroblasts and epithelial cells during wound healing and may play an important role in this process.


Lymphocyte depletion in patients with rheumatoid arthritis. Sixteen patients with severe rheumatoid arthritis, marked inflammation of the synonvial membrane and high rheumatoid titer were cannulated by the thoracic duct for a period rangin between 82 up to 100 days. The patients being not under any medication during that time. Quantitative and qualitative analysis of the lymphocytes were performed, as well as responses to mitogens, rheumatoid factor, circulating antibodies and delayed hypersensitivity. By the 14th day nearly all the patients had a partial or almost complete remission of their disease. No complications were observed. These results will be discussed.


Inflammatory mechanisms in the newborn.

Inflammatory mechanisms in the newborn. Both the vascular and cellular aspects of inflammation were studied in rats aged from 6 hours to 2 months. The onset of a vascular permeability reaction was found to vary according to the age of rat and type of permeability agent injected. Induction of acute inflammations (turpentine pleurisy, 48/80 and dextran-induced foot oedema) in new born rats revealed a marked reduction of exudate/oedema formation compared with adult rats. These observations were related to a lack of histamine and 5-HT-mediated increased vascular permeability during the inflammatory reactions of newborn rats. Qualitative differences were observed between the acute inflammatory pleural cell exudates of newborn and adult rats after intra-pleural injection of dextran. In contrast to adults, polymorphs were observed to dominate the newborn reaction, and the peak accumulation of these cells was delayed. The mononuclear cells of 4-day lesions induced by sub-cutaneous implantation of glass coverslips showed a higher rate of mitosis in newborn animals, compared with adults. Ultrastructural studies of the mononuclear cells of peritoneal exudates induced by carrageenan indicated that those of newborn rats contained fewer lysosomes than adults. The Golgi apparatus of newborn mononuclear cells was observed to be poorly-developed compared with adult mononuclear cells.


The interaction of leukocytes and their hydrolases with bacteria in vitro and in vivo: the modification of the bactericidal and bacteriolytic reactions by cationic and anionic macromolecular substances and by anti-inflammatory agents. Acid hydrolases from extracts of human blood leucocytes lyse Staph.aureus, Staph.albus and Strep.faecalis in vitro. The leucocyte enzymes can be substituted by a lytic mixture which contains crude trypsin, lysolecithin, phospholipase C and lysozyme, which lyse other bacterial species, e.g. E.coli and Listeria which are resistant  to leucocyte enzymes. Bacteriolysis by the lytic agents is strongly inhibited by the anionic polyelectrolytes, heparin, chondroitin sulphate, DNA, dextran sulphate and other sulphated mucopolysaccharides, by the cationic materials, histone, protamine sulphate, leucocyte cationic proteins and polylysine. Other strong inhibitors are trypsan blue and congo red, the phospholipids phosphatidyl serine and ethanolamine, gold thiomalate, extracts of coffee and tea and the anti-inflammatory agents, ultracorten-H, and ultracortenol. Bacteriolysis is also strongly inhibited by normal human serum and by synovial fluids from patients with a variety of joint diseases. The inhibitors in these body fluids are associated with the globulin fractions. Since mixtures of anionic and cationic polyelectrolytes, at equimolar concentrations, failed to inhibit bacteriolysis by leucocyte enzymes, it is postulated that a delicate balance between positively and negatively charged inhibitors control the degradation of cell wall components of bacteria in inflamed areas. Such bacterial components, induce 'storage type' granulomas. The possible role played by polyelectrolytes in the control of the inflammatory process induced by leucocyte hydrolases will be discussed.


Platelets, acute inflammation and inflammatory mediators. The anti-inflammatory activity of aspirin-like drugs could derive, at least in part, by inhibiting synthesis and release of prostaglandins or rabbit aorta-contracting substance from platelets. Indeed, aggregation of platelets and the consequent release of inflammatory mediators has been frequently evoked as a factor in the development of the inflammatory reaction. The participation of platelets in acute inflammation was tested in three types of trauma in rats rendered thrombocytopenic with anti-platelet serum. Oedema in response to carrageenin, anti-platelet serum or passive cutaneous anaphylaxis was no different from the controls in thrombocytopenic rats.


Some effects of non-steroidal anti-inflammatory drugs on leucocyte migration. The anti-inflammatory properties of 7 non-steroidal drugs have been examined in two animal models and one in vitro system. The models used were (1) carrageenin-induced paw oedema in rats previously depleted of polymorphonuclear cells, (2) carrageenin-induced rat pleurisy and (3) migration of rat peritoneal leucocytes from glass capillary tubes in vitro. All of the drugs suppressed oedema formation in rats depleted of polymorphonuclear cells. None affected the migration of polymorphonuclear cells into the inflamed pleural cavity. Four drugs suppressed the migration of mononuclear cells in the latter model. Of these, only phenylbutazone and indomethacin suppressed the random migration of leucocytes in vitro. It was concluded that the suppression of mononuclear cell migration is not a general property of non-steroidal anti-inflammatory drugs.


Objective methods to assess the anti-inflammatory activity of antirheumatic compounds. A review is to be made of the methods currently being used in the assessment of anti-inflammatory compounds in man. Many of the current methods suffer from the disadvantage of being subjective or depend on various outside factors. We will review methods such as arthroscopy, histopathology, electron microscopy, joint scintigraphy and enzyme determinations in synovial fluid. Arthroscopy will be described in detail and its application to the course of the disease and the effect of anti-inflammatory drugs. Joint scintigraphy using radioactive technetium and indium will be described, which we find easy and reproducible. Current work using such parameters as skin temperature and enzyme content of synovial fluid will be described.


Clinical and biochemical assessment of anti-inflammatory substances. To assess the efficiency of anti-inflammatory drugs in human beings one has first to choose between acute and chronic inflammatory diseases and the length of the trial according to their pharmacological properties determined in animal. Further clinical criteria of efficiency will be selected on the basis of their measurable and objective characteristics. Biological criteria becomes more and more useful to judge efficiency of the drugs which possess no or very little effect on acute phase of inflammation: inflammatory blood tests, urinary excretion of hydroxyproline and immunological analysis such as quantitative determinations of immuno-globulins and rheumatoid factors and lymphocytic functional tests. Finally, in vivo isotopic and thermometric methods also give interesting information on acute or chronic anti-inflammatory properties of drugs.


Metabolic perturbation of the inflammatory cells. An activation of the oxidative metabolism of phagocytes is a regular concomitant of phagocytosis as well as of other functions of these cells such as exocytosis, chemotactic locomotion, and immune-adherence. Several other substances, some of which may be found in the inflammatory site, are also able to stimulate the oxidative metabolism of phagocytes, for example phospholipases, antileucocyte antibodies, endotoxins, fatty acids, surfactants and fragments of complement. This paper deals with, (1) the molecular events occurring within the plasma membrane that trigger the stimulation of the oxidative metabolism. An experimental model is presented that involves redistribution of ions across the plasma membrane of leucocytes as the trigger of the stimulated respiration and exocytosis; (2) the intracellular localization of the enzymatic system that is the effector of the metabolic response. A scheme is proposed for the mechanism of this enzymatic system which accounts for the production of highly reactive compounds such as hydrogen peroxide, superoxide anion radical and hydroxyl radical during the metabolic activation of phagocytes.


The effect of complement-sufficient antiserum against pig erythrocytes on pig articular tissues in organ culture. Pig cartilage devoid of marrow or synovium is virtually unaffected by rabbit complement-sufficient antiserum to pig erythrocytes (AS + C'), probably because normal cartilage matrix excludes immunoglobulins. When synovium or invading marrow is present, AS + C' causes depletion of the proteoglycan, with consequent entry of IgG into the cartilage, followed by the breakdown of collagen; the chondrocytes assume a fibroblastic form and their reaction with the antiserum is greatly reduced. If degradation of the matrix has not advanced too far, new matrix is regenerated when the explant is transferred to control medium. Experiments on the depletion of pure cartilage by exposure to retinol, indicate that articular cartilage produces enzymes capable of degrading protoglycan but not collagen. The work was done in collaboration with colleagues at the Strangeways Laboratory and in the Division of Immunology, Pathology Department, University of Cambridge.


An approach to the characterization of mononuclear phagocytes involved in pathological processes. Cells participating in an inflammatory response are derived from the bone marrow (i.e. granulocytes and monocytes) or lymphoid organes (i.e. T and B lymphocytes), or of mesenchymal origin (i.e. fibroblast, reticulum cells). The identification of these different kinds of cell in the inflammatory exudate is often difficult, because the morphological characteristics are not specific enough. For example, in the morphological description of pathological processes often terms such as round-cell infiltration and mononuclear cells are used, which is confusing. For the clear understanding of the course of an inflammatory reaction and the effect of anti-inflammatory drugs it is necessary, however, to define exactly the participating cells. Such an identification can be performed on the basis of morphological, cytochemical and immunological characteristics of the cells, together with their kinetic parameters. These characteristics have been established for murine mononuclear phagocytes. Recently these characteristics have also been studied in human promonocytes, monocytes and skin macrophages. The results show that human mononuclear phagocytes are in many respects similar to those of mice. On this basis an outline for the participation of mononuclear phagocytes in pathological processes (i.e. inflammatory processes, neoplastic processes, and storage disorders) has been made.


Relactation.

Relactation. Relactation means reestablishment of a milk supply and nursing after the cessation of nursing for a variable period. Induced nonpuerperal lactation means establishing a milk supply in a woman who has never been pregnant. When motivation and the breasts have both been carefully examined, preparation includes breast stimulation (by hand or pump), nipple toughening and sometimes hormonal preparation. Careful management of supplemental feedings is important.


A pathophysiologic approach to managing hyperlipemia. Hyperlipemia is one of several risk factors for premature ischemic vascular disease. It usually represents a primary, lifelong metabolic disorder and control requires changes in life-style. These include a modification of diet (commonly caloric, cholesterol and saturated fat restriction), elimination of smoking and hypertension and, frequently, drug therapy. Drugs can attack endogenous triglyceride overproduction, lipoprotein lipase deficiency or defective remnant uptake, and can decrease cholesterol production and accelerate cholesterol degradation.


Riboflavin deficiency in infants and children with heart disease. Thirty-one infants and children with cardiac disease were randomly selected to determine whether riboflavin deficiency is more prevalent among those with cardiac disease than among a group of comparable socioeconomic status without cardiac disease. Riboflavin studies were initiated since it is a representative member of the B complex and a specific and sensitive biochemical method is available to detect deficiency of this vitamin. The method involves the determination of the degree of saturation of erythrocyte glutathione reductase. Twenty-seven of the subjects had congenital heart disease and four had rheumatic heart disease. Eleven of the 31 had evidence of riboflavin deficiency, a significantly higher prevalence than among the group without cardiac disease. The deficiency existed among those with congenital and acquired cardiac disease. There was a greater tendency for the vitamin deficiency to occur among those with congestive heart failure. These studies indicate that nutritional deficiencies may be more prevalent among infants and children with cardiac disease than was previously thought.


Hypomagnesemia in relation to digoxin intoxication in children. Serum magnesium estimation was done in 19 children who had heart failure of varied etiology. Five of nine toxic patients and three of 10 nontoxic ones had magnesium deficiency (serum magnesium less than 1.5 mEq. per liter). Mean serum magnesium level was significantly lowered (P less than 0.01) in 19 children and it was further lowered in nine toxic patients (P less than 0.001) as well as in eight hypomagnesemic patients (P less than 0.001) than in healthy control subjects. Mean serum digoxin level in toxic patients was significantly higher than in nontoxic ones (P less than 0.05). In three cases magnesium sulfate was successfully used for the management of cardiac arrhythmias.


Myocardial infarction with and without laboratory documentation--one year prognosis. This retrospective study indicates that patients admitted to our CCU  with a history typical for myocardial infarction appear to have a comparable in-hospital mortality rate after 48 hours, a comparable one-year mortality rate, and a comparable incidence of recurrent myocardial infarction during the first year, whether or not they develop confirmatory ECG or serum enzyme changes. Patients with chest pain typical of myocardial infarction, who fail to develop confirmatory ECG or serum enzyme changes, would appear to require the same care and follow-up as do those patients admitted with chest pain who do develop such ECG or serum enzyme changes.


Correlation coefficients for electrocardiographic and constitutional variables. The influence of noncardiac factors such as constitutional variables, sex, and age upon the orthogonal electrocardiogram (ECG) and vectorcardiogram was investigated in 300 normal Japanese subjects. Constitutional variables included body height (HT), body weight (WT), deviation from ideal body weight (DIW), chest transverse diameter (TD), chest sagittal diameter (SD), SD/TD ratio, and chest circumference (CC). Among these constitutional variables, HT was found to be the most important determinant of ECG, followed by WT, TD, CC, SD, SD/TD ratio, and DIW, in that order. An increase in HT resulted in the augmentation of magnitudes of a large number of the QRS and ST-T parameters. WT showed almost the same trends as HT. Of the four measurements of the chest configuration under study, TD proved to be the most powerful determinant. An increase in TD led to a significant increase in QRS duration and to a superior and anterior shift of the maximal T vector. The remaining constitutional variables revealed far less significant correlation with ECG measurements than did HT and WT. Besides the constitutional variables, sex and age were also proved to be important ECG determinants. Advancing age had the effect of reducing the magnitude of many of the QRS and ST-T measurements. It is also of interest that a majority of the QRS and ST-T parameters were larger in male than in female patients. It should be emphasized from the results of this study that normal ECG criteria must be established for each ECG determinant.


Living with prosthetic heart valves. Subsequent noncardiac operations and the risk of thromboembolism or hemorrhage. A total of 111 survivors of prosthetic valve insertion were followed an average of 4 years to assess the risk of thromboembolism or hemorrhage. Non-cloth-covered ball and/or disc valve prostheses were used, and all patients received long-term anticoagulant therapy. During the follow-up period the patients with mitral or combined valve replacement suffered four times more thromboembolic episodes and had a poorer survival rate than the patients with isolated aortic valve replacement. The management of anticoagulation and the complications resulting from 44 subsequent noncardiac operations were analyzed. Anticoagulation was discontinued before 25 noncardiac operations in patients with isolated aortic valve prostheses and there were no perioperative thromboemboli. Ten operations were performed on patients with mitral or combined valve prostheses with cessation of anticoagulation prior to surgery and there were two deaths due to perioperative thromboemboli. Unanticipated hemorrhage was encountered in four of nine patients in whom anticoagulation was maintained during surgery. Cessation of anticoagulation for 3 to 5 days appears safe in patients with aortic prostheses who require subsequent noncardiac operations. The incidence of thromboembolism in patients after mitral or combined valve replacement is high and constitutes a major risk whether or not a subsequent operation is required.


Clinical use and toxicity of intravenous lidocaine. A report from the Boston Collaborative Drug Surveillance Program. The clinical use and toxicity of intravenous lidocaine were surveyed in 750 hospitalized medical patients who received the drug for the treatment of cardiac arrhythmias. The majority of these patients were older than 60 years and most had diagnoses of cardiovascular disease. Lidocaine therapy was started within 48 hours of admission in 77 per cent of cases. Adverse reactions to lidocaine were reported in 6.3 per cent of patients, but only one in four reactions was considered life-threatening. Central nervous system disturbances and cardiovascular complications were the most common untoward effects. All but two adverse reactions occurred within the first 5 days of treatment. Adverse reactions were more common in elderly individuals, in those who died, and in those with long hospitalizations. Diagnoses of acute myocardial infarction or congestive heart failure, and low body weight were also associated with a higher frequency of unwanted effects. Serious adverse reactions to intravenous lidocaine were relatively uncommon. Patients with serious underlying disease or with diminished hepatic clearance of lidocaine appear to be predisposed to adverse effects from this drug.


Correlations between the spread of ventricular activation and map patterns of measured and difference maps. Three kinds of torso surface isopotential maps (measured, simulated, and difference maps) were delineated at every 1.5 (or 3) msec. during the QRS duration from the 85 unipolar lead ECG's led from the surface of a cylindrical torso model filled with perfusate and containing a canine heart undergoing Langendorff's perfusion. These three maps were compared as to the propagation process of ventricular activation obtained from the same heart and close correlations were found between the spread of ventricular activation and the map patterns of measured and difference maps. The difference map mainly reflected the proximity potential at each instant of ventricular activation in QRS duration and, when used in combination with the measured map, it was useful to estimate the spread of ventricular activation, especially around the stage of epicardial breakthrough of the activation front. It was confirmed that the interpretation of the difference map expressed in the present paper would not be misleading even if applied to a difference map obtained in a human torso model experiment.


Myocardial oxygen availability and cardiac failure in hemorrhagic shock. The relationships between left ventricular function and myocardial O2 availability and metabolism were studied in cats with hemorrhagic shock (AP=30 mm. Hg) with the use of a right heart bypass preparation. Aortic flow and heart rate were held constant. Oxygen-carrying capacity was reduced by diluting donor blood with an equal volume of 5 per cent glucose in saline. Oxygen availability was estimated as the product of arterial O2 content and coronary blood flow. All shock animals showed a progressive metabolic acidemia with time, and a fall in coronary flow concomitantly. Four control animals (AP=75 mm. Hg) as well as two shock animals with high arterial oxygen content and hematocrit showed no significant changes in myocardial O2 metabolism or performance over a period of 90 minutes. Nine shock animals with reduced hematocrit demonstrated a progressive reduction in ventricular function, myocardial O2 metabolism, and O2 availability. As O2 availability fell below 10 ml. per minute per 100 Gm. of heart weight, cardiac failure uniformly appeared and was accompanied by a reduction in O2 extraction and consumption. The correlation between left ventricular dP/dt max and O2 availability was highly significant (r = 0.75, p less than 0.01) in shock animals but not in controls. Thus a close relationship between myocardial O2 metabolism and function during the course of hemorrhagic shock has been demonstrated. Reduced myocardial O2 availability is directly linked with the appearance of cardiac failure.


The effect of isosorbide dinitrate following experimental coronary occlusion. The results of the present investigation indicate that ISDN infusion following experimental coronary occlusion in anesthetized dogs (1) lowers systemic, cardiac, and pulmonary blood pressures; (2) decreases systemic resistance; (3) has no significant effect on cardiac output, heart rate, and stroke volume; (4) decreases serum CPK levels; and (5) has little effect on blood biochemical parameters. These results suggest that ISDN may have a minimal effect on the ischemic heart by means of a slight decrease in peripheral vascular resistance and systemic blood pressure.


Differing mechanisms for ventricular vulnerability during coronary artery occlusion and release. The time course and mechanism of vulnerability to ventricular fibrillation (VF) a 10-minute occlusion of the left anterior descending coronary artery and following its release were studied in 48 dogs. VF threshold was determined by inducing a sequence of three extrasystoles (sequential R/T pulsing). Within 1 minute of occlusion, the fibrillation current decreased to the level required for eliciting a propagated diastolic response. This state of enhanced vulnerability lasted for approximately 6 minutes, after which the VF threshold returned to preocclusion values. The vulnerability changes upon reperfusion, by comparison, occurred within seconds of release and persisted only transiently. Three minutes of occlusion was the minimal time which resulted in a reduction in VF threshold after release. Alpha and beta-adrenergic blockade with phentolamine and propranolol, respectively, prevented the decrease in VF threshold during occlusion but were without effect upon threshold changes during coronary artery release. Lidocaine failed to alter the pattern of vulnerability. It is concluded that adrenergic mechanisms play a key role in the increased susceptibility to VF associated with acute myocardial ischemia, whereas the changes in VF threshold following reperfusion may be due to washout products of cellular ischemia. These findings support the view that protection against VF during coronary artery occlusion and release may require different antiarrhythmic measures.


Clinical evaluation of aortic and mitral valve prostheses. The clinical follow-up for a large number of patients with aortic and mitral valve prostheses is now the responsibility of the general internist and cardiologist, particularly those physicians who recommended operation. Proper follow-up of patients with prosthetic heart valves can be performed only if the physician is aware of the "natural history" of the patient following valve replacement as well as of the common complications associated with cardiac valve prostheses. This article discusses the hemodynamic changes which follow cardiac valve replacement, complications associated with valve replacement (congestive heart failure, suture disruption, "ball variance," thromboembolism, hemolysis, cardiomyopathy, etc.) and simple clinical means of detecting these complications. Some special techniques which may be useful in diagnosing complications of prosthetic cardiac valve malfunction are described. It is emphasized that the physician should not consider the patient "cured" once he has undergone cardiac valve replacement, but rather should consider him to be the subject of meticulous long-term medical care.


Fetal and neonatal rat pancreas in organ culture: age-related effects of corticosterone on the acinar cell component. Fetal rat pancreas (ages 16 to 22 days postcoitum) and neonatal pancreas (4 days postnatal) were grown in organ culture for four days. The medium consisted of chick embryo extract and rooster serum either with or without the addition of corticosterone (3 X 10(-5) M). Acinar cell differentiation was assessed using quantitative light microscopic linear scanning of tissue sections and enzymatic analysis of amylase in the culture media and in the explants. In the younger fetal tissue of 16 and 18 days postcoitum exocrine differentiation continued in vitro. The effect of corticosterone was an enhancement of the degree of in vitro differentiation. Even with corticosterone, however, the degree of differentiation in vitro was less than that observed during a similar period in vivo. In differentiated pancreas (20- and 22-day fetal neonatal) the acinar pancreas degenerated under control conditions and a selective growth of the endocrine pancreas was observed. The addition of corticosterone to the media resulted in a maintenance of the differentiated state of the acini except in 22-day fetal tissue in which the acini were not preserved. The differences between these results and the work of other investigators and the possible in vivo role of adrenocorticosteroids in exocrine pancreatic differentiation is discussed.


Topographical changes along the neural fold associated with neurulation in the hamster and mouse. The topography of the ectoderm was examined by scanning electron microscopy during neurulation in hamster and mouse embryos. Stages from the appearance of the neural folds to closure of the posterior neuropore were studied. Progressive development of a zone of altered cellular morphology was observed along the crests of the neural folds. This zone evolved from an abrupt transition between surface and neural regions of the ectoderm to a narrow band of flattened cells which exhibited numerous membranous "ruffles" in the mouse, or blebs and presumably degenerating cells in the hamster, immediately prior to contact between the folds. These alterations were more prominent along the anterior than the posterior portions of the folds. Contact of the folds occurred first between the flattened cells with subsequent union of the surface cells. Stages of neural crest cell formation was observed subjacent to the zone of alterations in histological sections. It is suggested that the observed surface alterations may reflect changes in the membrane properties of the altered cells which are correlated with both neural crest formation and initial adhesion between the folds.


Type II pulmonary epithelial cells of the newborn opossum lung. The air chambers of the newborn opossum are lined by a respiratory epithelium which appears similar to that lining alveoli of other species. The type II pulmonary epithelial cell is cuboidal in shape, shows apical microvilli, several Golgi complexes, lipid droplets, and numerous cytosomes. The cytosomes contain osmiophilic lamellae and are similar in appearance to whorls of osmiophilic material lying free within the alveolar lumina and on the surface of the respiratory lining epithelium. In the newborn opossum lung, examination of the air chambers with the scanning electron microscope permits the observation of several type II pulmonary epithelial cells in a single field. The potential use of the air chamber of the newborn opossum as an experimental model is suggested.


Cations in the rat pars distalis ultrastructural localization. Pituitary glands of female Sprague Dawley rats were fixed using the potassium pyroantimonate-osmium tetroxide technique by immersion or vascular perfusion. Both fixation procedures resulted in similar patterns of cation localization visualized as electron-dense precipitate within cells of the pars distalis. Nuclei were prominent sites of localization. Cytoplasmic precipitate occurred in association with the endoplasmic reticulum, typically within the cisternal spaces, and also was localized within the mitochondrial matrix and cristae, as well as Golgi membranes, small Golgi-associated vesicles, and multivesicular bodies. Immature secretory granules often contained precipitate between the core material of the granule and the enclosing smooth membrane. Frequently small antimonate-containing vesicles bordered the immature secretory granules. Precipitate was variable in secretory granules of more mature appearance although precipitate was apparent occasionally just within a granule's enclosing membrane. Granules closest to the plasma membrane often contained increased amounts of precipitate and small vesicles containing precipitate were observed fusing with them. Instances of granule release by emiocytosis often revealed a clustering of precipitate behind the core material away from the emiocytotic stoma, as well as at the stoma, and frequently an increased electron density of filamentous material radiating from the granules' enclosing membranes or from the adjacent plasma membrane. Exposure of section material to the chelating agents EGTA and EDTA indicate that calcium is the primary cation localized within the cytoplasm of these secretory cells. These findings are consistent with a role for calcium as a facilitator in the processes of transport and release of secretory granules.


The paraganglia, a persisting endocrine system in man. The paraganglia have been traced in surgical samples of para-aortic and pelvic retroperitoneal tissues using the formal-dehyde-induced fluorescence method for catecholamines. Clusters of catecholamine-storing cells were found in all (12) patients studied. Microspectrofluorometric recordings showed high amounts of catecholamine in the well-vascularized cell groups. A large proportion of the paraganglia, which are most prominent during the fetal period, also persist during postnatal life.


Postnatal development of acinar cells in rat submandibular gland as revealed by electron microscopic staining for carbohydrates. The postnatal differentiation of acinar cells in rat submandibular gland was studied by staining with periodic acid-thiosemicarbazide-silver proteinate to identify carbohydrate-containing macromolecules in the electron microscope. This method revealed glycogen particles and internal substructure in the secretory granules of developing acinar cells. On the basis of morphologic and histochemical criteria three phases of acinar cell development were defined. In the pro-acinar phase, during the first week after birth, pro-acinar cells and terminal tubular cells were the main components of the terminal tubules in the rudimentary gland. The secretory granules of the pro-acinar cells contained speckled or rod-like substructures which stained intensively for carbohydrates and were digested by proteolytic enzymes. During the second to third week after birth, which is the immature-acinar-cell phase, thread-like substructures were seen in the secretory granules. These structures, which were not digested by proteolytic enzymes, disappeared gradually. The acinar cells of 4-week-old or older rats displayed no particular substructure in the secretion granules and represented the final, mature phase of development.


Extra- and intra-cranial blood supply to brains of dog and cat. The dog and cat are useful experimental animals, and information regarding their cerebrovascular patterns and the source of blood supplying their brains is important. Blood vessels to brains and heads of cats and dogs were injected with various contrast media. Extracranial and intracranial arteries were studied grossly and in cleared sections. The proximal part of the internal carotid artery is small in the dog and non-functional in the cat. The largest single source of arterial blood supplying the brains of these species comes from the maxillary artery over an anastomotic ramus leading to an internal rete mirabile enmeshed in the cavernous sinus. The distal segment of the internal carotid arises from this anastomosis. The brain-stem of both animals is supplied by C1 branches of the vertebral arteries, and in the dog an occipital ramus makes a large contribution to it. In addition to an internal rete mirabile, the cat possesses a large external rete mirabile surrounding the maxillary artery and giving rise to all branches in the area. It is functionally equivalent to the ramus anastomoticus in the dog. Arterial patterns over brains of Carnivora are similar. They resemble those of lower mammals more than those of primates. Extensive extracranial arterial anastomoses located in the orbit, retia mirabilia and neck musculature are significant and make it difficult to render the brains ischemic.


An electron microscopic study on the type I pneumocyte in the cat: differentiation. This investigation describes the differentiation of the type I pneumocyte from undifferentiated pulmonary epithelium. Cells lining subpleural alveolar septa were photographed from serial sections with the electron microscope and a three dimensional representation of each cell was obtained by transferring the contours of the cell membranes from micrographs to transparent plastic sheets which were then spaced to scale and stacked. The results of this study indicate that: (1) the only reliable criterion for differentiating between type I and type II cells is the commencement of attenuation of the type I cell; (2) differentiation of the type I cell occurs via the formation of one or more cytoplasmic attenuations that eventually fuse peripherally, thereby surrounding the unattenuated cell soma; (3) with respect to individual cells, blood-air barriers tend to form in distal areas of the attenuating cytoplasm before proximal areas; (4) both type I and type II pneumocytes retain certain characteristics that reveal their common origin.


Scanning microscopy of pituitary vascular casts. Vascular casts of the pituitary-median eminence complex from seventeen adult female rabbits were examined with the scanning electron microscope. The results of this study confirm the presence of a single capillary bed common to the entire neurohypophysis. Arterial supply to the rabbit pituitary is only to the neurohypophysis. A direct supply to adenohypophysis was not found. Within the median eminence there are an external and internal capillary plexus. The internal capillary plexus is directed toward the infundibular recess of the third ventricle. It does not receive a direct arterial supply but derives its blood supply from the external plexus before draining to the adenohypophysis. Vessels of the posterior median eminence are confluent with vessels of the infundibular stem. On the basis of these studies, it is proposed that the entire neurohypophysis, not simply the median eminence, serves as the final common pathway to the glandular pituitary. It is also proposed that in the median eminence, vessels are organized to deliver blood containing hypothalamic releasing and inhibiting hormones as well as posterior lobe neural hormones (antidiuretic hormone and oxytocin) to the ventricular surface for subsequent transport to cerebrospinal fluid and distribution to the brain.


Prenatal development of the eye in the golden hamster. Prenatal development of the eye in golden hamsters is described at the light microscopic level as twelve periods based on salient morphological features. Period one includes shallow and deepened optic sulci in the cephalic neural plate and closing prosencephalon. Period two shows V-shaped prosencephalic evaginations, and Period three, bulbous vesicles. Contact of the retinal disc and lens placode at Period four precedes presumptive retinal invagination and lens pit formation during Period five. During Period six an open lens vesicle, precociously expanded dorsal and lateral optic cup regions and widespread optic fissure margins are evident. A spherical lens lumen, deepened optic cup and narrow optic fissure characterize Period seven. At Period eight posterior lens fibers are elongated, the optic cup is expanded ventrally, and optic fissure margins are juxtaposed or fusing. By Period nine the lens lumen is nearly or completely occluded, the optic fissure is essentially fused and axonal fibers are exiting from the globe. During Period ten corneal components are associated, axonal processes extend to the diencephalon, and lid folds cover more than half of the cornea. By Period eleven eyelids are fused. Anteriorly the pigmented epithelium is thickened and densely pigmented; outer and inner neuroblastic retinal layers are clearly distinguishable. Period twelve is marked by conspicuous anterior folds of pigmented epithelium; a relatively anuclear zone virtually separates outer and inner neuroblastic layers of the retina.


Proximal tubule tendrils: fact or artefact. Tendrils have been reported to radiate from luminal surfaces of proximal tubules in rat kidneys by Andrews and Porter ('74) using scanning microscopy, but they were not seen by Bulger et al. ('74). In this study, the perfusion procedure of Andrews and Porter was re-investigated. Tendrils were found only in regions which had characteristics of poor fixation. They were especially prominent if the perfusion pressure was purposely allowed to fall and subsequently increased to re-expand the tubules. The tendrils could then be seen in all portions of the proximal convoluted tubule and not exclusively in the initial portion as previously reported.


Osteopetrosis in the IA rat cured by spleen cells from a normal littermate. Osteopetrosis in ia rats has been cured by combining whole-body irradiation with infusion of spleen cells from a normal littermate. The cure, first seen radiographically and histologically as areas of resorption below the epiphyseal plates of long bones, progressed to produce marrow cavities of normal proportions. Treatment of ia rats with either radiation or normal spleen cells alone was not successful. Furthermore, osteopetrosis was induced in normal littermates when radiation was combined with infusion of mutant (ia) spleen cells. These results show that spleen cells contribute to the resorbing capacity of the skeleton and suggest that osteoclasts might have a hematogenous origin.


Ultrastructure of the thyroid in dwarf mice. The thyroid gland of Snell's dwarf mice consists of small follicles with flattened epithelium, partly differentiated cords and undifferentiated masses. Many adipocytes are found. The ultimobranchial cysts are well developed. Parafollicular cells are normal. In the partly organized cords, microfollicular cells are some small follicles limited by two or three cells are seen. The presence of these structures led us to think that they represent the first stages of normal folliculogenesis, described as the fusion of two adjacent unicellular microfollicles. Their further growth is the result of the coalescing of small adjacent follicles or of cellular multiplication. The presence of undifferentiated masses and partly differentiated cords, in dwarf mice, seems due to a developmental arrest rather than to aberrant development. This disorder of organogenesis is ascribed mainly to a lack of pituitary growth hormone.


Age-related changes in the intact and sympathetically denervated gerbil pineal gland. The pineal gland of four-month-old gerbils contains numerous calcareous deposits (corpora arenacea or concretions). Also, the tissue appears vacuolated due to the presence of a number of large rounded spaces. The deposits are usually associated with or lying within these "vacuoles". By eight months of age, the number of both the corpora arenacea and the "vacuoles" are increased over those present in the pineals of four-month-old gerbils. Bilateral superior cervical ganglionectomy at one month of age prevents the formation of both the concretions and "vacuoles". The cells in the sympathetically denervated pineal glands are smaller than those in pineal glands of animals that possess intact superior cervical ganglia.


Descending inputs to caudal cochlear nucleus in cats: a horseradish peroxidase (HRP) study. After HRP injections into the octopus cell area of the cat cochlear nucleus, only periolivary neurons of the superior olivary complex (SOC) reacted. Elongate neurons in the lateral periolivary nuclei (ipsilateral to the injection) and multipolar neurons in ventromedial periolivary regions (contralateral to the injection) contained granules. No neurons in the main SOC nuclei or higher auditory nuclei reacted, despite a wide range of HRP concentrations. Thus, neurons from the SOC to the octopus cell area of the cochlear nucleus seem to be entirely periolivary and not entirely equivalent to neurons providing collaterals to the olivocochlear bundle.


Selection of operating wavelength-pair for two-wavelength microspectrophotometry. The two-wave length method is the microspectrophotometric method of choice for thick specimens. Its accuracy is dependent on the accuracy of selection of the operating wavelenght-pair. The "slope zero test", offered as a check upon the accuracy of this selection (Garcia and Iorio, '66) is shown to be invalid by analysis of experimental data, by computer model and by mathematical derivation. A means of checking the accuracy of selection of the operating wavelength-pair via scanning measurements is suggested. A new formulation of the two-wavelength method, permitting use of different operating wavelength-pairs, is also given.


Zinc turnover in mice during pregnancy, lactation, and growth. The turnover of 65Zn was examined in mice. During pregnancy, lactation, and growth, the loss of 65Zn from the body was twice as great as that observed in mature, nonpregnant animals. The results of this study emphasize the need for consideration of zinc losses in the formulation of the minimum daily requirement for zinc in humans and other mammalian species.


Protein quality of two varieties of high-lysine maize fed alone and with black beans or milk to normal and depleted weanling rats. Opaque-2 corn, modified high-lysine corn with vitreous endosperm, and common corn were compared in rat growth studies. Corn alone supplied 8.6% protein; and at both 8.6 and 11.4% protein, corn furnished 60% of the protein and either milk or black beans supplied 40%. The modified corn, which also was high in both lysine and tryptophan, did not differ significantly from Opaque-2 corn in its ability to stimulate growth and nitrogen deposition in both well-nourished and partially protein-depleted rats; and both were significantly superior to common corn when fed alone. Milk was a more effective supplement for corn than black beans, especially when high-lysine varieties were fed, whereas beans exerted a similar effect on all varieties of corn. The depleted rats deposited more nitrogen as a result of eating most diets than did well nourished rats. Implications of these findings for preschool children are discussed.


Treatment of obesity by acupuncture.

Treatment of obesity by acupuncture. Twenty-four subjects ranging from 5 to 33% above ideal weight were weighted during a 3-week control period, and then treated for the successive 9 weeks with acupuncture therapy given in three different loci, and in random order for 3-week periods. The acupuncture needles were placed in unilateral loci used by oriental acupuncturists for weight loss, in the same loci bilaterally, and in unilateral loci not used by acupuncturists for weight loss. No undesirable effects were noted. No treatment was associated with weight reduction significant at the 0.05 confidence level. A study involving guinea pigs was run parallel with the above clinical protocol and also demonstrated no effect of ear acupuncture on weight loss.


An estimation of mineral losses through arm sweat of preadolescent children. Balance studies were conducted to determine the effects of three levels of nitrogen intake on the loss of nitrogen through sweat in preadolescent boys and girls. During the studies, the losses of calcium, iron, magnesium, manganese, potassium, sodium, and zinc were determined in the arm sweat of the subjects. Sweat from the forearm was collected in a  polyethylene bag for 1 hr on three different occasions. Using the concentrations of nitrogen in the arm bag and in the whole body collection and the concentration of minerals in the arm bag, the total body loss of minerals were estimated. Losses of minerals through sweat, expressed as a percentage of intake, ranged from 0.12 to 1.10%. Under conditions of these studies, sweat losses of the essential minerals were not a significant factor in estimating total losses.


Age differences in vitamin B6 status of 617 men. The effect of age on vitamin B6 metabolism was studied in 617 community-dwelling subjects, ages 18 to 90. These are, for the most part, clinically healthy, educated men whose intake of nutrients is not limited by economic factors. Plasma pyridoxal phosphate (PLP) was used as the primary criterion of vitamin B6 status. About one-third of the subjects were taking supplementary vitamins on their own initiative. The amount of pyridoxine-HCl varied from 0.1 to 105 mg/day. The average plasma PLP of the men not taking a supplement (N = 414) was 12.3 +/-0.3 ng/ml, with 25% of the values below 7.5 ng/ml and 7% below 5 ng/ml. There was a statistically significant decrease in plasma PLP with age of 0.9 ng/ml per decade. For those taking a supplement, the average plasma PLP was 20.5 +/- 1.0 ng/ml, with only 8% of the values below 7.5 ng/ml and none below 5 ng/ml. Glutamic-oxaloacetic transaminase activity in plasma (PGOT) and erythrocytes (EGOT) was determined on all subjects. The ratio of EGOT with in vitro stimulation by PLP to EGOT actual (alpha-EGOT) was also studied. These studies provide the most extensive normative data on vitamin B6 status available on men in the adult years of life.


Vitamin D resistance in magnesium deficiency. Four patients with gastrointestinal disorders, and one patient with chronic alcoholism presented with both hypocalcemia and hypomagnesemia. Pharmacological doses of either ergocalciferol or dihydrotachysterol did not correct the hypocalcemia except in one patient who had a minimal rise in serum calcium. Parathormone levels were high in three patients and exogenous parathormone given to the fourth subject failed to elicit a rise in serum calcium, implying impairment of the calcemic response to parathormone. Magnesium repletion simultaneously corrected the hypomagnesemia and hypocalcemia. Balance data suggested that the rise in serum calcium was in part, at least, due to increased mobilization of minerals from bone. While the mechanism remains speculative, it appears that magnesium facilitates the release of calcium from bone in the presence of adequate amounts of vitamin D and parathormone.


Food iron absorption in human subjects. III. Comparison of the effect of animal proteins on nonheme iron absorption. The ability of various animal proteins to enhance the absorption of dietary nonheme iron was evaluated by performing multiple radioiron absorption measurements in 70 volunteer subjects. Protein equivalent substitutions of nine animal foods were made in two basic test meals. The first was a standard meal of high iron availability (mean absorption, 8.3%) containing beef muscle as the animal protein. The second was a semisynthetic meal of low iron availability (mean absorption, 1.4%) containing ovalbumin as the protein source. Two categories of animal protein were defined. Substitution of beef, lamb, pork, liver, fish, and chicken for the egg ovalbumin in the sannisynthetic meal resulted in a significant, 2-fold to 4-fold increase in iron absorption whereas no increase was observed with milk, cheese, or egg. Reciprocal findings were obtained when these foods were substituted for the beef contained in the standard meal. All sources of animal proteins are not equivalent in their effect on nonheme iron absorption.


Behavior therapy for weight control: long-term results of two programs with nutritionists as therapists. Two studies examined the effectiveness of behavior modification techniques utilizing nutritionists as therapists. In study 1, therapist training on the use of behavioral techniques was done by self-study. Fifty-seven females at least 10% overweight (X = 20%, SD = +/- 14.0) were placed in one of three 10-week treatment conditions; 1) a multiple technique behavioral program, 2) food exchange treatment, and 3) delay treatment control. End of treatment weight losses averaged 3.0, 2.2, and 0.1 kg, respectively. When treated, the delay group lost 2.7 kg. One year post-treatment the behavior therapy subjects were maintaining approximately 70% of the weight lost during treatment; the other two groups maintained less than half of their achieved loss. In study 2, 54 female subjects 15 to 60% overweight (X = 39%, SD = +/- 12.3) underwent one of two 14-week behavioral weight control treatments. One was the same behavioral treatment used in study 1; the other was built around the concept of stimulus control. Both treatments included nutrition information. The therapists were trained by a behavioral psychologist. Weight loss at the end of treatment was 8.4 and 7.3 kg for the stimulus control and multiple technique conditions, respectively. There was a significant difference in favor of the stimulus control treatment at 3 and 6 months posttreatment. At the 18-month follow-up the stimulus control subjects were maintaining 80% of achieved weight loss; the other group only 50%.


Beneficial effects of a high carbohydrate, high fiber diet on hyperglycemic diabetic men. High carbohydrate diets rich in dietary fiber were fed to 13 hyperglycemic diabetic men; five men required 15 to 28 units of insulin per day, five men required sulfonylureas, and three men required 40 to 55 units of insulin. All 13 men were fed weight maintaining American Diabetic Association diets containing 43% of calories as carbohydrate for 1 week and then were fed 75% carbohydrate diets with 15 g of crude dietary fiber for approximately 2 weeks. After 2 weeks on the 75% carbohydrate diet, sulfonylureas were discontinued in all five men, insulin was discontinued in four men and decreased from 28 to 15 units in 1 man from the group requiring less than 30 units per day. Fasting plasma glucose values were significantly lower (P less than 0.001) in all 10 men. However, insulin requirements and fasting plasma glucose values were not changed in the three men requiring 40 to 55 units of insulin. Fasting serum cholesterol values were significantly (P less than 0.001) lower and mean fasting serum triglyceride values were 15% lower on the high carbohydrate diet than on the American Diabetic Association diet in these 13 men. Thus, a high carbohydrate diet with generous amounts of dietary fiber may be the treatment of choice of diabetic patients requiring sulfonylureas or less than 30 units of insulin per day.


Preliminary clinical and anthropometric findings from the first Health and Nutrition Examination Survey, USA, 1971-1972. Eight percent of Negroes between the ages of 45 to 59 had hepatomegaly. Tongue signs and absent knee and ankle jerks were more prevalent in Negroes ages 45 to 74; they also had lower urinary excretion of thiamine and riboflavin than Whites. Bowed legs and knock knees were more frequent in Negroes ages 1 to 17 and Negro women 18 to 44. Prevalence of bleeding, swollen gums was highest in Negroes ages 45 to 59. Both grade I and II goiter were more prevalent in Negroes at all ages except men 18 to 59. Chvostek's sign indicating possible calcium deficiency was more frequent in Negroes at all ages with two exceptions. Major anthropometric findings will also be presented.


Developing a rural mental health service from a base in an academic clinical psychology program. The development of a Community Mental Health Service for a multiethnic rural area by an academic psychology department clinical program was carried out for the purpose of providing relevant training for grauate students through realistic service functions. The population served was largely lower socioeconomic, and the available resources very limited. The Community Psychology course was used to assist the planning and negotiating for the clinic. Services provided during the first year are summarized. The graduate students' not-too-happy view of the program is presented. The problems and issues raised by this experience, for both training and service, are discussed.


Involuntary hospitalization: the social construction of danger. Petitions for 50 consecutive patients committed involuntarily to a western state hospital were examined to determine whether statements supporting such commitment reflected explicit or residual rule-breaking behaviors. In 46 cases, involuntary hospitalization was based upon residual rule breaking. Additionally, in only 5 cases did the petitioner perceive the patient as dangerous, while in all 50 cases, the two examining physicians certified him to be such. Results are discussed in the context of the psychiatrist's personality characteristics and his role as a social control agent.


Effects of a defendent's previous psychiatric hospitalization on the judgments of simulated jurors. Simulated jurors were asked to render judgements in a case involving either a violent or a nonviolent armed robbery. The defendent either did or did not have a stated history or previous psychiatric hospitalization. The former mental patient received fewer guilty verdicts than did the nonhospitalized defendant in the nonviolent robbery condition, while no difference existed in the violent robbery condition. It was predicted that, relative to the nonhospitalized defendant, subjects would be more punitive when the former mental patient was judged guilty of the violent crime than when he was judged guilty of the nonviolent robbery. This prediction was confirmed only for male subjects. The data suggest that while males responded in terms of conventional stereotypes about the mentally ill, females did not. Results are discussed in terms of attribution of responsibility and fear reactions toward the mentally ill.


The influence of supervision and facilitative conditions on the psychotherapeutic effectiveness of nonprofessional and professional therapists. Sixty poorly adjusted, fifth- and sixth-grade males were randomly assigned to experimental groups seen by professional, supervised nonprofessional, and unsupervised nonprofessional therapists, as well as to a no-treatment control. The therapists saw their clients 10 times. Excerpts from the 3rd and 7th sessions were rated by trained raters for facilitative conditions. Change in clients was studied through instruments which assessed change from three vantage points--the child's, his teacher's and his therapist's. Individual as well as group data demonstrated significant superiority of supervised nonprofessionals over unsupervised nonprofessionals. Changes in clients treated by professionals tended to cluster close to those treated by supervised nonprofessionals. Several significantly negative correlations between facilitative conditions and criteria of psychotherapeutic change were discovered.


The buddy system: mediator--target locus of control and behavioral outcome. The relative locus of control of mediator--target pairs was investigated within a contingency management program. As predicted, less improvement in target behaviors occurred for pairs in which the target scored lower in externality than the mediator. In addition, the greater externality of the mediator relative to the assigned target, the less improvement in target behavior (r=-.67). In contrast, improvement in target behavior bore no relationship with the locus of control scores of either mediators or targets correlated separately, nor with the differences between mediator--target locus of control scores within pairs in which the target scored equal to or higher in externality than the mediator.


Predicting resource utilization in a comprehensive center: an evaluation of three alternative methods. Three alternative methods for obtaining anticipated resource utilization information for comprehensive mental health centers are proposed. The methods differ on two dimensions, sample selection and statistical technique. Using an admission cohort rather than a discharge cohort and eliminating patients who terminated treatment against medical advice permitted a refined prediction. Although no significant differences were found between the chi-square and multiple-regression techniques, the latter resulted in a substantially greater degree of flexibility.


Attitudes and feelings of criminal justice personnel toward the mentally ill. The present study compared the attitudes and feelings of law-enforcement, corrections, parole and probation personnel, and college students toward mental illness. Modified versions of the Criminally Insane Scale (Khanna, Pratt, & Gardiner, 1962) and Attitudes Toward Mental Illness Scale (Cohen & Struening, 1962) were used in assessing these attitudes. Law-enforcement and corrections personnel tended to believe many of the stereotypic causes of mental illness, while the college students based their views on more current thinking. In addition, law-enforcement and corrections personnel indicated greater fear of the criminally insane than the other two groups. Possible causes and ramifications of these differences are discussed.


A test for abnormal hemoglobins in umbilical cord blood. This article describes a rapid, simple, and inexpensive method for testing the cord blood of infants for the common hemoglobinopathies by electrophoresis using cellulose polyacetate strips. In a study of 7,500 umbilical cord blood specimens, 11% were found to contain an abnormal hemoglobin. While the importance of evaluating cord blood in a screening program for hemoglobinopathies is evident, the procedure must be accurate, verified, and followed by proper counseling.


Determination of nicotine concentrations in human milk. A total of 34 samples of human milk from 15 donors was analyzed for nicotine content, using a new method of sample preparation and subsequent quantification by gas chromatography. Nicotine was not found in the six samples of milk from non-smokers. The 28 samples from smokers contained an average of 91 parts per billion (ppb) nicotine (ranging from less than 20 ppb to 512 ppb). While no adverse effects to the infant due to nicotine in human milk have been documented, this method of analysis will allow systematic monitoring of nicotine concentrations in the milk of lactating women. These results should not be used to deter breast-feeding; rather, they offer another reason for mothers to reduce or cease smoking.


Determinants of the neonatal mortality.

Determinants of the neonatal mortality. A recent sharp decline in the neonatal mortality in our medical center prompted a critical analysis of viral statistics of the newborn service during the years 1966 through 1973. The mean neonatal mortality for the entire period was 15.4 per 1,000 live births, and 11.0 in the period 1972 through 1973. The annual neonatal mortalities bore a direct relationship to the annual incidences of infants with birth weights of 1,500 gm or less. The reduction in the proportion of infants in the latter weight group during 1972 through 1973 accounted for three quarters of the improvement in the neonatal mortality as compared to that of the previous years. One quarter of the improvement could be attributable to a decrease in mortality that occurred only in infants in the latter weight group during the same period.


Hyperpyrexia in children. Eight-year emergency room experience. In an eight-year period, 100 children were seen in a pediatric emergency room with a temperature of 41.1 C or higher, hereafter called hyperpyrexia. There was a significantly greater occurrence of bacterial meningitis in the hyperpyrexia group, compared to a group of 264 children with temperatures of 40.5 to 41.0 C. Bacteremia and seizures were also more common. Children with hyperpyrexia require careful evaluation, especially of the central nervous system.


Hyperuricemia in the hemolytic-uremic syndrome. Elevated serum uric acid concentrations were found in 18 children with hemolytic-uremic syndrome. The highest recorded level in each patient ranged from 10 to 29 mg/100 ml, and nine patients had concentrations of greater than 20 mg/100 ml. During a 53-hour period of peritoneal dialysis, 5.5 gm of uric acid was removed from one infant. Although acute renal failure was probably the major factor, erythrocyte destruction and hyperlacticacidemia may also have been important in the pathogenesis of the hyperuricemia.


Cytogenetic variants in holoprosencephaly. Report of a case and review of the literature. A new infant with classical features of holoprosencephaly and multiple extracranial malformations was found to have abnormal karyotype: 47, XX, + 13. Although trisomy D has been reported in a few cases, our case is the first, to our knowledge, in which positive identification of trisomy 13 was made by banding technique in cebocephaly.


Anaerobic meningitis and bacteremia caused by Fusobacterium species. In the two cases of anaerobic meningitis and bacteremia caused by Fusobacterium species described, upper respiratory tract infection preceded the onset of meningitis. Isolation of the causative organism and appropriate antibiotic therapy resulted in cures in both patients. Although extremely rare, these organisms should be considered as possible causative agents in meningitis when routine cultures are negative, and appropriate anaerobic culture techniques should be employed, especially when sinus, otitic, or mastoid symptoms precede or accompany the onset of meningitis. Susceptibility testing of these organisms is necessary to ensure proper therapy because of the resistance of some anaerobes to antibiotics commonly employed in meningitis. In this regard, metronidazole, which provides excellent cerebrospinal fluid levels, may prove to be an effective agent in anaerobic infections of the central nervous system.


Bacteroides fragilis ventriculitis and meningitis. Report of two cases. Two patients with Bacteroides fragilis meningitis and ventriculitis were treated. In one infant infection developed at 2 1/2 months of age as a result of an infected ventriculoatrial shunt inserted to treat hydrocephalus. In the second patient ventriculitis and meningitis developed at 20 days of age, while he was convalescing from surgery for gastric perforation that had occurred at 5 days of age. Both patients were treated with ampicillin, chloramphenicol, and clindamycin, which sterilized the blood and lumbar cerebrospinal fluid but not the ventricular cerebrospinal fluid. The first patient received no further antibiotic therapy and died at 5 months of age. Metronidazole therapy sterilized the ventricular fluid of the second patient, who survived the infection. Ventriculitis should be suspected in patients with B fragilis meningitis. A brain scan should be done to detect signs of ventriculitis or brain abscess. Metronidazole may be the drug of choice in patients with B fragilis ventriculitis or meningitis who do not respond to chloramphenicol.


The effect of wheat bran upon bile salt metabolism and upon the lipid composition of bile in gallstone patients. When raw wheat bran was added to the diet of six subjects for 4-6 weeks, chenodeoxycholate (CDC) synthesis increased from 0.46 +/- 0.12 to 0.57 +/- 0.17 mmol/day pool increased from 1.72 +/- 0.47 to 2.19 +/- 0.74 mmol (rho less than 0.05). Deoxycholate (DC) pool size diminished from 1.20 +/- 0.29 to 0.80 +/- 0.16 mmol, but cholate synthesis and pool size were unaffected. Overall, the size of the bile salt pool did not change. In spite of this, when 10 patients with probable cholesterol gallstones took bran supplements for 4-6 weeks, their gallbladder bile aspirated from the duodenum became less saturated with cholesterol. The molar percentage of cholesterol fell from 10.1 +/- 3.1% to 8.6 +/- 2.7% (rho less than 0.01), and the saturation index of bile fell from 1.49 +/- 0.40 to 1.29 +/- 0.38 (rho less than 0.005). Bran probably operates primarily on the colon, reducing the formation or absorption of the bacterial metabolite DC, a substance which impairs CDC synthesis.


Electron microscopic study of the repair of aspirin-induced gastric erosions. To investigate the fine-structural events occurring during repair of aspirin-induced erosions, rats were killed at times from 2 to 48 hrs after a single aspirin dose. Erosions were rapidly covered by a line of flattened cells with little evidence of cytoplasmic specialization. Some of these cells lining early erosions contained a few mucous granules, but none showed features to suggest a derivation from parietal or zymogen cells. By 24-48 hr, considerable differentiation had accurred in the repairing epithelium, with many cells containing mucous granules and with "young" parietal cells being abundant. Some epithelial cells contained erythrocyte fragments, thus demonstrating phagocytic capability. It is concluded that dedifferentiation of surviving gastric epithelial cells occurs rapidly in response to aspirin injury and that the mucoid cells, rather than specialized glandular cells, are the likely source of the initial repair epithelium.


The inhibition of lysozyme by bile acids. The effect of bile acids on the bacteriolytic activity of lysozyme towards Micrococcus lysodeikticus was studied in vitro. All bile acids tested inhibited lysozyme activity. Conjugated bile acids were better inhibitors than their unconjugated homologs and sulfation resulted in still stronger inhibition. A study of UV-difference spectra of bile acid-lysozyme mixtures suggests that bile acids distort the tertiary structure of the enzyme. The inhibition-concentration curves of micelle-forming bile acids were bell-shaped, and peak inhibition was apparently related to the critical micellar concentration. The inhibition-concentration curves of sulfated bile acids, which do not form micelles, are characterized by a plateau of maximal inhibition. A mechanism of lysozyme activation by bile acid micelles is proposed. Our results illustrate the complex interactions between antibacterial compounds in the gut. As bile acids are known to inhibit lipase activity as well, these studies suggest that bile acids may have an important influence on intestinal enzyme activity in general.


Pulmonary function studies before and after jejunoileal bypass surgery. Nine out of twelve obese patients (75%) demonstrated diminished minute ventilation volume (MVV) prior to jejunoileal bypass surgery. Seven out of the nine patients (78%) showed improvement in the MVV as weight reduction ensued following surgery. Other parameters, including arterial blood gases, did not change after weight loss. Weight reduction as a result of jejunoileal bypass surgery brings about an improvement in pulmonary function.


Effect of alterations of blood glucose levels on gastric acid secretion, plasma gastrin, and plasma osmolality in man. In 16 experiments on 4 healthy subjects, the effect of procedures which alter blood glucose, ie, infusion of 0.2 units/kg body wt/hr insulin and/or 0.66 g/kg body wt/hr glucose, on gastric acid secretion, plasma gastrin, and plasma osmolality was studied, Each subject underwent four different experimental procedures, each lasting 4 hr. All had in common one basal hour and the infusion of insulin in the second hour, but differed in the time of infusion of glucose or isotonic saline. To control for order effects, the four procedures were applied to the subjects in the form of a Latin square. Acid output was measured continuously be means of intragastric titration and a telemetering capsule; blood glucose, plasma gastrin, and plasma osmolaity were determined in 15-min intervals. An inverse relationship between blood glucose and acid output was found: Low glucose levels were associated with high rates of acid secretion, high glucose levels with low acid secretion. No noticeable changes occurred in either plasma gastrin or plasma osmolality. These results reveal a determining influence of blood glucose levels on acid secretion. On the basis of earlier work in animals it is concluded that this influence is exerted via the reciprocal activities of the hypothalamic satiety and feeding centers.


Penumopericardium due to transdiaphragmatic perforation of a gastric ulcer. A 65-year-old man presented with cardiogenic shock and massive pneumopericardium. A gastropericardial fistula due to transdiaphragmatic penetration of a large fundal ulcer was documented radiographically and confirmed at autopsy. Previously recorded cases of penumopericardium complicating gastric ulcers or other diseases of the digestive tract are briefly reviewed.


X-chromosome inactivation in human liver: confirmation of X-linkage of ornithine transcarbamylase. Histochemical assay for ornithine transcarbamylase (OTC) activity in fixed frozen hepatic sections from a woman heterozygous for OTC deficiency revealed two populations of hepatocytes: those with normal activity and those with no activity. This observation, in conjunction with data from previous family studies, confirms the hypothesis that the gene for OTC is X-linked. It also provides the first cytologic demonstration of cellular mosaicism for a liver-specific cell product.


Low levels of beta hexosaminidase A in healthy individuals with apparent deficiency of this enzyme. Appreciable beta hexosaminidase A (hex A) activity has been detected in cultured skin fibroblasts and melanoma tissue from healthy individuals previously reported as having deficiency of hex A activity indistinguishable from that of patients with Tay-Sachs disease (TSD). Identification and quantitation of hex A, amounting to 3.5%-6.9% of total beta hexosaminidase activity, has been obtained by cellulose acetate gel electrophoresis, DEAE-cellulose ion-exchange chromatography, radial immunodiffusion, and radioimmunoassay. Previous family studies suggested that these individuals may be compound heterozygotes for the common mutant TSD gene and a rare (allelic) mutant gene. Thus, the postulated rate mutant gene appears to code for the expression of low amounts of hex A. Heterozygotes for the rare mutant may be indistinguishable from heterozygotes for the common TSD mutant. However, direct visualization and quantitation of hex A by the methods described may prevent false-positive prenatal diagnosis of TSD in fetuses having the incomplete hex A deficiency of the type described in the four healthy individuals.


Assignment of the structural gene for human beta glucuronidase to chromosome 7 and tetrameric association of subunits in the enzyme molecule. The structural locus for human beta glucuronidase is assigned to chromosome 7, a localization based upon concordant segregation of the expression of the human enzyme and the presence of human chromosome 7 in somatic cell hybrid clones derived independently from fusions of different human and mouse cells. Hybrid clones containing only human chromosome 7 are included in this study. Electrophoresis of beta glucuronidase also has revealed that human beta glucuronidase has a tetrametric structure.


The human gene for beta glucuronidase is on chromosome 7. Inconsistent assignments of the human gene for beta glucuronidase (GUS) to chromosomes 7 and 9 have previously been reported. In this study, we have correlated the expression of human GUS in 22 primary Chinese hamster/human hybrid lines with quantitative cytogenetic analysis. Eight hybrids were positive for human GUS as manifested by a five-band pattern on electrophoresis. All of them contained a human chromosome 7 in 34% or more of cells, and seven of them had not retained chromosome 9. One hybrid with only 6% of metaphases possessing a chromosome 7 had no detectable human GUS activity. Human GUS expression was absent in 10 hybrid clones containing chromosome 9 but not 7 and in control fibroblasts from a patient with GUS deficiency. These results support the assignment of presumably the structural gene for beta glucuronidase to chromosome 7.


Hb Grady and alpha thalassemia: a contribution to the problem of the number of Hb alpha structural loci in man. Hematological evaluation and data from chain synthesis analyses in six members of the family with two members having Hb Grady (i.e., and alpha chain variant with elongated chains due to an insertion of three amino acid residues [1]) indicate the presence of multiple nonallelic Hb alpha structural loci in the single Hb Grady heterozygote. The data support the earlier stated hypothesis that the Hb alpha Grady locus resulted from a crossing over between chromosomes of two tandemly repeated Hb alpha loci. The presence of an alpha thalassemia condition in one of the two Hb Grady heterozygotes increases the relative production of the alpha Grady chain by a factor of two.


Amylase polymorphism: studies of sera and duodenal aspirates in normal individuals and in cystic fibrosis. Prior genetic studies of the human pancreatic amylase (Amy2) locus have been directed principally to the electrophoretic analysis of serum and urine, on the assumption that these fluids receive negligible contributions from the salivary (Amy 1) locus. In support of that assumption was the observation that the isozyme bands were lacking in patients with cystic fibrosis and in a postpancreatectomy patient. We have examined the sera of 97 patients having cystic fibrosis and find normal levels of serum amylase. On electrophoresis, three-quarters of the cystic fibrosis patients have a pattern (F-pattern) not observed in normal sera. The pattern is characterized by the absence of Pa 1. Comparative electrophoresis and mixing experiments indicate that the F-pattern is of salivary origin and is unmasked in cystic fibrosis by the absence of a pancreatic contribution. The normal serum pattern is considered to be an admixture of salivary and pancreatic amylase. On the assumption that duodenal fluids might more closely reflect the pancreatic (Amy 2) locus, electrophoretic studies were performed on 148 normal individuals and 37 individuals with cystic fibrosis. Electrophoretic phenotypes in duodenal aspirates are more complex than previously reported in studies of urine and serum; presumably because of the higher concentrations of amylase in the aspirates. Comparative electrophoresis and mixing experiments indicate that the phenotypes observed in duodenal aspirates also reflect admixture of pancreatic and salivary amylase. This recognition of pancreatic and salivary admixture in sera fortunately does not alter our prior understanding of the genetics of the Amy 2 polymorphism. The extensive studies which led to the delineation of the Amy 2 polymorphism were essentially based on the presence or absence of a variant band which proves now to be outside the zone of admixture.


HLA antigens in Japanese populations.

HLA antigens in Japanese populations. HLA antigens in 841 healthy, unrelated Japanese from nine widely separated geographic localities were studied. The five most common antigens observed in order of decreasing frequency were for the HLA-A locus: HLA-A9, A2, A10, AW32 and A11; and for the HLA-B locus: HLA-'B5' (= HLA-B5+B17), BW40, B12, B14 and B8. The allelic frequency of undetected antigens of the HLA-A locus was .14-.37, and that of the HLA-B locus, .32-.67, indicating that there were serological difficulties in typing for Japanese antigens using antisera from Caucasians. Marked gene frequency clines were observed for HLA-A9 and HLA-A2 from south (Okinawa) to north (Nagoya). Two haplotypes, HLA-A9, B5 and HLA-A10, BW40 were shown to be in linkage disequilibrium in four of the nine subpopulations.


Congenital cleft lip and fluctuating dermatoglyphic asymmetry. Fluctuating asymmetry for the palmar atd angle was studied in propositi born with CL(P) and their normal parents and sibs. The propositi with a family history of this congenital malformation were significantly different from the controls for this type of asymmetry. The propositi without a family history and the normal parents and sibs of both types of propositi were similar to the controls. The difference between the two types of propositi suggests that in some individuals a genetic mechanism may account for CL(P) and increased fluctuating asymmetry for this dermatoglyphic trait.


Medication maintenance of mentally ill patients by a pharmacist in a community setting. The use of a community pharmacy as a facility for medication maintenance services usually provided by a mental health center was evaluated. The project pharmacist was affiliated with the community mental health center, the community pharmacy facility was borrowed for purposes of this study. Records and prepackaged medication were transported by the pharmacy-clinic. Medication histories were taken and maintained by the pharmacist. Problems such as medication noncompliance, drug side effects, drug interactions and minor alterations in the patients mental status were handled by the pharmacist. Telephone consultations with a psychiatrist were also available. Twenty-two patients were involved in the study over an eight-month period. The evaluation consisted of a patient acceptance questionnaire and a retrospective chart review analyzing the clinical response of patients. Data suggest that selected stabilized psychiatric patients can be safely maintained in the community pharmacy. A carefully structured program and a pharmacist with special competencies are felt to be prerequisites for this type of service.


Phlebitis associated with the intravenous use of cephalothin and cephapirin. The frequency and severity of phlebitis associated with cephalothin and cephapirin was compared in a double-blind study in 82 surgical patients with 149 different infusion sites. After treatment with the coded drug products, the status of each patient's veins was evaluated daily by i.v. therapists. Cephapirin was associated with a slightly lower rate of phlebitis, but the difference was not significant. For both drugs, the duration of therapy did not appear to have an effect on the rate of phlebitis. Scalp vein needles were associated with a lower rate of phlebitis than plastic catheters, but the difference was not significant.


Portland Retail Druggists Association vs Abbott Laboratories et al, part 2. The ruling of the U.S. Supreme Court in Abbot Laboratories et al vs Portland Retail Druggists Association is discussed as it relates to hospital pharmacy purchasing practices. Topics covered include: the applicability of the Robinson-Patman Act and its Section 13C exemption to various types of hospitals; definitions of "former patient" and "reasonable quantity"; and recordkeeping requirements. It is concluded that the Portland case should not deter expansion or innovation in health care delivery and ambulatory care services but must be accounted for in implementing new programs.


Developing Drug Reports for the Pharmacy and Therapeutics Committee. The role of a drug information center in working with a pharmacy and therapeutics committee is discussed. In order to add a drug to the formulary, physicians must complete a special form which asks for justification for the addition. In preparing a report for the pharmacy and therapeutics committee, the drug information pharmacist evaluates the request as it relates to: (1) the effectiveness of the drug in the stated anticipated uses, and (2) studies comparing the requested drug with similar drugs already in the formulary. Use of the form permits the pharmacist to focus on the specific claims made by the physician who is requesting the formulary addition.


Centralized drug list production in a multihospital system. A project established to maintain individualized station drug lists for a nationwide network of hospitals and clinics is described. The structure of the drug lists and procedures used in their production are described in detail. A central location controls keypunching, data processing and printing. The pharmacist at each station is responsible for drug list maintenance. Each staton's formulary is stored on digital magnetic tape. Sharing development costs by all stations and using a single printing facility resulted in a cost-effective system.


Plasma and erythrocyte kinetic considerations in lithium therapy. Developments in the analysis and pharmacokinetics of lithium, and the role of the pharmacist in the management of lithium therapy in affective disorders, are described. Research showing that lithium levels in the brain may be better predicted from erythrocyte lithium levels than plasma levels is reviewed. Also reviewed is lithium kinetics in affective disorders. The pharmacist (1) determines relevant aspects of the patient's condition, (2) develops an appropriate blood sampling schedule, (3) initiates and maintains a serial lithium erythrocyte and plasma patient profile, (4) evaluates erythrocyte and serum levels in relation to established criteria to provide a basis for differential diagnosis of the patient, and (5) individualizes lithium dosage and schedules. Four cases are used to illustrate this approach. It is suggested that outpatient mental health clinics would be likely settings for the further development of this clinical role.


Quantitative determination of benzyl benzoate in benzyl benzoate lotion NF. The development of a simple, shorter and more accurate method than the NF method for the determination of benzyl benzoate in Benzyl Benzoate Lotion NF is discussed. Hydrolyzed benzyl benzoate was measured spectrophotometrically. Interference from other ingredients of the lotion, oleic acid and triethanolamine was almost negligible. The proposed method was completed in approximately 15 minutes, as opposed to the two hours required by the NF procedure.


Activated charcoal-carboxymethylcellulose gel formulation as an antidotal agent for orally ingested aspirin. The in vivo effect on aspirin absorption of a potentially more palatable form of activated charcoal was compared to that of a simple aqueous slurry of activated charcoal. The experimental formulation consisted of 20.0 g of activated charcoal, 2.25 g of carboxymethylcellulose (CMC) and 42.8 ml of water; it was tested with and without chocolate syrup as a flavoring agent added just prior to administration. Six subjects were treated in crossover fashion following an aspirin dose of 972 mg. Total urinary excretion of salicylate was measured over 48 hours. Although all three treatments appeared to be effective in reducing the rate and extent of aspirin absorption, the slurry was significantly more effective in reducing the total amount absorbed than the charcoal-CMC gel with chocolate syrup. The slight difference in effectiveness between the gel formulation with and without the chocolate syrup was not significant.


An undergraduate medical technology clinical elective program. The University of Washington Medical Technology Program initiated an 11-week elective clinical curriculum in 1973. Sixty-six students have completed either a clinical specialist, research, or generalist program in various Seattle hospitals or in selected hospitals in rural Washington and in Alaska. Results indicate that there is a major correlation between elective choices and subsequent employment. In addition, this elective curriculum is not jeopardizing student performance on the national certification examination.


Long-term stability of a cyanmethemoglobin reference standard. A comparative analysis performed in late 1974 revealed that a cyanmethemoglobin secondary standard prepared by the laboratory at the Michigan Department of Public Health in 1966 was still suitable for use in hemoglobin assays. These results would suggest that the current one-year expiration time used for commercial standards could be extended considerably.


Special-class EMR children mainstreamed: a study of an aptitude (learning potential) X treatment interaction. Academic, personal, and social growth were compared for special-class EMR children who were assigned randomly to regular grades or retained in special classes at three time intervals: prior to the assignment, 2 month after assignment, and at the conclusion of the school year. There were no significant differences between the two groups prior to or 2 months after reintegration. After one school year, the reintegrated children were more internally controlled, had more positive attitudes toward school, and were more reflective in their behavior. The hypothesis that the more able students by the learning potential criterion would benefit more from regular than special-class placement was supported. These students expressed more positive feelings toward themselves as students, felt others perceived them as more competent, and behaved more reflectively when they were integrated than when assigned to special class. The high-able (learning potential) students performed more competently academically than the low-able (learning potential) students, regardless of placement.


Affective reactions of retarded and nonretarded children to success and failure. After performing a simple motor task, 208 mildly retarded and nonretarded girls and boys pointed to photographs of modeled affective facial expressions to indicate how they felt, wished to feel, and thought their teachers would feel about their performance. Children in both IQ groups frequently attributed positive affect to themselves and their teachers after success, although younger retarded children were less positive than were nonretarded children in teacher affect attributions. Following failure, retarded subjects were generally less frequently negative than were nonretarded subjects in affect attributions to themselves and particularly to their teachers. Emphasis on success and minimization of failure in classrooms for retarded children was offered as one possible explanation for the IQ group affect differences following failure.


Release from proactive interference in short-term memory in mentally retarded persons. Results of this study indicated that the accumulation of and release from proactive interference in mentally retarded persons parallels that observed in nonretarded subjects. Release from proactive interference in mentally retarded subjects suggests that they can organize and discriminate between items in short-term memory.


Stimulus overselectivity: a common feature in autism and mental retardation. Groups of children with different IQ levels were trained to discriminate between stimulus cards containing two or more pictures. In subsequent testing the pictures were presented singly in order to determine how many pictures the child had responded to during discrimination training. The data showed that the lower the IQ, the fewer pictures the child responded to. We speculated that intellectually retarded functioning may be related to problems in overselective attention; the lower a person's IQ level, the less of the environment becomes functional in controlling his behavior.


Effects of frequency of photic stimulation upon autistic and retarded children. The present study was designed to determine if frequency of repetitive photic stimulation could affect the response rate of an operant upon which such stimulation was made contingent. To test this hypothesis, we trained retarded and autistic children, equated for mental age, to pull a lever to obtain photic stimulation of different frequencies. It was found that (a) response rates of autistic children were related to the frequency of stimulation, while retarded children showed no such consistency. (b) The two groups did not differ in the average duration of time they engaged in stereotypies. (c) During a subsequent extinction session, two autistic children ceased responding, but one of two retarded children did not. (d) Noncontingent photic stimulation suppressed a food-motivated operant in one autistic child. These results were interpreted as evidence for frequency-dependent properties of repetitive visual feedback in autistic children. In addition, support was given to the position that performance deficits in autistic children correlating with the occurrence of stereotypies result from competition of different sources of reinforcement.