An unusual abnormality of human spermatozoa. A defect affecting 90% of the spermatozoa of an infertile man consisted of round heads and a loss of tails, probably caused by a developmental abnormality at the spermatid stage.


Protein patterns of human uterine flushings collected at various stages of the menstrual cycle. Uterine flushings and plasma collected from normal, parous women at various stages of the menstrual cycle were subjected to gel electrophoresis. The protein profiles of the flushings differed in many instances from the plasma pattern by the presence of between one and eleven non-plasma proteins. The distribution of the major non-plasma proteins during the menstrual cycle was not statistically significant but that of a pretransferrin, observed in uterine flushings and in peritoneal fluid, was significant. However, the appearance of this protein band could not be related to a particular phase of the cycle, and hence to a specific hormonal condition.


Post-ovulatory changes in the water content and inulin space of the rabbit oviduct. Measurement of the water content and inulin space of the tissues of the ampulla, ampullary-isthmic junction and proximal isthmus showed that the loss of oedema was related to the position of the ova, whether this was normal (after hCG), delayed (by oestrogen treatment) or accelerated (by progesterone treatment).


Chiasma counts and non-disjunction frequencies in a normal ram and in rams carrying the Massey I (t1) Robertsonian translocation. Testicular material from a normal ram (54XY), three rams heterozygous (53XYt1) and one ram homozygous (52XYt1t1) for the Massey I (t1) translocation was examined. The autosomal non-disjunction in the normal ram was 2.0% compared to a mean of 6.1% in the heterozygous animals. In the homozygous animal there were adhesions of the tunica vaginalis to the cauda epididymidis and extensive spermatogenic arrest.


Association of exogenous phospholipids with spermatozoa. Boar, bull and ram spermatozoa were studied after incubation in a medium containing phospholipids. Autoradiography and birefringent examination of spermatozoa after incubation with labelled phosphatidylcholine indicated that liposomes of this phospholipid associated with spermatozoa. The association was almost instantaneous. The large multilayer liposomes formed during the experimental procedure resulted in a few of the spermatozoa acquiring most of the phosphatidylcholine. Little phosphatidylcholine was observed unassociated with spermatozoa although measurements of the partition between spermatozoa and medium showed that only boar spermatozoa associated with almost all the phospholipid. No evidence was obtained that phosphatidylethanolamine or phosphatidylinositol associated with the spermatozoa.


Changes in serum testosterone concentrations in the male pig during development. Serum testosterone concentrations were elevated between 40 and 60 days p.c. but were low between 60 and 100 days p.c. when the testis descends. Elevated concentrations occurred in the perinatal period and from the 18th week after birth. Between 60 days p.c. and 16 weeks after birth the changes in serum testosterone concentrations parallel those of testicular development, as determined by morphology and steroid histochemistry, and peripheral LH concentrations.


CL regression in the pseudopregnant rabbit and the effects of treatment with prostaglandin F-2alpha and arachidonic acid. During pseudopregnancy in the rabbit, plasma progesterone levels in the posterior vena cava fell rapidly from maximal concentrations of 9.8 +/- 0.7 (s.e.m.) ng/ml on Day 13 of pseudopregnancy to 2.0 +/- 0.6 ng/ml on Day 15. There was no significant increase in PGF levels at this time, although administration of indomethacin to a similar group of does delayed functional regression for over 7 days. Subcutaneous injection of 1 mg PGF-2alpha or 35 mg arachidonic acid on Day 9 of pseudopregnancy resulted in loss of luteal function as plasma progesterone levels fell significantly from about 6 to less than 1 ng/ml within 24 h. These findings indicate that the uterine factor responsible for luteolysis in the pseudopregnant rabbit may not be released in the form of PGF-2alpha.


A reciprocal translocation, t(6p+; 14q-), in the pig. A reciprocal translocation, identified as t(6p+; 14q-), is described in a 38,XX intersex pig. It is the fourth reciprocal translocation to be reported for this species, whereas Robertsonian translocations, of frequent occurrence in cattle and sheep, are so far unknown in domestic pig breeds.


Correlation between cytological and morphogenetic effects of acute X-irradiation of preimplantation mouse embryos cultured in vitro. Inhibition of cavitation by acute X-irradiation of 2-cell stage eggs was due to the early killing of the cells. Eggs in which cavitation did take place had a smaller number of cells due mainly to mitotic delay, leading to lack of inner cell mass (ICM) and its derivatives in further development. A similar effect is responsible for the inhibition of ICM formation after irradiation of morulae.


Use of dithiothreitol for improved visibility of the F body in human Y-bearing spermatozoa. Dithiothreitol was used to decondense the nuclear chromatin before staining human spermatozoa with quinacrine for the F body present in Y-bearing spermatozoa. In unseparated fractions and those enriched in X- or Y-bearing spermatozoa, the number of spermatozoa with F bodies increased by 2-9% after dithiothreitol treatment.


Elimination of fetal mice with sporadic malformations by spontaneous resorption in pregnancies of older females. The frequency of offspring with sporadic spontaneous malformations in A/JKt mice was significantly smaller in litters from older mothers than in litters from younger mothers. Simultaneously the fetal resorption rate was significantly larger in the older group apparently accounted for most, if not all, of the reduced malformation rate in their surviving offspring. It therefore seems that the aged uterus and the abnormal fetus are involved in the process by which such offspring are eliminated.


N-Hydroxyamide metabolites of lidocaine. Synthesis, characterization, quantitation, and mutagenic potential. Two possible N-hydroxyamide metabolites of lidocaine were synthesized and characterized. A combined technique utilizing chemical-ionization mass spectrometry and stable isotope labeling demonstrated that these potentially carcinogenic N-hydroxyamides were neither present in human urine after oral lidocaine administration nor during intravenous infusion of lidocaine for the treatment of ventricular arrhythmias. However, small amounts of 2,6-dimethylphenylhydroxylamine were detected in the urine of all subjects. Mutagenesis assays using the Ames test showed that neither the N-hydroxyamides nor the N-hydroxyarylamine produced revertant colonies above background levels using the Salmonella tester strain TA-1538.


Metabolic fate of tolazamide in man and in the rat. The metabolic fate of tolazamide, 1-(hexahydroazepin-1-yl)-3-p-tolylsulfonylurea (1), was studied in man and in the rat using tritium-labeled 1. The metabolites were isolated in crystalline form from urine for structure determination. The crystal structure and final molecular structure of one of these, 1-(4-hydroxyhexahydroazepin-1-yl)-3-p-tolylsulfonylurea (5), were determined using single-crystal X-ray techniques. Following oral administration of tritiated tolazamide to male humans, 85% of the radioactivity was excreted in urine during a 5-day period. In addition to being excreted in urine unchanged, tolazamide was metabolized to 1-(hexahydroazepin-1-yl)-3-p-(carboxyphenyl)sulfonylurea (2), p-toluenesulfonamide (3), 1-(hexahydroazepin-1-yl)-3-p-(hydroxymethylphenyl)sulfonylurea (4), 1-(4-hydroxyhexahydroazepin-1-yl)-3-p-tolylsulfonylurea (5) and a labile, unidentified metabolite 6 by man. The relative amounts of these materials excreted in 0-24-h urine collections from eight subjects averaged 7, 17, 26, 10, 25, and 15% for 1-6, respectively. In the female rat, 79% of an orally administered dose of tritiated tolazamide was excreted in urine during a 5-day period as 1-4. The relative amounts of these materials excreted during the 24-h period following administration of tolazamide were 10, 5, 5, and 80% for 1-4, respectively.


Antitumor anthracycline antibiotics. Structure-activity and structure-cardiotoxicity relationships of rubidazone analogues. A series of rubidazone analogues (4-14) with varying phenyl group substituents was prepared. The effect of these compounds on inhibition of nucleic acid synthesis in cultured cells, on in vivo antitumor properties, and on cardiotoxicity was examined. Substituent effects on drug-DNA binding as indicated by DNA melting temperature measurements were also investigated. Substituent effects were essentially absent among the rubidazone analogues in in vivo and in vitro test systems which measure cytotoxic characteristics; however, the rubidazone analogues varied substantially in their cardiotoxic effects and this variation was closely correlated with the electronic character of the phenyl substituent.


Synthesis and antihypertensive activity of some ester progenitors of methyldopa. A variety of esters of methyldopa was synthesized with the objective of obtaining derivatives that would be more efficiently absorbed from the gastrointestinal tract than the free amino acid and would undergo conversion to methyldopa readily in the blood or target tissues. Two of the esters, alpha-pivaloyloxyethyl (4u) and alpha-succinimidoethyl (4w), were found to be more potent antihypertensive agents than methyldopa in animal models and were selected for further study in man. The amino esters were prepared by three different methods, including direct esterification of methyldopa without the use of N- or O-protecting groups.


Synthesis and analgetic activity of some 5-aryl-2azabicyclo[3.2.1]octanes. A series of 5-aryl-2-azabicyclo[3.2.1]octanes II has been synthesized and evaluated for analgetic agonist-antagonist activity. These compounds can be regarded as five-membered, conformationally more rigid analogues of the potent agonist-antagonist (-)-5-(3-hydroxyphenyl)-2-methylmorphan (I). Several of these compounds have demonstrated marked analgesic potency comparable to morphine in the mouse writhing assay. Structure-activity correlations, generated by varying N-substitution and O-acetylation of the phenolic function, seem to indicate that optimum activity is associated with an arylethyl side chain attached to the basic nitrogen. Among the most interesting compounds in this series are the phenethyl analogue 31 and its O-acetate 39; the former shows the profile of a well-balanced analgetic-antagonist virtually devoid of physical dependence liability as demonstrated in the rat infusion test.


Diuretic activity of Mannich base derivatives of ethacrynic acid and certain ethacrynic acid analogues. Various Mannich base derivatives of selected phenoxyacetic acid type diuretics were synthesized and their diuretic potency was evaluated in dogs. It is concluded that the Mannich bases possess little, if any, diuretic activity of their own. Those Mannich bases that do possess diuretic activity undoubtedly do so as a consequence of an elimination reaction (a retro-Michael type reaction) which yields the corresponding pharmacologically active alpha,beta-unsaturated ketone.


Synthesis and hypotensive activity of N-alkyl-N"-cyano-N'-pyridylguanidines. A variety of N-alkyl-N'-pyridyl-N"-cyanoguanidines III was prepared as potential bioisosteres of hypotensive N-alkyl-N'-pyridylthioureas Ia. Optimal activity of the N,N'-disubstituted cyanoguanidines III was assoicated with the presence of four to seven carbon branched alkyl and 3- or 4-pyridyl groups. Maximum potency was displayed by N-tert-pentyl-N'-3 pyridyl-N"-cyanoguanidine (20). This compound proved to be 200 times more potent than the corresponding thiourea in hypertensive rats and dogs. In comparison with guancydine, which is the de-3-pyridyl analogue of 20, a 150-fold increase of potency in spontaneously hypertensive rats was obtained with 20 and its tert-butyl analogue 19. The observed activity appears to be due to direct vascular relaxation. On a weight basis compounds 19, 20, 50, and 101 compared favorably with hydralazine.


Peptidyl transferase substrate specificity with nonaromatic aminoacyl analogues of puromycin. A series of puromycin analogues, 3'-N-(S-substituted L-cysteinyl) puromycin aminonuleosides, has been prepared and examined as substrates for ribosomal peptidyl transferase. S-Substituted N-tert-butyloxycarbonyl-L-cysteines were coupled with puromycin aminonucleoside using dicyclohexylcarbodiimide and N-hydroxysuccinimide. Removal of the t-Boc blocking group with anhydrous trifluoroacetic acid gave the desired puromycin analogues. Kinetic studies indicate that the nonaromatic aminoacyl analogues of puromycin are effective substrates for the peptidyl transferase reaction. In addition, the discovery of the existence of hydrophilic character beyond the region normally occupied by hydrophobic amino acid R groups of the aminoacyladenyl termini of tRNA molecules, and the proper exploitation of this information, has provided the first active purmoycin analogue possessing a hydrophilic amino acid.


Comparative analysis of the cytotoxicity of substituted [phenylglyoxal bis(4-methyl-3-thiosemicarbazone)] copper(II) chelates. 2. Parabolic correlations and their implications for selective toxicity. The synthesis of an extended series of para-substituted [phenylglyoxal bis(4-methyl-3-thiosemicarbazone)] copper(II) chelates is reported. Subsequent biological evaluation and regression analysis have been performed, correlating pI50 with extrathermodynamic substituent parameters. Parabolic correlations with pi have resulted which predict optimum lipophilic character of the para substituent with respect to Ehrlich ascites cytotoxicity (pi0 = -2.13) and with respect to ascites vs. liver slice cytotoxicity (pi0 = -1.31). Results indicated clearly that the chelate most toxic to the tumor cell model may not be the most selective.


Drugs derived from cannabinoids. 7. Tachycardia and analgesia structure-activity relationships in delta9-tetrahydrocannabinol and some synthetic analogues. delta9-Tetrahydrocannabinol (delta9-THC) and eight other synthetic analogues were found to induce a dose-related increase in heart rate in the conscious Wistar rat. Ina comparison of tachycardia with analgesic activity (mouse hot-plate and antiwrithing tests) it was found that the water-soluble ester derivatives of 2a, 1-hydroxy-3-(3-methyl-2-octyl)-6,6,9-trimethyl-7,8,9,10-tetrahydro-6H-dibenzo(b,d)pyran (DMHP), had the least potency for tachycardia and the greatest potency for analgesia. These findings suggest that these compounds may have promise as therapeutic agents.


Potential antitumor agents. Synthesis, reactivity, and cytoxicity of alpha-methylene carbonyl compounds. The alpha-methylene lactones 9, 12, 21, and 24 were prepared by a mild, convenient alpha-methylenation process using the alpha-ethyloxalyl derivatives in nonoptimized yields ranging from 23 to 90%. The rates of reaction of these and several other lactones with cysteine at pH 7.4 and their KB toxicities were measured. These studies showed that neither the strained trans-fused alpha-methylene lactone 12 nor the hydroxy-alpha-methylene lactones 5 and 6 reacted with cysteine with rates comparable to elephantopin. Based on these limited studies, the rate of cysteine addition appears to be relatively insensitive to changes in strain energy and neighboring groups. In addition, the rate constant for reaction with cysteine did not correlate with cytotoxicity.


Antitumor agents 32. Synthesis and antitumor activity of cyclopentenone derivatives related to helenalin. Several new cyclopentenones related to helenalin have been synthesized as potential alkylating antitumor agents. The procedure involved the transformation of 2-methyl-2-carbethoxycyclopentanone (2) to an ethylene ketal 3, bromination of 3 followed by dehydrobromination to yield a ketal olefin 5, reduction of 5 to the alcohol 6, conversion of 6 to the corresponding hydroxycyclopentenone 7, and estrification of 7 to afford the cyclopentenone esters 8--11. Biological assays indicated that only cyclopentenones possessing a conjugated ester side chain, such as 9 and 10, demonstrated significant in vitro cytotoxicity against the growth of tissue culture cells originating from human epidermoid carcinoma of the larynx (H.Ep.-2) as well as in vivo antitumor activity in Walker 256 carcinosarcoma in rats and P-388 lymphocytic leukemia in mice.


In vitro antiplaque properties of a series of alkyl bis(biguanides). A series of eight alkyl bis(biguanide) analogues of alexidine, N,N''''-1,6-hexanediyl bis[N'-(2-ethylhexyl)imidodicarbonimidic diamide] (1), was prepared. Five of these analogues constituted a series isolipophilic with 1 but with varying bridge length between biguanide moieties. The compounds were evaluated in vitro for antibacterial and antiplaque properties against Streptococcus mutans, Actinomyces viscosus, and Actinomyces naesludii. One analogue, N N,''''-1,6-hexanediyl bis[N'(n-octyl)imidodicarbonimidic diamide], appeared to be more effective than either 1 or chlorhexidine against this spectrum of dental plaque forming microorganisms.


8-Carboxy-6-sulfamyldibenz[b,f][1,4]oxazepines and -thiazepines as potential high-ceiling diuretics. The synthesis of several 8-carboxy-6-sulfamyldibenz[b,f][1,4]oxazepines and -thiazepines is described. The results of diuretic screening lend support to the thesis that activity is strongly dependent on the conformational mobility of 4-substituents in the 3-amino-5-sulfamylbenzoic acids.


The assessment of pain in advanced cancer. This is one of a group of papers read at the London Medical Group conference of "Pain: a necessity?",' which was held in Charing Cross Hospital Medical School, London in February 1978. Dr Twycross argues that complete assessment implies the ability not only to make a diagnosis but also to initiate appropriate treatment. Describing the site, severity and quality of the pain is only the first step. A doctor needs to: 1) Be aware of the range of diagnostic possibilities 2) Appreciate the influences of non-physical factors such as mood and morale 3) Be aware of the range of treatemnt options 4) Establish realistic objectives with the patient 5) Reassess at appropriate intervals to review treatment, monitor side-effects, and develop and maintain a good working relationship with the patient.


The value of clinics for the relief of chronic pain. This paper is another of the papers presented at a conference on Pain organised under the auspices of the London Medical Group. Mark Swerdlow deals with the work of pain relief clinics and explores their value. He gives the background as to what these clinics are, describes who is treated, how they are staffed and finally offers his opinion as to their effectiveness.


The place of pain in human experience.

The place of pain in human experience. In this last of our selection of papers from the London Medical Group Conference on Pain, Gilbert Lewis, through his experiences of living in New Guinea describes to us the various rites, rituals and uses of pain in societies other than our own. He outlines, by example, how what often seems the natural behaviour to us for helping a sufferer in fact, can make matters far worse for other peoples. Although different societies approach the problem of pain from many routes the aim of all is to relieve pain for the sufferers. If the sufferer says he feels relief then that is surely what counts.


Psychiatry as ideology in the USSR.

Psychiatry as ideology in the USSR. This paper was given as a talk at the Venice Biennale on 9 December 1977. It was part of a symposium on "The Freedom of Science--Problems of Science of Scientists in Eastern Europe". Dr Bloch details some of the problems of psychiatry and its vulnerability to improper use and thus the dilemmas which must ensue in day to day practice. He looks at psychiatry in the USSR and the system within which Soviet psychiatrists must work. The Communist Party and career advancement for psychiatrists would appear to be closely related and it is suggested that, in all probability, the majority of psychiatrists are as perturbed at the misuse of their profession as their Western colleagues, but act compliantly out of fear. Severe punishments have been imposed on those psychiatrists who have dared to speak out against the régime and the system as operated. Dr Bloch concludes by urging Western psychiatrists to do all they can to help their Soviet colleagues to initiate a return to an independent and automous psychiatric profession.


Bisexuality and the problem of its social acceptance. Professor Austin explores four main areas in this paper. First of all he outlines the physical development of sex differentiation in the embryo. He develops this by describing the clinical manifestations of abnormality which can appear at that stage. Professor Austin points out that there are relatively few people with abnormalities and that those who do show homosexual tendencies are not noticeably different from the norm in terms of their sexual equipment and hormone levels. It is much more likely that their psychological and social development has a greater influence in differentiating them sexually. The last section of the paper is a synopsis of society's reactions to homosexuality or bisexuality which term in Professor Austin's opinion is more accurate and descriptive of the condition.


On children and proxy consent.

On children and proxy consent. The meaning of valid proxy consent for children has recently been the subject of an important debate between Richard McCormick and Paul Ramsey on the ethics of experimenting with children. Ramsey is willing to agree with McCormick that parental consent for a child to undergo some medical procedure is valid only if parents consider what the child would consent to if he could. But beyond this, Ramsey has a fundamentally different conception of the child from McCormick, and therefore gives a very different interpretation to this standard for valid proxy consent. In Ramsey's view, McCormick's basic mistake is to think of the child as a small adult, thereby overlooking the child's peculiar vulnerabilities and needs. In particular, McCormick fails to attend to the child's needs for "preservation in life and healthful growth". In this paper, the author pursues Ramsey's suggestion that a correct analysis of valid proxy consent for children would replace the "language of consent" with the "language of need". He does this by sketching a theory of parenthood that rests on two central notions: that of primary goods, as found in the writing of John Rawls, and that of autonomy.


Academic and personal predictors of clinical success in medical school. Admissions interview data and college academic credentials of five classes of University of Missouri-Columbia medical students were evaluated as possible predictors of clinical success. Those students who were judged by admissions  interviewers to have high levels of maturity, nonacademic achievement motivation or rapport were approximately two to three times as likely to receive outstanding internship recommendations as those without such personal characteristics. Under-graduate grade-point average had a smaller but nevertheless significant relationship with clinical success as measured by internship letters. These data suggest that additional emphasis during selection upon applicants' personal characteristics would have enhanced the clinical success of these students.


A problem-based criterion-referenced examination of clinical competence. A model has been developed for a problem-based criterion-referenced test of clinical competence. The model, designed to increase the reliability and validity of traditional final year examinations for medical students, aims to provide a profile of student performance over a range of defined competence categories. The level of competence has been referenced to that expected of an intern. Both the content of the examination and the selection of test methods are based on patient problem blueprints which identify key areas that require testing. The content and test methods were incorporated, as appropriate, into either th;e written section or the practical section of the examination. The approach was found to be feasible and acceptable to staff and students.


Diagnosis and treatment of academic frustration syndrome. A random sample of medical students was compared with others who were unable to cope with unanticipated academic frustration. The noncoping students demonstrated higher levels of debilitating anxiety and lower levels of facilitating anxiety while their perceptions of locus of control tended to be more extreme. No difference was found in study habits and attitudes. Techniques of attribution therapy and desensitization in the counseling of these students proved to be effective in improving coping behavior in six of seven cases.


French medical education: years of change. In the 1960s medical education in France underwent major changes after nearly a quarter-century of efforts by a few leaders. The reforms were supported by students, externs, and interns but generally were opposed by hospital staff and administration and by those in organized medicine. Following student unrest in the late 1960s and evolving medical education in France and elsewhere in the western world, a new series of changes was introduced, several perhaps of more far-reaching consequence than those of the prior decade. Reviewed here is the impact on French medical education of the expansion in numbers of medical schools and students, introduction of a competitive examination to select students whose numbers are a function of the number of teaching hospital beds available, and governmental plans to effect a 20 percent reduction in the number of medical students by 1980.


Teaching occupational health to physicians. A comprehensive training program for physicians interested in occupational health is presented. The objectives are to prepare students to identify and prevent occupational disease, with an emphasis on the development of a public health perspective. Seven content areas are described: epidemiology and biostatistics, toxicology, industrial hygiene, safety and ergonomics, policy issues, administration, and clinical aspects. These are organized in a matrix to provide appropriate levels of training for medical students, resident physicians, and general practioners as well as physicians seeking specialty training.


Utilization of psychiatry in a primary care center. The pattern of use of psychiatry over a 12-month period in a university-based primary care center is reported. Interest in pursuing careers in family practice and amount of time spent in the center were related to seeking consultation. All nurse practitioners and social workers sought psychiatric consultations. The majority of patients received care for their psychiatric problems by their primary care clinicians after consultation rather than being referred to a traditional psychiatric clinic.


The community mental health center as a setting for a psychiatry junior clerkship. The implementation of a psychiatric outpatient experience for a first class of junior medical students in a nonmedical model community mental health clinic is presented. The advantages and disadvantages of exposing students to a community-oriented, rather than a medical-center-oriented, treatment system are discussed in some detail. Differences between the two settings of particular import were the stress placed by the clinic upon team decision-making, diffuse responsibility for client care, a somewhat antimedical orientation, and treatment of clients whose complaints are more often "problems of living" rather than of psychiatric illness. It is felt that the positive aspects of such an exposure outweigh the negative ones and that by careful planning many of the potential drawbacks of such a setting for a psychiatric outpatient rotation can be successfully avoided.


Ionic permeability of sarcoplasmic reticulum vesicles measured by light scattering method. The volume change of sarcoplasmic retriculum vesicles was followed by measuring the light scattering intensity. When the salt concentration of the suspension of sarcoplasmic reticulum vesicles was increased by using a stopped flow apparatus, the light scattering intensity rapidly increased at the beginning and then decreased. The fast increase in the light scattering intensity is caused by the decrease of the volume of sarcoplasmic reticulum vesicles due to the outflow of water. The following decrease in the light scattering intensity is caused by the increase of the volume due to the inflow of the solutes and water. From the former and the latter rates, the permeation times of water and the solutes could be calculated, respectively. According to the same method, permeation times of various salts were determined. The rate of the inflow of the salts was dependent on the movement of the slower ions, that is, ions move as a pair. In the case of potassium salts, an increase in the permeation rate of the salts was observed when valinomycin was added to the membrane suspensions. From these experiments, as a measure of permeability, half permeation times of various ions and molecules were determined. The following are typical results: water 0.1, Li+ 36, Na+ 26, K+20, Rb+ 16, Cl- 0.4, methanesulfonate 20, phosphate 10.5, oxalate 40 in seconds at room temperature. As a whole, sarcoplasmic reticulum was found to be an anion permeable membrane.


On the red blood cell Ca2+-pump: an estimate of stoichiometry. Efflux of Ca2+ from reversibly hemolyzed human red blood cells ghosts was determined by a Ca2+ selective electrode, by atomic absorption spectroscopy, and by the use of 45Ca. Hydrolysis of ATP was determined by measurement of inorganic phosphate (Pi). At 25 degrees C, ghosts loaded with CaCl2, MgCl2, Na2ATP, and Tris buffer (pH 7.4) extruded Ca2+, with mean rates ranging from 58.8 +/- 3.5 (SD) to 74.7 +/- 8.2 (SD) mumoles.liter ghosts -1.min-1 depending on the method of Ca2+ determination. The ratio of Ca2+ transport to Pi released in the presence of ouabain without correction for background ATP splitting was 0.83, 0.83, and 0.80, respectively, for the three methods of Ca2+ determination. Correction for the ATPase activity not associated with Ca2+ transport resulted in a ratio of 0.91:1. In other experiments, the use of La3+ to inhibit the Ca2+-pump allowed an estimate of the ATPase activity associated with Ca2+ extrusion. In the presence of various concentrations of La3+, the ratio of Ca2+ pumped to Pi liberated was 0.86 or 1.02, depending on the method of Ca2+ determination. It is concluded that the stoichiometry of the Ca2+-pump of the RBC plasma membrane is one Ca2+ pumped per ATP hydrolyzed.


Freeze-fracturing of biological material with a new specimen table. The freeze-fracturing of various biological material is described with the aid of a modified Balzers specimen table. The advantages of this table are easier and faster handling of the specimens and a better thermal contact between the specimen and the cold stage.


Distribution of membrane thickness determined by lineal analysis. The expected statistical distributions of intercept length are derived in terms of geometrical probability density functions pertaining to plates with known thickness penetrated by lines with random orientation. These expressions provide arithmetic and graphical solutions for obtaining distributions of membrane thickness and reciprocal membrane thickness from empirical distributions of intercept lengths. Furthermore, general relationships between probability density functions of distributions of intercept length and membrane thickness are derived as well as those between their moments. Examples of the application of the method to biological samples are given, and estimated distributions of glomerular basement membrane thickness are compared to those obtained by an independent, direct method. Various sources of bias, which in practice may occur due to departures from the sample model, are discussed and the influence of some of them is estimated. The knowledge of the probability density function of reciprocal intercepts makes it possible to perform a correction of the distribution of measured intercept length, which to some extent eliminates bias.


The relationship of a monoamine fiber system to a somatosensory tectal projection in the salamander Ambystoma tigrinum. After hemisection of the spinal cord and medulla oblongata, a projection has been traced to the inner half of the tectal white of the tiger salamander, using Fink-Heimer degeneration staining. By microelectrode recording it was found that the tectal projection forms a topographic somatosensory map of the contralateral half of the body. This map is in register with the overlying retino-tectal visual projection. Using the Falck-Hillarp technique, it was found that the somatosensory tectal input is associated with yellow-fluorescing 5-hydroxytryptamine fibers.


Genetic code correlations: amino acids and their anticodon nucleotides. The data here show direct correlations between both the hydrophobicity and the hydrophilicity of the homocodonic amino acids and their anticodon nucleotides. While the differences between properties of uracil and cytosine derivatives are small, further data show that uracil has an affinity for charged species. Although these data suggest that molecular relationships between amino acids and anticodons were responsible for the origin of the code, it is not clear what the mechanism of the origin might have been.


The genetic code as a periodic table.

The genetic code as a periodic table. The contemporary genetic code is reflective of a significant correlation between the properties of amino acids and their anticodons in a periodic manner. Almost all properties of amino acids showed a greater correlation to anticondonic than to codonic dinucleoside monophosphate properties. The polarity and bulkiness of amino acid side chains can be used to predict the anticodon with considerable confidence. The results are most consistent with predictions of the "direct interaction" and "ambiguity reduction" hypotheses for the origin of the genetic code.


A measure of the denseness of a phylogenetic network. The concept of phylogenetic denseness bears critically on the accuracy of evolutionary pathways inferred from experimentally sequenced proteins isolated from extant species. In this paper I develop an objective measure, rho, of denseness to supplement previous intuitive concepts and which permits one to use this concept in comparing the quality of different evolutionary reconstructions. This measure is used to examine several published phylogenetic trees: insulin, alpha-hemoglobin, beta-hemoglobin, myoglobin, cytochrome c, and the parvalbumin family. The paper emphasizes 1) the importance of denseness in accurately estimating the number of nucleotide replacements which separate homologous sequences when this estimation is made by the method of parsimony, 2) the value of this concept in assessing the quality of those estimates, and 3) the use of this concept as a biologically practical heuristic method for identifying poorly studied regions in a phylogenetic tree, whether or not the tree was obtained by the parsimony method.


The evolution of protein sequences by repetitious gene duplication: clostridial flavodoxin. Internal regularities of amino acid sequences of flavodoxins, FMN-containing, low molecular weight flavoproteins, were statistically examined using the minimum mutation method. The sequence of Clostridium pasteurianum flavodoxin shows statistically significant evidence of repetitious internal gene duplications at different levels of structure. Peptide pairs with a low chance probabilitiy of occurrence were frequently observed at a shift of 5 residues. The pairs with the lowest chance probabilities are a pair of heptapeptides at positions39--45 vs. 44--50, a 5 residue shift (p = 9 x 10(-6)). Most of the related pairs are consistent and could best be explained by the repeating pentapeptide sequence: (Lys-Gly-Ala-Asp-Val-)n and appropriate gaps. Internal repetitions with longer shifts were also suggested for other flavodoxins. Repetitious gene duplication is proposed for the early stages of flavodoxin evolution.


Archaebacteria.

Archaebacteria. Experimental work published elsewhere has shown that the Archaebacteria encompass several distinct subgroups including methanogens, extreme halophiles, and various thermoacidophiles. The common characteristics of Archaebacteria known to date are these: (1) the presence of characteristic tRNAs and ribosomal RNAs; (2) the absence of peptidoglycan cell walls, with in many cases, replacement by a largely proteinaceous coat; (3) the occurrence of ether linked lipids built from phytanyl chains and (4) in all cases known so far, their occurrence only in unusual habitats. These organisms contain a number of 'eucaryotic features' in addition to their many bacterial attributes. This is interpreted as a strong indication that the Archaebacteria, while not actually eucaryotic, do indeed represents a third separate, line of descent as originally proposed.


Non-aerated cultivation of Halobacterium cutirubrum and its effect on cellular squalenes. Halobacterium cutirubrum was successfully cultivated under aerobic and microaerobic conditions. The early stationary phase of growth was obtained at 2.2 days and 45--55 days for aerated and non-aerated cultures, respectively. The dry cell yields were 0.7--1.2 gm/1 in all preparations grown to early stationary growth phase. The cellular ratio of squalene to dihydro- and tetra-hydrosqualene decreased proportionately with decreased aeration rates.


Neutral changes during divergent evolution of hemoglobins. A comparison of the mRNAs for rabbit and human beta-hemoglobins shows that synonymous changes in codons have accumulated three times as rapidly as nucleotide replacements that produced changes in amino acids. This agrees with predictions based on the so-called 'neutral theory'. In addition, seven codon changes that appear to be single-base changes (according to 'maximum parsimony') are actually two-base changes. This indicates that the construction of "primordial sequences" is of limited signficance when based on inferences that assume minimum base changes for amino acid replacements.


Severe demyelinating diseases in childhood: a clinicopathological study. Case reports of six children seen by the author were selected to emphasize that severe demyelinating diseases occur in childhood, even if rarely. Cases include measles encephalitis, acute and chronic, subacute sclerosing panencephalitis, neuromyelitis optica, and multiple sclerosis, confirmed by pathologic findings, and, finally, a case of multiple sclerosis in a living child. Emphasis is directed to the clinical and pathological findings of demyelinating diseases associated with viral encephalitis caused by rubeola and vaccinia viruses. Photomicrographs illustrate the principal pathologic findings.


Smoker's lump.

Smoker's lump. The purpose of this report is to review personal experience with digital palpation of the nasopharynx, particularly as it relates to an apparently reversible posterior pharyngeal mass commonly found in patients who are heavy smokers.


Medical student attitudes about quality of care and training of minority persons. Ninety-five first year medical students agreed that there was differential medical treatment of minority vs majority persons. Implicated reasons for this phenomenon were lack of personal treatment of members of minorities, distrust of medical workers by minority members, and majority perceptions that minority persons are not good patients. Integrated treatment and training facilities, preferential academic treatment, special training for majority students, and philosophy of medical care are discussed in terms of improving medical care for all.


Sarcoidosis: multiple chest manifestations. The multiple roentgenographic appearances of pulmonary sarcoidosis, a well-known systemic granulomatous disease of undetermined etiology, are presented. The findings in the chests of 350 patients with diagnosis of Boeck sarcoid confirms the usual and unusual manifestations which have been described in the past.(1,2)


Complications of groin hernia repair: their prevention and management. An estimated overall complication rate of approximately ten percent is found in the half million patients who annually undergo groin hernia repair in the United States. Certain features in the operative technique are emphasized which should prevent many of these complications.Intraoperative complications during the groin hernia repair are primarily hemorrhage and injury to the vas deferens, the three nerves in the area, the vascular supply of the testis, and the abdominal and pelvic viscera. Miscellaneous intraoperative complications relate to problems associated with the repair of massive hernias, missed hernia, and the loss of strangulated bowel into the abdominal cavity.Early postoperative complications may be either systemic or local with cardiac and respiratory conditions comprising the former group. The early local complications are primarily wound problems of infection, hematoma formation, and scrotal swelling involving the skin and testis. High ligation in excision of the sac in all hernias, repair of the defect in the plane of its occurrence, and suture of fascia to fascia in the same plane without tension are the basic tenets of inguinal hernia repair which should result in a low incidence of recurrence.The most effective prophylactic measures necessary for the prevention of complications considered are a thorough knowledge of inguinofemoral anatomy, mature surgical judgment, and meticulous surgical technique.


Cancer of the tonsil--a retrospective study. Treatment of cancer of the tonsil continues to be a controversial matter. A review of the otolaryngological literature and a study of 155 patients treated at the University of British Columbia reveals that the cure rate remains unsatisfactory, particularly in patients with large tumors. We have concluded that early carcinoma of the tonsil should be treated with a full course of radiotherapy reserving surgical treatment for residual or recurrent disease. Advanced carcinoma of the tonsil requires planned combined therapy. Early results indicate that the addition of chemotherapy may significantly improve results over the usual combination of radiotherapy and surgery.


Laryngeal granuloma secondary to gastro--esophageal reflux. Approximately 60 per cent of patients with gastro-esophageal reflux have symptoms related to aspiration of acid and/or bile into the airway. Though many instances of lower airway involvement have been well documented, no mass lesion secondary to gastro-esophageal reflux involving the larynx has ever been demonstrated clinically. The purpose of this presentation is to define a recurrent granuloma of the posterior two-thirds of the left vocal cord, which appeared the result of gastro-esophageal reflux, including both bile and acid content. The relationship between the laryngeal granuloma and the gastro-esophageal reflux was both clinical and pathological; in particular, the histology of the lesion with its intact mucous membrane appeared virtually identical to that found in active reflux esophagitis.


The diagnosis of melanotic and other pigmented lesions of the lips and oral mucosa (dark spots in the mouth). Pigmented lesions of the oral mucosa may be due to collections of blood, metallic particles of melanin. Any of these substances will appear of a blue tinge if at any depth in the tissues, while superficial collections may be red, black or brown respectively. Lesions associated with blood will be hematomas, dilated veins, hemangiomas or telangiectases. Metallic particles are found in amalgam tattoos. Melanotic pigmentation may occur as a normal variation, following hormonal disturbance and inflammation, and sometimes iatrogenically. Benign and malignant melanoma of the oral cavity is highly lethal. 25% of malignant melanomas in this site present as nondescript brown spots, and isolated broid overlooking an early malignant melanoma.


Oncocytic lesions of the larynx.

Oncocytic lesions of the larynx. Eight cases of laryngeal oncocytic lesions treated at Toronto Western Hospital between 1957 and 1977 are reviewed. The typical clinical course was of a benign lesion with prolonged dysphonia. A smaller number with bulkier lesions developed symptoms of airway obstruction. The lesions were supraglottic and cystic. They were excised either endoscopically or via a laryngofissure. The pathologic features support the concept that the lesion represents a metaplasiahyperplasia, and therefore the term 'oncocytic cyst' is preferred to terms which imply a neoplastic process. Three patients with oncocytic cysts had associated squamous dysplasia of the vocal cord. Pathologically this supports the theory of tissue response to chronic irritation, since all three were heavy smokers. Clincially the finding necessitates longterm follow-up with a view to possible squamous cell carcinoma that may arise on the true cords. Follow-up in this series showed no recurrence of symptoms in six of eight cases, two being lost to follow-up.


Congenital tracheal web--a case report.

Congenital tracheal web--a case report. Congenital tracheal webs are rare. This report involves an eight year old girl presenting with a six year history of frequent colds, wheezing, and dyspnea in whom the tracheal web was successfully excised after failure of bronchoscopic dilation. Tracheal embryology is briefly reviewed and tracheal stenoses are classified. A history of recurrent chest infection and finding of stridor are the chief of recurrent chest infection and the finding of stridor are the chief features ot his lesion. Lateral chest roentgenogram, tracheal tomography, and bronchoscopy are useful in establishing the diagnosis.


[Nasotracheal intubation and tracheostomy in acute epiglottitis and laryngotracheal bronchitis]. Acute infectious respiratory distress in children has known different modalities of treatment during these past few years, but controversy remains between tracheostomy and naso-tracheal intubation as ways to cope with the problem. This study, which was undertaken at St. Justine's Hospital in Montreal, reports our complications with the two methods and shows that non-fatal complications are about the same but less serious with naso-tracheal intubation, whereas mortality was 3.2% with tracheostomy and 0% with naso-tracheal intubation. These results entitle us to think that naso-tracheal intubation is the treatment which should be used. This study also reviews different incidence in regards to age, sex, and seasonal prevalence between croup and epiglottitis and also compares the duration of hospital care between the two modalities.


The ipsilateral acoustic impedance artifact and Rayleigh's radiation pressure. This paper refutes the proposition that the ipsilateral acoustic impedance artifact is due to the effects of the radiation pressure of the stimulus sound field.


Surgery of the turbinates.

Surgery of the turbinates. It appears that a variety of surgical techniques are available to safely decrease the size of hyperplastic inferior turbinates; when used properly in appropriate patients they can provide significant improvement in the symptoms of chronic nasal obstruction.


Pathology and correction of the stenosed nasal vestibule. Stenosis of the nasal vestibule is a frequent cause of nasal obstruction. An anatomical study of the region will enable one to understand the physiopathology of the stenosis of the floor of the vestibule which frequently accompanies septal deformities in the premaxilla region, or which occurs after septal surgery. The correction of this circumferential stenosis has been handled satisfactorily by the use of a "Z" plasty of the floor of the vestibule. Pertinent anatomical material, schematic drawings, and clinical cases are presented.


Tympanoplasty grafting and ossicular reconstruction. Tympanoplasty is a surgical procedure that has been used in various modifications for the last 25 years for chronic ear disease. The goals of tympanoplasty are to control the infection and at the same time to restore the ear to a more normal state with the hope of improving hearing.


Malignant squamous papillomatosis of the mastoid. Benign squamous papilloma of the external ear is rarely reported in the literature. This paper describes the occurrence of an extensive benign squamous papillomatosis of the mastoid that showed an apparent malignant transformation with fatal results to the patient.


Sinogenic and otogenic brain abscesses--a review of 63 cases occurring at Toronto General Hospital, 1956-75. Sixty-three cases of brain abscess resulting from ear and paranasal sinus infections were reviewed. These patients were seen at the Toronto General Hospital from 1956-1965 and from 1969-1975. Comparisons are made relating to site, age and sex incidence, mortality rates, bacteriology, and rate of associated meningitis. Modern diagnostic methods are reviewed with particular emphasis on the use of the C.T. scanner.


The pathogenesis, differential diagnosis, and treatment of malignant otitis externa. Three cases of malignant external otitis with varied clinical causes are presented. It is most important to suspect the condition in any diabetic who has external otitis refractory to the usual treatment. Once the diagnosis is made, aggressive medical management is imperative to prevent progression of the disease.


Sudden bilateral hearing loss and meningitis in adults. Sudden profound bilateral sensorineural hearing loss is a serious complication of bacterial meningitis. With high dosage Dexamethasone it is possible to halt, and, in some instances, to reverse the progression of the hearing loss. The efficacy of treatment depends upon early diagnosis. Hearing may worsen upon steroid cessation and low dosage oral steroid may be required for several months. The eventual hearing loss may be considerably worse than anticipated. Two cases illustrating differing aspects of the disease are described.


Paroxysmal positional vertigo--a study of 255 cases. The clinical and electronystagmographic findings of 255 patients with paroxysmal positional vertigo are presented. We believe the disorder should be diagnosed on the basis of the history and clinical findings since we did not find any characteristic electronystagmographic findings other than the recording of an actual attack. Our observations lead us to believe that there is only one type of attack. We conclude that the nystagmus which occurs during the attack is generated by stimulation of the posterior semicircular canal of the lowermost ear.


Surgery of the facial nerve.

Surgery of the facial nerve. Microsurgical technique and new temporal bone operative procedures have revolutionized surgery of the facial nerve. The purpose of this paper is to describe the diagnostic evaluation of the patient with a facial paralysis including topographic site of lesion studies. Surgical techniques for exposing the facial nerve from the internal auditory canal to the stylomastoid foramen are discussed in detail.


[Electrophysiological evaluation of facial paralysis]. The purpose of this article is to present a new electrophysiological evaluation method to study facial nerve function. This technique studies the afferent sensory pathways and the efferent motor fibres. The study of the various parameters of those two functions allows us to draw certain conclusions relating to the prognosis and localization of facial nerve lesions.


Drawing: a universal language.

Drawing: a universal language. The authors insist on the importance of drawing through the centuries to recall ways of life. They try to pinpoint the utility of drawing in this day and age, making perioperative drawing reports concise and clear with a few lines. Basic sketches are explained and illustrated.


Abnormal facial appearance and delayed diagnosis of congenital hearing loss. Congenital hearing loss occurs in association with cranio-facial anomalies. Lay people and health professionals as well frequently regard individuals with cranio-facial anomalies as "stupid" or of lower than normal intelligence because of their odd appearance. Two case reports illustrate that this erroneous assumption will result in the delayed detection of significant hearing loss.


Juvenile laryngeal papilloma displaying malignant degeneration--a spectrophotometric investigation. Spontaneous malignant degeneration of juvenile laryngeal papilloma in the absence of radiotherapy is exceedingly rare, and few such cases have been reported. The patient reported here, now a woman of 48, has been suffering from recurrent juvenile laryngeal papilloma since she was 13. During the last six years the papillomas have displayed increasing atypia and have spread to the trachea and the bronchus of the right inferior lobe. Recent specimens from the trachea are strongly suggestive of micro-invasive squamous cell carcinoma. The slides from various periods have been reviewed and submitted to spectrophotometric examination to determine the nuclear DNA content and area. For the purpose of comparison, measurements have also been performed on normal squamous vocal cord epithelium, on two juvenile papillomas without atypia, and on one "adult papilloma" with severe atypia. The nuclear DNA absorbance recorded in the patient in question was initially comparable with those for the typical juvenile papillomas and the normal epithelium. The values for the later specimens with increasing atypia, especially those from trachea and bronchus, resemble more closely those for the "adult papilloma" with severe atypia. The results of the spectrophotometric examination are closely consistent with the histological findings.


Osteomas of the paranasal sinuses.

Osteomas of the paranasal sinuses. Twenty-eight cases of osteomas of the paranasal sinuses are reviewed. The most common localization was the frontal sinus, secondly the ethmoid sinus. Primary osteomas of the maxillary and sphenoid sinus are very rare. The most common complaint was pain. Clinical examination revealed deformity of the forehead and/or face in 13 patients, seven had dislocation of the eyeball as well. In eight cases x-ray, including tomography, and operation showed exposed dura. This gives a potential risk of intracranial complications, demonstrated by one of our patients who had a defect in the dura, and consequently meningitis. Osteomas encroaching on neighboring structures should be extirpated, while smaller osteomas can be left in place provided that they are controlled regularly. Recurrences are rare. When operating we feel that satisfactory cosmetic and functional conditions count more than radicality.


Sphenoid mucocele presenting as a pre-pontine mass. A patient with sphenoid sinus mucocele presented with destruction of the clivus and a pre-pontine mass mimicking a chordoma of the clivus.


New late gene, dar, involved in the replication of bacteriophage T4 DNA. III. DNA replicative intermediates of T4 dar and a gene 59 mutant suppressed by dar. A mutation in the dar gene of phage T4 restored the arrested DNA synthesis caused by the gene 59 mutation. We have studied the DNA replicative intermediates in cells infected with a dar mutant and a dar-amC5 (gene 59) mutant by velocity sedimentation in neutral and alkaline sucrose gradients. In T4 dar-infected cells, compared to the wild type, three kinds of abnormalities were observed in DNA replication (i) There were unusually rapidly sedimenting  intermediates (800S). (ii) When centrifuged in alkaline gradients, there was less single-stranded DNA exceeding 1 phage unit. (iii) The rate of repair of DNA intermediates was slower. It has been proposed by others that the 200S DNA replicative intermediates are required for DNA packaging, but our results showed that the 800S DNA of dar does not have to be converted into the 200S form to undergo conversion to mature viral DNA. Therefore, 200S DNA may not be an obligatory intermediate for mature viral DNA formation. In amC5 (gene 59)-infected cells, the DNA was completely converted 2 to 3 min after intiation of replication to the biologically inactive 63S DNA, and DNA synthesis was concomitantly arrested. However, in dar-am-C5 (gene 59)-infected cells, the formation of abnormal 63S DNA did not occur and 200S DNA appeared instead. An endonucleolytic activity, normally associated with the cell membrane and capable of making double-stranded cuts, was found in the cytoplasm of T4 dar-infected cells. Because the total activity of this endonuclease is the same for both wild-type T4D and the dar mutant, it seems unlikely that the dar protein has endonucleolytic activity itself. However, the finding does explain the abnormal sedimentation of dar DNA intermediates (800S) as well as the proposed suppression mechanism of the gene 59 mutation.


RNA associated with murine intracisternal type A particles codes for the main particle protein. Intracisternal type A particles were isolated from MOPC-104E myeloma grown subcutaneously and from N 4 neuroblastoma cells in culture. Polyadenylated RNA was prepared from the particles and tested in a cell-free translation system derived from rabbit reticulocytes. RNA from the two sources directed the synthesis of multiple polypeptides with similar distributions of electrophoretic mobilities in sodium dodecyl sulfate-containing polyacrylamide gels, including one conponent of the same size as the major A-particle structural protein (73,000 daltons). Analysis of the RNAs by electrophoresis in methyl mercury-containing agarose gels revealed a 35S component common to A-particles from both cell types. This was a major component of the N4 preparations, whereas a 28S species predominated in the case of MOPC-104E. These two RNAs (35S from N4 cells and 28S from MOPC-104E), when isolated on isokinetic sucrose gradients, each directed the synthesis of a 73,000-molecular-weight polypeptide that comigrated on gels with authentic A-particle structural protein. Idnetity of the cell-free product was confirmed by two-dimensional analysis of the [35S]methionine-labeled tryptic peptides. The N4 RNA preparations also contained a major32S component which did not code effectively for the A-particle structural protein.


Transcription of adenovirus RNA in permissive and nonpermissive infections. The mechanism of blocked replication of human adenoviruses in monkey cells was examined. Previous experiments have placed the replicative block at the level of transcription of translation of adenovirus mRNA. Coinfection of the monkey cells with simian virus 40 enhances adenovirus replication in these cells. We compared the adenovirus mRNA transcribed during infection of permissive human cells and enhanced and unenhanced monkey cells. Adenovirus mRNA from enhanced monkey cells appeared to be identical to adenovirus mRNA from human cells. This indicated that simian virus 40 coinfection did not overcome the blocked replication by substituting for a missing adenovirus transcript. Comparison of adenovirus mRNA from enhanced and unenhanced monkey cell infection revealed two types of transcriptional discrepancies. There was a decrease in both the complexity and the relative abundance of several regions of the enhanced adenovirus mRNA. However, neigher of these transcriptional defects was sufficient to totally explain the difference in yield of infectious virus and viral protein seen in these two types of infection.


In vitro packaging of bacteriophate T7 DNA synthesized in vitro. An in vitro DNA packaging system was used to encapsulate T7 DNA that had been synthesized by extracts prepared from gently lysed Escherchia coli infected with bacteriophage T7 carrying amber mutations in gene 3 or in both genes 3 and 6. Isopycnic centrifugation of density-labeled wild-type DNA was employed in an effort to separate product from template; suppressor-free indicator bacteria were used to eliminate contributions from endogenous DNA or contaminating phage. Additional controls indicated that fragmented DNA is packaged in vitro only with very low efficiency and that the frequency of recombination during packaging is too low to affect interpretation of these experiments. T7 DNA replicated by extracts prepared using T7 mutants deficient in both genes 3 and 6 could be packaged in vitro with an efficiency comparable to that found when highly purified virion T7 DNA was used. When T7 deficient in the gene 3 endonuclease but with normal levels of the gene 6 exonuclease was used, fast-sedimentingconcatemer-like DNA structures were formed during in vitro DNA synthesis. Electron microscopy revealed many branched and highly complex DNA structures formed during this reaction. This concatemer-like DNA was encapsulated in vitro with an efficiency significantly greater than that found for DNA the length of a single T7 genome.


Removal of carbohydrate from influenza A virus and its hemagglutinin and the effect on biological activities. Treatment of influenza virus and its purified hemagglutining with glycosidases from Diplococcus pneumoniae, which included beta-galactosidase, beta-N-acetylglucosminidase, and endoglycosidase D, released amino and neutral sugars from the virus and these as well as large oligosaccharides from the purified hemagglutinin. The released glucosamine-containing oligosaccharides were of one discrete size. Large oligosaccharides not removed by the glycosidases were found on the virus as well as the hemagglutinin. Some oligosaccharides on the virus were inaccessible to the enzymes, since they could be removed only from the purified hemagglutinin. Approximately 50% of the hemagglutinin carbohydrates could be removed without effect on hemagglutinating activity. Similarly, removal of 20 to 25% of the carbohydrates from intact virus particles did not alter infectivity.


Adsorption and penetration of enveloped and naked vaccinia virus particles. The adsorption and penetration of intracellular naked vaccinia virus (INV) and extracellular enveloped vaccinia virus (EEV) were examined. The adsorption kinetics of INV and EEV were similar, but INV adsorption was found to be more sensitive to the adsorption environment than EEV. The PFU-to-particle ratio for the two virus particles indicated that EEV was approximately two times as infectious as INV. Kinetic studies at 37 degree C showed that EEV penetrated cells more rapidly than INV. Penetration of EEV was unaffected by incubation in phsophate-buffered saline, but was somewhat reduced by incubation at 22 degree C. In contrast, INV penetration was effectively eliminated by incubation in phosphate-buffered saline or by incubation at 22 degree C. In addition, INV but not EEV pentration was sensitive to treatment with sodium fluoride and cytochalasin. B. These results are discussed with regard to the mechanism of INV and EEV penetration.


Polypeptide composition of extracellular enveloped vaccinia virus. Extracellular enveloped vaccinia (EEV) virus grown in SIRC and in HeLa cells was purified by consecutive equilibrium centrifugations in sucrose and cesium chloride gradients. A higher degree of purity was obtained with virus material prepared in SIRC cells. The polypeptides of purified EEV and INV (intracellular naked vaccinia) virus were compared in polyacrylamide slab gel electrophoresis. Three proteins (200,000 molecular weight [200K], 95K, and 13K) detected in HeLa-derived INV were absent in EEV. In addition, two INV proteins (65K and 30K) occurred in reduced concentrations in EEV, white another INV protein (27K) was increased in EEV. INV from SIRC cells showed similar alterations of these proteins (with the exception of the 30K and 13K proteins). Detergent treatment, ether extraction, and Pronase treatment showed that these six proteins are located at the surface of INV and are not cecessary for infectivity. Eight proteins (210K, 110K, 89K, 42K, 37K, 21.5K, 21K, and 20K) were detected in EEV that were absent from inv. Brij-58 treatment was employed to remove the envelope from EEV, resulting in the formation of naked particles and an envelope fraction which were separated on cesium chloride gradients. The envelope fractions contained all eight  proteins. Seven of the eight proteins were glycoproteins, with the 37K protein being the only unglycosylated protein. It is concluded that a processing of surface INV particle proteins occurs during evelopment. The resultant EEV particle is comprised of an INV particle with a modified surface composition enclosed in an envelope containing virus-specific proteins unique to EEV.


Adenovirus core protein synthesis in the absence of viral DNA synthesis late in infection. The acid extraction of the adenovirus type 5 core proteins V, VII, and pVII (the precursor to VII) from infected cells and the subsequent electrophoresis on a 15% acrylamide-2.5 M urea-0.9 N acetic acid (pH 2.7) gel, revealed that peptide VII has a similar electrophoretic mobility to that of histone H1. The core proteins, which are coded by late adenovirus mRNA, continued to be synthesized late in infection when viral DNA synthesis was inhibited either by cytosine arabinoside in wild-type infections or by shifting adenovirus H5 ts 125-infected cells to the nonpermissive temperature (40 degree C). Only the initiation, not the continuation, of viral DNA replication was essential for core protein synthesis. The synthesis of viral core proteins continued for over 8 h after the cassation of DNA synthesis. This was in contrast to the rapid shutdown of cellular histone synthesis in the absence of cellular DNA synthesis.


Defective interfering particles of parvovirus H-1. Defective interfering particles of the parvovirus H-1 were produced by serial propagation at high multiplicities of infection. Such particles interfere with the synthesis of capsid proteins and infectious virus of standard H-1. The interference is sensitive to UV irradiation, dependent on the multiplicity of the challenge virus, and is active in heterotypic infections against parvovirus H-3 or LuIII. Defective interfering particle genomes have alterations characterized by integral numbers (1 to 10 or more) of a 60-base-pair addition in the neighborhood of the origin of replicative-form DNA replication and deletions that are located primarily within two regions, 32 to 44 or 80 to 90 on the genome map. Some of the implications of these findings are discussed.


Multiple roles for ATP in the synthesis and processing of mRNA by vaccinia virus: specific inhibitory effects of adenosine (beta,gamma-imido) triphosphate. Adenosine (beta,gamma-imido)triphosphate (AMP-PNP) and guanosine (beta,gamma-imido)triphosphate (GMP-PNP) are analogs of ATP and GTP with non-hydrolyzable gamma-phosphates. Although both AMP-PNP and GMP-PNP were used in place of ATP and GTP by Escherichia coli RNA polymerase to transcribe vaccinia virus DNA, only GMP-PNP was used by the transcriptase present within vaccinia virus cores. AMP-PNP specifically prevented initiation of transcription, since RNA initiated in the presence of ATP, GTP, and CTP was subsequently elongated by incubating the washed cores in the presence of AMP-PNP, GTP, CTP, and UTP. The RNA formed in this manner, however, was (i) several times longer than normal transcripts, indicating a defect in chain termination and/or cleavage of nascent RNA, (ii) was not polyadenylylated (although free polyadenylic acid formed), and (iii) was not extruded from the virus cores. Nearest neighbor analysis demonstrated that AMP-PNP was incorporated adjacent to all four nucleotides, and hybridization to restriction endonuclease fragments of vaccinia virus DNA indicated that the high-molecular-weight RNA was transcribed from representative fractions of the entire genome. The possibility of a block in processing rather than or in addition to a block in chain termination was suggested by the cleavage of the high-molecular-weight RNA within the core after replacement of AMP-PNP with ATP. Cleavage of purified high-molecular-weight RNA by a soluble endoribonuclease extracted from vaccinia virus cores, however, was not dependent upon ATP, nor was it inhibited by AMP-PNP. The latter results suggest that AMP-PNP blocks a step preceding cleavage.


Isolation and characterization of bacteriophage T4 mutant preheads. To determine the function of individual gene products in the assembly and maturation of the T4 prehead, we have isolated and characterized aberrant preheads produced by mutations in three of the T4 head genes. Mutants in gene 21, which codes for the T4 maturation proteases, produce rather stable preheads whose morphology and protein composition are consistent with a wild-type prehead blocked in the maturation cleavages. Mutants in gene 24 produce similar structures which are unstable because they have gaps at all of their icosahedral vertices except the membrane attachment site. In addition, greatly elongated "giant preheads" are produced, suggesting that in the absence of P24 at the vertices, the distal cap of the prehead is unstable, allowing abnormal elongation of broth the prehead core and its shell. Vertex completion by P24 is required to allow the maturation cleavages to occur, and 24- preheads can be matured to capsids in vitro by the addition of P24. Preheads produced by a temperature-sensitive mutant in gene 23 are deficient in core proteins. We show that the shell of these preheads has the expanded lattice characteristic of the mature capsid as well as the binding sites for the proteins hoc and soc, even though none of the maturation cleavage takes place. We also show that 21- preheads composed of wild-type P23 can be expanded in vitro without cleavage.


Structure of native and chloroform-methanol-treated mycobacteriophage R1. The morphologies of native and chloroform-methanol-treated mycobacteriophage R1 were compared by electron microscopy, utilizing three negative stains. R1 was determined to be a complex phage. The head appears as an elongated cylinder with a pointed end (93 +/- 3 by 42 +/- 3 nm) constructed from an orderly arrangement of capsomeres. The phage tail measures 209 +/- 11 by 11 +/- 1 nm and possesses a striated surface with two base plates at its distal end. Treatment of R1 with chloroform-methanol resulted in disruption of both the head and tail structures and was accompanied by loss of infectivity. However, because no likely lipid-containing structure was observed in native phages, there is the possibility that the mechanism of chloroform-methanol inactivation is something other than lipid extraction.


Virus-specific RNA synthesis in interferon-treated mouse cells productively infected with Moloney murine leukemia virus. Mouse cells productively infected with Moloney murine leukemia virus were treated with interferon, and intracellular virus-specific RNA was studied by hybridization with complementary DNA. The steady-state concentration of virus-specific RNA in interferon-treated cells was somewhat greater than that in untreated cells, and the rates of virus-specific RNA synthesis were approximately equal in treated and untreated cells.


Synthesis of a mammalian parvovirus in Brij-58-lysed cells. An in vitro system was developed, prepared by lysis of parvovirus LuIII-infected cells with Brij-58. In this subcellular system, DNA of viral genome size and synthesized and subsequently packaged into particles with physicochemical properties of mature LuIII virions.


Pathology associated with Cryptobia infection in a summer flounder (Paralichthys dentatus). A laboratory-held summer flounder (Paralichthys dentatus) became moribund and presented gross ulcerative and hemorrhagic lesions, concomitant with a space-occupying lesion in the abdominal cavity and a prolapsed rectum. Edema, hemorrhage, and necrosis of the intestine and edema of the stomach wall were noted upon post-mortem examination. Microscopic examination revealed large numbers of Cryptobia in the submucosa of the gut and in the liver.


The prevalence of antibody of antibody to contagious caprine pleuropneumonia (Mycoplasma strain F38) in some wild herbivores and camels in Kenya. Sera of 11 species of wild herbivores were tested for antibody to Mycoplasma strain F38 which causes contagious caprine pleuropneumonia (CCPP) in Kenya. Antibodies were found in buffalo (Syncerus caffer) (32%), impala (Aepyceros melampus) (10%) and camels (Camelus dromedarius) (49%) but not in bushbuck (Tragelaphus scriptus), eland (Taurotragus oryx), Grant's gazelle (Gazella granti), kongoni (Alcelaphus buselaphus cokei), oryx (Oryx beisa), Thomson's gazelle (Gazella thomsonii), waterbuck (Kobus defassa) and wildebeest (Connochaetus taurinus).


Lungworms in coyotes on the Great Plains. A total of 395 coyotes (Canis latrans) was examined in the field for lungworms (Filaroides osleri and Capillaria aerophila) with 60 trachea and bronchial trees returned to the laboratory for detailed examination. Coyote carcasses were obtained from eight central states (Oklahoma, Colorado, Wyoming, Iowa, South Dakota, Nebraska, Texas, and three regions of Kansas). Cysts of F. osleri were present in the trachea or first division of bronchi of 68 (17%) of the coyotes examined. C. aerophila infections were identified during field examinations, primarily by the excess mucus in the bronchi, in 151 (38%) coyotes. Nearly 6% of the coyotes examined were infected with both lungworm species. A total of 195 (49%) coyotes had at least one species of lungworm. Filaroides was less frequent in Iowa and Kansas; Capillaria infections were present in at least 30% of the coyotes examined at all stations.


The January 1977 avian cholera epornitic in northwest California. A total of 844 birds were observed dead at three sites in Humboldt County and an estimated 6750 birds died at three sites in Del Norte County, California. Coots were the primary species affected. The isolation of Pasteurella multocida from a snowy egret (Egretta thula) is the first reported case of avian cholera in this bird. There was evidence for a distinct sequence in the bird species dying at one site; American coots (Fulica americana) appeared to be the first species to die.


Paragonimus westermanni in tigers (Panthera tigris) in India. Paragonimus westermanni was found in the lungs of two young tigers (Panthera tigris). Cysts were focally distributed in the lungs, initiating an emphysematous response together with extensive fibrosis in the vicinity of the cysts.


Tyzzer's disease in muskrats: occurrence in free-living animals. Tyzzer's disease was diagnosed in four muskrats (Ondatra zibethica) found dead over a 2 month period in a single feed-house in a Saskatchewan marsh. No dead animals were found elsewhere in the marsh, although several hundred apparently healthy animals were trapped during this period. Similarities in the pathology and epizootiology of Tyzzer's and Errington's diseases of muskrats support an hypothesis that these diseases are a single entity.


Parasites and diseases of bison in Canada IV. Serologic survey for brucellosis in bison in northern Canada. Serum samples collected from 2,365 free-roaming hybrid bison (Bison bison bison x Bison bison athabascae) in Wood Buffalo National Park and adjacent areas in the Northwest Territories were tested for brucellosis during the period 1959 to 1974. A positive reaction was obtained in 739 (31.2%) of the animals tested. The overall effect of brucellosis on this free-roaming bison population is unknown. The authors also dealt with some of the actual and possible consequences of the disease in this population.


Mycobacteriosis in mountain whitefish (Prosopium williamsoni) from the Yakima River, Washington. Mycobacteriosis was found in mountain whitefish (Prosopium williamsoni) taken from the Yakima River near Richland, Washington in 1975 and 1976. The disease appeared to affect about 8% of the population sampled. Gross lesions were present in most visceral organs, but were most common in the kidney, liver and pyloric caeca. Microscopically, the lesions consisted of large numbers of macrophages containing numerous intracellular bacilli. An organism was isolated and has been tentatively classified as Mycobacterium sp., Runyon group III.


Isolation of Edwardsiella tarda from three Oregon sea mammals. Edwardsiella tarda was isolated from the peritoneal exudate of a Steller's sea lion (Eumetopias jubata) with peritonitis resulting from a perforating colonic ulcer; from the liver of a harbor porpoise (Phocena phocena) with metritis and peritonitis sequela to dystocia; and from the liver of a California sea lion (Zalophus californianus) with peritonitis following fracture and necrosis of a lumbar vertebrae. These findings indicate E. tarda is a common opportunistic invader in sick or injured marine mammals.


The serologic and cultural prevalence of Leptospira interrogans serovar balcanica in possums (Trichosurus vulpecula) in New Zealand. In a serologic and cultural survey of 127 brush-tailed possums (Trichosurus vulpecula) occupying pasture land in New Zealand, leptospires of the Hebdomadis serogroup were obtained from 48 (38%) of the animals sampled. Eight isolates were identified by cross-absorption agglutin ation studies as being Leptospira interrogans serovar balcanica. There was a marked age difference in prevalence with 41 positive cultures from 64 mature adults (64%) and no recoveries being made from juveniles. Isolation of leptospires was aided by the use of a new technique involving the homogenation of whole kidneys in gamma sterilized plastic bags in a "Coleworth Stomacher". The use of this apparatus allowed the processing of whole kidneys and the technique was efficient in both the recovery of leptospires and the prevention of contamination. In view of the fact that serovar balcanica has been recorded previously only in East Europe in man, cattle and pigs, the high prevalence of infection in a wild animal population in New Zealand is an interesting development in the world distribution of this serovar.


Crop impactions in bobwhite quail in Louisiana. Crop impactions (solid, hard masses of seeds) caused by seeds of clammy weed (Cuphea carthagenensis) were found in bobwhite quail (Colinus virginianus) killed during the 1965-71 hunting seasons in Louisiana. Emaciation and weakened condition were associated with the presence of crop impactions in two quail, suggesting that physical obstruction of the crop by impactions may be of significant pathologic consequence.


Capillaria hepatica in small mammals collected from Shoa Province, Ethiopia. A total of 1,110 small mammals has been examined for Capillaria hepatica in Shoa Province, Ethiopa. Nineteen of 308 (6.2%) Rattus rattus and 1 of 212 (0.5%) Praomys albipes were infected. The data indicate that C. hepatica was essentially limited to commensal rats (R. rattus).


Parasites of red foxes in New Brunswick and Nova Scotia. Sixty-one red foxes from New Brunswick and Nova Scotia were examined for helminths. Alaria americana, A. arisaemoides, A. mustelae, Cryptocotyle lingua, Echinostoma revolution and Metorchis conjunctus, Capillaria aerophila, Crenosoma vulpis, Toxocara canis, Uncinaria stenocephala and Taenia crassiceps were found. Approximately 67% of the foxes examined were clinically affected with Sarcoptes scabiei mange.


Cholangitis associated with species of Progamotaenia (Cestoda: Anoplocephalidae) in the bile ducts of marsupials. Gross and histopathologic changes due to infection with Progamotaenia festiva and P. effigia in the bile ducts of the marsupials, Macropus rufus, M. giganteus, M. fuliginosus, Lagorchestes conspicillatus, Vombatus ursinus and Lasiorhinus latifrons are described. The integrity of the bile duct mucosa was not impaired but varying degrees of hyperplasia and hypertrophy of mucosa and mucosal glands, inflammatory infiltration and fibrosis were found. Portal fibrosis was the prominent reaction in Lasiorhinus latifrons. Reduced prevalence of cestode infection was recorded in two populations of M. giganteus in which Fasciola hepatica also was recovered.


Osteoarthrosis in a coyote x dog hybrid from Nebraska. Osteoarthrosis is described in a wild, 14-year-old coyote (Canis latrans) x dog (C. familiaris) hybrid shot in southeastern Nebraska. There was ankylosis of five vertebrae, the head of the left femur was absent, and periarticular osteophytes occurred throughout the skeleton. The age is significant because wild coyotes seldom live beyond 6 years and coyote x dog hybrids are considered to be less fit for survival in the wild than coyotes.


Doxorubicin cardiotoxicity. Serial endomyocardial biopsies and systolic time intervals. Doxorubicin, whose dose-limiting toxicity is cardiomyopathy, was given to four cancer patients. Endomyocardial biopsy specimens and test results of cardiac function were obtained  before, during, and after treatment. The biopsy specimens were examined by light and electron microscopy and were graded blindly. Evidence of specific doxorubicin injury was found in 3/4 patients with as little as 180 mg/sq m of the drug and became progressively more severe with higher doses. All test results of cardiac function, including systolic time intervals, remained normal. These data suggest that a specific, progressive subclinical injury to the heart occurs with doxorubicin therapy, which cannot be reliably detected by routine tests. This potential risk must be taken into account with the use of doxorubicin, especially when combined with synergistic agents.


Weight and blood pressure. Findings in hypertension screening of 1 million Americans. In the nationwide Community Hypertension Evaluation Clinic screening of more than 1 million people, the group classifying itself as overweight had prevalence rates of hypertension 50% to 300% higher than other screenees. Frequency of hypertension in overweight persons aged 20 to 39 years was double that of normal weight and triple that of underweight persons. Among those aged 40 to 64 years, the overweight group had a 50% higher hypertension prevalence rate than the normal-weight group and 100% higher than the underweight group. With each higher degree of blood pressure elevation, relative frequency of hypertension with overweight was larger. Thus this study confirms, in the largest group surveyed to date, similar findings in previous cross-sectional surveys. It is also consistent with data from longitudinal and intervention studies on the importance of overweight in relation to hypertension.


Bioactivity of instant glucose. Failure of absorption through oral mucosa. The efficacy of instant glucose as a potential treatment for hypoglycemia was studied in normal volunteers, with therapeutic doses administered in the buccal cavity. 2-Tritiated glucose (50 mu Ci) was homogenized into each dose before use. Mean blood glucose and serum insulin concentrations were unaltered by instant glucose. Glucose absorption was less than 0.05 mg at any time, and total glucose absorbed was less than 0.1 mg. For comparison purposes, volunteers swallowed a dose of instant glucose. Approximately 88% of the dose was absorbed during a 30-minute interval. Blood glucose and insulin levels increased. Instant glucose appears to be of therapeutic value only if swallowed by fully conscious, hypoglycemic patients. It should not benefit unconscious patients because of its poor absorption through the buccal mucosa.


SI units for clinical laboratory data.

SI units for clinical laboratory data. The international System of Units (SI) has not yet been accepted by American physicians because of reluctance to convert to a new system and the corresponding need for relearning. The impetus to introduce the SI came from European laboratory scientists; the system was later accepted (not always enthusiastically) by physicians after the same objections now voiced by their US counterparts were overcome. Now that many American laboratory scientists are actively studying and assessing the benefits of SI, we may have begun the chain of events that will lead to general acceptance by physicians in the United States.


Dermatopathic lymphadenitis presenting as lateral breast mass. Two cases of dermatopathic lymphadenitis involved external mammary lymph nodes and presented clinically as breast masses. The variable position and number of external mammary lymph nodes account for the difficulty in  differentiating intrinsic breast pathological conditions of the lateral margin of  the breast from lymphadenitis. Recent publicity may account for a lower threshold for detection of such lesions by patients as well as physicians. Dermatopathic lymphadenitis should be included in the differential diagnosis of persistent solid masses involving the lateral margin of the breast and should be confirmed by excisional biopsy.


Urticaria following intravenous doxorubicin administration. Urticaria developed above the site of injection with doxorubicin hydrochloride in 11 patients with malignant neoplasms. Generalized urticaria without anaphylaxis developed in one patient, while only local reactions developed in the other ten. A reaction developed in two patients on their first exposure to doxorubicin. Two of the seven patients who received subsequent doxorubicin therapy had further reactions. Urticaria does not seem to be a contraindication to further treatment with doxorubicin if the patient is closely observed. The value of prophylactic antihistamines of corticosteroids is not clear.


Giant meningiomas of the posterior fossa. Posterior fossa meningiomas ordinarily produce clinical signs appropriate to their location. Four cases of huge infratentorial meningiomas were associated with minimal clinical manifestations.


Lack of transmission of hepatitis B after surgical exposure. An orthopedic surgeon in whom hepatitis B subsequently developed participated in operations on 49 patients in the two months preceding his illness. Thirty of these patients were available for subsequent clinical and serologic follow-up: five had positive reactions for antibody to hepatitis B surface antigen (anti-HBs) and one had a positive reaction for hepatitis B surface antigen (HBsAg) at the initial examination an average of 77 days after surgery. No new patients had either clinical or serologic evidence of hepatitis B during four months of subsequent follow-up (mean of 6.7 months after surgery). A control group of 56 orthopedic patients had a 25% prevalence of positive reactions for anti-HBs and negative reactions for HBsAg- this was not significantly different from the exposed group. The risk to patients of acquiring hepatitis B after surgical exposure in this setting from a surgeon is low.


Thrombophlebitis in systemic lupus erythematosus. Thrombophlebitis occurred in 14 (12.2%) of 114 patients with active systemic lupus erythematosus (SLE). Abnormal clotting occurred despite the presence of thrombocytopenia or circulating anticoagulants in some of the patients, and the development of pulmonary emboli was verified in seven. Although infrequently reported, the association of thrombophlebitis with active SLE is apparently not uncommon. While there were no features that distinguished this group of patients from other groups of patients with SLE, there are some possible mechanisms. Recognition of this complication of SLE is important because of the frequent occurrence of SLE-induced pleuritis and its similarity to the pain of pulmonary emboli.


Direct transfer to operating room improves care of trauma patients. A simple, economically feasible plan for large hospitals. As evidenced in a nine-year experience with more than 4,000 patients, the operating room is an ideal receiving area for severely injured patients. This system, which reduces mortality, morbidity, and suffering incurred by severely injured patients, is both feasible and economical for many large metropolitan hospitals.


Estrogen and the postmenopausal breast. Mammographic considerations. Postmenopausal estrogen replacement therapy may produce changes in the breast demonstrable as cystic or dysplastic by mammography. Following cessation of hormone therapy, radiological regression of these changes may be seen. We suggest that in certain patients estrogen replacement therapy be discontinued in an attempt to reverse these dysplastic changes. Reliable radiologic as well as clinical evaluation of the breasts may be enhanced thereby, and if the presence of an associated malignant neoplasm is marked, it will be clarified radiologically and clinically.


Family physician pathway and medical student career choice. Ten years after curriculum change at the University of Washington. In 1968 the University of Washington School of Medicine initiated a new curriculum that included a family physician pathway. Six of these classes have now graduated. Two thirds of the planned strategies for the pathway were actually implemented. Approximately half of the students in each second-year class now choose this pathway. Ninety percent of those graduating have done so in the traditional four years. Seventy-three percent of those in the pathway actually pursued family practice training on graduation. Approximately one third of all University of Washington graduates now enter training for family practice, one third enter internal medicine, 10% enter surgical fields, and 8% enter pediatrics. These rates represent significant increases in the proportion of students entering directly into family practice, internal medicine, and pediatrics training.


Dysesthesia, witchcraft, and conversion reaction. A case successfully treated with psychotherapy. An intelligent, well-educated black woman from the rural South, through an interaction of psychopathology and cultural background, experienced dysesthesia as a conversion reaction and came to believe that she was the victim of witchcraft. After neurological evaluation showed no abnormalities, she was successfully treated with conventional psychotherapy. Belief in hexing or root work is still alive today and should be inquired about in patients with unusual symptoms and an appropriate cultural background.


Expanded polytetrafluoroethylene grafts in reconstructive arterial surgery. Preliminary report of the first 110 consecutive cases for limb salvage. One hundred ten arterial reconstructions, including several new and extended bypasses, were performed with polytetrafluoroethylene (PTFE) grafts and were observed for three to 16 months. Patency rates were 100% with 15 bypasses to the femoral artery, 95% with 66 bypasses to the popliteal artery, and 76% with 29 bypasses to the arteries of the leg and foot. These encouraging preliminary results justify continued use and evaluation of PTFE as an arterial prosthesis.


Toxicity of penicillamine. A serious limitation to therapy in rheumatoid arthritis. A retrospective study of penicillamine toxicity in 156 patients yielded a high incidence of toxic reaction (62%), necessitating discontinuation of the drug therapy in 36% of the patients. Of the total group, proteinuria occurred in 14%, hematologic toxic reaction in 11%, mucocutaneous toxic reaction in 28%, and gastrointestinal intolerance in 12%.


Outcome and cost for stroke patients in academic and community hospitals. Comparison of two groups referred to a regional rehabilitation center. Patients transferred to a regional stroke rehabilitation center from academic hospital centers (124 patients) and from community hospital centers (315 patients) were compared for outcome and cost of treatment. The two groups were matched for Amended International Classification of Diseases diagnostic category, age, sex, distribution of weakness, types of neurological deficits, time from the onset of the stroke symptoms to admission to the rehabilitation unit, and the concurrence of major medical problems thought to contribute to cerebrovascular disease. There was no statistically significant difference in functional outcome or length of stay, but acute health care costs for patients treated in community hospitals were about 50% less.


Changes in theophylline clearance during acute illness. Three patients demonstrated twofold to threefold changes in total-body theophylline clearance during the course of a single hospitalization for an acute illness. These changes paralleled the changes in the patients' clinical status. Theophylline clearance decreased in one patient with worsening airway obstruction, whereas clearance increased in one patient with resolving pneumonia and in one patient with improving congestive heart failure. Total-body theophylline clearance may be unstable in acute, severe illness. Close monitoring of plasma theophylline concentration in such situations will allow appropriate dose adjustments to be made and is, therefore, indicated.


Salmonellosis associated with homemade ice cream. An outbreak report and summary of outbreaks in the United States in 1966 to 1976. During the period 1966 to 1976, 22 outbreaks with 292 individual cases of salmonellosis associated with the  consumption of homemade ice cream were reported to the Center for Disease Control. Salmonella typhimurium accounted for 45% of the outbreaks. The source of eggs used was known in 13 outbreaks, and all were ungraded farm- or home-produced eggs, a potential source of salmonellae. In 11 outbreaks, the method of preparation was known, and in all, the ice-cream custard had not been cooked before freezing.


Evaluation of a new antidiuretic agent, desmopressin acetate (DDAVP). Desmopressin acetate is a synthetic vasopressin analogue administered by the intranasal route. It is long-acting and well tolerated and may be the agent of choice for treating central diabetes insipidus.


Ultrasound aortic measurement and elective aneurysmectomy. In a study of 53 cases, aneurysm size was measured with the use of preoperative physical examination, lateral abdominal roentgenography, and B-mode aortic ultrasonography for comparison with direct intraoperative measurement during aneurysmectomy. Mean aneurysm diameter on the basis of physical examination overestimated aortic size by 1 cm; physical examination measurement was within 0.5 cm of true aortic size in 38% of patients and within 1 cm in 58% of patients. The lateral roentgenogram also overestimated mean aortic diameter by 1 cm and was within 0.5 cm of true aortic size in 44% of patients and within 1 cm in 72% of patients. Measurement using B-mode aortic ultrasonography closely approximated intraoperative aneurysm measurement. Measurement was identical in 34% of patients and was within 0.5 cm and 1 cm in 75% and 92% of patients, respectively.


Staffing pattern of a health maintenance organization. A systems approach. A systems analysis approach was applied to a study of health provider jobs in a health maintenance organization to develop a proposal for an improved staffing pattern and an appropriate training curriculum for the provider. Physicians reported performing 512 ambulatory care tasks; health associates, 372; and health assistants, 284. Overlap was found among each group, especially in data-gathering tasks. This led to reallocation of tasks, with the most complex but smallest number assigned to the physician, and the least complex but highest number assigned to the assistant. In turn, a staffing pattern was suggested whereby a team of two physicians, four associates, and eight assistants would be able to manage the visits of 10,000 patients.


Screening for hypertension in the emergency department. Review of emergency department charts at three university-affiliated hospitals showed that less than half of all patients who had elevated blood pressure (BP) recorded were recognized by physicians to be hypertensive. At the primary teaching hospital, less than one third of patients with the greatest BP elevation (greater than 20 mm Hg above normal) were sent for some type of hypertension follow-up care.


Ligamentous laxity in secondary school athletes. An increase in ligamentous laxity has been said to predispose athletes to injury of the joint. To evaluate the usefulness of testing ligamentous laxity to predict a predisposition to injury in secondary school athletes, 166 male football players, 84 female basketball players, and 32 male basketball players were tested. The results were compared with those for 167 males and 223 females in high school but not involved in interscholastic sports. No correlation could be found between ligamentous laxity and the occurrence or type of injury.


Conjunctivitis and skin erythema. Outbreak caused by a damaged high-intensity lamp. Eighty-one members of girls' basketball teams were exposed to ultraviolet light while sitting in the bleachers of a school gymnasium. A mercury high-intensity discharge lamp lighting the bleacher area had a hole in its outer envelope that allowed the emission of ultraviolet light. Sixty-nine (85%) of the 81 girls were affected; 49 (71%) had symptoms of conjunctivitis and 63 (91%) had symptoms of erythema.


Jaundice, choledocholithiasis, and a nondilated common duct. In two cases of jaundice due to choledocholithiasis, the biliary tree was not dilated on skinny-needle transhepatic cholangiography. Visualization of the biliary tree before arriving at a diagnosis in certain cases of jaundice is needed.


Minoxidil treatment of malignant hypertension. Recovery of renal function. We treated eight severely hypertensive, long-term hemodialysis patients who failed to respond to ultrafiltration or conventional medication with minoxidil rather than with bilateral nephrectomy. Control of blood pressure and relief of symptoms was achieved in all eight. In addition, three of the patients, who were all severely oliguric, recovered sufficient renal function to allow the discontinuation of dialysis. Two are presently doing well, while one died of causes unrelated to uremia or minoxidil therapy. We presently reserve bilateral nephrectomy for those hypertensive dialysis patients who are awaiting transplantation.


Cystic fibrosis. Problems encountered with sweat testing. The sweat test is the only practical and reliable laboratory test for confirmation of the diagnosis of cystic fibrosis. Among 234 patients referred to The Johns Hopkins Hospital for sweat testing, 62 had had a previous test; 29 tests had been reported as negative, and 33 tests had been reported as positive. Results of quantitative pilocarpine-iontophoresis sweat tests at this center led to a change in diagnosis in 27 (43.5%) of these 62 patients. Most of the errors were false-positive.