Chlamydia shedding by four species of wild birds. Four wild bird species--great-tailed grackle (Cassidix mexicanus), common grackle (Quiscalus quiscula), brown-headed cowbird (Molothrus ater), and mourning dove (Zenaidura macroura)--were either inoculated intratracheally with Chlamydia psittaci or exposed indirectly as uninoculated cagemates. Shedding of chlamydiae was monitored by inoculating mice with suspensions of material eluted from cloacal swabs collected from all birds, usually at 3-day intervals. Sporadic shedding of chlamydiae was demonstrated in three species (great-tailed grackle, brown-headed cowbird, and mourning dove) that were inoculated, and also in uninoculated grackles of both species exposed to inoculated great-tailed grackles. All inoculated birds except one mourning dove developed antibody detectable by complement-fixation (CF). Of the exposed birds, only grackles had antibody. However, two great-tailed grackles which did shed chlamydiae did not develop CF antibody. The modified direct CF (MDCF) method was slightly more sensitive than the direct CF method. The agar-gel precipitin method was not entirely reliable for antibody detection, for it did not correlate with CF serology and shedding of chlamydiae. It is concluded that: 1) grackles are potential reservoir hosts that could be important in the transmission cycle of C. psittaci in nature; and 2) epidemiologic studies of chlamydiosis in wild birds should include both serologic testing (preferably by the MDCF method) and attempts to isolate chlamydiae from cloacal swabs.


Studies on Pasteurella multocida. VI. Nature of systemic immunity and analysis of the correlation between levels of immunity induced by various fowl cholera vaccines and protection against challenge. The nature of the systemic immunity induced by various vaccines against fowl cholera disease in turkeys was investigated. Used as vaccines were three avirulent strains (CU, M2283, and P1580) of Pasteurella multocida administered in the drinking water and a bacterin administered parenterally. A passive hemagglutination test was developed to measure levels of systemic humoral immunity. Systemic cell-mediated immune response was assayed by an in vitro immunostimulation microculture system utilizing peripheral blood lymphocytes. The bacterin induced high levels of systemic humoral and cell-mediated immune responses which respectively persisted for 8 and 6 weeks. The CU strain of live vaccine induced average levels of systemic immunity (humoral and cell-mediated) which respectively persisted for 4 and 6 weeks. The M2283 strain of live vaccine also induced average levels of systemic immunity (less than induced by the CU strain) which respectively persisted for 4 and 6 weeks. The P1580 strain of live vaccine induced low levels of systemic immunity which persisted for only 2 weeks. Results from data generated from an analysis of correlation between levels of immunity and protection indicate that systemic immunity (humoral and cell-mediated) played a significant role.


Innate and acquired immunity vs. anticoccidial medication in managing coccidiosis in turkeys. Turkeys 2, 6, or 10 weeks old that had been reared free of coccidial infection were susceptibe to infection with Eimeria meleagrimitis, E. adenoeides, and E. gallopavonis. The 6- or 10-week-old birds were more resistant to infection than the 2-week-old birds (no deaths from coccidiosis vs. 100% mortality). Lesion scores were lower in 10-week-old birds than in 6-week-old birds, but significantly greater weight losses occurred in the older birds. Turkeys reared in floor pens contaminated experimentally with coccidia were immune to homologous challenge at 10 weeks old, with only slight (numerical) reduction of weight gains following challenge with 50,000 oocysts/bird of each species. These results demonstrated some degree of innate resistance associated with age, although not enough to protect against heavy challenge. The resistance of birds reared in floor pens was due largely to acquired immunity resulting from infection with coccidia. Amprolium (125 ppm), monensin (100 ppm), or Polystat (250 ppm) protected the turkeys against experimental infections in floor pens, as measured by weight gains, feed efficiency, death due to coccidiosis, and lesion scores.


Serological and cultural studies on broiler breeder multiplier flocks infected with Mycoplasma synoviae. Nine broiler breeder flocks found infected with Mycoplasma synoviae (MS) at 17 to 42 weeks of age were used for serological tests and isolations of MS. Five live females and 20 to 30 serums were brought to the laboratory from each flock on three occasions. Serums from flocks naturally infected reacted to the serum plate agglutination and hemagglutination-inhibition tests throughout one laying season. MS was isolated from the trachea, turbinates, sinus, lung, and air sacs throughout one laying season. The medium with 0.1 g NAD isolated MS more efficiently than the medium with 0.01 g NAD. MS was isolated more frequently from the trachea, turbinates, and sinus than from the lung and air sacs.


Slide-agglutination test of Haemophilus gallinarum antigen treated by trypsin to inhibit spontaneous agglutination. Spontaneous agglutination of Haemophilus gallinarum (HG) cells cultured in Kato's broth was inhibited by trypsin treatment. The treated cell had the same antigenicity as the common antigen prepared from chicken meat infusion broth. Trypsinized antigen could be used in the slide-agglutination test to detect HG antibody in chicken serum.


Renal coccidiosis caused by Eimeria gaviae n. sp. in a common loon (Gavia immer). Renal coccidiosis was diagnosed in a common loon (Gavia immer). This is the first report of coccidium from the kidney of a member of the Order Gaviiformes. Morphologically, the coccidium was considered to be an Eimeria sp. distinct from Eimeria truncata, and was named Eimeria gaviae n. sp.


Experimental and natural infections of Eustrongylides sp. (Nematoda: Dioctophymatidae) in waterfowl and shore birds. The occurrence of Eustrongylides sp. is reported for five species of fish-eating birds collected in the western-basin region of Lake Erie. Mature specimens of E. tubifex were recovered from 5 of 74 laboratory-reared Mallards (Anas platyrhynchos) infected experimentally with larval worms taken from Yellow perch, Perca flavescens.


Giardia infection in parakeets.

Giardia infection in parakeets. Giardia infection causing high morbidity and mortality in parakeets in 3 commercial aviaries is described. The disease was successfully treated with dimetridazole.


Studies on the use of mumps virus for treatment of human cancer. Purified mumps virus (Urabe strain) was given mainly by intravenous injection to a total of 200 patients with cancer. The only adverse clinical reaction was transient mild fever in about half the patients. The beneficial clinical effects were as follows; decrease or disappearance of ascites and edema of the lower limbs at high rates (26/37 and 4/4, respectively), usually within a week after treatment: decrease or stoppage of cancerous bleeding in 30 of 35 patients: decrease or disappearance of pain in most of the patients: and tumor regression in 26 patients with cancer of the breast, rectum, ileocaecum, thyroid gland, uterus, skin, etc. Histologically, the virus-treatment caused shrinkage of nuclei and vacuolization of the cytoplasma of tumor cells, but the degenerative changes of tumor cells were not so great as those after chemotherapy or radiotherapy. Infiltration of lymphocytes, fibrosis and collagenesis occurred around tumor tissues, where necrosis or exfoliation of tumor cells was frequently observed.


Hormonal and metabolic control of proteolysis. Proteolysis in heart muscle is regulated by hormonal and metabolic factors. In the absence of insulin, protein degradation accelerated, autophagic vacuoles appeared within the heart and latency of lysosomal enzymes decreased. Addition of insulin prevented or reversed these changes. Provision of leucine inhibited proteolysis in control hearts. Addition of the products of transamination and oxidative decarboxylation of leucine, isoleucine and valine had similar inhibitory effects. Protein degradation was inhibited in ischaemic or anoxic hearts, but latency of lysosomal enzymes was decreased. Inhibition of degradation in energy-poor tissue may represent both an energy-requirement for proteolysis and inhibition by accumulation of metabolic products, such as lactate.


Hormonal regulation of ketone-body metabolism in man. The main hormones involved in ketone-body metabolism are the anabolic hormone insulin and the primarily catabolic hormones, glucagon, cortisol, catecholamines and growth hormone. These hormones may regulate ketone-body metabolism at three sites: adipose tissue, by regulating fatty acid supply to the liver; the liver itself, by determining the relative activities of the re-esterification and fatty acid oxidation pathways; and the periphery, by influencing the rate of extrahepatic utilization of ketone bodies. The first two are quantitatively the most important. Insulin acts on all three regulatory sites. In adipose tissue lipolysis is inhibited and re-esterification enhanced with consequent decrease of fatty acid release. Both these processes are extremely insulin-sensitive. In the liver insulin increases fatty acid synthesis and esterification. At the same time malonyl-CoA formation is increased, which inhibits the acylcarnitine transferase system and thus decreases the transport of fatty acids into mitochondria and hence fatty acid oxidation and ketogenesis. Insulin also has a small stimulatory effect on extrahepatic ketone-body utilization. The effects of glucagon depend on whether insulin is present. In normal man glucagon stimulates insulin secretion and the predominant effect is that of insulin, i.e. decreased ketogenesis. In insulin deficiency glucagon has a mild stimulatory effect on lipolysis, increasing fatty acid supply to the liver. The main effects of glucagon are, however, on the liver. It activates the carnitine acyltransferase system through inhibition of malonyl-CoA synthesis. Fatty acid oxidation is increased and ketogenesis enhanced. The overall effect on the liver depends on the relative amounts of insulin and glucagon present. Studies with somatostatin show that glucagon can increase ketogenesis acutely when insulin secretion is inhibited in normal man, but the effects are short-lived. Cortisol has similar effects to glucagon. In the presence of insulin there is a small increase in fatty acid mobilization from adipose tissue, secondary to impaired glucose entry, and perhaps a small effect on lipolysis itself. This fatty acid is, however, directed to triacylglycerol in the liver. In insulin deficiency, again demonstrated by somatostatin infusion, the incoming fatty acidstone-body formation. The mechanism remains obscure. Catecholamines, in contrast, have their most potent effects on adipose tissue, stimulating lipolysis and fatty acid release even in the presence of insulin. They thus act mainly by enhancing precursor supply and have only minor effects on liver and no effect on peripheral utilization. Growth hormone, like glucagon, has little effect in the presence of insulin, but can enhance ketogenesis in insulin deficiency, although again the mechanism is unknown. Thus in normally fed man the effects of insulin will be overriding and little ketogenesis occurs because of limited fatty acid availability in the liver...


[Neuropsychopharmacological effects of TCDD]. It has been found that TCDD (2,3,7,8-tetrachlorodibenzo-p-dioxin), in rats, endoperitoneally or orally administered at dose of 1-10 mcg/kg, provokes irritability, aggressivity and restlessness (increase of spontaneous crossings in the shuttle box). The TCDD does not modify the conditioned avoidance (C.A.) or the conflictual situation. In "vitro" the TCDD stimulates directly the striatal and hypothalamic adenylate cyclase of rat. The TCDD increases the stimulation produced by dopamine on striatal adenylate cyclase. Haloperidol (dopamine antagonist) inhibits the stimulation produced by TCDD. TCDD does not significantly modify the stimulation by hystamine on hypothalamic adenylate cyclase. Cimetidine (H2) antagonist) causes a remarkable increase of the TCDD stimulating effect.


[Interaction of calcium and some neuropharmacological agents on the isolated nerve fiber]. It has been suggested that calcium interferes with the effect of the local anesthetics (Blaustein and Goldman, 1966). Experiments were therefore made with the anionic phenobarbital and the cationic procaine and chlorpromazine in high (18 mM/1) and in low (0,18 mM/1) calcium concentration. These experiments showed that the effect of drugs used, and of changes in calcium concentration were independent of each other.


Changes of granulopoiesis during and after adjuvant chemotherapy of breast cancer. Adjuvant chemotherapy allows a study of the effects of cytotoxic drugs on natural human haematopoiesis. We describe serial studies of granulopoiesis performed during and after intermittent adjuvant chemotherapy for breast cancer (adriamycin plus cyclophosphamide, given for six courses at monthly intervals). After drug administration, a sequential wave of depletion and regeneration through successive granulopoietic compartments was observed. With repeated chemotherapy, moderate neutropenia developed, and the blood CFU-C pool size became progressively reduced. After the sixth chemotherapeutic course, granulopoietic regeneration was delayed. Following discontinuation of chemotherapy, a long-lasting (greater than 200 d) reduction of the blood CFU-C pool size, together with neutropenia and reduction of marrow segmented neutrophils, was observed, suggesting a defect of granulopoiesis with persistent granulopoietic hypoplasia. In patients with expected long survival, residual bone marrow damage should be added to the list of potential late side effects of cytotoxic drug therapy.


Ultrastructural analysis of haemopoiesis in W/Wv anaemic mice. This study is an ultrastructural analysis of haemopoiesis in W/Wv anaemic mice in whom the anaemia is caused by a defect in the haemopoietic stem cell. Cellularity of marrow is normal but there is an increase in the proportion of less mature cells suggesting a delay in maturation. In addition, heterochromatin constitutes a higher proportion than normal of the nucleus in most stages of maturation suggesting a defect in DNA activation. The findings suggest that in this strain not only the differentiation of the haemopoietic stem cell but also the maturation of the committed cell is defective.


Splenic red cell pooling: a diagnostic feature in polycythaemia. Total red cell volumes and splenic red cell pools were measured in 31 patients with polycythaemia. 22 had polycythaemia vera (PV), 12 of whom had clinically detectable splenomegaly, and nine patients had secondary polycythaemia (PS). The mean red cell pool was 192.8 ml (SD 126.6) in PV (all cases), and 130.9 ml (SD 28.4 ml) in PV without splenomegaly; it was 61.1 ml (SD 8.3 ml) in PS. When expressed relative to spleen size (in cm), differences were even more striking: PV (all cases)--mean 13.7 ml/cm (SD 4.3); PV without splenomegaly--mean 12.7 ml/cm (SD 2.2); PS--mean 6.6 ml/cm (SD 1.2). Measurement of splenic red cell pool thus appears to be a valuable diagnostic tool for distinguishing between PV and PS. The findings point to the presence in PV of a splenic structural abnormality which is not simply an effect of the increased circulating red cell mass.


Erythrocyte delta-aminolaevulinic acid dehydratase activity and changes in delta-aminolaevulinic acid concentration in various forms of anaemia. Whole blood delta-aminolaevulinic acid (ALA) concentrations and erythrocyte ALA dehydratase activity have been measured in patients with iron deficiency anaemia, megaloblastic anaemia and secondary anaemia, and in normal subjects. ALA concentration was found to be significantly increased in all types of anaemia compared with normal. Erythrocyte ALA dehydratase activity was significantly increased in iron deficiency and megaloblastic anaemia but not in secondary anaemia.


Fetal haemoglobin production and the sickle gene in the oases of Eastern Saudi Arabia. Fetal haemoglobin (HbF) levels have been measured in 137 normal (AA) subjects, 109 with the sickle-cell trait (AS) and 237 with sickle-cell anaemia (SS) from the oasis population of Eastern Saudi Arabia. In addition the proportion of F-cells has been estimated in 71 AA, 51 AS and 34 SS subjects. The mean HbF% (and the range of F-cells %) were: AA 0.77 (0.3--18), AS 1.38 (2.3--43) and SS 25.56 (33--98). The distribution of Hb F was always heterocellular. The influence of pregnancy accounts for most of the excess female subjects with sickle-cell trait showing raised Hb F and F-cells. Whilst the normal Arabs and those with sickle-cell trait did not differ from comparable groups of American blacks, both the % Hb F and % F-cells in Saudi Arabian patients with sickle-cell anaemia were much higher than in Blacks. The high Hb F levels in individuals with sickle-cell anaemia are not due to coexistent glucose-6-phosphate dehydrogenase deficiency or alpha-thalassaemia trait, and the Hb F level showed an inverse correlation with the degree of haemolysis. These findings indicate that the unusually elevated levels of Hb F are not due to an associated high frequency of a gene for hetero-cellular hereditary persistence of fetal haemoglobin in the oasis population, but rather from a genetically determined absolute increase in Hb F production related in some way to the SS genotype.


The determinants of irreversibly sickled cells in homozygous sickle cell disease. The relationship between the irreversibly sickled cell (ISC) count and other haematological parameters has been investigated. Positive correlations occurred with the MCH, MCHC, and with two expressions of intracellular Hb S content. Since the ISC has a high MCHC, the positive correlations with MCHC and with factors derived from the MCHC may be difficult to evaluate. Negative correlations occurred with total haemoglobin and Hb F. The MCHC was found to affect the relationship between HbF and ISC count, a low MCHC being associated with, and probably determining, lower ISC counts at any level of Hb F. It is proposed that a low MCHC may inhibit ISC formation and the practical implications of this are discussed.


IgM inhibitors of the contact activation phase of coagulation in chlorpromazine-treated patients. In this report we have described three patients with chronic schizophrenia on long-term chlorpromazine therapy who developed asymptomatic IgM inhibitors of the intrinsic phase of blood coagulation. The anticoagulant resulted in decreased measurements of all of the plasma clotting factors in the intrinsic pathway (factors VIII, IX, XI, XII, Fletcher factor and Fitzgerald factor). Using crude coagulation reagents, the serum of these patients interfered with the clot promoting activity of contact product. To determine the relationship between drug therapy and these IgM inhibitors, we have studied nine additional schizophrenic patients on long-term chlorpromazine therapy. All nine chlorpromazine-treated patients had significantly increased levels of serum IgM and asymptomatic inhibitors of coagulation. We conclude that long-term high-dose chlorpromazine treatment of schizophrenic patients results in an increased concentration of IgM which has inhibitory activity in the contact phase of blood coagulation.


Plasma levels of platelet factor 4 measured by radioimmunoassay. A radioimmunoassay has been developed to measure platelet factor 4 (PF4) in biological fluids both in vitro and in vivo. The assay has been shown to be highly specific for PF4 and has a sensitivity of 0.08 ng/assay tube and 1.6 ng/ml of plasma. The preparation of plasma for the measurement of in vivo levels of PF4 requires the use of an anticoagulant containing EDTA, theophylline and prostaglandin E1, the immediate cooling of the blood and high speed or prolonged centrifugation to reduce platelet contamination. Plasma levels of PF4 are normally between 4 and 24 ng/ml with a median of 7.4 ng/ml. Plasma PF4 levels are markedly increased during cardiopulmonary bypass surgery with shortened 51Cr-labelled platelet survival times and during arterial thrombosis. However, despite similarly shortened platelet survival times, the level of PF4 is normal in immune thrombocytopenia. Elevations of plasma PF4 levels are found following surgery, acute myocardial infarction and frequently during acute infections and in inflammatory states. On the contrary, normal levels are usual in disseminated malignancy, in severe hepatic and renal disease and in chronic arterial disease. The measurement of PF4 is a useful addition to the study of platelet pathophysiology. It is apparent, however, that raised levels are by no means specific for thromboembolic disease and similarly platelet destruction is not invariably associated with abnormally increased plasma PF4 levels.


Visual behavior, eye and retina of the parasitic fish Carapus mourlani. 1. This is the first transmission electron microscope description of the retina of a parasitic fish. 2. The retina is well supplied with capillaries, some of which occur on the inner surface of the retina. An unusual and possibly primitive type of capillary junction is described. 3. The outer segments of the retina of Carapus mourlani, which measure approximately 2 micron in diameter, are of one type only. A certain degree of banking was observed. Outer segments are not isolated from each other by screening pigments; they are, however, surrounded by about 15 calycal processes. 4. Typical spheroids or conoids were not seen in the outer plexiform layer. The inner nuclear layer consists of only one or two layers of nuclei. The inner plexiform layer is unusually wide and some amacrine synapses can be identified. There are few ganglion cells and the ratio of nuclei in the outer nuclear layer to those of the inner nuclear layer to ganglion cells is approximately 100:10:1. 5. The eye of C. mourlani combines features of degenerated photoreceptors, characteristic of cave-organisms, with adaptations which are commonly found in nocturnal and deep-sea forms. 6. The visual behavior of the animal indicates that the eye is fully functional in spite of its corneal keratosis and small number of optic nerve fibers.


Cellular morphology and architecture during early morphogenesis of the ascidian egg: an SEM study. 1. Cellular morphology and architecture during early morphogenesis of the ascidian embryo were examined by SEM. 2. The outer surface of the embryo was essentially smooth. The blastocoel could be seen in the dissected blastula. On the cell surface bordering the blastocoel, numerous pseudopodia extended from cells onto adjacent cells. These pseudopodia were suggested to contribute to cell-to-cell adhesion. 3. Before the initiation of gastrulation, a layer of the cells of the animal (ventral) hemisphere and that of the cells of the vegetal (dorsal) hemisphere adhered closely together. The blastocoel could no longer be observed. 4. The gastrulation began during the seventh cleavage. The gastrocoel was formed by a folding of the two layers of the cells. Examinations of the dissected gastrulae suggested two cooperative forces for the gastrulation: first, the epibolic or enfolding movement of the ventral ectoderm cells and secondly, the change in shape of the constituent cells. 5. The neural tube formation progressed in a similar fashion to that of vertebrates.


Cortical potential correlates of selective attention in multidimensional scaling. Cortical evoked potentials were recorded from the vertex of subjects performing a similarity rating task. Proximity data were analysed according to INDSCAL (Carroll and Chang, 1970). Brain activity was averaged separately for different stimulus attributes and different stages of the judgement process. The amplitudes of the two positive deflections of the averaged evoked potential, peaking around 160 and 330 msec after stimulus onset respectively, were systematically influenced by two factors: The weight, which the evoking attribute received in the overall dissimilarity judgement, and the position of the evoking attribute in the stimulus train. The results support the hypothesis that differences in the perception of similarity are due to differences in attentional set. Reference is made to the 'additive-difference model' of scaling behaviour (Tversky and Krantz, 1970) and Broadbent's (1970) distinction between stimulus set and response set attention.


Short-term memory and the EEG: effects of instructions to rehearse. Transoccipital EEG was analyzed during the performance of a task involving the presentation and recall of auditorily presented nine-digit strings. Three strategies of processing were imposed by instruction: (i) passive listening without recall; (ii) passive listening followed by attempted recall; (iii) active rehersal followed by attempted recall. Phasic EEG arousal (8.5-12.5 Hz), inferred from the decline in abundance during string presentation, was found to be a function of the level of 'engagement' in the task. This finding was viewed as supporting an earlier phenomenological description of the task demands involved in recall. Tonic levels of arousal were found to be frequency dependent. At low frequencies (8.5-10.5 Hz) EEG abundance was inversely related to engagement but at higher frequencies (10.5-12.5 Hz) abundance was directly related to the level of engagement. The results are discussed in terms of a possible functional dissociation of EEG arousal within the alpha frequency band.


Efficacy of pattern feedback for the dissociation of heart rate and respiration rate. The present study assessed the efficacy of pattern feedback for producing integrative and dissociative patterns of heart rate (HR) and respiration rate (RR). 60 uninformed subjects were assigned to six groups in which beat-by-beat feedback was contingent upon production of a specific pattern of increased ( ), decreased ( ), or unchanged (=) HR and RR during 11 feedback trials. Concomitant changes in respiratory volume and general activity (GA) were also recorded. Groups given feedback for HR and RR changes in the same directions (HR RR and HR RR ) ANd for changes in opposite directions (HR RR and HR RR ) were generally unable to produce the respective patterns, indicating that pattern feedback does not enable subjects to produce a wide range of HR-RR patterns. However, evidence of dissociation of HR and RR was obtained in the HR RR= and HR RR= groups in which HR changed significantly in the appropriate directions without significant changes in RR. These results are not consistent with the view that RR changes are necessary for HR control, although significant concomitant changes in respiratory volume and GA indicated that HR control was non-specific relative to these variables.


Within-subject covariation of reaction time and foreperiod cardiac deceleration: effects of respiration and imperative stimulus intensity. The warned foreperiod reaction time (RT) task is claimed to provide data supportive of the Laceys' visceral afferent feedback theory. However, although there are many reports of significant between-subject correlations between heart rate (HR) and RT, more direct tests examining within-subject covariation show, at best, inconclusive results. These studies suggested several procedural refinements which could produce stronger within-subject relationships. The procedures adopted in this investigation included manipulating attentional involvement by varying imperative stimulus (IS) intensity, using a respiratory control and a repeated measures design, recording electromyographic RT, employing a contact switch manipulandum with no moving parts, and having subjects initiate trial presentation. 40 males were divided between normal breathing and hold breath groups. Subjects received three blocks of 24 trials with the IS at either 10, 50, or 80 db. A variety of measurement and statistical approaches yielded generally negative results, with an overall mean within-subject correlation in the predicted direction of -0.06.


A simple method for estimating stresses in natural and prosthetic heart valves. Flexible-leaflet prosthetic heart valves offer certain advantages over the lateral-flow central-occluding devices in current use. However, achieving sufficient strength and fatigue resistance in the flexible leaflets is a difficult design problem. The present paper contributes to the solution of this problem by describing a simple step-by-step method for estimating the stress in a flexible leaflet valve. The method is especially suited for evaluating preliminary proposed designs since it requires only a few simple measurements and calculations. An example is presented in which stresses estimated by the method are compared with those obtained from a finite element analysis. In addition, an error is pointed out in a previously-published method for estimating stresses in leaflet valves.


Dental implant fixation by electrically mediated process. II. Tissue ingrowth. The effect of electrical stimulation on the interfacial strength of the porous polymethylmethacrylate implant/oral tissue union and the amount of tissue growth was investigated in the fourth premolars of dogs. The study indicates the interfacial strength peaks at about three weeks and decreases thereafter for both control and the stimulated specimens. The stimulated side showed consistently higher strength than its paired control. There was a positive relationship between implant period and amount of tissue in the pores although the latter was not correlated with the interfacial strength. Microradiographs showed a different pattern of new bone formation on the stimulated side when compared to the control. On both sides, bone formation occurred upward from the bottom of the tooth socket while on the stimulated side, new bone also developed from the sides of the tooth socket which was minimal in the controls. It is proposed that the direction of oral tissue formation is responsible for the different results obtained in this study compared with a similar study on long bones.


Reinforced expanded polytetrafluoroethylene (Gore-Tex) grafts for haemodialysis. Twenty-five vascular grafts made of expanded reinforced polytetrafluoroethylene (PTFE) were inserted as arteriovenous fistulae in 20 patients requiring intermittent haemodialysis. Thirteen grafts were placed in the forearm, either as a looped or straight configuration, and 12 straight grafts were placed in the thigh. Whereas only 45% of the forearm grafts functioned adequately, 92% of the thigh grafts supported haemodialysis satisfactorily. It is suggested that when a vascular graft for haemodialysis is required, then an arteriovenous connection of expanded PTFE placed in the thigh achieves reasonable success.


The effect of the physiological environment on the mechanical properties of biomaterials in cardiovascular applications. The long-term biocompatibility and physical performance of polymeric materials in the physiological environment depend both on adsorption and absorption processes. While the former has received significant attention in the literature, the latter has not been sufficiently appreciated. Accelerated testing of prosthetic devices in the wrong media and temperatures yield misleading information as exemplified by pumping bladders of heart assist devices and heart valves. Although glutaraldehyde-treated porcine heterograft heart valves performed better than expected in humans over a period of several years, physical degradations that have been observed may be associated with the breakdown of the cross-links. Appropriately selected smooth-surfaced biomaterials and hydrogels are far better suited for temporary blood contacting prosthetic applications such as left ventricular heart assist devices (LVADs) than polyester flocked fibril surfaces that result in the deposition of a thick layer of fibrin/cellular mesh with clot-like morphology with inherent dangers of loss of polyester fibrils, and the shedding of clots as the result of cyclic flexing of the pump bladders. With the proliferation of various medical devices, the possibility of increased litigations with secondary and tertiary liabilities involving not only physicians, surgeons, and device manufacturers, but also suppliers of materials and components, it is essential to select pertinent rather than complex test procedures.


Intramedullary fixation of implants pre-coated with bone cement: a preliminary study. A preliminary study on the feasibility of implants pre-coated with an acrylic bone cement has been performed. Four types of implants, an actual canine femoral prosthesis, a polished steel rod (0.49 cm dia. x 13 cm long) with and without pre-coating, and a sand-blasted steel rod with pre-coating were implanted into canine femurs in vitro to evaluate the interfacial shear strengths. After serial sectioning the samples in discs, push-out tests were made. The weakest interfacial shear strength was exhibited by the polished rod/cement interface (0.5 MPa) while the strongest was the "old" and "new" cement interface (23.4 MPa). The bone/cement interfacial strength was in between (1.17 MPa). The shear strength of rod/cement interface increased substantially by sand-blasting (6.84 MPa or 585% increase). The proposed method increases the modified implant's interfacial shear strength by 337% (from 1.17 to 3.84 MPa) over the conventional implants. It may furthermore reduce the setting temperature, the shrinkage, and the amount of monomer released during operation due to the reduced amount of cement at the time of implantation. The more gradual transmission of load from implant to bone and "auto-centering" of implants during operation by pre-coating, are thought to be advantageous over conventional cement fixation method.


Exploratory analysis of disease prevalence data from survival/sacrifice experiments. The paper considers the problem of analyzing disease prevalence data from survival experiments in which there may also be some serial sacrifice. The primary objective of the analysis is to describe the composition of the treated and control populations, in terms of age-dependent disease prevalences, by removing distortions in the data caused by the biased nature of the primary sampling mechanism (death). The statistical model which is utilized for this purpose is parameterized in terms of illness state prevalences and lethalities. It does not require determination of cause of death; nor does it assume that diseases progress independently. Methods are presented for estimating various quantities of interest, including disease-specific relative risks and measures of association among diseases. An application of this analysis is shown, using data from a large experiment to investigate the effects of low-level radiation on laboratory mice.


A linear models application of competing risks to multiple causes of death. An analysis is performed to ascertain the joint incidence of two causes of death, acute myocardial infarct and stroke, for the deaths of residents of Massachusetts and North Carolina in 1969. To assay their association an explicit biological model of the nature of the relation is posited. It is shown that, under this model, Chiang's (1968) theory of competing risks may be extended to the case in which an individual's death may have multiple causes. Furthermore, techniques are developed which allow us to model the survival parameters derived under the model by categorical data procedures of the type introduced by Grizzle, Starmer and Koch (1969). The study shows that there is a greater incidence of the joint occurrence of stroke and myocardial infarct on death certificates in North Carolina than in Massachusetts, a pattern consistent with the generally higher stroke mortality in North Carolina. Furthermore, the incidence of the joint occurrence of the two diseases shows a clear age "gradient" increasing through the age range of the analysis. Males and females show somewhat different patterns of age variation in that state-by-age interaction terms are more prominent in the model fitted for females than for males.


A semi-Markovian model for predator-prey interactions. In the study of population dynamics, the predator-prey system is recognized as a vitally important aspect in natural population control. On aspect of predator-prey interactions is studied in this paper. The attack cycle of a predator is assumed to consist of four different activities, namely, search, pursuit, handle and eat, and digestion. A semi-Markovian model is proposed to obtain the number of prey devoured by a predator during the activity of a day. The advantages of a new semi-Markovian model to the queueing model developed by Curry and DeMichele (1977) is demonstrated, as the results from the semi-Markovian model are closer to Holling's (1966) experimental data than their results, which were based entirely on Poisson assumptions.


A stochastic model for cell survival after irradiation. A theory of cell survival after irradiation has been developed based on a single compartment model of a living cell and taking into account a recovery phenomenon. The basis of the model is the assumption that once a cell is repaired, it will behave like a normal cell if irradiated further. Theoretical expressions for the probability of survival or damage of an irradiated cell at an arbitrary instant in time have been obtained for a constant damage rate and a general repair-time distribution. An application of these derived expressions has been made to experimental data.


An exact confidence region for a relative potency estimated from combined bioassays. A distributionally exact confidence region is derived for a relative potency estimated from several parallel line assays. This is compared with the approximate confidence region derived from the likelihood ratio statistic.


The effect of accessing medical records by date of death on estimates of survival. An inefficient, but quickly and easily calculated, estimate of a survival-time distribution is described. Conditions for the estimate to be unbiased specify bounds on the length of time a study has been in progress and the way in which people must enter a study. These appear to be frequently met when a large medical registry is examined with a view to establishing base line survival experience for a selected class of patients.


The analysis of pair-matched case-control studies, a multivariate approach. In matched case-control studies one frequently must consider more than one variable in the analysis and in this paper a log-linear model is presented to meet this objective. A conditional argument yields a method for making inferences on the parameters measuring the association between the variables and disease. The result is similar to the problem of fitting a Bradley-Terry model when one has paired comparisons. Two methods of obtaining maximum conditional likelihood estimates of the parameters are possible: (i) fitting a quasi-independence model in the usual log-linear models context and (ii) fitting a linear logistic model. The results are illustrated with examples.


Strategies for the selection of log-linear models. In a multidimensional contingency table strategies have been proposed to build log-linear models using either stepwise methods or standardized estimates of the parameters of the saturated model. Brown (1976) proposed a two-step procedure to screen effects and then test a subset of models. Alternate methods of model building are discussed with respect to the final choice of model and with respect to intermediate information available to the data analyst during the selection process.


Biological conversion of beta-phenylhydracrylic acid to hippuric acid. Loadings in rats with 4-deuterium labeled beta-phenylhydracrylic acid results in the excretion of large amounts of deuterium labelled hippuric acid. Labelled benzoic acid was also detected.


Negative ion mass spectrometry of phenothiazines. Mass spectra of a number of phenothiazines have been obtained by negative chemical ionization and compared with the corresponding mass spectra by positive chemical ionization and conventional electron impact. NH3, CH4, and N2O were used as reagent gases for negative chemical ionization, iso-C4H10 and CH4 for positive chemical ionization. The negative chemical ionization technique gives significant information regarding the molecular weight and the ring system of this group of compounds. As a complementary method to positive electron impact, negative chemical ionization is more informative than positive chemical ionization. Phenothiazines with two, but not three, methylene groups between the ring and the sidechain nitrogens given an intense rearrangement anion due to loss of the substituted nitrogen in the sidechain and two additional hydrogens. A 5-membered ring structure is postulated for this anion, which is formed with the reagents NH3 and CH4. but not with N2O. Apart from this peculiarity, the negative chemical ionization spectra are easy to understand.  With NH3 as reagent, the anions representing the ring system and [M -- 1]- dominate the anion current. With CH4, both quasimolecular ions [M + 1]- and [M -- 1]- can be detected along with the much more intense ring anion. The reagent N2O yields cluster anions by oxidation of the ring and the molecule with the negatively charged oxygen formed in the ion source.


Plasma amino acid quantitation using gas chromatography chemical ionization mass spectrometry and 13C amino acids as internal standards. A specific and sensitive method for the quantitation of 16 alpha amino acids has been developed. The technique employed uses methane chemical ionization gas chromatography mass spectrometry of the carboxy-n-butyl, N-trifluoroacetyl amino acid derivatives. A commercial 13C amino acid mixture provided individual internal standards for 14 alpha amino acids. A computer controlled quadrupole mass spectrometer was used for selected ion monitoring of those ions characteristic of each N-trifluoroacetyl amino acid/13C amino acid pair. A BASIC computer program located peak maxima and background intensities in each selected ion recording. Standard curves for each amino acid/13C amino acid pair were utilized by the program to calculate the plasma concentration of each detected amino acid. The total instrumental analysis occupied 30 min with sample preparation and derivatization accounting for an additional 2 h. Based on the detection of known amounts of standard amino acids the method will quantitate at the 1-5 nanogram level of detection.


Study of the metabolic pathways of alprenolol in man and the dog using stable isotopes. The metabolic pathways of alprenolol have been investigated in man and the dog, using an ion doublet technique of deuterium labelling combined with gas chromatography mass spectrometry. The drug is eliminated mainly by aromatic hydroxylation and glucuronidation. Specific analytical methods are applied to demonstrate that allylic oxidation and oxidative deamination are quantitatively of minor importance. The mechanism for oxidative deamination via an intermediary aldehyde could be elucidated by using the deuterium labelled compound. A method for characterization of 4-hydroxy-alprenolol glucuronides based on formation of stable derivatives and the following enzymatic hydrolysis is described. This approach has a general applicability to hydroxylated metabolites from compounds with an aminopropanol structure common for beta-adrenoceptor antagonists, for example. The metabolic routes for alprenolol in man and the dog are almost identical and in man more than 95% of a given dose can be accounted for.


"No-effect-level" of malathion (o,o'-dimethyl dithiophosphate of diethyl mervaptosuccinate) in Bubalus bubalis. An oral dose of 0.5 mg/kg/day malathion continuously administered for one year has been investigated to produce no change in biochemical (RChE, PChE, aspartate- and alanine aminotransferases, blood glucose, serum urea and plasma total proteins) or haematological (Hb, PCV, tRBC and tWBC) parameters and, therefore, considered to be "no-effect-level" in Bubalus bubalis. However, the administration of higher doses (1.0 and 1.5 mg/kg/day) produced significant (P less than 0.05) changes in all biochemical parameters studied. With these doses leucocytosis was evident among haematological parameters measured.


Trace element concentrations of the rough limpet, Acmaea scabra, in California. The trace element (Ag, Cd, Cu, Fe, Mn, Ni, Zn) concentrations of the rough limpet, Acmaea scabra, were determined at twelve locations along the california coastline. The mean silver concentration of the organisms was highest at Pt. La Jolla, but no elemental concentration exhibited measurable geographic differences. Simple linear correlation coefficients and multiple analysis of variance statistics indicated a general independence of the elemental concentrations from each other and from other biological and geographic variables, in the total sample.


Endosulfan: lack of cytogenetic effects in male rats. Cytogenetic effects of endosulfan (Thiodan) a member of the chlorinated hydrocarbon insecticide was tested in male albino rats. The insecticide was administered orally to rats at 0, 11.00, 22.00, 36.60 and 55.00 mg/kg daily for 5 days. The highest doses were associated with clinical signs of insecticide poisoning and death. Cytogenetic analysis of bone marrow cells and spermatogenial cells did not reveal any significant effect of the insecticides on chromosomes. The ratio of mitotic index and frequency of chromatid break in the two cell types had no correlation with the doses tested and was not very different from those of the control group.


Effects of a single dose of fluoride on calcium metabolism. Fluoride 27 mg was given perorally to 14 subjects. It was found that the serum fluoride concentration increased followed by a decrease to normal levels during 24 h. Serum concentrations of calcium and phosphate decreased initially whereas those of serum immunoreactive parathyroid hormone increased. After 24 h the measured quantities were within normal limits. The results are discussed with reference to mineralization of hard tissues and to fluoride treatment of osteoporotic patients.


Correlation of freeze-fracture and scanning electron microscopy of epiphyseal chondrocytes. Chondrocytes in epiphyseal cartilage were examined by scanning electron microscopy (SEM) and transmission electron microscopy (TEM) using freeze-fracture techniques. Freeze-fracture replicas showed large numbers of fingerlike, 0.11-0.15 micrometer diameter, projections from the chondrocyte surface, with numerous 95-180 A diameter intramembranous particles associated with both the cell membrane surface and these projections. With SEM, these cytoplasmic projections were also obvious, but appeared collapsed into clusters of globular-shaped projections on the surface of the chondrocytes. With freeze-fracture techniques, in which shrinkage artifacts were essentially eliminated, the cytoplasmic projections were often seen in intimate contact with the extracapsular matrix. However, with chondrocytes prepared by both SEM and conventional TEM, there was evidence of shrinkage, the cytoplasmic projections having little contact with the extracapsular matrix. These findings show that the cytoplasmic processes are not artifacts of tissue processing and provide morphological evidence in support of the hypothesis that matrix vesicles are of cellular origin.


Stimulation of duodenal and ileal absorption of phosphate in the chick by low-calcium and low-phosphorus diets. The intestinal absorption of phosphate has been studied in vivo in the chick using ligated segments of duodenum and ileum. Feeding diets low in calcium (0.1%) and/or low in phosphorus (0.25%) caused an increase in the absorption of phosphate from both the duodenum and ileum. These changes are consistent with a putative increase in the renal production and mucosal uptake of 1,25-dihydroxycholecalciferol.


Lead-loaded ion-exchange resin bead as a calcergen. Several heavy metals have direct calcifying effects in connective tissues; most notable among them is lead (Pb), whether administered topically (1) or systemically with local injury (2). The mechanisms of metal-induced soft tissue calcification have been studied by injecting salts of known in vitro calcifying potential into subcutaneous connective tissue (3); of the metals used, only lead and holmium produced an early accumulation of minerals on collagen in vivo. Lead is also claimed to accelerate bone healing in the rabbit leg with no toxic effects (4). Lead-loaded ion-exchange resin beads, implanted into surgically prepared subcutaneous pouches in rats, rapidly induced subcutaneous calcification which has been studied by microradiography and electron-probe microanalysis.


Natural calcification of the prosomatic endosternite in the Phalangiidae (Arachnida:Opiliones). Extracellular masses of crystals are present in the endosternite of certain opilions (Phalangium, Odiellus, and Leiobunum). X-ray spectrography and secondary-ion analysis have shown them to be rich in calcium but poor in phosphorus and other elements. The associated anion has not been identified, but is most probably organic in nature and perhaps an oxalate.


Ultrastructure, histology, and innervation of the mantle edge of the freshwater pulmonate snails Lymnaea stagnalis and Biomphalaria pfeifferi. The mantle edge of the freshwater pulmonate snails Lymnaea stagnalis and Biomphalaria pfeifferi was investigated with histochemical and ultrastructural methods. The mantle edge gland, which is involved in shell formation, consists of the periostracal groove and the belt. This belt appears to be composed of various regions. In the area of the periostracal groove a number of subepithelial gland cell types occur; these release their products into the groove. Between the groove cells ciliated free nerve endings terminate; the corresponding perikarya occur in the subepidermal connective tissue. Also in the posterior belt region free nerve endings were observed between the epithelial cells; in addition, a particular type of subepithelial gland cell was found in this area. The epithelial cells of this part of the belt have the ultrastructural characteristics of ion and water transporting cells; they are probably involved in calcium deposition and resorption. The possible role of the free nerve endings and of the subepithelial gland cells is discussed.


Application of 125I radioimmunoassay to measure inhibition of precipitin reactions using carbohydrate-specific antibodies. Antibodies raised to an artificial antigen with beta-D-galactopyranosyl groups as antigenic determinants were purified using an immunoadsorbent prepared from the hapten involved in the synthesis of the antigen. In order to study the specificity of these antibodies, 125I radiolabelling of either the artificial antigen or the antibody was used in the study of inhibitions of the precipitin reaction. The method, involving labelling of the artificial antigen and counting radioactivity in the supernatant, was found to be more accurate and faster than the usual methods based on measuring the amount of protein precipitated by chemical or spectroscopic methods.


A new recirculation reactor system for kinetic studies of immobilized enzymes. A new recirculation reactor for kinetic studies of immobilized enzyme is proposed. The reactor consists of two tubes in the same thermostatting jacket. One of the tubes is filled with the immobilized enzyme, the other is filled only with the support. During the approach to steady-state temperature, the circulation is carried out only in the inactive tube. Subsequently, when temperature is stable, the active reactor is used and the solution is not recirculated.


Evidence for an in vivo conformational change in ribulose bisphosphate carboxylase-oxygenase from Puma rye during cold adaptation. Ribulose bisphosphate carboxylase-oxygenase (RUBPCase) from leaves of cold-hardened and unhardened Puma rye was purified by gel filtration and ion exchange chromatography. Chemical properties that might be associated with a previously demonstrated difference in molecular charge of purified RUBPCase from cold-hardened and unhardened Puma rye were investigated. Amino acid analyses indicated no significant differences in amino acid composition or average hydrophobicity per residue. Enzymes from hardened and unhardened rye were reversibly cold inactivated at 0 degrees C. However, the former was more stable at this temperature than the latter. Titration with 5,5'-dithiobis(2-nitrobenzoic acid) (DTNB) indicated the presence of fast and slow titrating sulfhydryl groups in both enzyme preparations but there were 50% fewer SH groups titrated in the enzyme from hardened rye in 30 min that in the enzyme from unhardened rye. Activation of both enzymes by HCO-3 enhanced the reactivity of sulfhydryl groups to titration with DTNB. According to the kinetics of the slow titrating SH groups, the enzyme from hardened rye was less susceptible to denaturation by sodium dodecyl sulfate than was the same enzyme from unhardened rye. It is concluded that the tertiary structure of RUBPCase from Puma rye is affected during low-temperature adaptation.


Inhibition of cell-free protein synthesis by analogues of aurintricarboxylic acid. Aurintricarboxylic acid is a potent inhibitor of cell-free protein synthesis by the post-mitochondrial supernatant of chick brain and the translation of mRNA by wheat germ lysate. Comparison of commercially available and chemically synthesized analogues of aurintricarboxylic acid indicates that the unique aurin triphenyl methane ring system and the carboxylic acid groups are both necessary for inhibition of cell-free protein synthesis in both systems.


Regional diastolic coronary blood flow during diastolic ventricular hypertension. The effect of diastolic ventricular hypertension on regional diastolic coronary flow was measured with radioactive microspheres in the canine heart paced at a constant rate and perfused only during diastole with a constant coronary perfusion pressure. Diastolic ventricular hypertension produced an homogenous increase of diastolic flow across the left ventricular wall when the metabolic coronary autoregulation was intact, but produced a decrease in subendocardial diastolic flow when the autoregulation was abolished. These results suggest that diastolic ventricular hypertension produces a higher subendocardial than subepicardial mechanical resistance to diastolic coronary flow.


A study of the labetalol-induced changes in conductivity and refractoriness of the dog heart in situ. The effect of labetalol, an alpha- and beta- adrenergic receptor blocking agent, on the electrophysiology of the dog heart in situ was studied. Pentobarbital anaesthesia which is known to increase the sympathetic tone was used. Labetalolol in doses of 0.5 to 4.0 mg.kg-1 injected intravenously caused a slight decrease in median heart rate and a slight reduction in the median conduction velocity in the atrioventricular (A-V) node in six dogs. A significant increase in the functional refractory period of the A-V node occurred at doses of 1.0 to 4.0 mg.kg-1. The functional and the effective refractory periods of the right atrium and ventricle were increased by labetalol at all doses tested. The plasma concentrations of labetalol were in the range 0.05 ot 0.8 microgram.cm-3 in five out of six dogs at the three lowest doses tested which is far below the values which could be expected to cause a membrane-stabilising effect. The alpha and beta adrenoreceptor blocking effects of labetalol on cardiac electrophysiology in vivo are discussed.


Spontaneous heart rate, propranolol, and ischaemia-induced ventricular fibrillation in the dog. Abrupt coronary occlusion was performed in anaesthetised, open-chest dogs with pre-occlusion arterial blood PO2 ranging from 8.0 to 10.7 kPa (60 to mmHg). Ventricular fibrillation occurred in 15/19 dogs with high spontaneous heart rate (less than 155 beats.min-1) and in 0/8 dogs with low spontaneous heart rate (less than 155 beats.min-1). Dogs with low spontaneous heart rate fibrillated when paced at a fast rate (200.min-1) (4/5). In dogs with high spontaneous heart rate fibrillation occurred in 0/5 dogs when propranolol reduced spontaneous heart rate, but in 3/5 dogs when reduction in spontaneous heart rate in response to propranolol was prevented by pacing.


Transmural triglycerides in acute myocardial ischaemia. The effect of coronary artery occlusion on endogenous triglycerides of left ventricular subepicardium and subendocardium was studied in the open-chest anaesthetised dog. Under control conditions, the subepicardium was found to have a greater concentration of triglycerides than the subendocardium. Thirty minutes after acute coronary artery occlusion there was a decrease followed by a steady increase at 60, 120, and 240 min in subepicardial triglycerides of the ischaemic region. No change in triglycerides in the subendocardium of normal or ischaemic regions was observed. The initial decrease of subepicardial triglycerides in the ischaemic region was blocked by administration of propranolol or bevantolol (CI-775; a specific beta 1 antagonist) given 30 min before occlusion. It is concluded that the effect of coronary artery ligation on transmural endogenous triglycerides is biphasic with an initial period of increased mobilisation followed by a period of increased deposition.


Anatomical arrangement of muscle tissue in the anterior mitral leaflet in man. Muscle tissue in atrioventricular (A-V) cardiac valve leaflets was studied in 35 human hearts and was found to be more prominent in the anterior leaflet of the mitral (MAL) than in the other valve leaflets. From serial sectioning and wax model reconstruction, the anatomic arrangement of the muscle in the MAL indicates bundles passing from the two commissural regions towards the mid-zone of the valve. Age did not appear to reduce the mass of muscle tissue in the MAL. The possibility of muscle contraction in the MAL increasing leaflet tension and accelerating post-artial movements received support by comparisons of the anterior and posterior leaflets of the mitral valve in their movements towards closure.


Assessment of refractoriness of the human Purkinje system. In 35 unselected patients premature right ventricular stimulation during a constant right ventricular drive rhythm was performed at the rates of 80, 100, and 120 per min. Several surface ECG leads and intracardiac electrograms were simultaneously recorded. To assess the beginning of decreased conductivity of the His-Purkinje system for retrograde conduction the premature test pulse interval was measured when the retrograde intraventricular conduction to the bundle of His prolonged for the first time. This interval was defined as the beginning of relative refractoriness of the Purkinje system. Additionally, the effective refractory period of the right ventricular muscle was determined. A rate dependancy between the beginning of relative refractoriness of the Purkinje system and the effective refractory period of the right ventricular muscle, as it is known from animal experiments, could be established with significantly different (P less than 0.001) mean values at the three different heart rates. The method described may be the only means by which to obtain approximate information about normal and abnormal conductivity of the human Purkinje system. It is inferred that critical prolongation of refractoriness of the Purkinje system relative to the refractoriness of the myocardium may be relevant to the occurrence of ventricular arrhythmias.


Proliferative activity of myocardial capillary wall cells in dipyridamole--treated rats. The hearts of rats treated with dipyridamole were studied by light microscope autoradiography and measurement of tissue radioactivity after intravenous injection of 3H-thymidine. Total tissue radioactivity was significantly increased in the hearts of the dipyridamole-treated animals. Only capillary wall cells were labelled in the autoradiograms. The observations indicate a proliferation of capillary wall cells, suggesting a neoformation of myocardial capillaries during dipyridamole treatment.


Correlations between experimental chemotherapy in the murine glioma and effectiveness of clinical therapy regimens. Intracerebral murine glioma 26 was used as a model system for evaluating two-drug combinations of antitumor agents, BCNU was combined with either procarbazine, dianhydrogalactitol, or ellipticine. CCNU was combined with procarbazine. All combinations were more active than the individual drugs alone. The most potent combinations achieved 85-100% tumor "cure" at 120 days, with combined toxicity indices of 0.25 (CCNU-procarbazine) to 1.30 (NCNU-dianhydrogalactitol). The experimental data were compared to clinical studies with CCNU, procarbazine, and vincristine, and BCNU-procarbazine.


In vivo toxicity to lymphoid tissue by 2'-deoxycoformycin. The enzyme adenosine deaminase has an essential role in lymphocyte metabolism. To examine the in vivo effects of inhibition of this enzyme healthy BDF1 mice were injected intraperitoneally with 2'-deoxycoformycin, a stoichiometric tight-binding inhibitor of adenosine deaminase. Of the treated animals, 20% died of overwhelming infection, and histopathological examination of these, and surviving animals sacrificed 10 days following treatment indicated a selective toxicity to lymphoid cells. No toxicity to tissues other than the lymphoid system was observed, which is consistent with the hypothesis that 2'-deoxycoformycin offers a new and selective approach to the treatment of lymphoid malignancies.


Antitumor activity of 1-alkylcarbamoyl derivatives of 5-fluorouracil in a variety of mouse tumors. The antitumor properties of 1-alkylcarbamoyl derivatives of 5-fluorouracil were examined in various mouse tumor systems to select promising compounds for clinical use. Almost all alkylcarbamoyl derivatives were active against various tumors when given by oral administration. Among them, 1-methyl, 1-ethyl, 1-isopropyl, 1-hexyl and 1-octyl carbamoyl derivatives of 5-fluorouracil were moderately or markedly active in six mouse tumor systems tested. However, 1-methyl, 1-ethyl, and 1-isopropyl carbamoyl derivatives were toxic to mice, though not lethal. As a result, 1-hexyl and 1-octyl carbamoyl derivatives were selected as the best candidates for antitumor agents in further study.


Pharmacokinetics of intravenous cyclophosphamide in man, estimated by gas-liquid chromatography. A simple gas chromatographic assay utilising alkali flame ionisation detection is described for the estimation of cyclophosphamide as its trifluoroacetate derivative from plasma. Examination of five patients following intravenous cyclophosphamide gave values of 8.9 h (SD 2.7) for the half-life and 0.061 liters/h/kg (SD 0.011) for whole-body clearance of the drug.


Relationship of 1,3-bis(2-chloroethyl)-1-nitrosourea (BCNU) and 1-(2-chloroethyl)-3-cyclohexyl-1-nitrosourea (CCNU) pharmacokinetics of uptake, distribution, and tissue/plasma partitioning in rat organs and intracerebral tumors. To obtain a clearer definition of the relationship between the structure of BCNU and CCNU and their antitumor activity, we determined the uptake, distribution, and tissue/plasma partition ratios of both compounds in normal organs and intracerebral (ic) 9L tumors in rats. Greater uptake, distribution, and tissue/plasma partition ratios were obtained for parent CCNU in fat, liver, and brain, and for parent BCNU in kidney. CCNU distributes more rapidly and extensively than BCNU only in fatty tissues. BCNU distributed more extensively in kidney and liver. Rats received bolus IV injections of 14C-labeled BCNU or CCNU in increasing doses; measurements taken 30 min after injection showed that three- to fourfold more BCNU than CCNU was bound to nucleic acids in brain and ic 9L tumor tissue. Because the chloroethyl group is the alkylating moiety for both drugs, these findings implied that BCNU biotransformed to its reactive intermediate more rapidly than did CCNU. These observations, together with previous findings, indicate that one reason for the greater effectiveness of BCNU than CCNU against ic 9L tumors is its superior ability to form an intermediate that can bind to ic 9L tumor cell nucleic acids.


Effect of various substitutions in positions 1, 2, 3, and 4 of 4-demethoxydaunorubicin and 4-demethoxyadriamycin. Previous studies on structure-activity relationships of anthracycline antitumor antibiotics have shown that removal of the methoxyl group at position 4 of the aglycone causes a marked increase in the potency of the compounds: 4-demethoxydaunorubicin and 4-demethoxyadriamycin had an antitumor effect similar to that of the parent compound at doses five to eight times lower, and they were active even when administered orally. This paper reports the effects of further substitutions at positions 1, 2, 3, and 4 of 4-demethoxy aglycone. The introduction of methyl groups at positions 2 and 3, or 1 and 4 resulted in decreased cytotoxicity and biological activity. The addition of a benzoyl ring at positions 2 and 3 decreased the activity further. 1,4-Dichloro-4-demethoxydaunorubicin and 2,3-dichloro-4-demethoxydaunorubicin were respectively as active and 2.5 times less active than was daunorubicin against HeLa cells in vitro while they were inactive against P388 and L1210 leukemias in vivo. 2,3-Dimethyl-4-demethoxyadriamycin showed an antitumor activity against mouse leukemias that was slightly higher than was that of adriamycin.


Metabolism of factor B of serum complement in rheumatoid arthritis. An increased rate of catabolism of radio-iodinated Factor B has been shown in five out of ten patients with rheumatoid arthritis. Serum levels of Factor B were normal, the increased catabolism being matched by increased synthesis. The patients showing high catabolic rates had more manifestations of extra articular disease than did those with normal catabolic rates and they had higher rheumatoid factor titres. In seven patients, the catabolic rate for Factor B correlated significantly with the rate of IgG catabolism. In this series, the Raji-cell assay for immune complex-like material was in the normal or near normal range in all but one patient.


Absence of IgG lymphocytotoxins in untreated Hodgkin's disease (HD) patients. Six of twenty-three sera (26%) from patients with Hodgkin's disease (HD) contained IgG antibody with an affinity for human lymphocytes and lymphoblastoid cell lines. All sera were negative for complement-dependent and antibody-mediated cell cytotoxicity against human lymphoid cells irrespective of their binding capacity. It is suggested that the antilymphocyte antibodies seen in HD are not of pathogenic significance but are a non-specific consequence of B-cell stimulation.


Immunoglobulins in myasthenia gravis. Kinetic properties of the acetylcholine-receptor antibody studied during lymph drainage. A specific immunoglobulin, the receptor antibody, can be found in most patients with myasthenia gravis. In order to study the kinetic properties of this antibody, serial determinations of receptor antibody, total IgG and IgG 3 were made during drainage of thoracic duct lymph in three patients. The values obtained were used in a mathematical model to calculate some kinetic parameters. Values for T 1/2 and fractional rates of synthesis and catabolism obtained for total IgG and IgG 3 by this method were shown to agree with those found with other techniques. Most of the receptor antibody activity was found in the IgG 3 fraction but the receptor antibody had a shorter T 1/2 and higher fractional rates of synthesis and catabolism than IgG 3. These kinetic characteristics are consistent with rapid variations in plasma concentration of the receptor antibody. The cause of this rapid turnover could be strong antigenic stimuli and rapid elimination by the antigen, the cholinergic receptor protein.


Measurement of IgG, IgA and IgE antibodies to Dermatophagoides pteronyssinus by antigen-binding assay, using a partially purified fraction of mite extract (F4P1). An extract of Dermatophagoides pteronyssinus culture has been fractionated by chromatography on Sephadex G-100 and Pevikon block electrophoresis to obtain a partially purified allergen (F4P1). This preparation has a molecular weight of between 15--25,000 Dalton, migrates slowly on electrophoresis, and is colourless in solution. The skin-test reactivity of F1P1 was comparable to that of crude D. pteronyssinus extract. F4P1 was radio-labelled with 125I and used in an antigen-binding radioimmunoassay to measure IgG, IgA and IgE antibody (ab) to D. pteronyssinus. IgG, ab was detected in serum from 32/34 (94%) mite-allergic persons, and from 10/31 (30%) nonallergic persons. IgA ab and IgE ab were found in sera from 22/34 (65%) and 37/34 (79%) allergic persons respectively. Neither IgA nor IgE ab could be detected in sera from non-allergic persons. An excellent correlation was found between radioallergo-sorbent technique (RAST), using crude D. pteronyssinus extract and IgE-binding activity (BA) for F4P1, (r=0.94, P less than 0.001). The antigen-binding assay for IgE BA was as sensitive as RAST, but less sensitive than PK testing. There was a very good quantitative correlation between IgG BA and IgE BA (r = 0.84, P less than 0.001). IgG BA was shown to rise in the serum of three patients treated with injections of D. pteronyssinus extract.


Inhibition of neutrophil Fc receptor function by cotricosteroids. The ability of hydrocortisone sodium succinate to inhibit the adherence of IgG-sensitized erythrocytes (EA) to human peripheral blood neutrophil monolayers is described. The steroid inhibitory effect was dose-dependent with a 32.4+/-2.4% decrease in EA binding at 2 X 10(-4)M. There was no difference between the addition of hydrocortisone prior to or at the same time as EA and steroid interference with EA binding was completely reversible. In addition, hydrocortisone was unable to displace bound EA. These findings suggest that hydrocortisone interferes with the availability of the neutrophil Fc receptor for binding and provides further insight into the host factors which are compromised during corticosteroid administration.


Circulating IgG complexes in primary biliary cirrhosis. A serial study in forty patients followed for two years. Several antibodies are present in sera of patients with primary biliary cirrhosis (PBC). We have looked for evidence of antigen-antibody complexes in sera of PBC assuming that some of the antibodies may circulate complexed with an antigen. The Raji cell radioimmunoassay, which determines complement-bound immune complexes, was used to determine the levels of such complexes in serial samples of sera from forty patients with PBC followed for 2 years. Twenty-four patients (60%) were found to have significantly elevated levels of circulating complexes. In the majority they were detected from the beginning of the study and the high levels persisted. In seven patients whose sera initially had normal levels of complexes, the levels increased to become abnormal during the following year. These complexes sedimented at greater than or equal to 19S in the majority of patients studied. The mean level of C3 but not C4 was lower in patients with elevated complexes than in those with normal complexes. A significant correlation was observed between the presence of elevated complexes and the severity of the inflammatory cell infiltrate surrounding intrahepatic portal tracts and serum IgG and IgM levels. There was also a significant correlation with titres of antimitochondrial antibody, but not with the histological stage of disease or with the collagen and copper content of the liver. Although the method of detection of immune complexes is indirect and the antigen is unknown, the presence of such high levels of complexes suggests a possible role of immune complexes in the pathogenesis of PBC.


Receptors for immunoglobulin and complement on sheep RBC-binding lymphocytes in newborn infants. Sheep erythrocyte-binding human peripheral blood lymphocytes bearing receptors for the Fc-part of IgG and/or complement were studied in twenty newborn pre-term and term infants and fifteen adult controls. A technique with mixed rosettes and fluorescein-labelled sheep erythrocytes was used. The newborn infants had a significantly lower proportion of lymphocytes with receptors for sheep erythrocytes and the Fc-part of IgG (1.6%) than the adults (6.7%). Also the percentage of lymphocytes binding both sheep erythrocytes and complement-coated indicator cells was significantly lower in the newborn infants (2.6%) than in the adults (8.9%). A significantly higher proportion of lymphocytes had receptors for sheep erythrocytes and complement than for sheep erythrocytes and the Fc-part of IgG in both newborn infants and adults. There was no correlation between the values of lymphocytes binding sheep erythrocytes, or the Fc of IgG or complement and the proportion of mixed rosettes.


Transfer of experimental allergic orchitis with immune RNA studies in vivo. Ribonucleic acid extracts (RNA) obtained from the lymph nodes and spleens of guinea pigs, which were immunized with testicular antigen emulsified in Freund's complete adjuvant (FCA), were injected intraperitoneally into normal guinea pigs. The transferred guinea pigs developed a delayed hypersensitivity to sperm antigens and testicular lesions which resembled the lesions obtained in the donor RNA guinea pigs. When the transfer was performed with RNA extracted from guinea pigs immunized with FCA alone or with 'immune' RNA treated with Ribonuclease, neither cellular immunity nor testicular lesions were observed.


Comparison of human myofibrillar protein catabolic rate derived from 3-methylhistidine excretion with synthetic rate from muscle biopsies during L-[alpha-15N]lysine infusion. 1. Urine was collected in five healthy men over 10--14 days, with fasting blood samples on days 1, 5 and 10, whilst they consumed a standard creatine-free diet, which was quantitatively related to their body surface area. 2. The urinary excretion of 3-methylhistidine fell to a plateau by day 5 in all subjects. Myofibrillar protein catabolic rate calculated from the mean value of 3-methylhistidine excretion from day 5 to day 10 averaged 1.21 g day-1 kg-1 body weight. The average turnover of muscle myofibrillar protein was calculated to be 2.16%/day. 3. From a previous study using continuous intravenous infusion of L-[alpha-15N]lysine with serial muscle biopsies on the same subjects, the mean myofibrillar protein synthetic rate was calculated to be 0.82 g day-1 kg-1 body weight, and the mean turnover rate was 1.47%/day of total muscle myofibrillar protein. 4. The estimations of myofibrillar protein turnover rate derived from the two methods are compared and the differences discussed.


Total body water, total exchangeable sodium and related variables in the Ghanaian. 1. Standard radioisotope dilution techniques employing [3H]water and [22Na]sodium chloride have been used to determine the total body water and total exchangeable sodium of 20 male and 10 female normal Ghanaians (Africans) aged 19--25 years. 2. Lean body mass and total body fat are calculated as a percentage of body weight; the total exchangeable sodium values have been expressed in relation to lean body mass. 3. Comparison of the data for Ghanaian subjects with published figures for Caucasian subjects of similar age shows that the Ghanaian men have much less total body fat and the women a little less total body fat than their Caucasian counterparts. 4. Total exchangeable sodium expressed in terms of lean body mass shows close agreement in both men and women.


Renal vascular response to haemorrhage in the rabbit after pentobarbitone, chloralose-urethane and ether anaesthesia. 1. Total renal blood flow and its cortical distribution were measured by the microsphere technique before and after haemorrhage in conscious rabbits, and after haemorrhage in rabbits anaesthetized with pentobarbitone, chloralose-urethane or ether. 2. The average blood loss necessary to achieve a fall in systolic blood pressure to about 65 mmHg was 101 ml in conscious rabbits and 38, 90 and 118 ml in weight-matched groups of rabbits anaesthetized with pentobarbitone, chloralose-urethane and ether respectively. 3. After haemorrhage in conscious rabbits total renal blood flow fell by 25%, this fall being confined to the superficial renal cortex. 4. In rabbits subject to haemorrhage under pentobarbitone anaesthesia renal blood flow fell by a further 23% when compared with the conscious bled rabbits. This reduction in blood flow was confined to the superficial cortex. 5. Haemorrhage in the rabbits subjected to chloralose-urethane anaesthesia caused no significant change in renal blood flow, as compared with conscious bled rabbits. 6. Haemorrhage under ether anaesthesia was associated with a further 33% fall in total renal blood flow, as compared with conscious bled rabbits. This was associated with a fall of 32% and 34% in superficial and deep cortical blood flow respectively. 7. Animals subjected to general anaesthesia may be particularly susceptible to the renal haemodynamic effects of haemorrhage.


Effect of hyperosmolar stimuli and coeliac disease on the permeability of the human gastrointestinal tract. 1. Oral loads have been used to assess the permeability of the human gastrointestinal tract, with lactulose (mol. wt. 342), raffinose (mol. wt. 504), stachyose (mol. wt. 666) and a fluoresceinlabelled dextran (mol. wt. 3000) as marker substances. Timed urinary recovery of these substances, which are not metabolized, was measured by quantitative paper chromatography and direct fluorimetry, and the results were used as an indication of passive intestinal permeability. 2. Results in healthy adults showed that permeability to these markers was dependent on molecular size, even after correction for aqueous diffusion differences, such that a profile of restricted permeability could be described for this range of markers. Interpretation in terms of conventional pore theory suggested the presence of more than one population of pores. 3. Ingestion of solutions made hyperosmotic by inclusion of glycerol resulted in a large increase in permeability, in a pattern that suggested an increase in either the size or frequency of a range of smaller pores. 4. A similar increase in permeability and alteration in the profile of restriction was found in patients with coeliac disease. 5. The possible location of such pores in the gastrointestinal mucosa is discussed in relation to the cell membrane, the intercellular junction, and the sites of cell exfoliation.


Effects of acute acid--base alterations on glutamine metabolism and renal ammoniagenesis in the dog. 1. The effects of acute acid-base alterations on renal ammonia production and glutamine metabolism were studied in anaesthetized dogs. 2. Plasma glutamine rose with acidosis and also when both PCO2 and plasma HCO-3 were raised isohydrically. 3. Blood urea fell when acidosis was induced with hydrochloric acid. 4. The renal production of ammonia per ml of renal blood flow was increased in acidosis, but this was independent of the amount of glutamine delivered to the kidney. 5. The results indicate that acute acidosis affects production of urea and glutamine and increases the capacity of the renal cells to extract glutamine from blood.


Determination of human leg blood flow: a thermodilution technique based on femoral venous bolus injection. 1. A thermodilution method was developed for the determination of human leg blood flow. The method is based on bolus injection of an indicator distally into the femoral vein, at room temperature, and recording of the dilution curve in the same vessel at the level of the inguinal ligament. The blood flow was computed automatically with two thermistors and an integrator. 2. The leg blood flow determined by this method at rest and during exercise at work loads of 50, 100 and 150 W in six healthy subjects was found to agree closely with measurements by an intraarterial indicator-dilution technique. A linear relationship was found between leg blood flow and work. The reproducibility of the blood flow determinations, expressed as the coefficient of variation for a single determination, was 12.9 at rest and 5.3 or less during exercise. 3. The method was used in two patients with occlusive arterial disease of the leg. Extremely low leg blood flows were found in these patients when they were forced to interrupt the exercise by severe calf pain


Saline-induced natriuresis in the dog without prior exposure of the kidney to the physical effects of expansion of the extracellular fluid compartment. 1. Experiments were carried out in dogs in which renal perfusion pressure was reduced 40 min before beginning expansion of the extracellular fluid space by 10% with isotonic sodium chloride solution. Sodium excretion increased up to 590% of control values in spite of the fact that the filtered load of sodium was below that of the control period and circulating mineralocorticoids were not suppressed. 2. The findings indicate that, in the dog, prior exposure of the kidney to the volume-expanded state is not a prerequisite for natriuresis to occur.


An evaluation of bilirubin kinetics with respect to the diagnosis of Gilbert's syndrome. 1. The kinetics of the plasma disappearance of bilirubin (2 mg/kg intravenously) were studied in 106 patients with Gilbert's syndrome and in 13 normal subjects. 2. All patients had significant decreases in hepatic bilirubin clearance and transfer rates from plasma to liver, resulting in increased values for plasma retention at 4 h. The calculated value for unconugated bilirubin production was normal in 40% of patients and increased in the remainder. 3. In 29 of the Gilbert's patients their bromosulphthalein kinetics were studied 1 week before the bilirubin test. These results were essentially normal and it was concluded that the hepatic clearance mechanisms for bilirubin and bromosulphthalein are different. 4. In 10 patients the bilirubin transport maximum (Tm) was found to be low whereas the relative storage capacity (S) was normal. Phenobarbitone treatment in four patients resulted in an increase in Tm, and S decreased in two patients and remained unchanged in the other two. 5. These results support the hypothesis that there are several variants of Gilbert's syndrome and that the bilirubin tolerance test is a useful diagnostic test.


The organelle pathology and demonstration of mitochondrial superoxide dismutase deficiency in two patients with Dubin--Johnson--Sprinz syndrome. 1. Liver biopsies from two patients with the Dubin-Johnson-Sprinz syndrome were subjected to analytical subcellular fractionation by sucrose-density-gradient centrifugation and enzymic microassays. 2. A selective deficiency of mitochondrial superoxide dismutase has been demonstrated in these patients. 3. The significance of this enzyme deficiency is discussed in relation to the organelle pathology of the syndrome.


Effect of saralasin and serum in myohaemoglobinuric acute renal failure of rats. 1. In rats deprived of food and water for 24 h acute renal failure was produced by the intramuscular injection of glycerol. Eight hours later plasma urea concentration had increased threefold despite a small rise in urine volume. Plasma concentrations of renin and renin substrate were elevated. 2. When saralasin, a competitive antagonist of angiotensin II, was infused for 8 h after glycerol injection, urine volume and plasma urea were similar to values in rats that had received an infusion of saline. 3. Administration of rat serum (4.5 ml h-1 kg-1) for 4 h suppressed plasma renin concentrations, but plasma urea increased to the same extent as in rats without serum. 4. When saralasin and serum were infused at the same time, urine volume, urine osmolality and solute excretion increased and the rise of plasma urea was diminished. 5. Saralasin has a protective effect against glycerol-induced acute renal failure only when volume is replaced concomitantly.


Renal prostaglandins in renal hypertensive dogs. 1. Hypertension produced in two-kidney Goldblatt dogs was accompanied by a transient fluid retention, reaching a maximum 4 days after clamping. 2. Prostaglandin E and F concentrations in venous blood from the intact kidney also rose transiently, showing a maximum by the fifth day. 3. The rise in prostaglandin release from the intact kidney may be related to the fluid retention.


Effect of zinc on leucocyte sodium transport in vitro. 1. In a preparation of human leucocytes maintained in tissue culture fluid, increasing the extracellular zinc concentration leads to a significant increase in both ouabain-sensitive sodium efflux and in sodium influx. 2. Cell water and sodium content do not alter significantly with increasing extracellular zinc concentration. 3. A small increase in the ouabain-insensitive sodium efflux can be demonstrated when the external zinc concentration is raised from 0.75 mumol/l to 90 mumol/l.


Rapid detection of amphetamine in urine by micro thin-layer chromatography and fluorescence. A rapid, inexpensive, and simple screening procedure for the detection of amphetamine abuse was developed for use by laboratories without sophisticated equipment. A small volume of extract from a pH-adjusted urine specimen is used to spot a high-resolution micro TLC plate. The developed TLC plate is sprayed with a solution of fluorescamine in dry acetone. When viewed under ultraviolet illumination, amphetamines and other compounds with a primary amino group complexed with fluorescamine appear as greenish or bluish-white fluorescent spots. Secondary or tertiary amines do not react with fluorescamine. About 20 min is required to perform the procedure; the lower limit of detectability is approximately 100 ng/ml urine.


Comparison of two procedures for determination of cholinesterase in livestock. Our data indicate that the serum or plasma Bio-Dynamics/bmc automated procedure may be substituted satisfactorily for, or used as an alternative method to the Radeleff procedure for determining cholinesterase activity in cattle, swine, and sheep. The automated procedure is capable of 77 determinations/hr, and the Radeleff procedures about 20/hr. Either serum or plasma may be used, but the sample must be hemolyzed.


Establishment of a regional poison center. Since its inception in 1972, the San Diego Poison Center has made considerable progress towards achieving its goal of developing a poison care system which will decrease incidence, morbidity, and cost of poisonings. A systems approach has been developed to care for patients at all levels of severity. Subregional centers have been identified and linked to the poison center. Education of the region's emergency medical personnel and the public have been actively pursued. Calls to the center have increased from 6829 in 1972 to 25,949 in 1976. Eighty-five percent of poisoning calls in 1976 were managed at home over the telephone. A follow-up call at 24 hours for each case revealed that less than 1% sought additional medical care. The percent of all emergency department visits resulting from poisoning in a tracer group (children under age 12 leaving emergency department asymptomatic) dropped from 6.1% in 1971 to 1.9% in 1976. The percent of hospital admissions due to poisoning in children under 10 years also dropped by 40% between 1971 and 1974. Estimated cost savings to the community by preventing emergency department visits alone each year covers the cost of operation of the poison center itself.


Basic principles in selecting animal species for research projects. One of the most important facets of biomedical research is selecting the species of laboratory animal best suited for a particular purpose. The four major categories of animal models are experimental, spontaneous, negative, and orphan. The experimental model is the one most frequently used, but each category has a place in medical research. Once the investigator has decided which type of model the project calls for, numerous other factors must be considered: ease of handling and surgical manipulation; size, docility, and body conformation; cost of the animal and its related supplies (food, bedding, and caging); the accessibility of superficial blood vessels; and the investigator's familiarity with the various species which are available. Among the biologic factors which should be considered are resistance to natural diseases, nutritional requirements, genotype, anatomy, physiology, and biochemistry.


First experience of a rehabilitation centre for schizophrenics in a developing country. The mental health services in Pakistan are still at the elementary level. There are only a few mental hospitals to look after the psychiatric needs of the country. The discharged patients from the mental hospitals find great difficulty in rehabilitating themselves in the community, particularly when the period of hospitalization has been long. This article discusses a new approach in psychiatric rehabilitation which is relevant to the needs of developing countries.


Using television for health education in rural India. The author relates his experiences in adapting the medium of television to the purpose of health education in rural India. Working under the auspices of the Indian Ministry of Information and UNESCO, he gained experience in the "appropriate" application of sophisticated Western technology to the needs of an underdeveloped area. Television is not a panacea for health education needs, but is nevertheless an important element in an overall health care strategy which must also involve the efforts of health administrators and practitioners at every level of society to further public education and the cultivation of preventive measures.


Effects of the first (ether) extract of ginseng on the cardiovascular dynamics of dogs during halothane anesthesia. An electromagnetic flowmeter probe was chronically implanted around the ascending aorta in ten dogs. Subsequently, these animals were maintained under halothane (0.75%) anesthesia during the intravenous administration of an ether extract (40 mg/kg) of ginseng. Five other dogs were anesthetized without injecting ginseng. Eleven cardiovascular variables including cardiac output, stroke volume, heart rate, mean arterial pressure, pulse pressure, central venous pressure, total peripheral resistance, pH, PaCO2, PaO2 and base deficit were compared during the ensuing 120 minutes. The heart rate was significantly decreased and central venous pressure increased significantly following ginseng. There were no other meaningful changes in either group.


Febrile spontaneous abortion and the IUD. A case-control study was done to determine the risk and pathogenesis of febrile spontaneous abortion for intrauterine device (IUD) wearers compared to non-wearers. Four groups of women coming to a large city hospital between 1970 and 1975 were compared: 1) women presenting with febrile spontaneous abortion, 2) women presenting with afebrile spontaneous abortion, 3) women presenting with afebrile spontaneous abortion which subsequently became febrile, and 4) women delivering a live infant. Pregnant women with an IUD in situ had a 5-fold higher risk of both febrile and afebrile spontaneous abortion compared to pregnant women without an IUD in situ. Women who had a spontaneous abortion that shifted from afebrile to febrile were somewhat more likely to be IUD wearers than the other 2 spontaneous abortion groups. In our study population, the increased risk of febrile spontaneous abortion for IUD wearers appeared primarily due to the increased risk of the spontaneous abortion event itself, rather than a primary IUD-related infection causing febrile spontaneous abortion.


Radioimmunoassay of norethindrone : serum levels of norethindrone in lactating women after insertion of a single Silastic implant releasing norethindrone acetate. A specific radioimmunoassay was developed for the estimation of norethindrone levels in the serum of lactating women. A conjugate of norethindrone-3-BSA was synthesized and antiserum raised against it in rabbits. The antiserum showed high affinity (1.5 x 10(9)M/L) and titer and was specific. The sensitivity of the assay was 125 pg/ml serum. Serum levels of norethindrone were estimated in 25 lactating women, inserted with subdermal implant releasing about 150 ug of norethindrone acetate daily. The norethindrone levels were initially high in the first two months. From there onwards the levels of norethindrone remained constant with an average value of 1.0 ng/ml up to six months. These values were comparable to those obtained in non-lactating women. Thus, lactation does not seem to alter or affect the release of norethindrone acetate from the subdermal implant or its metabolism.


A radioimmunoassay for norethindrone (NET): measurement of serum NET concentrations following ingestion of NET-containing oral contraceptive steroids. A sensitive and reliable radioimmunoassay (RIA) for the measurement of norethindrone (NET) in serum has been established employing anti-11 alpha-hydroxynorethindrone 11-hemisuccinyl-bovine serum albumin serum in conjunction with norethindrone-3-(0-carboxymethyl) oximino-[125I]-iodohistamine. Of a number of ring A reduced NET metabolites, only 17 beta-hydroxy-17 alpha-ethinyl-5 beta-estran-3-one (43%) and 17 alpha-ethinyl-5 alpha-estrane-3 beta, 17 beta-diol (15.7%) cross-reacted appreciably in this RIA. Ethinyl estradiol (EE2) and mestranol (MEE2) exhibited cross-reactions of only 1.1 and 0.4%, respectively. Serum NET levels were measured in four groups of 3 women, each ingesting either 1 mg NET plus 0.05 mg MEE2 (Norinyl 1 + 50 or Ortho Novum 1/50), 0.5 mg NET plus 0.035 mg EE2 (Brevicon) or only 0.35 mg NET (Micronor) daily for 5 consecutive days. Peak serum NET levels were observed within 1/2 to 4 hours after oral intake and fell precipitously thereafter. After reaching a maximum, serum NET concentrations declined in a manner consistent with at least two disposition phases. The average half-life for the first disposition phase was 2.3, 3.4, 3.9 and 4.4 hours in subjects ingesting Norinyl 1 + 50, Ortho Novum 1/50, Brevicon and Micronor, respectively. Peak and 3-hour post-ingestion serum NET concentrations were dose-related but showed considerable subject-to-subject variations. Following discontinuation of tablet intake, serum NET levels remained detectable (greater than 0.05 ng/ml) for at least 5 days in all 3 women who had taken Ortho Novum 1/50, but in none of the other 9 volunteers. These results suggest that different preparations of identical doses and combinations of oral contraceptive steroids may yield different serum NET profiles. However, due to considerable subject-to-subject variations, larger numbers of subjects are required for a conclusive investigation.


Termination of second trimester pregnancy with intraamniotic administration of 16-phenoxy-omega-tetranor-PgE2-methylsulfonamide (SHB 286) alone and combined with oxytocin and calcium gluconate. Midtrimester abortion was succesfully induced within 30 hours in 62 out of 90 patients by intraamniotic administration of 16-phenoxy-omega-17,18,19, 20-tetranor-prostaglandine-E2-methylsulfonamide. The Pg-analogue was tested in 5 groups of patients which received 1,2 or 3 mg. In group IV, 2 mg of the analogue was combined with oxytocin. In group V, 3 mg of the analogue was combined with 2.75 grams of calcium gluconate. The success rate was significantly influenced by the amount of the drug administered. Side effects were minimal. Multiparous women respond better to the therapy than nulliparous patients. The combination with oxytocin was more effective than the Pg-analogue alone and the combination of sulprostone with calcium gluconate was 87% succesful within 30 hours and 100% succesful within 36 hours.


Use of intra- and extra-amniotic prostaglandins for the termination of pregnancies--report of multicentric trial in India. The Indian Council of Medical Research initiated a multicentric trial with prostaglandins in 1976 to assess the safety and efficacy of their use in midtrimester abortions. PGF2 alpha and 15-Me-PGF2 alpha were compared using the intra-amniotic (I.A.) route. 15-Me-PGF2 alpha was also evaluated by extra-amniotic (E.A.) route. With intra-amniotic instillation, success rate was 88.1 per cent with PGF2 alpha and 93.0 per cent with 15-Me-PGF2 alpha within 48 hours and by the extra-amniotic route it was 78.1 per cent within 36 hours. The mean induction-abortion interval was 19 hours with I.A. and 14.8 hours with E.A. Abortions were complete in 48.8 per cent of the women following I.A. PGF2 alpha, 56.0 per cent following I.A. 15-Me-PGF2 alpha and only 23.0 per cent following E.A. administration. Vomiting and diarrhoea were the most commonly reported side effects. Cervical injuries were 4.7 per cent with I.A. PGF2 alpha, 1.4 per cent with I.A. 15-Me-PGF2 alpha and only 0.6 per cent with E.A. route.


Prenatal progesterone. I. Its effect on development and on intellectual and academic achievement. The development of two groups of children whose mothers had been given progesterone supplements during pregnancy to relieve symptoms of toxaemia was assessed, one group at 2 yr of age and the other at 16 yr of age. There was no evidence that progesterone supplements accelerated development in the 2-yr-old age group or enhanced intellectual and academic attainment in the 16-yr-old age group. In addition, the evidence regarding the reported beneficial effects on intellectual attainment of in utero exposure to excess sex steroids is discussed.


Prenatal progesterone II. Its role in the treatment of pre-eclamptic toxaemia and its effect on the off-spring's intelligence: a reappraisal. Dalton's results concerning the beneficial effect of progesterone supplementation in preventing pre-eclamptic toxaemia [16] and in enhancing intellectual potential [17,18] were reappraised. We could find no evidence in the data that progesterone supplementation was any better at preventing pre-eclamptic toxaemia than treating the disorder symptomatically. Nor could we find any convincing evidence that excess progesterone enhances development at 1 yr of age, academic attainment at 9--10 yr of age, or success in school leaving examinations and improves the chances of continuing further full-time education after leaving school.