Collecting and processing records from the ultracentrifuge in "real-time" using an on-line computer. An analytical system consisting of an analytical cantrifuge coupled 'on-line' to a computer was assembled and tested. Collection of records from up to 9 solutions was achieved through programmes which sum readings to reduce noise as well as controlling the positioning of the scanner. With this system it was found that the limit on accuracy for molecular weights at concentrations less than 0.01 g cm-3 was +/- 3% estimated from sedimentation equilibrium experiments. The same system was used to collect records for similar concentrations from velocity experiments by employing a scanning schlieren. In this case the accuracy in estimating sedimentation coefficients was similar to those found when measuring photographs. Since the collection yields detailed information about the shape of the sedimenting boundary, the centroids of the boundary were routinely computed by second moment analysis rather than relying on the position of the maximum of the schlieren peak. In the same analysis estimates of diffusion coefficients were made routinely by calculating corrected height/area ratios for each scan. These calculations were made during the real-time of the experiment, so making available molecular parameters rather than records which must be evaluated some time after stopping the experiment.


A television scanner for the ultracentrifuge. II. Multiple cell operation. The "Optical Multichannel Analyzer" (OMA) is a commercially available instrument that with the absorption optical system of the ultracentrifuge, provides an entire 500 channel intensity profile of a cell in real time. With its own analog-todigital converter, the OMA integrates a selectable number of 32.8 msec scans to provide a time-averaged image in digital form. This paper describes an interface-controller for operation of the OMA with single- and double-sector cells in multi-cell rotors, simulating double-beam measurement required for absorbance determinations. The desired sector is selected by "gating" the intensifier stage of a "Silicon Intensified Target" vidicon (SIT) used as the light detector. The cell location in the rotor and the position of the gate relative to the cell centerline is obtained from a phase-locked loop circuit which divides each rotation of the rotor into 3600 parts independent of rotor speed. (This circuit employed with photo-multiplier scanners would select the gate position for integration of photomultiplier pulses.) From examination of appropriate signals with an oscilloscope, it was verified that gate positions and widths are located with an accuracy of 0.1degree or better and with a precision of +/- 0.1 mus. The light intensity profile for any desired cell can be examined in "real time", even during acceleration of the rotor. Additional circuits employing a 10 MHz crystal clock 1) control the automatic collection of data for all sectors in multicell rotors at digitally selected time intervals, 2) display the rotor speed, and 3) indicate the elapsed time of the experiment. Constructed but not tested are additional circuits for pulsing a laser into the absorption or Rayleigh optical system. The accuracy of the pulsed SIT has been demonstrated by measurement of absorbances of solutions and also by sedimentation equilibrium experiments with myoglobin. The estimated error is 0.003 for absorbances ranging from 0 to 1. The interface-controller operates extremely well, but problems related to the pulsed SIT (optimum gate position relative to the sector opening shape of high-voltage pulse, slight pincushion distortion) require more work.


MaD, an automated precise analytical ultracentrifuge scanner system. The various hardware components of this scanning system, a mechanical split-beam scanner with its photomultiplier measuring slit, minimum analog electronics and an important digital part (computer, interface), are intimately interwoven by an elaborate software. A high degree of automation and sophistication is thus reached. On the one hand, all the photoelectrons coming from each light pulse are integrated. The result, after conversion to digital form enters the computer; a high precision is thus reached: 10(-5) absorbance unit (A.U.) under very favorable conditions, and 10(-4) A.U. for conventional sedimentation studies. On the other hand, during its motion along the image, the precise slit position is permanently known by the system: the sector image is thus segmented into precisely defined zones, inside which the average absorbancies are determined, punched, plotted and printed. New and very useful utilizations and improvements of analytical ultracentrifugation are now possible: the fixed radius mode, permits precise s determination by following the radial dilution; s can be precisely measured by time difference curves even when the solution absorbancy is comparable to the base line variations (0.01 A.U.); round trip analyses permit very long analyses without the absorbancies distributions distorsions due to very long one-way scans during sedimentations runs; reductions of the effect of the stray light by a factor of ten. This system has been in routine use for four years.


Some general aspects regarding the interpretation of binding data by means of a Scratchard plot. The question is quantitatively examined which general information can be obtained from experimental data of ligand binding to macromolecules if represented by a Scatchard plot. In particular, the curvature as well as the intercepts and slopes at both coordinate axes are analyzed assuming rather general conditions including cooperative behavior (with applications to some simplified cases of interest in practice). The results should provide a basis for attempts to elucidate the binding mechanism of a system encountered in experimental work.


Studies on the origin of the tip potential of glass microelectrode. 1. Tip potential (TP) of glass microelectrodes filled with 3 M KCl increased remarkably with the increase in the storage period in 3 M KCl solution at 37 degrees C, while the electrode resistances decreased gradually. 2. The electrical conductivity through the thin glass wall near the tip was found to increase in parallel with the TP increase. 3. The e.m.f. across the thin glass wall in the tip region was directly measured. This seems to contribute to the TP generation of the microelectrode when the conductivity of the glass wall is significantly high in the tip region. 4. Effects of the acid treatment of glass employed and the acidification of fillant electrolyte solution suggested that fixed negative charges on the glass wall play a fundamental role in the TP formation. 5. Based on these experimental results, it was concluded that not only the diffusion potential through the tip pore but also the interfacial potential through the thin glass wall near the tip contributes to the TP generation, and the contribution of the latter increases with a long exposure period of the electrodes to electrolyte solution. 6. In this connection, technical problems related to reduction of the tip potential were also discussed.


Subunit symmetry of tetrameric phosphorylase a. Native crystallographic data of tetrameric phosphorylase a crystals, space group P21, have been collected photographically to 3 A resolution. These data have been used in Patterson search methods in reciprocal and real space. The tetramers were found to exhibit molecular 222 symmetry. The cross vector between the centres of the two symmetry related tetramers in the unit cell was determined by two different translation function methods. On the basis of these rotation and translation function results a model for the arrangement of monomers within the tetramer and of tetramers in the unit cell is proposed; The 222 symmetry of the tetrameric molecule is found only when high resolution diffraction data are included (i.e. higher than 6 A). At lower resolution other symmetries dominate. Calculations with the proposed model have shown that these spurious symmetries result from the nonspecific overlap of protein-protein and solvent-solvent cross vectors. These results emphasize the importance of high resolution data when noncrystallographic symmetry of globular proteins is studied.


Measurements on fast light-induced light-scattering and -absorption changes in outer segments of vertebrate light sensitive rod cells. Flash-induced changes of light-absorption and of light-scattering of vertebrate rod outer segments (ROS) from frog and cattle in suspension were measured at 380 and 800 nm. The photometer used allows the observation of light intensity changes under well defined angles. We studied the successive decrease of the signal amplitude in series of flashes. One flash bleaches about 1% rhodopsin. The following results are discussed: 1. The signal at 380 nm is a superposition of the absorption change caused by formation of metarhodopsin II and of a biphasic additional signal. The latter exists only for the initial range of bleaching (15 to 25% rhodopsin). 2. At 800 nm three scattering signals are observed which are characterized by their successive amplitude decrease and time course: N: A small signal with time course and successive amplitude decrease comparable to the metarhodopsin II absorption change, probably arising from a structural change within the disc membrane. Ni: A slow signal, disappearing with the first flash, which may be understood as an outer membrane effect. P: A biphasic signal with a successive decrease rate, by a factor of 10 to 20 higher than that of the metarhodopsin II signal. The two kinetically different components are separated by variation of the observation angle. Two regions of different extension appear to change structurally with different time course. "P" may reflect an influence of the light-induced transmitter release on disc shape and/or mass.


Evidence for chromophore-chromophore interactions in the purple membrane from reconstitution experiments of the chromophore-free membrane. We recently presented evidence showing that the visible CD spectrum of the purple membrane from Halobacterium halobium consists of two contributions: a broad positive band centered at the absorption maximum due to the interaction of the chromophore with the protein to which it is bound, and an exciton coupling band due to the interaction between chromophores of adjacent bacteriohodopsin molecules in the hexagonal surface lattice (Heyn et al., 1975); This interpretation receives strong support from the present experiments in which the chromophore-free membrane is reconstituted by the addition of retinal. Since the coupling signal arises from the interaction between pairs of neighboring chromophores, its contribution to the spectrum would be expected to be very small in the initial stages of the titration experiment, but increasing quadratically with the percentage reconstitution. The broad positive band, on the other hand, is expected to increase linearly with the percentage reconstitution. On the basis of these considerations a satisfactory explanation of the CD reconstitution experiments could be given. Since it appears to be impossible to explain the titration experiments without the quadratic term, we conclude that chromophore-chromophore interactions play an important role. No significant changes in secondary structure upon reconstitution should be detected consistent with our binding model which neglects cooperativity;


Some similarities between processes at biological membranes and lipid bilayers. Several processes at biological membranes can be simulated by experiments with artificial lipid bilayer membranes. Three selected examples are discussed: The uncoupler induced proton permeability of lipid bilayers, the initiation of action potential like voltage responses in lipid membranes, and the reconstitution of active cation pumps across planar lipid bilayers or lipid vesicles.


Investigation of the relation between structure and function in myelinated nerve fibres with be aid of ultraviolet radiation. Ultraviolet radiation induces two photochemical alterations relevant to excitability in the nodal membranes: A selective blocking of the sodium permeability and a potential translation of the voltage dependent kinetic parameters of sodium inactivation and activation along the potential axis in the negative direction. The underlying processes are two different photoreactions, since 1) the action spectrum of the blocking effect shows a marked peak near 280 nm and rapidly decreasing sensitivity towards higher and lower wavelengths, while the action spectrum of the potential shift increase with lower wavelengths; 2) the blocking effect is enhanced by a more positive holding potential, while the potential shift is decreased; 3) the potential shift can be prevented intraaxonal application of l-cysteine or 2-mercaptoethanol, but the blocking effect is not affected.


The structure of two alanine containing ferrichromes: sequence determination by proton magnetic resonance. Metal coordination confers an extraordinary structural stability to the ferrichromes which, independent of their variable amino acid composition, results in a basically unperturbed conformation for all the homologous peptides in the series. The proton magnetic resonance (pmr) characteristics for Al3+ analogues (alumichromes) reflect this conformational isomorphism in usual solvents so that single site substitutions are clearly recognized in the pmr spectra. Thus, the substitution of glycine by L-alanine or L-serine introduce new resonances characteristic of the sidechains and alter the pattern of the amide NH pmr region in that doublets substitute for glycyl triplets at the same site. Since for glycine- and L-serine containing alumichromes the resonances have already been identified, it is possible to unequivocally establish the primary structure of the two L-alanyl homologues ferrichrome C (see article) and sake colorant A (see article) on the basis of the comparative pmr spectra of their Al3+ analogues, namely, alumichrome C and alumisake. The resonance assignment, and hence the site occupancy, is substantiated by the temperature coefficients of the NH chemical shifts, rates of 1H-2H exchange and homonuclear proton spin decoupling experiments centered on the NH spectral region. Occupancy of site 1 by a glycine residue is observed for all known ferrichromes, which serves to conserve a "hairpin" turn. This method of obtaining sequence information should prove of general use for other systems of homologous polypeptides, provided their conformations are not affected by the residue substitutions.


Optical and electrical studies on dansyllysine-valinomycin in thin lipid membranes. Dansyllysine-valinomycin, a fluorescent analogue of the ionophore valinomycin was synthesized and incorporated into black lipid membranes. Its concentration inside the membrane was measured fluorometrically and was also determined from electrical relaxation experiments, which were analyzed on the basis of a previously proposed carrier model. The results of both methods agreed within less than one order of magnitude. This appears satisfactory in view of the sources of error inherent in both procedures. A conductance increment per carrier molecule of about 3 - 10(-17) omega-1 was obtained for dansyllysine-valinomycin in diphytanoyllecithin membranes at 25 degrees C and 1 M RbCl in the aqueous phases. This is about 400 times smaller compared to unmodified valinomycin in monoolein membranes. The difference is mainly caused by the change in the membrane properties and to a smaller extent by the structural modification of the carrier.


The effect of temperature on canine papillary muscle. Measurements of the total duration, tA, of the action potential for canine papillary muscle in the temperature range 25-45 degrees C are shown to follow the law ta = tau exp (Q/kBT), with tau and the activation energy Q independent of temperature, T, and kB equal to Boltzmann's constant. The value obtained for Q = 0.65 +/- 0.10 eV. Results are also presented for the temperature dependence of points V(x) on the action potential curve, where x is the percentage of repolarisation within the range 30% less than x less than 100%.


Applications of computerized pattern recognition: a survey of correlations between pharmacological activities and mass spectra. Correlations between mass spectra and pharmacological activities were surveyed by means of computerized learning machine and cluster analysis. The principal component analysis and the nonlinear mapping techniques were used for the feature selection of the data set.


Mass spectral study of derivatives of the four bilirubin-IX isomers. The beta, gamma and delta isomers of bilirubin-IX show a decreased stability as compared with the IXalpha isomer; characteristic mass spectra are obtained only for the tetrakis-(trimethylsilyl) derivatives of the IXalpha and IXgamma isomers. Hydrogenation of the vinyl substituents increases the thermal stability of the bilirubins and gives rise to a characteristic mass spectrum for the tetrakis-(trimethylsilyl) derivative of meso-bilirubin-IXdelta. The ethyl anthranilate azopigments derived from the four bilirubins yield characteristic mass spectra, except for the two unstable divinyl substituted azodipyrroles (mol. wt. 416), derived from bilirubin-IXbeta and IXdelta. The corresponding mol. wt. 420 azopigments derived from the hydrogenated bilirubins are thermally stable. Elucidation of mass spectral fragmentation pathways is facilitated by the varying positions of the substituents and by deuterium labelling, and permits the assignment of structures to the various isomeric azodipyrroles.


Trimethylsilyl group migration during electron impact and chemical ionization mass spectrometry of the trimethylsilyl ethers of 20-hydroxy-5alpha-pregnan-3-ones and 20-hydroxy-4-pregnen-3-ones. The electron impact and chemical ionization (isobutane) mass spectra of the TMS derivatives of 20-hydroxy-5alpha-pregnan-3-ones and 20-hydroxy-4-pregnen-3-ones include ions [M--44]+-attributable to loss of a CH3CHO fragment from C-17 with migration of the TMS group to the charge-retaining fragment. Mass spectra of isotopically labelled ([3-18O], [20-18O] and [2H9-TMS]) analogues are consistent with this mechanism; [2H9-TMS] labelling further indicates that subsequent loss of a methyl group from [M--44]+-ions does not involve the TMS group. Corresponding ions are not observed at significant abundance in the spectra of 20beta-trimethylsilyloxy-5alpha-pregnane and 20beta-trimethylsilyloxy-4-pregnen-3-one 3-O-methyloxime. In the electron impact mass spectrum of the t-butyldimethylsilyl ether of 20beta-hydroxy-4-pregnen-3-one, an ion is observed corresponding to loss of 44 atomic mass units from the intense [M--C4H9]+ ion.


Mass spectrometry of N-acylated daunorubicin derivatives. The mass spectra of peracetylated daunorubicin, N-octanoyl-, N-dodecanoyl- and N-(N'-dodecanoyl-glycyl)daunorubicin, and perdeuteroacetylated N-dodecanoyldaunorubicin were analyzed. Major fragmentation pathways were suggested and ion compositions were determined by high resolution measurements.


Field desorption mass spectrometry of phospholipids. II--Fragmentation of dipalmitoylphosphatidyl choline from comparison of d0, d4 and d9 species. Field desorption mass spectra have been obtained for dipalmitoylphosphatidyl choline-d0, -d4 and -d9. The two latter compounds were synthesized from dimethylene-d4 choline bromide and trimethyl-d9 choline bromide, respectively. Comparison was made of spectra of these three compounds obtained at different field anode temperatures in order to establish the composition of the major cleavage, rearrangement, and association ions. At low anode heating currents (less than or equal to 20 mA) the most intense peak is [M + 1]+ which accounts for c. one-third of the total ionization. At higher temperatures various fragmentation processes, some of which are without analogy in electron impact mass spectrometry, become more important. The presence of an intermolecular methyl transfer process had been confirmed.


Electron impact-induced reactions of N6-(3-methyl-2-butenyl)adenosine and related cytokinins. Fragmentation reactions of the biologically important N6-(3-methyl-2-butenyl)adenyl moiety have been re-examined with the aid of systematic deuterium labeling in the sidechain and by examination of the 1- and 7-deazanucleoside analogs. It is concluded that the diagnostic reactions which involve expulsion of C3H7 proceed predominantly by ring closure from the sidechain double bond to N-1 (ion a). Base-containing ions m/e 135 and 148 were confirmed to arise mainly by rearrangement of hydrogen from the methyl terminus to N6 and simple cleavage, respectively, but with significant contribution from other pathways involving transfer of sidechain hydrogens to the base.


Quantitative determination of salbutamol in plasma, as either its trimethylsilyl or t-butyldimethylsilyl ether, using a stable isotope multiple ion recording technique. Two methods are described for the determination of salbutamol in human plasma. The drug is extracted from the plasma as a salbutamol tetraphenylboron ion pair and determined by gas chromatography mass spectrometry. Trideuterio-salbutamol is used as an internal standard. In the first method an extensive purification procedure is used to separate salbutamol from plasma cholesterol which interferes in the assay. Salbutamol is then determined as its TMS-ether using a multiple ion recording technique to measure the intensity of the fragment ion m/e 369 and the ion m/e 372 from the TMS ether of trideuterio-salbutamol. The second method is based on the ion pair extraction of salbutamol into heptan-3-one and its determination by gas chromatography mass spectrometry as the t-butyldimethylsilyl ether. The base peak in the mass spectrum of the t-butyldimethylsilyl-salbutamol is an ion of m/e 495, which is of sufficiently high mass to distinguish it from any of the ions which arise from t butyldimethylsilyl-cholesterol. Six replicate analyses of plasma samples containing 1 ng salbutamol ml-1 were carried out using both methods. When the first method was used the mean value obtained was 1.3 ng ml-1 and the coefficient of variation was 17.7%. When the second method was used the mean value obtained was 0.95 ng ml-1 and the coefficient of variation was 10%. The second method is more rapid and therefore preferable for use in clinical pharmacological studies. This method has been used to determine the plasma salbutamol concentrations at varying times after either a 4 mg oral or a 200 mug intravenous dose of salbutamol to man.


The use of N-succinyl derivatives in the study of amino acids and peptides by mass spectrometry. The terminal amino group of amino acids and peptides is blocked as the N-succinyl derivative by reaction with succinic anhydride. The product is then converted to the N,O-permethyl derivative in order to increase its volatility for use in mass spectrometry. The permethylated N-succinyl derivative retains the advantages of the permethylated N-acetyl derivative in regard to ease of preparation on a small scale, volatility and the presence of characteristic fragmentation patterns in their mass spectra. However, peaks in the high mass region are more abundant due to loss of CH3O-from the N-succinyl carbomethoxyl group as well as from the C-terminal carbomethoxyl group. Ions characteristic of the sequence and of individual amino acids are observed, and molecular weight can be determined from the relatively abundant ion at [M--CH3O]+ and from the weak molecular ion.


Identification of N-nitrosodimethylamine in ambient air by capillary gas-liquid chromatography mass spectrometry computer. Organic vapors in ambient air, at or near an industrial site in Baltimore, Maryland, were collected by adsorption on a sorbent of porous polymer (Tenax GC, 35/60). The pollutants were recovered by thermal desorption and analyzed by gas-liquid chromatography mass spectrometry computer using capillary glass SCOT columns. N-Nitrosodimethylamine was identified from its mass spectrum as a constituent of the atmosphere in the areas sampled. The identification of this compound was confirmed by comparison of its mass spectrum with that of authentic N-nitrosodimethylamine; identical retention times of unknown and authentic compound on three different capillary columns were observed.


Use of a tapered fluidized bed as a continuous bioreactor. Reactor systems based on tapered fluidized beds are being developed for aqueous bioprocesses in which adhering microorganisms or immobilized active biological fractions are used. The use of a fluidized bed prevents biomass buildup, accommodates particulates in the feed stream, is compatible with gas sparging, and allows easy removal or addition of the active materials. The tapered reactor tends to stabilize the fluidized bed, thus allowing a much wider range of operating conditions. Preliminary experimental results and an empirical mathematical model of the tapered bed indicate that bed stability is associated with a decreasing velocity and void-fraction profile up the bed and the pressure drop across the bed decreases with increasing flow rates. The tapered fluidized bed bioreactor is being evaluated for use in the enzymatic production of hydrogen, microbiological denitrification, and microbiological degradation of coal conversion aqueous waste streams. The enzyme catalyzed conversion of lactose to glucose and galactose was used in the evaluation of the reactor concept.


Automatic membrane-filtration system for the "on-demand" supply of large volumes of sterile medium in continuous culture. The construction and use of an automated membrane filtration system is described which produces 300 liters per day of sterile medium over at least four months of continuous fermentation. The capacity of the system is limited only by choice of filter type and has applications in continuous pilot plant work or medium-scale batch fermentation, in the bulk supply of communally used laboratory medium, in supplying banks of small-scale continuous fermentors, and for remote control of medium supply in hazardous fermentations (e.g., methane) with great savings in time and materials. Only two sterile storage jars are needed, irrespective of the total demand for the medium.


Aerobic microbial growth in semisolid matrices: heat and mass transfer limitation. A conceptual model of aerobic microbial growth in semisolid matrices were developed as a first step in the prediction of the rate of breakdown in semisolid cellulosic material. The conceptual model was described by a series of equations simplified by the assumption of steady-state microbial activity, and heat and mass transfer limitation. Temperature and oxygen distribution in compost piles were measured experimentally at the Butler County Mushroom Farm, Butler County, Pennsylvania, to test the validity of these assumptions. The compost piles consisted of ground corn husks, straw, and race horse manure. The data fit with the model was excellent with deviation between model predictions (as solved by an anglog computer) and actual temperature measurements never exceeding 3 degrees C. The effects of compost pile geometry, external temperature, compost density, external oxygen concentration, and insulation at the bottom of the pile were then predicted using a digital computer to solve the model. The predicitions show that the maximum breakdown rate occurs for an optimum height (which depends upon the system), insulating the base increases the breakdown rate, increasing the external temperature increases the initial breakdown rate but decreases the pseudo-steady-state breakdown rate and the uniformity and any increase in the external oxygen concentration increases the breakdown rate but decreases the uniformity.


Utilization of cellulosic materials through enzymatic hydrolysis. II. Preliminary assessment of an integrated processing scheme. An integrated processing scheme is described for the conversion of a celluosic waste (newsprint) to sugrsa by enzymatic hydrolysis and then to ethanol and yeast by fermentation. The unconverted solids are burned to produce process energy requirements and surplus electrical power. Preliminary designs and cost studies are developed to provide a rough perspective on the potential economic feasibility of this method of cellulose utilization.


A clinical study of the lupus anticoagulant. Eighty-three patients with circulating anticoagulants were studied at The New York Hospital. The lupus-type anticoagulant, an inhibitor of the prothrombin activator complex, was demonstrated in 58 patients. The inhibitor was identified using the blood and tissue thromboplastin inhibition tests. Inhibition by the lupus anticoagulant was augmented in 67% of these patients by a cofactor present in normal plasma. The lupus inhibitor was detected primarily because of an unsuspected abnormal coagulation test. One-half of the patients with the lupus-type anticoagulant did not have systemic lupus erythematosus.


Acquired storage pool disease in platelets during disseminated intravascular coagulation. A patient with clinical and laboratory evidence of disseminated intravascular coagulation associated with deep-vein thrombosis and pulmonary embolism developed a qualitative platelet abnormality characterized by a defective release reaction. Second-phase aggregation induced by ADP and adrenaline was impaired, and reduced collagen-induced aggregation was accompanied by defective release of ADP and ATP. The decrease in total platelet ATP and ADP, the high ATP:ADP ratio in the presence of normal amounts of metabolic adenine nucleotides, and the low content of serotonin associated with abnormal uptake and metabolism of the exogenous amine suggested that the defective platelet function was due to lack of the platelet organelles in which serotonin and nonmetabolic adenine nucleotides are normally stored. Acquired storage pool disease is likely to be related to exposure of circulating platelets to aggregating agents, with their degranulation occurring during disseminated intravascular coagulation.


A platelet abnormality in the Chediak-Higashi syndrome of man. Platelets from two probands homozygous for the Chediak-Higashi syndrome have approximately 10% of the normal number of serotonin-containing dense bodies as visualized electron microscopically in air-dried whole mounts. Since transport of serotonin across the platelet plasma membrane proceeds at a normal rate, and the few dense bodies present appear to store normal amounts of serotonin, the absence of dense bodies may account for the low platelet serotonin values found in these patients.


Immunologic characterization of canine factor VIII. Canine factor VIII (FVIII) preparations isolated from cryoprecipitates by gel chromatography were pooled to provide one batch of antigen for simultaneous immunization of two rabbits and a goat. The goat and rabbit antisera had similar FVIII-neutralizing titers, but the latter had seven to ten times more precipitating titer for FVIII-related antigen (FVIII-RA). Absorption with material low in FVIII had little effect on the precipitating titer of the rabbit antibody, but it abolished the precipitating capacity of the goat antibody and caused a 20% reduction in the neutralizing titer of both antisera. Results obtained in the Laurell assay with the two different antisera were similar. This finding was true whether the FVIII-RA levels were reduced, normal, or elevated, as well as for heat-treated and frozen-thawed plasmas. Both antisera were neutralized by the same canine plasma to a similar extent. Analysis of FVIII concentrates by crossed immunoelectrophoresis suggested that canine FVIII-RA was heterogeneous, with slow-and fast-migrating components. The presence of more than one antigenic site on the FVIII complex was also supported by the disparity between the FVIII-neutralizing and -precipitating titers of goat antiserum and by the demonstration that FVIII-RA, FVIII-neutralizing antigen, and procoagulant activity varied independently.


Relationships between thrombopoiesis and erythropoiesis: with studies of the effects of preparations of thrombopoietin and erythropoietin. The effects of administration of partially purified human urinary erythropoietin and rabbit thrombopoietin, and of endogenously produced erythropoietin and thrombopoietin on both red cell and platelet production were examined in mice. Partially purified thrombopoietin was prepared from rabbit plasma by sequential fractionation with ammonium sulfate precipitation, and DEAE and Sephadex G-100 chromatography. Preparations of thrombopoietin and partially purified human urinary erythropoietin (NIH No. H-11-TaLSL) were administered subcutaneously to normal mice, and the rate of incorporation of selenomethionine-75 Se into platelets was measured as an index of thrombopoietic activity of the infused material. Erythropoietin and thrombopoietin were assayed for erythropoietic activity by measuring the rate of appearance of 59Fe in the red cells of posthypoxic polycythemic mice. Preparations containing thrombopoietin had barely measurable erythropoietic activity, and 7 units of partially purified erythropoietin had little thrombopoietic activity. When endogenous levels of erythropoietin were increased by hypoxia, platelet production was not enhanced. Similarly, increased levels of thrombopoietin, induced in response to thrombocytopenia produced by platelet antiserum, did not alter red cell production. These data suggest that physiologically increased levels of thrombopoietin do not stimulate erythropoiesis, and that physiologically increased levels of erythropoietn do not stimulate thrombopoiesis. However, currently available, partially purified preparations of erythropoietin and thrombopoietin may be capable of stimulating both platelet and red cell production if used in sufficient quantities.


Duplication of part of the long arm of chromosome 1 in marrow cells of a treated case of myelomatosis. In a case of classical myelomatosis treated with melphalan, a clone of cells with a chromosomal abnormality was found in the bone marrow during remission. There was good reason to think that the hemopoietic cells, rather than plasmacytoma cells, were implicated. Although the clone persisted, no evidence of leukemia developed over a period of observation of 2 yr. The anomaly was interpreted as a duplication of part of the long arm of chromosome 1, which appeared to involve the segment q21 to q31.


Some observations of the hematopoietic status in vivo and in vitro on mice of genotype S1/S1d. Studies on the mechanism of anemia in mice of genotype S1/S1d have implicated the hematopoietic stroma (the hematopoietic inductive microenvironment, HIM) rather than hematopoietic stem cells as the site of the defect. Using methylcellulose-supported bone marrow culture systems, we have observed, in addition to classical hematopoietic colonies, the formation of surface associated fibroblastic plaques that could stimulate hematopoietic colony growth. These plaques were hypothesized to be derived from bone marrow stroma precursors. In view of the reported stromal-based defect in S1/S1d mice, studies were initiated, using our culture system, to determine if abnormalities exist in the plaque-forming potentials of these mice. Relative to controls, bone marrow derived from S1/S1d mice exhibited a significant decrease in hematopoietic colonly-forming units in culture, but no differences were apparent in the absolute numbers of fibroblastic plaque-forming units or in the ability of such plaques once derived to stimulate hematopoietic colony growth when overlain with fresh normal bone marrow preparations. Quantitative studies on the bone marrow of the S1/S1d mice revealed a marked reduction in total nucleated cells per femur. The importance of evaluating the results of bone marrow cultures in an absolute (i.e., number of units per femur) rather than a relative (i.e., number of units forming in a constant cell inoculum) term was underlined by these studies.


Synthesis of cobalamin coenzymes by human lymphocytes in vitro and the effect of folates and metabolic inhibitors. The uptake of 57Co-cyanocobalamin (CN-Cbl) and its conversion to 5-deoxyadenosylcobalamin (Ado-Cbl), methylcobalamin (Me-Cbl), and hydroxocobalamin (OH-Cbl) has been studied in phytohemagglutinin (PHA)-transformed lymphocytes from normal subjects and patients with patients with pernicious anemia. Uptake and conversion were much greater by PHA-stimulated lymphocytes than by mature non-transformed lymphocytes. In normal cells, uptake of 57Co-CN-Cbl and synthesis of the cobalamin coenzymes were approximately linear between 3 and 48 hr incubation. Ado-Cbl was the major cobalamin formed, and after 72 hr the cells contained about twice as much Ado-Cbl as Me-Cbl. Uptake by lymphocytes from patients with untreated pernicious anemia (PA) was greater than that by normal lymphocytes, but the proportions of Ado-Cbl and Me-Cbl synthesized by each were similar. Folic acid and methyltetrahydrofolate enhanced synthesis of Me-Cbl both in normal and in PA cells, while methotrexate and 5-fluorouracil depressed it. This depression was overcome by 5-formyltetrahydrofolate, suggesting that an uninterrupted folate cycle may play an important role in Me-Cbl synthesis.


Detection of carriers of hemophilia by hemorrhagometry. Hemorrhagometry measures bleeding time, bleeding intensity and blood loss from a small standardized skin wound. In patients with hemophilia these values are within the normal range when hemorrhagometry is performed at room temperature (24 degrees C). However, when the wound is cooled to 17 degrees C (cold tolerance test), bleeding time is abnormally long in hemophiliacs. Therefore we applied this test to carriers of hemophilia. The cold tolerance test was performed in 16 proven and 6 probable carriers (criteria according to Nilsson). 14 proven and 4 probable carriers showed abnormal bleeding times of 15 min and more. When hemorrhagometry was performed at room temperature, the carriers could not be distinguished from normal control persons. Of 15 sisters and aunts of hemophiliacs without male offspring (potential carriers) 9 had abnormal cold tolerance test findings, in fair agreement with the probability of 0.5 to be expected theoretically. Thus the hemorrhagometry cold tolerance test seems to be helpful in detecting carriers of hemophilia.


Erythroid colony formation (CFUe) in fetal liver and adult bone marrow and spleen from the mouse. The methyl cellulose modification of the CFUe technique has been applied to 14 day fetal liver and adult bone marrow and spleen from CBA/CA mice. Optimized doses of fetal calf serum, alpha-thioglycerol, erythropoietin and cell suspensions have been obtained from dose response curves in order to standardize the technique. The slopes of the erythropoietin and cell dose response curves indicate a greater sensitivity by fetal liver to the hormone than bone marrow or spleen. The proportion of cells in the DNA synthesis phase of the cell cycle, as measured by the CFUe technique, has been estimated by administering hydroxyurea. Two hours after the drug was injected, 89% of fetal liver cells, 71% of bone marrow cells and 81% of spleen cells were found to be in the S-phase.


Evaluation of the humoral immune response of children with low lead exposure. Twelve lead-exposed children, with evidence of metabolic impairment, and seven non-lead exposed children were examined for evidence of impairment of their immunological response. There were no differences between the control group and the lead exposed group with reference to complement levels, immunoglobulins, or anamnestic response to the tetanus toxoid antigen. It remains to be demonstrated whether or not there is deficient response to primary immunization, whether other antigens are more affected by lead, or whether impairment of humoral immune response requires a more serious degree of lead intoxication.


Isolation and identification of polychlorinated styrenes in Great Lakes fish. Octachlorostyrene was prepared by two independent synthetic routes, and GC retention time data as well as a mass spectrum of the standard were obtained. A comparison of these data with those observed for a component in fish from Lake Huron, Lake Ontario, and the lower Detroit River indicates that octachlorostyrene is present in fish residues from these sources. In addition, mass spectral data indicated the presence of several hepta and hexachlorostyrene isomers in these fish. Further studies should be concerned with quantification of OCS and evaluation of possible sources of these compounds, such as impurities in products produced by exhaustive chlorination or as by-products in the electrolytic production of chlorine.


Organochlorine insecticide residues in ducklings and their dilution by growth. Residues of DDT, DDD, DDE, and dieldrin in 7 species of ducklings from Alberta, Canada, were measured. Levels of DDT and metabolites ranged from 0 to 36.48 ppm in fat of 96% of the birds and from 0 to 0.97 ppm im muscle from 67% of the birds. Residue levels of dieldrin ranged from 0 to 2.62 ppm in fat and from 0 to 0.11 ppm in muscle of 43 and 19% of the birds, respectively. Growth dilution was considered to be the most significant factor in reducing the insecticide residue levels in the ducklings. DDT (total DDT, DDE, and DDD) residue levels were decreased with increased weight of pintail (A. acuta), baldpate (Mareca americana), and gadwall (A. strepera) ducklings. Dieldrin used in grasshopper control did not contribute to residue levels in the ducklings. Contamination by DDT was considered to have originated from outside the habitat. No dieldrin or DDT residues were found in ducklings' food sources analysed.


Methoxychlor effects on hepatic storage of vitamin A in rats. Sixty Sprague-Dawley rats were fed diets containing 0, 10, 100, 1,000, and 10,000 ppm of methoxychlor for 16 weeks under ad libitum- and restricted-feeding regimens. Methoxychlor at 10,000 ppm was lethal to some rats, reduced food consumption and growth, and increased liver weight relative to body weight. Methoxychlor at 1,000 ppm reduced food consumption and growth of rats fed ad libitum but did not reduce growth of restricted-fed rats. Reduced hepatic storage of vitamin A was detectable when methoxychlor was fed at levels of 100 ppm or higher.


Effects of daily oral subtoxic doses of a wet lead-based paint on cattle. Cattle were dosed daily with a wet lead-based paint at a rate of about 6 mg of lead per kg per day for 60 weeks. The cattle did not exhibit overt symptoms of lead toxicosis. Blood and fecal samples collected during the study, and tissue samples obtained at slaughter of the animals were analyzed for lead by atomic absorption spectrophotometer equipped with a graphite furnace. Levels of lead in whole blood generally did not exceed 0.5 ppm. The residues of lead in feces reached as high as 1000 ppm. Highest residues in tissues were in calcified bone, the kidney cortex, kidney medulla, and then in liver. Residues of lead in muscle, brain, spleen, and bone marrow were similar to residues of lead in the control animal. Calves born to 2 test animals had elevated levels of lead in bone, kidney and liver.


The activity of delta 5-3 beta hydroxysteroid dehydrogenase enzyme in the interrenal tissue of rainbow trout (Salmo gairdneri Richardson) exposed to sublethal concentrations of zinc. The effects of exposure of rainbow trout (Salmo gairdneri Richardson) to three sublethal concentrations of zinc (0.248, 0.528 and 1.14 ppm) on delta 5-3 beta-hydroxysteroid dehydrogenase (delta 5-3 beta HSDH) enzyme activity in the head kidney tissue was investigated. The activity of this enzyme was localized by the reduction of a tetrazolium salt to formazan at the site of activity. Using subjective methods to indicate the degree of activity and indirectly assess the degree of corticosteroid production, the zinc-exposed rainbow trout showed a greater degree of delta 5-3 beta HSDH activity compared to the control fish. This increase in enzyme activity has been associated with the stimulation of the pituitary-interrenal axis by the noxious stress of zinc.


The effect of lead and cadmium on liver, kidney, and brain levels of cadmium, copper, lead, manganese, and zinc, and on erythrocyte ALA-D activity in mice. Lead and cadmium were administered intraperitoneally, singly and jointly, to the mice. The levels of cadmium, copper, manganese, lead and zinc were determined in liver, kidney and brain by atomic absorption spectrophotometric technique and delta-aminolevulinic acid dehydratase (ALA-D) activity was determined in erythrocytes. The tissue levels of some of these metals were found significantly altered by cadmium and lead both, but cadmium was found to have no effect on blood on ALA-D activity.


The toxicity of benomyl, thiophanate-methyl, and BCM to four freshwater organisms. The EC50 or LC50 values after a 2-day exposure of the three fungicides benomyl, thiophanate-methyl and BCM, have been determined using four freshwater organisms: Chlorella pyrenoidosa, Daphnia magna, Lebistes reticulatus and Salmo gairdneri. The influence of BCM on the reproductive capacity of Daphnia was also investigated and from these data provisional ecological limit was established.


Tolerance pattern of the anorexigenic action of amphetamines, fenfluramine, phenmetrazine and diethylpropion in rats. The tolerance pattern to anorectic drugs was studied in starved rats by measuring two consecutive 2 h food intakes. 2 There was a reduction in the first 2 h food intake with development of complete tolerance after fenfluramine and phenmetrazine, and of partial tolerance after amphetamine, (+)-amphetamine and diethylpropion. 3 During the second 2 h intake, the anorectic effect was transient after fenfluramine and diethylpropion; while there was an absolute increase in the intake after amphetamine and (+)-amphetamine. 4 A pair-feeding experiment revealed that the increase in the second 2 h food intake was not a direct effect of the drug but a consequence of the deficit in food intake during the preceding 2 hours. 5 There was an overall correlation between the food and water intake. 6 A significant loss in body weight was observed after amphetamine, fenfluramine and phenmetrazine but not after (+)-amphetamine or diethylpropion. 7 The results indicate that so-called tolerance to the anorexigenic effect of drugs is apparent rather than real and that the duration of food access is a determining factor. The body weight changes may be brought about by the metabolic effects of these drugs rather than their effect on food and water intake.


Oestrogenic, anti-oestrogenic and fertility effects of some triphenylethanes and triphenylethylenes related to ethamoxytriphetol (MER 25). Five triphenylethylenes, a triphenylethane and a triphenylethanol, carrying methyl substituents ortho to one or both of the ring oxygen functions, have been examined for oestrogenic, and antioestrogenic activity in mice, and three of the compounds, alpha-[4-(beta-diethylaminoethoxy)-3, 5-xylyl]-alpha-phenyl-beta-4-methoxyphenyl-ethanol (IV), alpha'-[4-(beta-diethylaminoethoxy)-3, 5-xylyl]-4-methoxy-bibenzyl (V) and alpha'-[4-(beta-diethylaminoethoxy)-3, 5-xylyl]-4-methoxy-stilbene (VI), were tested for their effects on fertility in mice. 2 Orthomethylation reduces oestrogenic and/or anti-oestrogenic activity compared with the reported activities of non-methylated analogues. 3 The anti-oestrogenic ethamoxytriphetol (MER 25) reduced fertility in mice whereas its inactive dimethylated analogue (IV) was ineffective. The weakly active anti-oestrogens, V and VI, did not affect fertility in mice.


Dual effects of aspirin in guinea-pig lungs. Dual effects of aspirin were demonstrated in guinea-pig lungs: (a) aspirin (3.3 mg/kg i.v.) antagonized bronchoconstriction induced by slow reacting substance of anaphylaxis (SRS-A); (b) aspirin produced bronchoconstriction when injected in the presence of propranolol into guinea-pigs in vivo at 330 mg/kg, or into guinea-pig isolated lungs in vitro as a 4% solution (40 mg/ml). 2 The severity of bronchoconstriction following administration of aspirin was directly related to the degree of beta-adrenoceptor blockade and to the age of the guinea-pigs. Aspirin-induced bronchoconstriction was prevented in vivo and in vitro by atropine and it could be reversed in vivo by atropine. Aspirin-induced bronchoconstriction was not inhibited by vagotomy or phenoxybenzamine. 3 These data suggest that the mechanism involved in aspirin-induced bronchoconstriction may be local cholinergic stimulation and that reduced beta-adrenergic drive may be a predisposing factor.


The ionization of phenolic amines, including apomorphine, dopamine and catecholamines and an assessment of zwitterion constants. The dissociation constants of many phenolic amines, including benzylamines, phenethylamines, phenylethanolamines, phenylpropylamines, catecholamines, and apomorphine have been measured by potentiometric titration at 25 degrees C. Measurements have also been made with many of their methoxy derivatives and with series of phenolic quaternary ammonium salts. Some compounds were also studied at 37 degrees C. 2 Usually at least five titrations were made with each compound and Debye--Hückel theory was applied to convert concentrations to activities but the estimates of pKa were not constant and found to increase with increasing concentration. The range studied was usually 5-15 mM and a least-squares line-fit, based on the empirical assumption that pKa varies with (concentration)1/2, has been used to calculate values for 10 mM solutions and to extrapolate to infinite dilution and to 100 mM. The dependence of pKa on concentration was much less at 37 degrees C than at 25 degrees C. 3 At 37 degrees C the pKa values of many biologically interesting compounds in the group, dopamine, noradrenaline, adrenaline and isoprenaline, coryneine (the trimethylammonium derivative of dopamine) and apomorphine are within 1 log unit of physiological pH, indicating the presence of a significant proportion of either the zwitterion or of the uncharged phenolic amine. 4 Zwitterion constants have been estimated from the pKa values of the phenolic amines and those of their methoxy and quaternary trimethylammonium analogues. Zwitterion formation does not appear to be associated with activity at alpha-adrenoceptors and probably not with activity at beta-receptors. The active species seems likely to contain the unionised phenolic group but at dopamine receptors this may be in the uncharged phenolic amine rather than in the phenolic ammonium salt.


Calcium depletion of synaptosomes after morphine treatment. It was confirmed that morphine administration in vivo produced a selective decrease in the calcium content of synaptosomal fractions prepared from rat cerebral cortices. This effect was prevented by naloxone. 2 After morphine or naloxone, there were no changes in the sodium, potassium and magnesium contents of any of the seven subcellular fractions tested. 3 Since the selective calcium loss was found to occur from fractions similar to those reported to exhibit opiate receptor binding, it is concluded that calcium may play a role in the action of narcotic agonist drugs.


Effect of ionizing radiation on prostaglandin-like activity in tissues. One to 7 days after whole body exposure of mice to a single dose of 700 R of x-rays, little or no change was detected in prostaglandin-like activity in the brain, blood and seminal vesicles. Slight increases in intestinal and renal tissue were not significant. In the lung, mean activity rose from 62 ng/g to a transient peak of 145 ng/g wet weight on the fourth day (P less than 0.05). In the spleen, mean levels rose steadily from 13.2 ng/g to 259 ng/g on the fourth day (P less than 0.01), and were still 184.4 ng/g on the seventh day. 2 Prostaglandin-like activity was measured 4 days after single doses of 200-700 R. In the lung, a significant rise was produced by 600 and 700 R, and in the spleen by 200-700 R. 3 Thin layer chromatography showed that part of the prostaglandin-like activity in spleen extracts had RF similar to that of [3H]-prostaglandin E1, and part to that of [3H]-prostaglandin F2alpha. 4 Splenic tissue from mice exposed to 700 R four days earlier, inactivated prostaglandin E1 less potently than did tissue from non-irradiated mice.


Interactions of isoprenaline and prostaglandin E2 with respect to myocardial contractile force, coronary vascular resistance and myocardial oxygen consumption in guinea-pig isolated hearts. Left ventricular pressure (LVP), left ventricular pressure derivative (LV dp/dtmax), coronary vascular resistance (CVR) and myocardial oxygen consumption (Qo2) were measured simultaneously in isolated, electrically driven hearts of guinea-pigs at constant perfusion rate. 2 LVP, LV dp/dtmax, CVR and Qo2 were greatly decreased by either the addition of prostaglandin E2 (50 ng/ml) to the perfusion fluid or pretreatment of the animals with reserpine. 3 Isoprenaline (0.5 nM to 100 nM) induced increases in LVP, LV dp/dtmax and Qo2. In the presence of prostaglandin E2, there was a parallel shift of the isoprenaline concentration-response curve for LVP and LV dp/dtmax. This effect was not seen, after the animals had been treated with reserpine. 4 Qo2 was also decreased by prostaglandin E2 only in non-reserpine treated animals. 5 CVR was diminished by isoprenaline in the untreated group. However, there was increase in CVR, when isoprenaline was added to either prostaglandin E2 or reserpine-pretreated hearts which was enhanced in the reserpine plus prostaglandin E2-treated group (P less than 0.01). 6 The results give evidence for different actions of prostaglandin E2 on isoprenaline concentration-response curves for LVP, LV dp/dtmax and CVR.


The effects of morphine on the release of noradrenaline from the mouse vas deferens. Electrical field stimulation of the mouse vas deferens (TO and C57/BL strains) caused the release of noradrenaline into the bathing medium. 2 Phenoxybenzamine (30 muM) or phentolamine (36 muM) plus cocaine (13 muM) caused a considerable increase in the noradrenaline output. 3 In the vasa deferentia from TO mice the output per pulse of noradrenaline was constant at frequencies of stimulation from 0.5 to 15 Hz whereas in the vasa deferentia from C57/BL mice the output per pulse of noradrenaline increased two-fold from 1.5 to 15 Hz. 4 Morphine (2 muM) inhibited the contractions of the vasa deferentia from TO mice. This effect was greater at low (0.1-1 Hz) than at high (10 Hz) frequencies of stimulation. Morphine (2 muM) did not inhibit the response of the tissue to exogenous noradrenaline. 5 Morphine (1 muM) reduced the noradrenaline output from the vasa deferentia of TO mice stimulated at 1.5 Hz but did not reduce the noradrenaline output at 15 Hz. At 1.5 Hz the reduction of noradrenaline output was reversed by naloxone (0.05 muM). 6 Morphine (5 muM) did not inhibit the uptake of [3H]-noradrenaline into the vasa deferentia from TO mice. 7 Only in high concentrations (ID50 30.88 muM) did morphine inhibit the contractions of the vasa deferentia from C57/BL mice. 8 Normorphine (100 muM) did not reduce the noradrenaline output from vasa deferentia of C57/BL mice.


The vasodilator actions of isoprenaline, histamine, prostaglandin E2, glucagon and secretin on the hepatic arterial vascular bed of the dog. The sympathetically-innervated arterial vascular bed of the dog's liver was perfused from a femoral artery. Arterial blood flow and perfusion pressure were measured continuously, and the hepatic arterial vascular resistance calculated. The preparation provided a means of assessing hepatic arterial vasodilatation quantitatively. 2 Isoprenaline, histamine, prostaglandin E2, glucagon and secretin were injected intra-arterially and all evoked dose-dependent vasodilatation of the hepatic arterial vascular bed. 3 The maximum reduction in the calculated hepatic arterial vascular resistance of 37-38% was the same for each of the five substances. 4 Comparisons on a weight basis revealed that prostaglandin E2 was the most potent, followed in potency order by secretin, isoprenaline, histamine and glucagon. 5 Comparisons on a molar basis showed that secretin and prostaglandin E3 were intrinsically considerably more potent than isoprenaline, histamine or glucagon. 6 The onset of the vasodilatator responses to secretin, isoprenaline, histamine and prostaglandin E2, was rapid, and the duration of their actions was brief. 7 The onset of the vasodilator effects of glucagon was slow and its duration of action very prolonged. 8 The implications of these observations with respect to the physiological control of the hepatic arterial vascular bed of the dog are discussed.


A rapid method for the estimation of prostaglandin 15-hydroxydehydrogenase activity and its application to pharmacology. A novel double-isotope assay for prostaglandin 15-hydroxydehydrogenase (PGDH) is described. 2 The assay is simple, rapid, precise, completely specific for PGDH, and free from artefacts. The results obtained correlate well with a conventional assay. 3 The method is versatile, being applicable to estimations of enzyme activity in cell-free systems as well as perfused organs, and is well suited to the assay of PGDH inhibitors.


Noradrenaline modulation of the responses of the cerebellar Purkinje cell to afferent synaptic activity. Noradrenaline, applied by microiontophoresis to rat cerebellar Purkinje neurones, selectively depressed spontaneous neuronal discharge. Simple spike and complex spike excitations, evoked by stimulation of the mossy and climbing fibres, were relatively preserved during the inhibition of spontaneous activity, and the number of full-sized action potentials in the complex spike increased. Inhibition mediated by the basket and stellate cells was augmented. Thus, relative to the change in spontaneous activity, noradrenaline increased the responsiveness of the Purkinje cell to afferent input.


The influence of family and social factors on the course of psychiatric illness. A comparison of schizophrenic and depressed neurotic patients. This study is a replication and extension of past work carried out by Brown, Birley and Wing (1972) concerning the influence of family life on the course of schizophrenia. In the original research the index of emotion expressed by a key relative about the patient at the time of key admission proved to be the best single predictor of symptomatic relapse in the nine months after discharge from hospital. In the present study this main finding of Brown et al has been replicated for two clinically different groups of psychiatric patients. The expressed emotion of the relative again seems to be associated with relapse independently of all other social and clinical factors investigated. In addition, important additive effects between various social influences and pharmacological treatments have been revealed which make it possible to predict relapse patterns in schizophrenia with considerable precision. The patterns of these relationships with relapse are different for the two clinical groups studied, patients with schizophrenic psychosis and with depressive neurosis.


Rationing out-patients: a defence of the waiting list. New psychiatric out-patients were offered immediate or delayed appointments (average delay 12 weeks) in random order. The two groups thus formed, comprising 234 patients, were shown to be comparable in some important respects. Immediate appointments were taken up significantly more frequently than delayed appointments, and 12 per cent of immediate and 22 per cent of delayed patients did not receive any psychiatric service. No evidence was found that delay increased other medical services supplied. Non-attenders were presumed to suffer from "neurosis" and "personality problem". Initial attenders used more services than those who failed to keep their first appointment but came later. A waiting list is proposed as a screening device to limit out-patient referrals.


Some possible childhood indicators of adult schizophrenia inferred from children of schizophrenics. Prospective developmental data on 33 children of consensus diagnosed schizophrenic parents were compared to control samples of children of other psychiatric patients and children of normal parents. Contrary to several reports the children of schizophrenics, observed from birth to age seven, were remarkably normal on a host of pregnancy and delivery variables, neurological examinations, physical growth measures, and psychological tests. However, a combination of three indicators characterized five of the 116 children, and all five were offspring of schizophrenics (17 per cent of the high risk sample), thus matching the expected lifetime risk for schizophrenia previously observed in such samples. Case histories show that all five children have enduring patterns of maladjustment and exhibit behaviours often reported in the premorbid histories of schizophrenics. Most have family histories heavily loaded with schizophrenia. In terms of a diathesis-stress model, these five children appear especially vulnerable to future schizophrenia in the absence of rational methods of prevention.


Trainees' competence in psychiatric case writing. An assessment was made of 100 case records written by junior medical staff working in a psychiatric teaching hospital. Thirty-nine items were rated, and considerable gaps were found in the records. The Mental State was more poorly recorded than the History; the Formulation and Summary were more satisfactory. Possible reasons for the findings are discussed, including methodological difficulties, administrative considerations, and attitudes of junior staff. The implications for the training and assessment of junior psychiatrists are explored.


The differentiation of paranoid from affective psychoses by patients' premorbid characteristics. Various premorbid characteristics of a group of patients aged 50 or over suffering from paranoid psychoses (N = 54) were compared with those of patients of similar age suffering from affective psychoses (N = 57). (The diagnoses were those of the consultants.) The presence of deafness was investigated in the manner described by Cooper et al(1974). Using the discriminant function method, the diagnostic groups were highly significantly differentiated by six independent variables, which in combination predicted 40 per cent of the variance. These were: a 'schizoid personality' factor, the number of surviving children, precipitating events, deafness, family history and social class.


Deafness and psychiatric illness.

Deafness and psychiatric illness. Review of the literature concerning the relationship between deafness and psychiatric disorder reveals differences in the pattern of illness depending on the severity of deafness and the age of onset. In particular, the prevalence of schizophrenia in the prelingually deaf is similar to that found in the normal population, whereas the hard of hearing are over-represented among samples of patients suffering from paranoid psychoses in later life. Possible modes of action of long-standing hearing loss in the aetiology of paranoid illnesses are considered: the psychological and social consequences of deafness, the possible contribution of sensory deprivation phenomena, and the interference of hearing loss in attention, perception and communication. Finally, possible future lines of research are suggested.


Platelet monoamine oxidase in schizophrenia and manic-depressive illness. Monoamine oxidase (MAO) is an important enzyme in the catabolism of brain biogenic amines. Platelet MAO has been reported to be moderately reduced in manic-depressive patients and markedly reduced in schizophrenic patients. This enzyme's activity has been shown to be under a large degree of genetic control and has been proposed as a 'genetic marker' in schizophrenia. A transcultural replication of the finding of low platelet MAO in schizophrenia and manic-depressive illness was carried out at the Jerusalem Mental Health Centre. Manic-depressive patients were found to have higher platelet MAO activity than schizophrenic patients, as reported previously, but control individuals were as low as the schizophrenic patients. It is unlikely that platelet MAO activity is a transculturally-valid marker for schizophrenia.


Whole blood adenosine triphosphate in manic-depressive illness. Whole blood cell ATP concentration was estimated in a group of manic and depressed patients and in a group of normal subjects. There were no significant differences between patient and control groups, nor in the patient groups were there any significant changes with recovery.


Thyroid dysfunction in female psychiatric patients. Biochemical screening for thyroid dysfunction in 98 unselected female psychiatric admissions led to the diagnosis of hypothyroidism in three cases which would otherwise have passed unrecognized. It is suggested that female psychiatric patients over the age of 40 should routinely be screened for thyroid disorder.


Polygenic inheritance of epilepsy and febrile convulsions: analysis based on a computational model. Two series of patients with epilepsy and with febrile convulsions were analysed on Slater's computational model for evidence on the mode of inheritance. The study demonstrated that in both series a polygenic inheritance may be more likely than an autosomal dominant or recessive inheritance.


Physique, personality and mental illness in southern Chinese women. A number of anthropometric measurements were made on Southern Chinese women. These were 317 schizophrenics, 44 with affective disorder, 47 neurotics and normal controls. All groups and sub-groups compared were matched for mean age and socio-economic status. It was found that the intercorrelations between body build, personality and type of mental illness were on the whole similar to those reported for Caucasians.


Marriage and neurosis in a modern residential suburb: an application of the Ryle Marital Patterns Test. The Ryle Marital Patterns Test measures the affection and domination aspects of marriage. Its original administration illustrated a partial association between poor marital adjustment (as measured by low affection scores and non-egalitarian domination scores) and neuroticism (as measured by CMI score). The present paper confirms these associations using a group of suburban women defined as neurotic by their GP. Related studies suggest similar patterns.


Help-seeking in depressed out-patients following maintenance therapy. This paper reports on the clinical status, help-seeking and subsequent treatment experiences of 150 women one year after they had completed out-patient maintenance treatment by amitriptyline and/or psychotherapy for a depressive episode. While the majority of patients were asymptomatic at follow-up, a substantial minority had a return of acute symptoms and 2 per cent made minor suicide attempts during the year. Admission to hospital was rare. However, only 30 per cent of the patients did not seek any treatment during the year and the majority received some psychotropic medication. The findings support the long-term need for prompt access to treatment by patients who have recovered from an acute depression.


Socio-cultural determinants of attempted suicide among West Indians in Birmingham: ethnic origin and immigrant status. The author studied the significance of ethnic origin and immigrant status in attempted suicide. Epidemiological data (1969-72) indicated that self-poisoning among West Indian immigrants in Birmingham was less prevalent than among natives there but more prevalent than in the West Indies. The association of recent pregnancy with attempted suicide among young immigrant patients was noteworthy. Attempted suicide among immigrants was often relatively benign; few abused alcohol or drugs or made repeated attempts. The markedly lower male rate of attempted suicide, and its rarity in older persons, confirms previous findings.


The aftermath of parental suicide for children. Thirty-six children between the ages of 2 and 17 bereaved by the suicide of a parent were followed up after 5 to 17 years. The children's home life before bereavement had been abnormal because of mental illness, and family disruption and pre-suicide stresses were significantly related to present functioning. An incidence of psychological morbidity greater than that of a comparison group was observed. Some children appear to cope with the experience of parental suicide without serious consequences; for a few there was relief from an insupportable situation.


The effect of microwave therapy upon muscle blood flow in man. Muscle blood flow was measured using a radioactive tracer technique in five normal subjects. Flow values obtained during application of 2450 MHz microwave therapy were compared with resting values and in each case the treatment produced a significant increase; the mean values being 2.9 ml/100g/min at rest and 11.4 ml/100g/min during application of the microwave therapy. Comparison is made with previous studies using other therapeutic agents and it is concluded that the most significant effect on muscle blood flow is produced by microwave therapy.


Some reactions to a dry-land training programme for dinghy sailors. A dry-land winter training programme for dinghy-sailors is described. Individual elements include circuit training, specific exercises for muscle strength and endurance, and distance running. Ten international-class sailors followed a progressive regimen of this type for 14 weeks after completion of the 1973 season. Excess weight and skinfold thicknesses were reduced, while muscle strength, endurance and anaerobic capacity increased. Aerobic power remained substantially unchanged, although a smaller oxygen debt was incurred in reaching maximum effort. Team members were enthusiastic about the benefits gained from the training, commenting on their greater tolerance of the hiking position and all proposed to continue or to increase their efforts during subsequent winters. Racing results during 1974 were also an improvement on the 1973 record. However, it was difficult to link physiological gains to improvements in the relative rankings of individual competitors under either light or high wind conditions; the main factor changing relative standings seems to have been the additional year of competitive experiences in younger team members.


British pilot study of exercise therapy. I. Middle-aged men. The physiological and biochemical effects of a carefully graduated course of vigorous gymnasium training with two or three weekly exercise sessions lasting only 15 minutes have been studied in middle-aged London business men. Activity diaries and psychological questionnaires indicated that these men had a positive attitude to exercise which was probably greater than average. The gymnasium exercises caused a large oxygen debt and considerable rises in plasma catecholamines and lactate levels. A close correlation was found between the pulse rate during exercise and the Borg scale of perceived exertion, so that both could be used to ensure that short periods of exercise were sufficiently vigorous to produce a training effect, and protect against over-exertion. The acceptability of this particular exercise regime was shown by the low fall-out and injury rate. It is suggested that this exercise training programme possesses many features which are advantageous if increased physical activity is to be more widely used as a method of reducing some of the risk factors in coronary heart disease.


British pilot study of exercise therapy. II. Patients with cardiovascular disease. Two groups of middle-aged men, one with and one without overt cardiovascular disease, were studied while they were taking part in a specially designed course of exercise therapy in a gymnasium. The "patients" group had at least two months pre-treatment to allow physical recovery and mental re-education before their initial very small test dose of exercise. Using short periods of progressive, mainly weight-loaded, isotonic exercises carefully regulated by control of pulse rate and avoidance of symptoms of over-exertion, both groups showed large increases in effort capacity and reductions in resting pulse rate, blood pressure and plasma lipid levels within two months. The safety of this particular form of exercise was shown in this high-risk population by the low drop-out rate and the absence of cardiovascular accidents in the gymnasium over a ten year period. It is suggested that, given suitable training of the staff and using the safeguards described, the presence of doctors and a cardiac resuscitation team is unnecessary in a gymnasium specializing in cardiac rehabilitation. This makes it possible for rehabilitation and physiotherapy departments throughout the country to carry out this effective and positive form of exercise therapy.


Maximal exercise studies in Scottish athletes. We have studied maximal oxygen uptake, maximal heart rate, maximal exercise ventilation and the ventilatory response to exercise in 24 male and 14 female Scottish athletes. The values for maximal oxygen uptake are similar to those reported in other international studies. In eight athletes repeat measurements of maximal oxygen uptake 7-11 months after the initial study showed no change from the initial values. The values for the ventilatory response to exercise in our athletes were normal. The relationship is discussed between maximal oxygen uptake and ventilatory responses to exercise, hypoxia and hypercapnia and it is suggested that these may be related to athletic event.


The reproducibility of submaximal work heart rates-an interim report. Work heart rates were taken from four subjects performing standardized bouts of work on the Monark Ergometer. Whilst a linear relationship was observed between heart rate and work intensity on any one day, it is evident that day to day variations in the position (intercept) of these lines exists. The slopes are virtually identical for all subjects and for different days, however the position of the lines differs widely both between and within subjects. The best linear regression equation developed for the prediction of heart rate after 180 seconds of work from pre-exercise heart rate and work intensity was found to have 95% confidence limits of +/- 12.7 beats. Heart rates are reproducible 95% of the time to within +/- 12.2 beats when pre-exercise heart rate is ignored.


A simple new formula for relating changes in renal length to changes in renal volume. A simple new formula for relating changes in renal length to changes in renal volume is derived. It is not assumed that the kidney is any given shape, but it is assumed that a kidney does not change its shape when it enlarges. It is shown that the fractional change in renal volume equals three times the fractional change in renal length plus three times the fractional change in renal length squared. Examples of applications of the formula using figures for changes in renal length, published elsewhere in the literature, are given for renal hypertrophy in both childhood and adult life and for volume changes during excretion urography.


Thallium 201 chloride uptake in tumours, a possible complication in heart scintigraphy. An abnormal uptake pattern of 201Tl thallous chloride observed during myocardial scintigraphy of a patient with known thoracic tumour localization suggested the possibility that thallous chloride may also accumulate in tumours. This was confirmed by observing 201thallous chloride accumulation in rhabdomyosarcoma implants in rats. Thallium 201 accumulation in tumour cells should be borne in mind as a possible complicating factor when using this reagent for the evaluation of cardiac conditions in oncological patients.


Pharmaco-cholangiography with anticholinergic drugs in the dog. The effect of atropine and pipenzolate bromide (PB) in different dosage levels was investigated in intravenous cholangiography with 0.6 ml/kg iodipamide infused over 30 minutes in six cholecystectomized dogs (20-36 kg) equipped with Thomas cannulas through which the common bile duct could be cannulated. Doses of 1 mg atropine and 20 mg PB, half the dose given intravenously just prior to the contrast agent and the other half with the iodipamide infusion, had the greatest effect in decreasing the bile flow (atropine-24% at 60, PB-23% at 30 minutes) and increasing the bile iodine concentration (atropine + 16%, PB + 14%). The biliary iodipamide excretion rate was not affected.


Liver volume determination by ultrasound: a feasibility study. The feasibility and precision of an ultrasound method for determining the volume of the liver have been assessed using a Nuclear Enterprises B-scan machine. A relation between estimated liver volume and body weight has been established, showing that liver volume can be determined with a precision of +/- 195 cm3 (P less than or equal 0-05). With the standard non-grey-scale imaging technique employed there is a degree of uncertainty in deciding the liver boundaries, and this constitutes the major source of error.


The analysis of radioisotope brain scans by comparison with normal patterns of uptake. A previously described method for the computer analysis of radioisotope brain scans has been further developed. A patient scan is matched with a series of "normal" scans to find the closest fit and the "normal" scan is then subtracted from the patient scan. The results are displayed in terms of the standard deviation from the normal. In a clinical trial the computer assessments were found to be less accurate than those of two groups of observers. One reason for these disappointing results is related to the simple criteria used to choose and fit the best "normal" to a particular patient scan. A second reason is the optimization of the scanner/photoscan combination to 99Tcm pertechnetate as a brain scanning agent which results in patient-to-patient variation becoming more important. This reduces the potential of a simple numerical analysis to improve results.


Vaginal ureterolithotomy.

Vaginal ureterolithotomy. The vaginal approach to the low ureteric calculus may provide an easy, rapid and safe solution to a difficult surgical problem. It is important to select the case with care and, provided basic surgical principles are followed, the complications should be minimal. 3 recent successful cases are described and a further 2 in which the technique failed due to proximal displacement of the stone. The importance of adequately immobilising the calculus prior to ureterotomy is emphasised.


The use of bromocriptine in the treatment of the unstable bladder. Initial experience with the use of bromocriptine in 24 patients with troublesome micturition symptoms associated with an unstable bladder is described. 14 patients responded symptomatically to treatment with bromocriptine and these results were confirmed by a double blind trial in this group. 11 of these patients had previously failed to benefit from treatment either with drugs or vesical distension. It is concluded that bromocriptine has a part to play in the treatment of some cases of primary detrusor instability.


Bladder and urethral innervation in multiple sclerosis. Bladder and urethral innervation was studied in 52 patients with multiple sclerosis using a signal tracing technique (evoked reflex latency measurement).  The majority of the patients showed prolonged signal transit times indicative of demyelinating plaques localised to the lumbosacral spinal cord.  Futhermore, impairment of the corticospinal innervation of the pudendal nucleus was found in 29 patients indicating lesions of the pyramidal tract.


Chronic bacterial prostatitis: new therapeutic aspects. 6 cases with chronic bacterial prostatitis were reviewed. The effort and patience required to diagnose this condition accurately by means of differential urine and prostatic secretion cultures is extremely worthwhile. Cotrimoxazole, which has been suggested as a most effective antibacterial drug in chronic bacterial prostatitis, cured only 3 out of our 6 patients and then only after continuous treatment for 4 months. 2 of the remaining patients were cured by a 10 to 14 days' course of kanamycin and the third was probably cured by streptomycin. On theoretical grounds neither of these lipid insoluble drugs should be capable of penetrating the prostatic epithelium. The implications of these findings are discussed.


Random bone marrow biopsy in the staging of carcinoma of the prostate. Random bone marrow biopsies were examined in 28 patients with proven carcinoma of the prostate. In 6 cases (28-5%) bony metastases were demonstrated and in 2 of these X-ray skeletal surveys were negative. It is suggested that bone marrow biopsy should be done in the staging of carcinoma of the prostate when other investigations are negative, especially when an occult primary is suspected, when radical treatment is contemplated and in clinical trials.


Vasoplasty: a new technique.

Vasoplasty: a new technique. A technique by which plain catgut is used as an internal splint in vasoplasty is described. 28 cases have been carried out, of which only 4 have failed.


Comparison of sterile bag, clean catch and suprapubic aspiration in the diagnosis of urinary infection in early childhood. Bag, clean catch and suprapubic specimens of urine were taken on the same day in a group of 30 unwell infants and young children. On microbiological grounds suprapubic aspiration was far superior to clean catch collection and clean catch collection superior to bag collection in the diagnosis of urinary tract infection.


Comparison of hydrophilic polymer-coated latex, uncoated latex and PVC indwelling balloon catheters in the prevention of urinary infection. Latex, hydrophilic polymer-coated latex and PVC balloon indwelling urethral catheters were compared in respect of the urinary tract infections arising in association with their use in male patients. The polymer (Hydron) coating conferred no benefit over uncoated latex which in turn was indistinguishable from PVC. No significant differences in the spectra of infecting organismns were observed between the 3 catheter types.


Colo-anal sleeve anastomosis in the treatment of diffuse cavernous haemangioma involving the rectum. An operative technique, involving a colo-anal sleeve anastomosis, is described for the treatment of cavernous haemangioma of the rectum. All the patients with this condition treated since 1930 at St Mark's Hospital are reviewed, and the presentation and results of treatment in the last 5 patients who have had a resection and colo-anal sleeve anastomosis are discussed.


The effect of an infusion of low molecular weight dextran on peripheral resistance in patients with arteriosclerosis. Low molecular weight dextran is frequently given to improve the flow of blood to the periphery, but its mode of action is uncertain. We measured the effect of an infusion of 500 ml of Dextran 40 on the peripheral resistance in 12 patients undergoing reconstructive surgery for atherosclerotic occlusion of the superficial femoral artery. After the infusion, values of packed cell volume and blood viscosity indicated haemodilution. There was a consistent increase in mean flow and a fall in peripheral resistance. There was no correlation between change in viscosity and change in peripheral resistance, but there was a good correlation between the percentage change in resistance and the initial resistance. This suggests that the increase in flow of blood was due to reflex vasodilatation rather than to any reduction in viscosity.


Plasma fibrinolysis and postoperative deep vein thrombosis. In 23 high risk patients the change in plasminogen activator activity in response to surgical operation was studied by euglobulin lysis time (ELT) and fibrin plate lysis before, during and for up to 6 days following a major surgical procedure. Fibrin degradation products (FDP) were also measured. The aim was to relate any changes to postoperative deep vein thrombosis (DVT) as diagnosed by the 125I fibrinogen test. Peroperative increase and postoperative inhibition of fibrinolytic activity were seen in all the patients. Changes in fibrinolytic activity as measured by the ELT and during the first 24 hours by the fibrin plate technique were similar. This suggests that during this period the response was independent of plasma fibrinogen changes. There was no significant difference in these parameters between patients who developed DVT and those who did not. The relationship between venous thrombo-embolism and elevation of serum FDP was confirmed.


Benign oesophageal stricture following oral potassium chloride therapy. A patient is described who developed a benign oesophageal stricture following cardiac surgery. A brief review of the literature is given and the possible dangers of oral potassium cholride therapy in patients with dysphagia are highlighted.


Perforated peptic ulcer: a comparison of long term results following partial gastric resection or simple closure. The results of simple closure were compared with those of partial resection in the treatment of perforated peptic ulcer. The investigation was carried out 7-13 years after the primary operation on 126 patients who had been allotted to one of the two treatment methods on the basis of an almost randomized schedule. Better late results were obtained with partial resection than with simple closure in patients in the age range 50-59 years at operation, with short duration of perforation and with a long history of symptoms before perforation. None of the patients treated with partial resection later underwent surgical treatment for recurrence of symptoms. In the simple closure group 27.3 per cent needed further surgery at 3 months to 10 years after perforation.


Functional results of different reconstructive procedures after total gastrectomy. In 181 patients six reconstructive procedures were performed after total gastrectomy: Roux-en-Y (95), Henley (42), omega (21), Tomoda (16, Rosanov (4) and neogastrium (3). The functional results 2-4 months after operation were studied and compared by medical observers independently of the surgeons who had selected and performed the reconstructive procedures. Analysis of the functional results, and consideration of the degree to which the functional disorders associated with the various reconstructive procedures lend themselves to treatment, suggest that the Henley reconstructive procedure is the best, with the Roux-en-Y as a good second-best.


Duodenoscopic papillotomy and gallstone removal. Using an experimental insulated duodenoscope and a diathermy wire, papillotomy has been performed on 10 patients under diazepam sedation. Seven patients had common bile duct stones (6 following cholecystectomy) and 3 had papillary stenosis. Nine of the patients had severe medical or surgical contraindications to further operative treatment. Papillotomy was successful in all patients, with no significant bleeding or other complications. Repeat endoscopy 6-14 days after papillotomy demonstrated a healed biliary orifice of 7-10 mm diameter. Stones had already passed in 3 of the 7 patients; in 2 others, stones were extracted using balloon catheters or Dormia type baskets. Two larger stones could not be removed; in one of these patients the stone and basket became impacted at the papilla and had to be removed surgically 2 days later. Endoscopic papillotomy is an acceptable alternative to surgery in high risk patients, particularly in the treatment of retained common bile duct stones. If long term results prove satisfactory, the technique will have wider application.


An acute abdomen: spontaneous rupture of liver during pregnancy. Spontaneous rupture of liver during pregnancy is presented as an example of an acute abdomen admitted to a casualty department of a general hospital. The literature is reviewed and emphasis is placed on clinical awareness and earlier diagnosis as a means to reduce the high mortality.


The microflora of the obstructed bowel.

The microflora of the obstructed bowel. A study of the alterations of intestinal microflora that occur in acute small and large bowel obstruction is presented. The results are discussed in relation to the duration of obstruction, the site of obstruction, the recovery following relief of obstruction and the septic complications which profoundly affect the prognosis of these common surgical emergencies.


Malignant cold thyroid nodules in hyperthyroidism. In 65 hyperthyroid patients with a cold nodule a carcinoma was found at operation in 14 cases, i.e. a malignancy incidence of 21-5 per cent. In 859 euthyroid cases with a cold thyroid nodule 104 malignant lesions (12-1 per cent) were found. The difference is statistically significant. Surgery in cases with a cold thyroid nodule is strongly indicated if this occurs in a hyperthyroid gland.


Active observation in management of acute abdominal pain in childhood. Out of 363 children admitted to a surgical unit with acute abdominal pain only 126 (35%) had an operation. Of these, 20 first underwent a period of "active observation." This procedure, used to help reach a diagnosis or decision in doubtful cases, is safe and useful and may be applied at home or in hospital.


Prevalence of primary and secondary hypertension: studies in a random population sample. The prevalence of primary and secondary hypertension was determined in a random sample of 7455 Swedish men aged 47 to 54 years. Three hundred and sizty-one men were undergoing treatment for hypertension. Seven hundred and ninety-eight men who had blood pressures above 175/115 mm Hg at preliminary screening were recalled for further blood pressure measurements. Those on treatment and all the untreated men whose blood pressures were still over 175/115 mm Hg then underwent extensive investigation for secondary hypertension. Renal parenchymal hypertension was found in 25 (3-6%) patients, renovascular hypertension in four (0-6%), and other forms of secondary hypertension in 11 (1-6%). The investigation led to surgical treatment in only two cases (0-3%). The low prevalence of secondary hypertension, especially surgically curable forms of hypertension, makes routine screening for these cases unnecessary, at least when patients with hypertension have been found at screening. These data must be taken into account in planning community control programmes in hypertension.


Hepatitis B virus infection in dental surgical practice. Sixty-one dental surgeons at King's College Hospital were interviewed to establish the incidence of attacks of viral hepatitis and to relate this to environmental risk factors. Six (10%) had a history of hepatitis, in one case due to infection with the hepatitis B virus. Screening blood for HBsAg by radioimmunoassay showed no carriers of the antigen, but transient antigenaemia was observed in one dentist. Antibody to HBsAg, tested by radioimmunoassay, was detected in four dentists (7%), only one of whom had had clinical hepatitis. Dental surgeons may be more at risk from infection with the hepatitis B virus than the general population, although this should be minimised in hospital practice, where the most infected patients will already have been identified and appropriate precautions can be taken. The risk of transmission from an antigen-positive dentist to his patients is probably much smaller, and there is no evidence to restrict his clinical activities.


Career problems of women doctors.

Career problems of women doctors. Information was received from 61 women doctors who were having difficulty continuing with medical careers. Two main problems were disclosed. Firstly, despite the special arrangements made for women doctors, it is difficult to obtain postgraduate training. The provision of supernumerary posts does not seem to offer a satisfactory solution. Secondly, doctors who have completed postgraduate training but cannot yet return to full-time work are unable to obtain posts at an appropriate level. Both of these problems stem primarily from the need for part-time work by the mothers of young children. Most of the doctors wish to return to full-time or nearly full-time work when family responsibilities are fewer. In view of the increasing proportion of women doctors it seems important that large numbers are not unnecessarily lost from professional work. Some possible approaches to solving the problems are suggested.


Use of creatine kinase for detecting severe X-linked muscular dystrophy carriers. Women thought to be at risk of being carriers of Duchenne muscular dystrophy were given "odds" against their having an affected child. These were calcuated from a combination of the genetic risk from the family history and an estimation of the biochemical risk from measuring the serum creatine kinase concentration. The women were told the actual risk estimate and it was put into perspective for them as a high, medium, or low risk. Of 25 women at high risk six have had children, all girls; the two in the medium-risk group have had no children; and the 46 women at low risk have had 19 boys and 25 girls. None of the boys has the disease. With detailed counselling most potential carriers of this disease reach decisions in child bearing that are in line with their degree of risk.


Intracranial aneurysms: analysis of results of microneurosurgery. Subarachnoid haemorrhage from intracranial aneurysms has a poor prognosis. Operative management of intracranial aneurysms was once considered ineffective. The first 100 cases treated by micorsurgery were analysed to see whether mortality and morbidity were reduced. Modern surgical techniques halved the total mortality but the morbidity was unaltered. Results can be improved by delaying surgery seven days and by treating any hypertension before surgery.


Diagnostic and therapeutic assessment by telephone electrocardiographic monitoring of ambulatory patients. The electrocardiograms of ambulatory patients have been monitored over the telephone by staff of the intensive cardiac care unit using equipment in the unit. Telephone monitoring is a useful way of diagnosing transient symptomatic arrhythmias and a reliable aid in supervising the patient's rhythm at the beginning or end of treatment. The doctor has direct contact with the patient at the time of his symptoms so that he can reassure or instruct him. This system costs relatively little in manpower and equipment and permits relatively long periods of follow-up. It is effective, however, only in symptomatic cases in which the rate or rhythm disturbances last long enough to be transmitted. Also important are the negative findings when the patient complains of symptoms and abnormal findings during routine telephone transmissions. Accurate detection of transient ischaemic changes seems to be less reliable, and further technical improvements are required.


A new look at the neonatal electrocardiogram. Among 818 newborn babies whose electrocardiograms (ECGs) were recorded between April 1975 and April 1976 were 57 babies with recordings that fell outside the accepted normal range. Preliminary observations have identified the need to define more clearly the range of normal variation. Twelve babies showed asymptomatic conduction abnormalities, three of which were thought sufficiently serious to need treatment. Two babies died suddenly, one of whom had abnormal conduction on the ECG and histologically demonstrated abnormalities of the conducting system. This continuing prospective study may indicate a link between conducting tissue abnormalities and the sudden infant death syndrome. Ten babies had congenital cardiac anomalies, four of which were first discovered because of an abnormal screening cardiogram. Electrocardiography, a simple and noninvasive procedure, may be a valuable addition to the routine neonatal examination.


Cutaneous ectopic schistosomiasis.

Cutaneous ectopic schistosomiasis. Two cases of cutaneous schistosomiasis due to ectopic ova have recently been seen. Both patients presented with abdominal papular lesions, which were found on biopsy to contain schistosoma ova. To reach these abdominal sites mature worms probably migrate from the portal circulation to the paraumbilical veins, where they anastomose with veins of the caval system.


Career preferences of doctors graduating in 1974. Questionnaires were sent to all 2348 doctors who had graduated from medical schools in England, Scotland, and Wales in 1974 asking about their career preferences. Most were in their second preregistration post, and the response rate was 86-1%. The most popular first choice of career was general practice (665 of the responders; 32-9%), followed by medicine (454; 22-5%), surgery (321; 15-9%), and paediatrics (129; 6-4%). Only 507 of the responders (25-1%), however, stated that their preference was "definite". First choices differed widely between men and women graduates and between graduates of different medical schools.


Animal model studies of genital chlamydial infections. Immunity to re-infection with guinea-pig inclusion conjunctivitis agent in the urethra and eye of male guinea-pigs. A previous report demonstrated that male guinea-pigs could be infected in the urethra with guinea-pig inclusion conjunctivitis (GPIC) agent and that the infection was transmitted during mating from infected males to females. In the experiments reported here, inoculation of male guinea-pigs in the urethra with GPIC organisms resulted in infection which subsided spontaneously in about 2 weeks. Males were demonstrated to be completely resistant to urethral challenge with 10(3)ID50 when tested 6 weeks after urethral infection. These guinea-pigs, immune to re-infection of the urethra, remained susceptible to infection of the eye, but this ocular infection was shorter in duration than that in previously uninfected control animals. Infection in the eye resulted in immunity to both ocular and urethral infection when animals were challenged 6 weeks after the ocular infection.


Distribution of eight serotypes of Ureaplasma urealyticum in cases of non-gonococcal urethritis and of gonorrhoea, and in healthy persons. The isolation rate of Ureaplasma urealyticum was 57 per cent. from 47 patients with non-gonococcal urethritis, 40 per cent. from forty patients with gonorrhoea, 47 per cent from healthy sailors, and 53 per cent. from healthy students and laboratory technicians. No difference in distribution of eight serotypes among 45 isolates from these groups was demonstrated and no particular serotype could be correlated with disease symptoms.