Estimates of doses of antiinflammatory drugs in man by testing for analgesic potency. I. 1-isopropyl-4 phenyl-7-methyl-2 (1H) quinazolone versus aspirin. Dosage estimates of antiinflammatory drugs in human arthritis Phase II trials are difficult to obtain and prolong such trials unnecessarily. Antiinflammatory drugs almost always have analgesic properties in man and good dose estimates for analgesic activity can be obtained. In 140 patients with surgical pain, 300, 600, and 1200 mg of aspirin were compared to 75, 150, and 300 mg of 43-715 (1-isopropyl-4-phenyl-7-methyl-2 (1H) quinazolone), an antiinflammatory quinazolone derivative, for analgesia in a double-blind trial using subjective response methodology. The test drug was shown to be analgesic at a level four times more potent, milligram for milligram, than aspirin, an estimate that should be useful for later definitive Phase II trials in arthritis.


Family study of systemic lupus erythematosus: analysis of the clinical history, skin immunofluorescence, and serologic parameters. The clinical history, deposition of IgG, IgM, IgA, C3, C4 and properdin at the dermal-epidermal junction (DEJ) of clinically normal skin, serum ANA, DNA-binding, C3, C4, Factor B, and properdin were compared in 27 systemic lupus erythematosus (SLE) probands, 21 first-degree household contact relatives (FDHCR), 19 first-degree nonhousehold contact relatives (FDNHCR), 15 spouses, 26 controls, and 16 chronic discoid lungs lupus erythematosus patients. Female consanguineous relatives of SLE patients had a higher incidence of rheumatic symptoms than male relatives (P less than 0.01). Female FDHCR and male spouses had a higher incidence of protein deposition at the DEJ than sex-matched controls (P = 0.026 and 0.0028). The incidence of protein deposition at the DEJ in FDNHCR did not differ from sex-matched controls. ANA titers of the consanguineous relatives were significantly higher than those of the spouses or sex-matched controls irrespective of household contact with their proband. The observation of protein deposition at the DEJ in normal appearing skin of FDHCR and spouses suggests the importance of environmental factors, whereas the elevations of ANA titers in consanguineous relatives suggests the importance of genetic factors in the pathogenesis of SLE.


Effects of tilorone hydrochloride on cellular immunity (leukocyte inhibiting factor production from human lymphocyte stimulated by E. coli lipopolysaccharide). Tilorone hydrochloride, a drug able selectively to affect T-lymphocyte fuction, when incorporated (at three different concentrations 0.1, 0.04, 0.02 microgram/ml) in lymphocyte culture, stimulated by 50 microgram/ml of E. coli LPS (026:B6 W), is able to abolish LIF production, due to endotoxin stimulation. Such effect is, may be, due to an impairment of T-cell activity, since tilorone at the same concentration decreases the number of ARFC and TRFC, which are specific markers for T-cells.


Anti-Candida albicans precipitating antibodies in the sera of surgery patients. In healthy subjects and in subjects undergoing surgical intervention for neoplastic and other diseases, the behaviour of precipitating antibodies against soluble Candida albicans natigens was studied. In 13,7% of healthy controls the Ouchterlony test was positive. In subjects suffering from intestinal tract neoplasia, the percentage of positive tests was 26,6% before and 66,6% after the intervention. In other two groups of patients affected by neoplasia, the per cent positive results of the tests after intervention were, respectively, 50% and 63,1%. Among non neoplastic patients undergoing surgical treatment, after intervention 35% too proved positive. The data were confirmed by P.E.T. (partigen elution test): specific anti-Candida IgG, and in some cases IgA, could be demonstrated. The diagnostic value of positive Ouchterlony's test against superficial soluble Candida antigens after surgical intervention has been discussed.


Further potential sources of energy modifying the multiplication of Mycobacterium leprae. The multiplication of Mycobacterium leprae was modified by graded dilutions of organic acids. 0.01%-0.05% gluconic acid inhibited its multiplication. 0.005% of it promoted the growth of 2 out of 6 strains. 0.2% - 1.0% glucuronic acid promoted the multiplication of the majority of strains. 2.0% inhibited their multiplication, and 0.05% promoted the growth of one strain. Galacturonic and pyruvic acids were active in 0.2 - 2.0% concentrations, while the activity of citric acid was mainly noted at 1.0 and 2.0% concentrations.


[Infection of the urinary tract, its association with local predisposing factors]. A total of 167 cases of children with the diagnosis of urinary infection seen through the last five at the Hospital Infantil de México were studied with the purpose of investigating the frequency of the association of obstructive urologic malformations or vesicoureteral reflux with urinary infection and their role in the infection. Out of this number, there were 127 cases with urologic malformations, especially of the upper urinary tract. The most frequent symptoms were enuresis, lumbar pain and hematuria. Out of this group, 53 patients (41%) showed recurrent infections in contrast with only 4 out of 40 cases (10%) without malformation. Out of 167 cases, 64 recovered: 30 of the total of 40 who showed no malformations and only 34 out of 127 with malformations. Twelve cases in this group showed chronic renal insuficiency as final outcome, but none of the patients without malformation followed this course. Analysis of this clinical material shows a high incidence of urologic malformations in patients complaining of urinary infection which has an important role in mortality and lethality of this process. Thus, it is concluded that obstructive uropathy must be investigated in every case of urinary infection, especially if enuresis, lumbar pain or hematuria are present.


Effect of positive and negative expiratory pressure on renal function. The effects of positive and negative end expiratory pressure on renal function have been studied in adult greyhounds with a normal blood volume and without evidence of cardiorespiratory disease. Positive expiratory pressure (+ 10 cm H2O) resulted in a decrease of urine volume, glomerular filtration rate and renal blood flow which returned towards normal following removal of the positive pressure. Negative expiratory pressure (-6 cm H2O) resulted in opposite changes in renal function.


Buprenorphine: a new potent long-acting synthetic analgesic. Comparison with morphine. A new thebaine derivative, buprenorphine, 0.6 mg, was compared with morphine 15 mg in a  double-blind trial, in patients recovering from elective Caesarean section. Within 1 h of administration analgesia was obtained with both drugs and was sustained for 7-8 h with buprenorphine, and 3-4 h with morphine. Buprenorphine caused a greater decrease in diastolic arterial pressure than did morphine, but arterial systolic pressure and heart rate were not influenced by either drug. No serious side-effects were encountered in this study.


Anidoxime: a clinical trial of an oral analgesic agent. The new oral analgesic drug anidoxime was compared with dihydrocodeine. There were no side-effects, and no significant differences between the effects of dihydrocodeine 50 mg, anidoxime 75 mg or anidoxime 100 mg.


Anaesthesia for major surgery in a patient with a transplanted heart. A 29-year-old male presented for elective hip replacement surgery 26 months after cardiac transplantation. The principles involved in the anesthetic management of this patient include sterile management of the airway, maintenance of an adequate intravascular volume, and immediate detection and treatment of hypotension and arrhythmia should they occur. The patient made a good recovery from both anaesthesia and operation.


Comparison of i.v. diazepam and hydroxyzine as surgical premedicants. Diazepam and hydroxyzine as i.v. surgical premedicants were compared. A double-blind randomized sequence was used employing 7.5 and 15 mg of diazepam v. 75 and 150 mg of hydroxyzine. Each group consisted of 35 patients. Anxiety relief, sedation, lack of recall and patient acceptance were the principal assessments. Diazepam was superior to hydroxyzine in all respects. No serious side-effects were noted with either drug.


Comparison of buprenorphine, pethidine and pentazocine for the relief of pain after operation. The analgesic effects of buprenorphine 2 microgram/kg--1 and 8 microgram. kg--1 were compared with those of pethidine 1 mg. kg--1 and pentazocine 0.6 mg.kg--1 in 172 patients recovering from surgery. The drugs were given by i.m. injection in the period immediately after operation and the quality of pain relief was assessed at intervals for at least 4h. Buprenorphine 4-8 microgram-kg-1 was shown to be an effective analgesic, superior in some cases to the other drugs in the doses employed in the study.


Atenolol once-daily in hypertension.

Atenolol once-daily in hypertension. 1 The effect of atenolol, a cardioselective beta adrenoceptor antagonist, was studied in a double-blind crossover trial in twenty-one carefully selected hypertensive outpatients. Each patient received atenolol (50 mg/day, 100 mg/day, 200 mg/day) and placebo according to a randomized sequence in a once-daily dose. Wash-out periods on a matching placebo were included between the treatment periods. 2 The effect of lying, standing and post-exercise blood pressure of atenolol 50 mg once-daily was not significantly different from atenolol 100 or 200 mg once-daily. The reduction in lying and standing blood pressure was approximately 23/16 and 22/18 mm Hg from levels at the end of a run-in period on matching placebo of 167/108 and 162/112 mm Hg respectively. 3 The study shows that atenolol is an effective hypotensive agent in a once-daily dose.


Metabolic effects of fenfluramine in obese diabetics. 1 In a single-blind, cross-over study fenfluramine in a daily dose of 120 mg was found to reduce the daily blood glucose level moderately in hospitalized obese diabetics treated with a 1200 calorie diabetic diet. 2 After 7 days of treatment, fenfluramine was found not to influence the intravenous glucose tolerance, the insulin response to intravenously administered glucose, or the growth hormone  response to arginine. 3 No changes in blood levels of lactate, beta hydroxybutyrate, triglycerides or cholesterol were seen during fenfluramine treatment.


Pharmacokinetics of nomifensine in impaired renal function. 1. In uremia, an increased frequency of adverse drug reactions is observed at elevated plasma levels of active drug. This is a consequence of decreased renal elimination of unchanged drug or pharmacologically active metabolites. 2. To study the pharmacokinetics of nomifensine in uremia, a single dose of nomifensine maleate 50 mg was given to 10 patients with a glomerular filtration rate between 0 and 61 ml/min. In three additional patients on maintenance haemodialysis, the influence of dialysis on the elimination of nomifensine after single oral doses of 50 mg was studied. 3. Blood samples were obtained before and at regular half-hourly or hourly intervals after administration. Plasma levels of nomifensine were examined using a radioimmunological determination method and pharmacokinetic parameters were calculated by computer program. 4. Whereas in healthy subjects the half-life of nomifensine was found to be 1.8 h, this parameter was found to be prolonged in renal patients. In a patient with a creatinine clearance of 0 ml/min the elimination half-life was 46 hours. Nomifensine is not eliminated by haemodialysis. 5. Our findings suggest that nomifensine should not be administered to renal patients with a glomerular filtration rate below 25 ml/minute.


Kinetic interaction of nomifensine with a 1, 5-benzodiazepine (clobazam). 1. Among the numerous possibilities of drug interactions, pharmacokinetic interactions may cause mutual changes in absorption, distribution, metabolism and elimination of either drug. In the present study this approach was used to investigate pertinent effects of nomifensine and clobazam. 2. Ten normal subjects participated in an intra-individual comparison of nomifensin 75 mg alone and in combination with clobazam 15 and 30 mg. The study design was carried out according to a Latin square in double-blind conditions. One-week wash-out periods were used between the trial days. Serum levels of nomifensine were measured by radioimmunoassay (RIA) and of original clobazam by gas chromatography (GC). Classical criteria for bioavailability (peak serum levels, time of peak, area under the serum level time curve) and the half-life of elimination from the serum were used for retrieval of pharmacokinetic information. 3. Results showed no relevant differences in the criteria mentioned above, after administration of each drug alone or in combination. Therefore, extrapolations were made to multiple dose kinetics based on assumptions derived from practical therapy. They showed comprehensive agreement with therapeutic results in depressed patients. 4. The use of the classical criteria for bioavailability, in addition to the calculation of the half-time of elimination from serum, provides sufficient information for the decision whether pharmacokinetic drug interaction is present or absent. There was no such interaction after single doses of nomifensine or clobazam.


Dynamic interaction of nomifensine with alcohol. 1. Nine healthy volunteers participated in a comparative study of the effects of nomifensine, nomifensine plus alcohol, and placebo plus alcohol, on aspects of psychomotor performance. 2. The study was carried out according to a Latin square design and each treatment was separated from the preceding treatment by 7 days. 3. Placebo plus alcohol impaired performance, increased pulse rate and blood pressure, and increased feelings of activity and euphoria. 4. Nomifensine plus alcohol produced the same subjective and objective changes as placebo plus alcohol, but in no instance were changes any greater. 5. Nomifensine alone produced none of these changes. 6. It was concluded that single doses of nomifensine did not potentiate the effect of alcohol.


Repeated dose comparison of nomifensine, imipramine and placebo on subjective assessments of sleep and objective measures of psychomotor performance. 1. Nine normal subjects volunteered to participate in a randomized single-blind crossover study of nomifensine 75 mg and two comparators, imipramine 75 mg and placebo. 2. Each volunteer received placebo for 3 d, then the first test drug for 4 days. This sequence was repeated twice more, so that each subject received each comparator. All medication was taken three times daily. 3. Assessments were made on days 3, 5 and 7 of each sequence, and consisted of a Sleep Evaluation Questionnaire, a test of Critical Flicker Fusion and a measure of Complex Reaction Time (CRT). 4. There were no significant differences in the CRT. There was a significant increase in critical flicker fusion with nomifensine. 5. Although both nomifensine and imipramine disturbed the quality of sleep, only imipramine produced a hangover.


Laboratory investigation of effect of acute doses of nomifensine on a simulated aspect of night-time car driving performance. 1. Six healthy volunteers received single doses of either nomifensine 100 mg, nomifensine 50 mg or placebo at weekly intervals in a randomized double-blind crossover study. 2. Subjects were subjected to a simulated test of car driving at night. 3. Testing lasted about 1.5 h and consisted of measuring responses to light stimuli, a modification of a test designed by Baker & Theologus (1972). 4. Nomifensine 100 mg reduced the latency of response significantly when compared with placebo (P less than 0.05). Nomifensine 50 mg had no significant effect. 5. It was concluded that nomifensine was unlikely to impair night driving performance.


Controlled study comparing nomifensine and clomipramine in unipolar depression, using the probenecid technique. 1. Central dopamine turnover may be lowered in patients with unipolar endogenous depression particularly when associated with retardation. 2. Nomifensine selectively activates the central dopaminergic system and may be of special therapeutic value in patients with motor inhibition. 3. A double-blind comparison of clomipramine and nomifensine was carried out in patients with recurrent unipolar depression. Biochemical and clinical assessments were carried out weekly for 4 weeks. 4. The mean homovanillic acid level in cisternal liquor of those patients who responded to nomifensine, was significantly lower than the mean level of the total group. 5. The factor "retardation" on the Hamilton Depression Scale was improved more with nomifensine than with clomipramine.


Nomifensine in parkinsonism.

Nomifensine in parkinsonism. 1. The effect of nomifensine was compared with that of placebo in a double-blind crossover study in patients with parkinsonism. 2. Of the 29 patients who entered the study, three were previously untreated and 26 continued their L-DOPA or other antiparkinsonian therapy, or both, during the trial. 3. Clinical assessments were made at fortnightly intervals throughout the study. 4. The most noticeable improvement during active treatment--namely, tremor, facial expression and finger flexion were moderate in extent. 5. When placebo was substituted for active drug a significant deterioration of physical signs and functional disability occurred (P less than 0.001). 6. Elderly patients fared less well than younger patients, and the most common adverse effect was involuntary movements.


Nomifensine in Parkinson's disease.

Nomifensine in Parkinson's disease. 1. Eight patients who failed or ceased to respond to levodopa, or who had developed the "on-off" phenomenon were treated additionally with nomifensine. 2. The dosage of nomifensine started at 50 mg, was increased to 150 mg daily, and other medication was continued unchanged. The duration of treatment was from 2-5 months. Assessments were carried out at 2-week intervals using a validated rating scale. 4. Loss of dopaminergic nigrostriatal neurones characterizes Parkinson's disease, and it is probably for this reason that indirect dopamine (DA) agonists, whose actions depend on intact presynaptic mechanisms, are less active. 3. Nomifensine was not shown to be of antiparkinsonian value in these patients but may be of value as an antidepressant in patients with Parkinson's disease.


Comparison of nomifensine and placebo.

Comparison of nomifensine and placebo. 1. Methodological reasons are discussed which make placebo-controlled trials on antidepressant drugs necessary. 2. The ethical problem of treating a sick patient with an inactive compound are shown to have an impact on the methodology of such trials. 3. Three double-blind placebo-controlled trials with nomifensine are reviewed; one in neurotic depression, one in psychotic depression and one in geriatric patients showing depressive symptoms. 4. In all three trials the effect of nomifensine has been shown to be superior to that of placebo.


Controlled randomized group comparison of nomifensine and imipramine in depressive illness. 1. Nomifensine, an isoquinoline dopaminergic agonist, was investigated in a randomized double-blind group comparison with imipramine, in 40 out-patients with depression. 2. Assessments were made at weekly intervals for 4 weeks using the Hamilton Depression Scale and the Beck Depression Inventory. Blood, kidney and liver function were also monitored weekly. 3. Nomifensine was shown to be at least as effective as imipramine in relieving depression and to relieve tha anxiety component of the disease significantly more rapidly. Neither drug produced serious unwanted effects.


Dopaminergic agonist nomifensine compared with amitriptyline: a double-blind clinical trial in acute primary depressions. 1. Nomifensine (8-amino-2-methyl-4-phenyl-1,2,3,4,-tetrahydroisoquinoline) is a new antidepressant which displays an interesting pharmacological profile and acts as a potent dopaminergic agonist. 2. In a double-blind clinical trialnomifensine was compared with a standard and widely tested antidepressant amitriptyline. A total of 24 patients with primary acute depressions, defined by research criteria, were treated for 8 weeks and their clinical condition and laboratory values monitored at regular intervals. The dosage schedule was a flexible one, with a daily dose range from 50-200 mg for nomifensine and 50-225 mg for amitriptyline. 3. Nomifensine and amitriptyline were found to be equivalent in their antidepressant efficacy. Nomifensine, however, showed a trend towards more rapid effect and was relatively free of side-effects. 4. As nomifensine combined antidepressant activity with low frequency of adverse effects, it would seem to be suitable for wider use in the treatment of primary depressions. The results of our study have to be generalized with caution because of the limited sample size.


A clinical comparison of nomifensine and amitriptyline. 1. The study consists of a double-blind evaluation of nomifensine and amitriptyline in a group of 37 patients with primary depressive illness. 2. The patients were referred by their family doctors on the basis that they would ordinarily have been prescribed a tricyclic antidepressant drug. Random allocation to the treatment groups took place. Assessment took place at weekly intervals over a 4-week period using the Visual Analogue Scale for depression and anxiety, and a side-effects check-list. Patients were also assessed on the Hamilton Depression Scale before the onset and at the end of the trial. 3. No significant difference was found between the two groups as regards relief from depression and anxiety, although marginal differences were found in favour of the amitriptyline group. 4. The overall frequency of side-effects was similar in the nomifensine and amitriptyline patients, But the development of severe side-effects was significantly more common in the amitriptyline group.


A review of controlled studies with nomifensine, performed outside the UK. 1. Double-blind controlled comparisons of nomifensine with placebo, imipramine, desipramine, viloxazine, nortriptyline, a combination of amitriptyline and chlordiazepoxide, and diazepam have been carried out in various parts of the world. 2. Dosage ranged from 50-225 mg daily, and treatment lasted from 2-26 weeks. 3. Nomifensine was shown to possess useful antidepressive activity, to counteract inhibition, to restore drive and to relieve anxiety. 4. Adverse reactions were uncommon, particularly anticholinergic effects, and nomifensine was not shown to cause sedation or to interact with alcohol. No withdrawal phenomena were observed after 6 months' treatment. 5. Nomifensine is not suitable for severely agitated patients.


The role of the plasmalogen in the cross-reaction between group A streptococcus and human myocardium. Ethanol-soluble mycardial material which reacts with anti-streptococcal sera in a number of immunological tests has been isolated and identified as ethanolamine plasmalogen. The reactions of cardiac plasmalogen with antistreptococcal sera was specific and could be inhibited by streptococcus-derived materials. Guinea-pigs sensitized to streptococci gave positive skin reactions when challenged with myocardial plasmalogen. The pattern of the immunofluorescent staining given by antiplasmalogen sera was very much like that given by antistreptococcal sera. Nevertheless, the plasmalogen failed to compete for tissue-bound myocardial antigens when tried as an inhibitor of the immunofluorescent staining of myocardium either by antistreptococcal sera or by antiplasmalogen sera. A hypothesis of the role of the plasmalogen in the formation of complexes between streptococci and myocardium-derived material in the initiation of autoimmune processes is presented.


Atypical fibroxanthoma of the skin. Presentation of 5 cases and a review of the literature. A typical fibroxanthoma is a solitary tumour of the skin, which occurs mostly on sun-exposed areas in elderly people. The diagnosis can only be made with certainty on the typical histological findings, which suggest a bizarre malignant tumour. Although metastasizing tumours are reported in the literature, the authors believe that the true atypical fibroxanthoma is benign. Correct diagnosis obviates the need for unnecessary radical surgery. The possibility of atypical fibroxanthoma should always be considered when a histologically bizarre tumour is found on sun-damaged or irradiation-damaged skin in elderly patients or on previously traumatized sites. In this paper five cases are added to the 346 cases culled from the literature. Electron microscopic investigations in one case demonstrated cells with delicate cytoplasmic fibrils in small bundles. This does not necessarily suggest filaments of myofibroblasts, as has been previously reported.


The relationship between impaired selective attention and severity of psychopathology in acute psychiatric patients. Thirty acute psychiatric patients were administered a battery of selective attention and cognitive ability measures to determine whether there is a differential deficit in filtering capacity with increasing degrees of psychopathology. Susceptibility to intrusions in the early stages of auditory selective attention was positively related to degree of disturbance, but no more so than were other cognitive disabilities. Slowness of information processing, rather than impaired selective attention, bore the strongest relationship to severity of disturbance and appeared to be the best index of general cognitive inefficiency. It was concluded that the defective filter theories of schizophrenic deficit hold little promise for explaining how psychopathology affects cognitive functioning across a continuum of levels of disturbance.


Effect of ovarian wedge resection for the Stein-Leventhal syndrome on plasma FSH, LH, oestradiol and testosterone levels and on the responses of the pituitary to intravenous LHRH. We studied basal plasma FSH, LH, testosterone and oestradiol levels and post-OHRH plasma FSH and LH levels in ten patients both before and after a wedge resection of the ovaries for Stein-Leventhal syndrone. We compared the results with those obtained in 15 healthy patients between the third and seventh day of a normal menstrual cycle. Before operation, patients with the Stein-Leventhal syndrome had raised basal and post-LHRH LH levels and raised plasma testosterone levels. All these abnormalities disappeared after wedge resection of the ovaries. Both before and after operation patients with the Stein-Leventhal syndrome had low plasma oestradiol levels. These results are used to formulate a hypothesis about the aetiology of the Stein-Leventhal syndrome.


Isolation and characterization of independently folding regions of the beta chain of Escherichia coli tryptophan synthetase. It had been reported previously that the beta2 subunit of Escherichia coli tryptophan synthetase [L-serinehydrolyase (adding indole) EC 4.2.1.20] can be cleaved by trypsin into a nearly functional dimeric protein, the monomer of which consists of two large, nonoverlapping, polypeptide fragments. In the present paper, it is shown that these fragments can be separated after denaturation. Upon removal of the denaturing agent, the isolated fragments spontaneously refold into conformation, which, by various physical-chemical criteria, are shown to approximate the conformations of the corresponding fragments associated within the native protein. Furthermore, it is demonstrated that, upon mixing, these renatured fragments reassociate to form the renatured nicked protein which, by all the physical and functional criteria used, is indistinguishable from the native nicked protein. These results are taken as strong evidence that the isolated fragments can be considered as independently folding regions corresponding to intermediates in the folding of the intact protein.


Ribonucleotide reductase from Escherichia coli. Identification of allosteric effector sites by chromatography on immobilized effectors. Ribonucleotide reductase is responsible for the production of deoxyribonucleotides by catalyzing the reduction of ribonucleoside diphosphates. The enzyme is allosterically regulated in a complex way by the nucleoside triphosphates, ATP, dTTP, dGTP, dCTP, and dATP. Ribonucleotide reductase consists of two nonidentical subunits, proteins B1 and B2. Both substrates and allosteric effectors bind exclusively to B1. Binding of protein B1 to dTTP or dATP covalently coupled to Sepharose and elution with concentration gradients of the different nucleoside triphosphate effectors gave information about (1) the arrangement of the effector binding sites on protein B1 and (2) the affinity of the effectors for these sites. Protein B1 thus has two classes of effector binding sites. One class binds all effectors, as demonstrated by elution of the protein from dTTP-Sepharose with dATP, dGTP, ATP, or dCTP. The second class binds only dATP or ATP, since dATP and ATP were the only nucleotides which eluted protein B1 from dATP-Sepharose. These results confirm earlier data obtained by dialysis binding experiments. The eluting concentrations obtained for the different nucleoside triphosphates in experiments with dTTP-Sepharose could be used to calculate unknown dissociation constants for protein B1 -effector binary complexes. This was possible, since a plot of the eluting concentrations vs. known dissociation constants was linear.


Incorporation of purine nucleoside 5'-[gamma-S]triphosphates as affinity probes for initiation of RNA synthesis in vitro. Synthetic DNA templates were transcribed by Escherichia coli RNA polymerase using nucleoside 5'-[gamma-S]triphosphates as one of the nucleotide substrates. Substitution of the thiol analogues for the normal nucleotides had no effect on the rate of RNA synthesis. RNA synthesized with either adenosine 5'-[gamma-S]triphosphate or guanosine 5'-[gamma-S]triphosphate was isolated with high efficiency on mercury-agarose columns prepared by activation with low concentrations of cyanogen bromide. Sulfur was shown to be incorporated at the 5' end of RNA by identification of the tetraphosphate HSpppA32p liberated after alkaline hydrolysis of HS(A-32pU)n (alternating copolymer synthesized by the action of E. coli RNA polymerase on d(A-T)n-d(A-T)n with adenosine 5'-[gamma-S]triphosphate and uridine 5'-[alpha-32P]triphosphate as substrates). Transcripts elongated but not initiated with these thiol analogues did not bind to the affinity column. This technique provides an extremely sensitive assay for RNA synthesis initiation in vitro, since initiated transcripts containing radiolabel throught the entire transcript can be isolated.


Evidence for an essential glutamyl residue in yeast hexokinase. Yeast hexokinase is rapidly inactivated by 1-cyclohexyl-3-(2-morpholinoethyl)carbodiimide metho-p-toluenesulfonate and nitrotyrosyl ethyl ester. Sugar substrates afford a partial protection, which is increased by the addition of ADP. Inactivation of the enzyme takes place concomitantly with the incorporation of 1 mol of nitrotyrosine per mol of 50 000-dalton subunit. Exhaustive proteolytic digestion of the modified protein and isolation of the nitrotyrosyl peptide by affinity chromatography, followed by electrophoresis, lead to the identification of the modified residue as a glutamyl residue. This modification of hexokinase occurs without gross conformational changes. The enzyme still binds its substrates, though binding of the nucleotides is perturbed. While the substrates afford a partial protection, they increase the incorporation of nitrotyrosine ethyl ester into the enzyme. This may be attributed to local conformational changes which their binding induces. It is concluded that a glutamyl residue is essential for yeast hexokinase activity and its catalytic function is discussed.


Yeast mitochondrial DNA specifies tRNA for 19 amino acids. Deletion mapping of the tRNA genes. We have previously identified 14 aminoacyl tRNAs that are specified by yeast mitochondrial DNA (mtDNA). We now report four more amino acids (Arg, Cys, Trp, Thr) that acylate tRNAs which hybridize with mtDNA. Furthermore one of the two mitochondrial tRNAs that we had earlier demonstrated to be directly charged with glutamic acid responds to glutamine but not to glutamic acid codons. Thus Gln-tRNAGln appears to be formed by transamidation of a missense intermediate Glu-tRNAGln. This brings to 19 the number of amino acids which have corresponding tRNAs specified by mtDNA. Only tRNAAsn has not yet been shown to be a mtDNA transcript. We have also mapped the genes for the newly identified mitochondrial tRNAs, as well as several others that were previously identified but unmapped, by hybridization to the mtDNA of a series of petite deletion mutants. We now have ordered 20 mitochondrial tRNA genes (including two methionyl-tRNAs) wtih respect to the antibiotic resistance markers chloramphenicol (CR), erythromycin (ER), paromomycin (PR), and oligomycin I and II (ORI, ORII). Eighteen tRNA genes map between the C and E resistance markers. Only the serinyl-tRNA and glutamyl-tRNA genes are localized near the OI and OII resistance markers.


Yeast mutants blocked in removing the methyl group of lanosterol at C-14. Separation of sterols by high-pressure liquid chromatography. Sterols of a nystatin resistant mutant of the wild type parent of Saccharomyces cerevisiae were separated by a newly developed procedure involving high-pressure liquid chromatography and were identified. The mutant contained larger amounts of squalene and lanosterol (I) than the wild type, as well as 4,14-dimethylcholesta-8,24-dien-3beta-ol (II), 4,14-dimethylergosta-8,24(28)-dien-3beta-ol (III), and 14-methylergosta-8,24(28)-dien-3beta-ol (IV), which were not hitherto found in yeast. These results indicated a block in removal of the methyl group at C-14 of lanosterol. An ergosterol requiring derivative of the mutant which carried in addition a mutation in heme biosynthesis had the same sterols as the parent, but at one-third the concentration. The low level of sterols may be due to a requirement for a heme or cytochrome in oxygenation reactions between lanosterol and ergosterol.


Repair of nitrous acid damage to DNA in Escherichia coli. A number of mutant strains of Escherichia coli have been examined for their sensitivity to nitrous acid and in some instances to methylmethanesulfonate. All ung- mutants tested are abnormally sensitive to nitrous acid. Since the ung mutation is phenotypically expressed as a defect in uracil DNA glycosidase, this observation supports the contention that treatment of cells with nitrous acid causes deamination of cytosine to uracil. In addition the observed sentitivity indicates that the ung gene is involved in the repair of uracil in DNA. Studies with other mutants suggest that both exonuclease III and DNA polymerase I of E. coli are involved in the repair of nitrous acid damage in vivo.


Analysis of in vitro transcription of duck reticulocyte chromatin using mercury-substituted ribonucleoside triphosphates. We have employed mercury-substituted UTP to study the transcription of duck reticulocyte chromatin in vitro by Escherichia coli RNA polymerase. We find that the use of this method results in large overestimates of the amount of de novo synthesis of globin-specific RNA sequences. The artefact arises because endogenous globin RNA can serve as a template for the RNA polymerase, resulting in the formation of a duplex product in which one strand is the endogenous message, and the other is the mercury-labeled complementary strand. Subsequent purification of the mercury-substituted RNA on thiol-agarose results in copurification of endogenous globin sequences. We document the details of this mechanism and describe methods which will eliminate the artefact.


The dynamic structure of the Escherichia coli cell envelope as probed by 15N nuclear magnetic resonance spectroscopy. Proton decoupled 15N NMR spectroscopy is shown to be a useful tool for probin the dynamic structure of the bacterial cell envelope. The proton decoupled 15N NMR spectra of Escherichia coli whole cells, cell envelopes and outer membranes were obtained and displayed resonances originating from protein side-chain groups, phosphatidylethanolamine, and peptidoglycan. Removal of phospholipids from the cell envelope resulted in a decrease in the motional freedom of peptidoglycan and cell envelope proteins. The mobility of the protein Arg side-chain groups is increased in the absence of peptidoglycan. These data provide insights into the effect of supramolecular organization on the dynamic structure of the E. coli cell envelope.


Synthesis of complementary RNA on RNA templates using the DNA-dependent RNA polymerase of Escherichia coli. It is shown that the DNA-dependent RNA polymerase of Escherichia coli can synthesize complementary RNA (cRNA) directly on rRNA and mRNA templates. Synthesis occurred preferentially in the presence of Mn2+ and at relatively high substrate and enzyme concentrations. No primer was required, and addition of oligo-U to a mRNA-dependent reaction gave no marked stimulation. Sedimentation analysis of cRNA made on different templates indicated that the products were mainly 2-4 S, but a fraction of the product was larger. Fingerprints of 32P-labelled cRNA made on 5 S rRNA and 18 S rRNA indicated that the complexity of the cRNAs was related to the size of the template, suggesting that a substantial portion of the templates were copied. This reaction provides a simple method for preparing cRNA of high specific activity for use in hybridisation studies, and possibly in sequence analysis. 32P-labelled cRNA made on 18 S and 28 S rRNA was a sensitive hybridisation probe for detection of the specific fragments of mouse DNA containing the rRNA genes.


A comparison of small circular DNA molecules in psi+ and psi- strains of Saccharomyces cerevisiae. The psi+ and psi- phenotypes, which affect the efficiency of ochre suppression in yeast, are inherited in a non-Mendelian fashion. There is no apparent difference in length or in length distribution of 2 micronm circular DNA molecules between psi+ and psi- strains. It seems that the psi genetic determinant is probably not connected with the presence or absence of these small circular DNA molecules.


Purification by affinity chromatography of yeast glutathione reductase, the enzyme responsible for the NADPH-dependent reduction of the mixed disulfide of coenzyme A and glutathione. Glutathione reductase (NAD(P)H : oxidised-glutathione oxidoreductase, EC 1.6.4.2) was purified from baker's yeast by a new procedure involving affinity chromatography on 2',5'-ADP-Sepharose 4B. The yield was 65% of essentially homogeneous enzyme. The activity was assayed with both glutathione disulfide (GSSG) and the mixed disulfide of coenzyme A and glutathione (CoAssg). The two disulfide substrates gave coinciding activity profiles and a constant ratio of the activities in different chromatographic and electrophoretic systems. No evidence was obtained for the existence of a reductase specific for CoASSG distinct from glutathione reductase. It is concluded that normal baker's yeast contains a single reductase active with both GSSG and CoASSG.


Affinity chromatography od Klebsiella arylsulfatase on tyrosyl-hexamethylenediamine-beta-1,3-glucan and immunoadsorbent. A simple and convenient method for preparation of a highly purified arylsulfatase (EC 3.1.6.1) from Klebsiella aerogenes has been developed. Specificity of purification was achieved by using affinity chromatography on a tyrosyl-hexamethylenediamino-beta-1,3-glucan or on a solid phase immunoadsorbent. By using affinity chromatography a homogeneous enzyme was obtained with high yield. It is also proposed that the beads of curdlan type polysaccharide consisting of beta-1,3-glucan can be used as a good matrix for affinity chromatography.


The collagen of heart valve.

The collagen of heart valve. A hydroxylysine-rich type I collagen has been isolated from pepsin-digested porcine heart valve. The ratio of alpha1 to alpha2 in the isolated molecule was 2:1. The component alpha chains exhibited unusual chromatographic behavior in comparison to corresponding chains from human dermis and lathyritic rat skin collagen. The composition of component cyanogen bromide peptides identified the alpha chains as authentic type I chains and demonstrated hydroxylysine enrichment throughout the length of the chain. delta6-Dehydro-5,5'dihydroxylysinonorleucine, a collagen cross-link derived from two hydroxylysyl residues and ordinarily found in hard tissue collagens was found to be the predominant cross-link in heart valve.


Investigations on isolated islets of langerhans in vitro. 16.Modification of the glucose-dependent inhibition of glucagon secretion. Investigation of glucagon secretion in isolated Wistar rat islets was carried out to elucidate further the regulatory function of glucose and arginine on pancreatic A-cells. The suppressive effect of D-glucose could also be demonstrated with L-glucose, D-mannose, D-fructose, D-galactose, D-glyceraldehyde and DL-dihydroxyacetone, but not in the presence of 3-O-methylglucose or mannitol. Sugars other than D-glucose inhibited glucagon secretion only at much higher concentrations than those at which D-glucose was effective. Furthermore, although 7.5 mM D-glucose up to 80% inhibition, the effects of other sugars appeared to level off at only 50--60% inhibition. The inhibitory action of D-glucose or D-glyceraldedyde on glucagon secretion could not be overcome by L-arginine, but 3-O-methylglucose, mannoheptulose, 2-deoxy-D-glucose, iodoacetamide, theophylline, epinephrine and acetylcholine were effective. The insulin secretion in response to glucose was inhibited by the metabolic inhibitors used, whereas the B-cell response in the presence of glyceraldehyde was diminished by iodoacetamide only. Like D-glucose, a variety of other sugars markedly reduced the stimulatory effect of L-arginine in glucagon release. The results show that the suppression of glucagon secretion is not specific for D-glucose and not strongly connected on a stimulated insulin secretion.


[Purification and properties of glucoamylase from Endomycopsis sp. 20-9]. Homogenous yeast (Endomycopsis sp. 20-9) glucoamylase was isolated from cultural medium. The homogeneity of the enzyme preparation is demonstrated by means of polyacrylamide gel disc electrophoresis, isofocusing and ultracentrifugation. Amino acid composition, molecular weight (53 000), sedimentation constant (4.3S) and isoelectric point (pI 3.80-3.82) of the enzyme are determined. Glucoamylase is found to be glucoprotein.


Enzyme immunoassay for the serodiagnosis of parasitic infections. A review of some applications of the Enzyme-Linked Immunosorbent Assay (ELISA) for the serodiagnosis of parasitic infections is presented. Examples are given of applications with trichinellosis, hydatidosis, schistosomiasis, toxoplasmosis, african trypanosomiasis and amoebiasis. ELISA is believed to be a valuable addition to existing serological tools, especially due to its sensitivity and ease of performance.


The influence of poly I: poly C on kinetics of the primary immune response to sheep erythrocytes in the mouse spleen. In several mouse strains, which exhibited variability in degree of immune responsiveness, concomitant i.p. injection of antigen (sheep erythrocytes) and poly I: poly C enhanced the early rate of increase in antibody plaque-forming cells (PFC) in the spleen. This adjuvant effect of poly I: poly C was most marked in LACA mice and was demonstrable over a range of antigen and polynucleotide concentrations. The double-stranded RNA did not however, affect the number of PFC at the peak of the primary response. Stimulation was dependent on the temporal relationship between antigen and adjuvant administration--injection of poly I: poly C 24 and 48 h prior to antigen causing suppression of humoral immunity. Poly I: Poly C had a progressively more marked enhancing effect on PFC production at high (thymus-independent) doses of erythrocytes. This suggests that its adjuvant action may be mediated via cells other than T cells. Administration of poly I: poly C caused an initial depression followed by stimulation of spleen weight and nucleated cell numbers in sensitized animals. The possible mechanism(s) of action of this polynucleotide adjuvant are discussed in the light of these and other findings.


[Distribution of the dimensions of cells and intracellular structures of biosystems from measurements of the diffusion of water by the impulse gradient of the NMR spin echo method]. The method of impulse gradient of NMR spin-echo was applied for studying limited water diffusion in yeast cells and embryons of wheat caryopsis. Results are presented of measuring the amplitude of the echo signal depending on the intensity of the impulse gradient of the magnetic field reaching the values up to 1.7 kGs/cm. The method is suggested of determining on the basis of experimental data the distribution function parameters of the sizes of limiting cell compartments taking into account the permeability of their walls (membranes).


[Influence of soluble H-2 antigens on the cytotoxic effect and adsorption of immune lymphocytes]. Serologically active preparations of soluble H-2 antigens were obtained by 3 M KCl extraction from the ascitic cells of leukemia L 1210 (H-2d) and sarcoma MX-11 (H-2b). These preparations had no specific influence in vitro on the cytotoxic effect of immune lymphocytes on target cells, and did not inhibit the lymphocyte adsorption on the monolayer of the corresponding target cells.


Some effects of intravenous prostaglandin E, and endotoxin in young chickens. 1 The effects of intravenous prostaglandin E1 and endotoxin were studied in young chickens (11-17 days old). 2 At a thermoneutral ambient temperature (31 degrees C), intravenous prostaglandin E1, produced behavioural and electrocortical sleep, increased oxygen consumption and, after an initial fall, elevated body temperature. Below thermoneutrality (16 degrees C), the initial hypothermic effect was more marked and oxygen consumption was lowered. 3 The soporific actions of prostaglandin E1 were sufficient to counteract dexamphetamine-induced behavioural and electrocortical arousal and vocalization. 4 Intravenous injection of the O-somatic antigen of Shigella dysenteriae evoked, after a latent period, long lasting hyperthermia. This indicates that in young chicks the blood brain barrier is probably permeable to endotoxins.


Some effects of prostaglandins E1 and E2 and of endotoxin injected into the hypothalamus of young chicks: dissociation between endotoxin fever and the effects of prostaglandins. Prostaglandins E1 and E2 elevated body temperature of young chicks when injected into the hypothalamus at thermoneutrality (31 degrees C). In contrast, they lowered body temperature when so injected below thermoneutrality (16degreesC): the relation of the fall in body temperature to increased heat loss and decreased heat production was examined. 2 The above effects below thermoneutrality were potentiated by pretreatment with inhibitors of prostaglandin synthetase and possible reasons for this potentation are given. 3 The O-somatic antigen of Shigella dysenteriae consistently evoked hyperthermia when injected into the hypothalamus, irrespective of whether the chicks were within or below thermoneutrality. 4 Pretreatment with prostaglandin synthetase inhibitors failed to prevent the onset of endotoxin fever; however, duration of the fever, induced by intrahypothalamic injection of the O-somatic antigen of Shigella dysenteriae was reduced. 5 The intrahypothalamic injection, belwo thermoneutrality of prostaglandins E1, E2, noradrenaline, 5-hydroxytryptamine or carbachol reversed endotoxin fever, inducing even substantial falls in body temperature. 6 While the results cast some doubts on the role of prostaglandins of the E series as mediators of endotoxin fever in chicks, they cannot be eliminated as mediators until the significance of the reduction in duration of the pyrexic response by indomethacin and 5,8,11,14-eicosatetraynoic acid, and the degree of synthesis inhibition attained, are known.


Psychiatrists and a computer as interrogators of patients with alcohol-related illnesses: a comparison. A computer-administered 'interview' was developed for eliciting evidence relating to alcohol problems. Thirty-six volunteer male patients on their first visits to a specialist alcohol clinic were interviewed three times, by two psychiatrists and by the computer; information was sought about 72 pre-defined indicants concerning alcohol consumption, drinking behaviour, and symptoms. Each patient was asked to complete an attitude questionnaire anonymously. The extent of agreement between the evidence elicited by the computer and by the psychiatrists was quite high, and their estimated error rates were very similar, all between 10 per cent and 12 per cent in total. With respects to amounts of alcohol consumed, patients reported significantly greater amounts to the computer than they reported to the psychiatrists. The median amounts of pure ethanol consumed ranged from 1-19 kg per week calculated from reports made to one of the psychiatrists, up to 1-58 kg per week calculated from reports made to the computer. The results from the attitude questionnaire indicated a high level of acceptability to patients of computer interrogation.


The effect of mental state on EPI scores. This paper develops a structural equation model to assess the effects of mental state on EPI scores. This model is applied to results obtained from a clinical population. The findings show that :(a) the E scale is not influenced by mental state as measured by the Hamilton Anxiety Scale (HAS); (b)) the N scale is influenced by HAS. An attempt to revise the N scale to produce an uncontaminated score is discussed.


High dosage haloperidol in chronic schizophrenia. In a double blind chlorpromazine-controlled trial, high dosage haloperidol (100 mg daily) given for three months, appreciably improved the mental state of male chronic 'drug resistant' schizophrenic inpatients in the rehabilitation/long-stay unit of one psychiatric hospital. The results of a three-month follow-up suggested that the improvement could be maintained in some patients on lower doses of the drug. Serious extrapyramidal side effects were not seen at high doses. However, the majority of patients on haloperidol showed a deterioration in ward behaviour, possibly related to drowsiness, and developed raised serum alkaline phosphatase levels. These side effects disappeared in the follow-up period when either the drug was discontinued or the dose of haloperidol reduced.


Angiotensin blockade in renovascular hypertension: a controlled, prospective study. Saralasin, a specific competitive inhibitor of angiotensin II, was administered in a controlled, prospective study designed to test the hypothesis that this agent is a useful tool for the detection of renovascular hypertension. 13 patients, 11 with renovascular hypertension and 2 with high-renin essential hypertension, showed a gross, readily apparent decrease in blood pressure after receiving saralasin. 8 patients with essential hypertension and normal or low renin levels exhibited no depressor response to the drug. In the patients with renovascular hypertension, blood pressure response during angiotensin blockade compared favourably with renal vein renin determinations as a predictor of operative results. Because saralasin testing has resulted in few if any falsely positive or negative results when considered as a diagnostic procedure for renin-mediated hypertension, and because it is safe, it may become an ideal initial screening procedure. The saralasin test (either bolus injection or sustained infusion) is completely valid only if the patient is mildly salt-depleted, is not taking other antihypertensive medication, and is genuinely hypertensive at the time of the test.


Oral contraceptive use and venous thromboembolism: absence of an effect of smoking. We conducted a case-control study to test the hypothesis that women smokers who use oral contraceptives have an increased risk of developing venous thrombosis. Patients and controls were drawn from two sets of hospital patients already included in the Boston Collaborative Drug Surveillance Programme. Sixty patients with uncomplicated thromboembolism were matched with 180 controls with other diagnoses; all were premenopausal women taking oral contraceptives. Patients with conditions that might predispose to thromboembolism or be related to smoking were excluded. We found no association between smoking habits and thromboembolism. Similarly, we found no association between thromboembolism, smoking, and duration of oral contraceptive use. Thus we conclude that differences in fibrinolytic activity between smokers and non-smokers are not major factors in the aetiology of uncomplicated thromboembolism in women using oral contraceptives.


Immunosuppressive properties of sera and urine dialysates from kidney-graft recipients treated with azathioprine, prednisolone, and niridazole. Niridazole, an antischistosomal agent, was given to renal transplant recipients in addition to azathioprine and prednisolone, as there is experimental evidence that this combination of drugs is highly immunosuppressive. Sera obtained from kidney-graft recipients during the first two weeks after transplantation were examined for their ability to inhibit the one-way mixed lymphocyte reaction (MLR). Sera from seven patients receiving azathioprine, prednisolone, and niridazole (triple-drug treatment), five patients receiving azathioprine and prednisolone, and two other patients treated with niridazole alone for schistosomiasis produced MLR inhibition by comparison with pretreatment (control) sera.A mean of 78% inhibition was observed with sera taken after one day's treatment with the three-drug combination, whereas this level of in-vitro immunosuppression occurred only after eight days of treatment with azathioprine and prednisolone. Niridazole alone produced an effect similar to azathioprine and prednisolone. Concentrated dialysate of urine from a patient receiving triple-drug treatment not only inhibited the MLR but also significantly prolonged the survival of heterotopic heart allografts in rats, whereas dialysate from the same patient after niridazole had been stopped gave less MLR inhibition and failed to prolong heart allograft survival.Since niridazole thus increased the in-vitro and in-vivo immunosuppressive action of azathioprine and prednisolone, we suggest that this triple-drug combination might be useful for preventing early acute kidney graft rejection.


Cimetidine in patients with gastric ulcer: a multicentre controlled trial. Forty-five adult outpatients with endoscopically confirmed gastric ulceration completed a double-blind trial of either cimetidine (1 g/day) or placebo. After six weeks 18 of the 23 patients receiving cimetidine showed complete ulcer healing compared with only six of the 22 patients receiving placebo. The cimetidine group also had fewer days with pain than the placebo group but the difference was not statistically significant. Cimetidine therefore seems to promote healing of gastric ulcers without severe side effects, although its effect on pain is less pronounced than in patients with duodenal ulcers.


Identification of a coenzyme A--glutathione disulfide (DSI), a modified coenzyme A disulfide (DSII), and a NADPH-dependent coenzyme A--glutathione disulfide reductase in E. coli. The nucleotides DSI and DSII induced during a slowdown in growth of E. coli have been characterized using chemical and biochemical analysis and by enzymic and alkaline fragmentation. DSI consists a coenzyme A and glutathione joined by a disulfide linkage. DSI could be isolated either containing Fe(III) with an A250:260 ratio of 1.05 or not containing iron with an A250:260 of 0.87. DSII (isolated in 10% the yield of DSI) is a coenzyme A disulfide dimer that also contains two molecules of glutamic acid. DSI was a substrate for NADPH-dependent CoAS-SG reductase (EC 1.6.4.6) which was present in crude extracts of E. coli. The specific activity of CoAS-SG reductase increased during growth from early log phase into stationary phase and during a shift from aerobic to anaerobic growth.


Proteolytic digestion and labelling studies of the organization of the proteins in the outer membrane of Escherichia coli. The arrangement of the proteins in the outer membrane of Escherichia coli was examined by treating intact cells and isolated membrane preparations with fluorescamine and with pronase. Intact wild-type cells, or those of a mutant in which the core region of the lipopolysaccharide was absent, were equally resistant to pronase treatment. The protein components of isolated outer membrane preparations varied in their rate of digestion and labelling with fluorescamine. The N-terminal portion of protein B was removed by pronase to yield a fragment (protein Bp) still embedded in the membrane. Protein Bp was not significantly enriched in nonpolar amino acids, suggesting that protein B may not be held in the membrane primarily by hydrophobic interactions. This was confirmed by reconstitution experiments in which protein B could be reassociated with itself, without lipopolysaccharide or phospholipid, in the presence of divalent cation such that pronase digestion of the reassociated material gave protein Bp.


Use of computers in clinical electrocardiography: an evaluation. The use of computers in clinical electrocardiography is increasing rapidly; however, the role of computers with respect to the electrocardiographer has not been established. At present all electrocardiograms (ECGs) processed by computer are also interpreted by electrocardiographers; hense effort is duplicated. In an investigation of whether conditions can be defined under which the electrocardiographer can use the computer more profitably by eliminating some of the duplication, ECGs recorded in a university teaching hospital were processed by a computer program and subsequently reviewed by 1 of 10 electrocardiographers. For ECGs interpreted as showing normal sinus rhythm the rate of agreement between computer and human reviewer was 99%. For those showing a normal ECG pattern (contour) the rate of direct agreement was only 88%. However, the rate of occurrence of clinically significant differences was only 1.64%; hence the rate of essential agreement for this classification was 98.36%. Other classifications with good agreement were myocardial infarction, sinus bradycardia and sinus tachycardia. Therefore, in circumstances comparable to those of this investigation it is feasible for electrocardiographers to use computers to reduce greatly their workload without compromising the quality of the service provided.


Survival of patients treated for end-stage renal disease by dialysis and transplantation. The results of treatment in 213 patients with end-stage renal disease who underwent hemodialysis, peritoneal dialysis or transplantation, or a combination, between 1962 and 1975 were analysed. Comparison by censored survival analysis showed significantly better (P less than 0.01) patient survival with the integrated therapy of dialysis and transplantation than with either form of dialysis alone. There was no significant difference in survival of males and females but survival at the extremes of age was poorer. Analysis of survival by major cause of renal failure indicated best survival in patients with congenital renal disease. Graft and patient survival rates at 1 year after the first transplantation were 42% and 69%. The major cause of death in this series was vascular disease but infection was responsible for 50% of deaths after transplantation. While integration of dialysis with transplantation produces best patient survival, this course is possible only when sufficient cadaver kidneys are available.


Toxoplasmosis in Greater Victoria.

Toxoplasmosis in Greater Victoria. Titres of antibody to Toxoplasma gondii were determined in 596 inhabitants of Greater Victoria who were either patients at two hospitals or healthy volunteers. The survey included 404 women of childbearing age, 305 of whom had just given birth. The proportion of persons with antibody to T. gondii at a titre of 1:8 or greater as determined by a methylene blue dye test was 28%. Titration of IgM antibody specific to T. gondii by the indirect fluorescent antibody test, performed in the serum samples with a titre of 1:8 or greater by the dye test, indicated that 3% of the 596 patients had recently acquired infection with T. gondii. The proportion of women with antibody to T. gondii among those who had just given birth was 25%, but the proportion among women aged 31 to 35 years who had just given birth was 37%.


Importance of donor site selection in skin grafting. Skin grafting has been done for over 100 years, and the importance of the type of graft--split thickness, full thickness or composite--has been well established. However, the importance of selecting a donor site that is appropriate to the type of graft and to the patient's age and sex has received scant attention, despite the fact that, in many cases, the scar at the donor site may prove to be of greater long-term concern to the patient than the initial injury. Examples of malchosen donor sites are presented and a plea is made for more careful selection by all concerned with skin grafting.


Histopathologic review of lymphoma cases from the Southwest Oncology Group. Lymphoma Pathology Panel and Repository (LPPR) review of pathologic material from 354 patients registered on Southwest Oncology Group clinical trials substantiated the diagnosis of Hodgkin's disease (Lukes-Butler classification) in 175 (94%) of 186 cases and the diagnosis of non-Hodgkin's lymphoma (Rappaport classification) in 162 (96%) of 168 cases. However, complete agreement (type and subtype) between institutional and LPPR review diagnoses was found in only 66% of confirmed cases of Hodgkin's disease and in only 58% of confirmed cases of non-Hodgkin's lymphomas. In 26 (16%) of 160 cases of non-Hodgkin's lymphoma, the initial interpretation of pattern (nodular vs diffuse) differed: 20 (25%) of 81 nodular lymphomas had been thought to be diffuse and 6 (8%) of 79 diffuse lymphomas had been diagnosed as nodular. The frequency with which initial diagnoses were confirmed on LPPR review was highest for three subtypes of lymphoma: nodular sclerosis Hodgkin's disease (88%), diffuse histiocytic lymphoma (86%), and nodular lymphocytic lymphoma (78%); rates of confirmation for all other subtypes ranged from 13-50%. The results of this analysis emphasize the necessity of having pathologic review of all cases entered on major lymphoma studies so that comparability of cases can be assured and the results of those studies placed in proper perspective.


The role of radiotherapy in the management of malignant hemangiopericytoma: report of eleven new cases and review of the literature. The response of hemangiopericytoma to radiation therapy was studied in 11 patients treated at Memorial Hospital. Response of greater or lesser degree was noted in 26 of 29 radiation therapy courses administered. These included 14 instances of complete tumor regression. Dose and tumor size were the main factors influencing response. The tumors tend to regress slowly and incompletely; yet effective relief of symptoms and long term local control (average duration 27 months) usually was achieved. These results and those reported by others believe the alleged inefficacy of radiation therapy in the management of these tumors. Palliative radiation therapy seems to be worthwhile even in advanced cases. Because of the high rate of local recurrence after surgical excision, treatment strategies combining local excision of large primary tumors with wide-field, high-dose radiation therapy are worthy of trial.


Metastatic choriocarcinoma transplanted with cadaver kidney: a case report. A unique case of a metastasising choriocarcinoma, inadvertently transplanted to a man from a female cadaver kidney is reported. When the kidney was removed six days after transplantation, arterial blood vessel infiltration by chorio-carcinoma cells and high levels of human chorionic gonadotropin (HCG) in the serum of the recipient indicated an haematogenous dissemination of viable neoplastic cells. The immunosuppressive therapy was discontinued after removal of the graft and the HCG levels in the recipient gradually decreased over a periode of eight weeks, indicating a slow immunologic rejection of the tumor cells. The recipient committed suicide seven months after the transplantation had failed. No metastases were found at a legal autopsy. It seems advisable, whenever there is evidence that neoplastic cells might have been transfered by a homograft, to remove the graft and discontinue the immunosuppressive therapy. Neoplastic cells already disseminated can still be eliminated when the immunologic system is intact and not suppressed.


Comparison of the action of glucoamylase and glucosyltransferase on D-glucose, maltose, and malto-oligosaccharides. The action patterns of glucoamylase (amyloglucosidase) and glucosyltransferase (transglucosylase) on D-[1-14C]glucose, [1-14C]maltose, and [1-14C]malto-oligosaccharides (labeled at position 1 of the D-glucose group at the reducing end) have been investigated by paper-chromatographic and oligosaccharide-mapping techniques. Under the conditions of the experiments, the extent of conversion of D-glucose and of maltose into new oligosaccharides was 2.2 and 1.9% with glucoamylase, and 5.7 and 33% with glucosyltransferase. The major oligosaccharides produced by both enzymes were isomaltose (6-O-alpha-D-glucopyranosyl-alpha-D-glucose), panose (O-alpha-D-glucopyranosyl (1 leads to 6)-O-alpha-D-glucopyranosyl-(1 leads to 4)-alpha-D-glucose), and nigerose (3-O-alpha-D-glucopyranosyl-alpha-D-glucose). The glucosyltransferase also synthesized oligosaccharides from malto-oligosaccharides of higher molecular weight to yield compounds having alpha-(1 leads to 6)-linked D-glucosyl groups at the non-reducing ends. Glucoamylase exhibited little, if any, such activity on malto-oligosaccharides.


Metabolism of the polysaccharides of human dental plaque. Part II. Purification and properties of Cladosporium resinae (1 leads to 3)-alpha-D-glucanase, and the enzymic hydrolysis of glucans synthesised by extracellular D-glucosyltransferases of oral streptococci. Cladosporium resinae (1 leads to 3)-alpha-D-glucanase has been characterized as an endoglucanase capable of completely hydrolysing insoluble (1 leads to 3)-alpha-D-glucans isolated from fungal cell-walls. D-Glucose was the major product, but a small amount of nigerose was also produced. The enzyme was specific for the hydrolysis of (1 leads to 3) bonds that occur in sequence, and nigerotetraose was the smallest substrate that was rapidly attacked. Isolated (1 leads to 3)-alpha-D-glucosidic linkages that occur in mycodextran, isolichein, dextrans, and oligosaccharides derived from dextran were not hydrolysed. Insoluble glucan synthesised from sucrose by culture filtrates of Streptococcus  spp. were all hydrolysed to various limits; the range was 11-61%. A soluble glucan, synthesised by an extracellular D-glucosyltransferase of S. mutans OMZ176, was not a substrate, whereas insoluble glucans synthesised by a different D-glucosyltransferase, isolated from S. mutans strains OMZ176 and K1-R, were extensively hydrolysed (84 and 92%, respectively). It is suggested that dextranase-CB, a bacterial endo(1 leads to 6)-alpha-D-glucanase that does not release D-glucose from any substrate, could be used together with C. resinae (1 leads to 3)-alpha-D-glucanase to determine the relative proportions of (1 leads to 6)-linked to (1 leads to 3)-linked sequences of D-glucose residues in the insoluble glucans produce by oral streptococci. The simultaneous action of the two D-glucanoses was highly effective in solubilizing the glucans.


Phagokinetic tracks of 3T3 cells: parallels between the orientation of track segments and of cellular structures which contain actin or tubulin. Phagokinetic tracks were used to determine the current direction of migration in 3T3 cells. Comparing this direction with the orientation of actin or tubulin-containing cellular structures by indirect immunofluorescence, the following results were obtained. First, the main actin-containing bundles were located at the bottom and tail end of 3T3 cells and ran parallel to the current or preceding direction of migration. Second, the 3 micrometer long rod-like structure (primary cilium), which contains tubulin and which has been observed by other investigators in transmission electron microscopy (Barnes, 1961; Sorokin, 1962; Wheatley, 1969) and in indirect immunofluorescence (Osborn and Weber, 1976), was oriented predominantly parallel to the substrate and to the current movement direction. It seems possible that the primary cilium has a role in the directional control of a migrating 3T3 cell, and that the main actin containing bundles act as substrate-attached rails along which the nucleus and bulk cytoplasm slide during displacement of the cells.


RNA synthesized in vitro by calf thymus RNA polymerase III (C), as well as by E. coli RNA polymerase, is restricted to a subset of calf thymus DNA. RNA synthesized in vitro from chromatin and DNA by calf thymus RNA polymerase III was evaluated by hybridization in vast DNA excess. The RNA contains RNA complementary to both moderately repeated and unique DNA sequences. Very highly repeated DNA is not transcribed. A greater portion of RNA transcribed from DNA by RNA polymerase III hybridizes to moderately repeated DNA than RNA transcribed by Escherichia coli RNA polymerase. In studies utilizing DNA absorbed to filters, RNA transcribed from chromatin in short incubations hybridized to a greater extent than RNA transcribed for longer times. Similar results were obtained with RNA transcribed from DNA by E. coli RNA polymerase. These results suggest: 1) RNA polymerase III may be responsible for the synthesis of RNA species in addition to tRNA and 5 S ribosomal RNA and a portion of this RNA is transcribed from unique DNA; and 2) in vitro there may be selectivity in the initiation of transcription by both E. coli RNA polymerase and calf thymus RNA polymerase III.


Anomalous pulmonary venous return with intact atrial septum: diagnosis and pathophysiology. Twenty-one patients with partial anomalous pulmonary venous drainage with intact atrial septum have been studied. These include 13 patients not previously reported from our laboratories and eight patients with complete hemodynamics reported by others. Methods for identification of this abnormality and for identification of an intact atrial septum are described, including differential indicator dilution curves, catheter probing of the atrial septum and pulmonary angiography. Blood flow through anomalously draining lobes of the lung is usually higher than through normally drainage lobes attributable to the higher pressure differences across the anomalous lung, right atrial pressure being uniformly lower than left atrial pressure. The pulmonary vascular resistance when "standardized" to the flow of blood normally present in different portions of the lung indicated that no significant differences existed between normally and anomalously draining lobes. Six patients had coexisting rheumatic mitral stenosis and one had congenital mitral stenosis. Its influence on the hemodynamic changes produced by PAPVD is discussed.


Adenosine deaminase activity in lymphocytes of normal persons, leukemic patients, and kidney-transplant recipients. We determined the activity of adenosine deaminase in normal lymphocytes from peripheral blood, leukemic cells from patients with various hematologic malignancies, and mononuclear cells from kidney-transplant patients, by adapting the method of Hopkinson et al. [Ann. Hum. Genet. 32, 361 (1969)] to the centrifugal analyzer. Normal lymphocytes separated on Ficoll-Hypaque from peripheral blood had a mean activity of 1.42 U/10(9) cells (SD = 0.57; N = 33). Cells similarly isolated from patients with acute lymphoproliferative and myeloproliferative disease generally showed greater values, but the ranges overlapped. Cells from patients with chronic lymphocytic leukemia had activities that were within or below the normal range. Mononuclear cells isolated from the peripheral blood of 15 stable renal allograft recipients showed a mean activity of 1.90 U/10(9) cells (SD = 0.59), not significantly different from normal. In contrast, cells from five patients with biopsy-proven allograft rejection showed a mean activity of 12.84 U/10(9) cells (SD = 10.10), which was significantly different from that of the stable patients.


Detection of endotoxins in human blood and plasma. An improved in-vitro pyrogen test. We describe an improved in-vitro procedure for detection of endotoxin in human blood and plasma by use of Limulus amoebocyte lysate. Increasing concentrations of Escherichia coli endotoxin added to a constant amount of the lysate cause a proportional increase in protein precipitated by the endotoxin. By measuring the amount of protein precipitated, it was possible to determine the equivalent E. coli endotoxin concentration in unknown samples, when samples were run with E. coli endotoxin standards and negative controls. The E. coli endotoxin, present in human whole blood and platelet-rich plasma, failed to react with the lysate. However, the concentration of endotoxin in whole blood and platelet-rich plasma could be measured with this Limulus test after lysing the platelets to release the endotoxin and subsequently removing the inhibitory proteins by chloroform precipitation. With this procedure it was possible accurately and repeatedly to determine E. coli equivalent endotoxin concentrations as low as 195 ng per liter of whole blood or 49 ng per liter of platelet-rich plasma.


Ascertainment in the sequential sampling of pedigrees. One aim in the analysis of pedigree data may be to infer the mode of inheritance of a characteristic. If only "interesting" pedigrees are analysed, the ascertainment bias may lead to some modes of inheritance being unintentionally preferred. Also, it is clearly most efficient in attempting to make such inferences, if a decision on whether to continue sampling a pedigree is made conditional on the types of individuals who have been observed; an a priori decision to examine 500 members of a pedigree may lead to much wasted effort, since the pedigree may prove to be largely uninformative. The present paper shows that provided all observed families are included in the analysis, even those which appeared "uninteresting" or "sporadic" and were not sampled further, and provided a decision to continue sampling is made conditional on types observed up to that point, the correct likelihood for the mode of inheritance may be easily computed. This opens the way for a more detailed study of the wider problem of optimal samplings rules on pedigrees.


Chronic lymphocytic leukaemia and its relationship to other lymphoproliferative disorders. Chronic lymphocytic leukaemia is a disorder with variable clinical presentation, but with constant and easily recognizable morphological features. The majority of cases are of B-cell lineage, the cells being characterized by IgM and IgD surface markers. In occasional cases monoclonal gammopathies with idiotypes identical to those of the SIg are produced. Some cases of CLL may be confused with Waldenström's macroglobulinaemia. The clinical and morphological features of certain other lymphoproliferative disorders have been summarized. Finally, a progression of B-cell differentiation along an immunoexpressive spectrum has been described and the relative position of CLL defined. A correlation of cell morphology and function is possible in most cases. The possibility that CLL may terminate in an acute blastic crisis or histiocytic lymphoma is raised. It is emphasized that LPD include a wide range of diseases, some being non-malignant, others of questionable malignancy, and still others being frankly malignant. Clinical, morphological and immunological data are required for diagnosis in some cases.


Cell kinetics in chronic lymphocytic leukaemia (CLL). The fractional production rate of CLL lymphocytes, certainly in the peripheral blood and possibly in the lymph nodes, is often lower than normal. On the other hand, the absolute production in CLL blood and in lymph nodes seems to be considerably increased in most cases. Arguments for an increased lymphocyte life span in CLL, although fragmentary and dispersed, exist. The blood CLL lymphocytes, as normal lymphocytes, exchange rapidly with an extravascular pool of lymphocytes. However, recirculation of lymphocytes--from blood to blood via the lymph node and the thoracic duct--does not proceed normally in CLL. Whether this is related to the B nature of the CLL lymphocyte, to the leukaemic nature of the CLL lymphocyte or to mechanical factors--crowding of the extravascular pool--is still debatable.


Radiotherapy as primary treatment for chronic lymphocytic leukaemia. Conventional chemotherapy and local radiotherapy have failed to reverse the progressive haematological and immunological deterioration that characterizes the natural history of chronic lymphocytic leukaemia. At the National Cancer Institute, we have demonstrated that treatment with fractionated total-body irradiation has induced remissions sufficiently complete to modify the manifestations of disease which affect survival adversely. One-third of patients with active CLL have experienced responses distinguished by complete resolution of symptoms and palpable disease, correction of anaemia, restoration of the leucocyte count and differential to normal, clearing of the lymphocytic bone-marrow infiltration, and recovery from immunological incompetence. A distinct correlation has been observed between the response to therapy and the subsequent clinical course. The quality of life has been improved and the duration of survival prolonged in the group of patients who obtained the most favourable response (Type 1) to treatment. This establishes a rational for future attempts at reducing still further the tumour-cell burden. This view is in contrast to the generally accepted view that treatment has little if any influence upon the course of the disease or its prognosis.


The cytogenetics of chronic granulocytic leukaemia. The chromosome abnormalities associated with the classical type of chronic granulocytic leukaemia (CGL) involve a deletion of chromosome number 22 (Ph1) and translocation of the deleted material to another autosome, usually a number 9, t(9;22) (q34;q11). There is no clinically detectable difference between patients showing usual or unusual sites of translocation of 22q. In the chronic phase the typical translocation without additional abnormalities accounts for about two-thirds of the cases. Additional abnormalities include -Y and +8; difference of prognosis in association with aneuploidy has not yet been demonstrated. The presence of Ph1-negative cells in the chronic phase may be related to the time of ascertainment. The isochromosome for the long arm of number 17 is pathognomonic of impending metamorphosis. Additional chromosomal abnormalities are found in the majority of cases in the acute phase. Recent advances in immunological techniques for distinguishing different cytological types of blast cells, in patients who present with acute leukaemia with the Ph1 chromosome, have provided insight into the relationship of the Ph1 chromosome to the pathogenesis of the disease.


Human lymphocyte differentiation markers and their application to immune deficiency and lymphoproliferative diseases. The study of human lymphoid cell differentiation markers has recently yielded many insights into the pathogenesis of certain diseases which primarily affect the immune system. The application of these markers has, however, generated a host of new questions. Both technical difficulties and uncertainties concerning the significance of particular markers limit their routine application at the present time. Indeed, many studies in the literature, both in the diseases reviewed above, and perhaps to a greater degree in other conditions ('autoimmune' diseases, sarcoidosis, hepatitis and various infections) require re-evaluation in the light of recently increased sophistication about cell surfaces. Because of these qualificatins, the application of multiple characterizations of lymphoid cells using independent methodologies is necessary before any firm conclusions can be drawn in a particular clinical or experimental situation.


Radiographical and pathological assessment of the activity of Paget's disease of bone. Because specific medication to treat Paget's disease of bone is becoming available, it is important to assess the activity of Paget's disease in order to select appropriate treatment programs for individual patients. Clinical radiographs and pathological specimens demonstrate that specific morphological changes occur in an affected bone over the course of time. In the initial phase osteoclastic resorption of previously existing bone is prominent. Replacement of the normal bone with a type of rapidly remodeled bone is characteristic of the active phase of the disease. Because the new bone may be relatively osteoporotic, collapse of the structure of vertebral bodies is possible. Muscle pull and weight-bearing forces on remodeling cortical bone produces a marked reduction in the numbers of osteoclasts and osteoblasts with the bone marrow reverting to fat cells. The defferentiation between this inactive type of tissue and tissue with active disease is so difficult in routine roentgenograms that reliable evaluation of patients with Paget's disease requires more sensitive methods.


Do diuretics have antihypertensive properties independent of natriuresis? To ascertain whether diuretics have an antihypertensive effect independent of natriuresis, 12 stable patients on maintenance hemodialysis underwent a crossover evaluation with hydrochlorothiazide, 50 mg daily, metolazone, 5 mg daily, or placebo in 4-wk treatment periods for 6 mo. Compliance was assured by pill counts and serum drug concentrations. All patients had daily urine less than 100 ml. Pre- and postdialysis blood pressure, body weight, plasma volume, and plasma renin activity were monitored. Over the 6-mo study period there were no statistically significant changes in any parameter related to diuretic therapy. It is concluded that a functioning kidney with the ability to respond to diuretics with a natriuresis is necessary for the antihypertensive action of diuretics. Direct vascular effects of diuretics to lower peripheral resistance could not be demonstrated in this unique patient population.


Naturally occurring toxic substances in foods. Numerous chemical toxins, including normal components of natural foods, e.g., mycotoxins, and toxic chemicals as contaminants such as pesticides, fertilizers, food additives, and preservatives, which are potentially toxic to humans, are discussed. Potential toxicity, the hazard to man represented by most of these chemicals, may be low because the concentration in food may be low. The gap in our knowledge of long-term effects makes rational decisions as to allowable levels of these substances a major problem. On the other hand, nitrosamines and aflatoxins are toxins for which there exists a voluminous literature documentaing extreme biologic activity in experimental animals and indirect evidence for activity in man. Epidemiologic evidence has linked them to human cancers, and because of increasing evidence of long-term human exposure to these toxins either as inadvertent contaminants during food preparation or as the metabolites of mycotic infestation this possible hazard demands intensive investigation. An exhaustive review of data from epidemiologic surveys in various parts of the world, as well as from long-term laboratory studies, represents an impressive start in this direction.


Regulation of cytochrome P-450-dependent microsomal drug-metabolizing enzymes by nickel, cobalt, and iron. The effects of metals as modifiers of the activity of microsomal drug-metabolizing enzymes were studied with the use of nickel, cobalt, and iron. These metals were found to impair cellular heme-dependent metabolism by affecting both the heme biosynthetic and heme degradative pathways, inhibiting the former and inducing the latter. As powerful cellular toxins, metals depress respiratory activity and indirectly reduce drug-detoxifying ability of cells. Metals also perturb cellular glutathione content and thus may alter the activity of glutathione-dependent enzymes. The toxicity of metals is cumulative depending on concentration and degree of cellular exposure to one or to several closely related metals. On the other hand, these metal effects on cellular heme metabolism could also have selective therapeutic application in circumstances in which it may be desirable to suppress heme synthesis in order to decrease drug biotransformation, i.e., when a certain drug metabolite is more toxic than the parent compound.


The treatment of burned children.

The treatment of burned children. Burn shock in infants and children is satisfactorily treated by the initial intravenous administration of balanced hypertonic sodium solutions; monitoring of plasma sodium and/or osmolarity permits necessary adjustment of the sodium concentration of administered fluids. This approach has been safe. Its principal advantage is in minimizing acute gains in body weight, which may be alarming otherwise, especially in children. Clinical and bacteriological data are presented indicating that cerium nitrate-silver sulfadiazine cream is a highly efficient topical antiseptic agent for both major and minor burn wounds and that it has low toxicity. Cerium nitrate-silver sulfadiazine cream can be readily employed in any clinical setting.


Practical bacteriologic monitoring of the burn victim. A comprehensive picture of the burn wound microflora is now possible as a result of recent technologic advances. The microflora of the burn wound can be characterized with respect to its number, type, location, and antibiotic sensitivity. These parameters can be measured in sufficient time to influence the decision of the burn surgeon. The microflora of the surface of the burn wound and the burn wound itself are examined separately by different sampling techniques. For the surface microflora, the gauze capillary techniques employed, while incisional biopsies are used to monitor the organisms in the burn wound. After sampling, suspensions of the specimens are created which in turn are subjected to direct microscopic measurement, quantitative culture procedures, and immediate antibiotic sensitivity testing. Histologic examination of the burn wound is performed concomitantly with this bacteriologic examination to determine the depth of bacterial invasion as well as to detect the presence of either mycotic or herpetic infections.


Craniofacial surgery in children: concepts and questions. Craniofacial surgery is an exciting new subspecialty of medicine. It is strictly a team project that will function well only in a tertiary medical center. Particular coordination is needed among the plastic surgeon, neurosurgeon, anesthesiologist, and pediatrician. This article considers many of the potential advantages and some of the disadvantages of performing craniofacial surgery on infants. It is difficult or impossible, based on current knowledge, to predict the ultimate limits of such new techniques. The history of surgical evolution, however, continues to demonstrate that what "at first observation" was thought to be impossible or undesirable often evolves, with more understanding, to be the desired course of action. It was entirely appropriate that the initial craniofacial surgical efforts be generally confined to adult-type patients, but the currently available technical refinements have developed such procedures to the point where they now have a definite place in infant surgery as well. Continued clinical investigative research will provide further information regarding the eventual benefits and perhaps will lead to surgical techniques in neonates that will actually prevent the development of certain predictable deformities.


Preliminary report of the effects of propranolol HCl on the discomfiture caused by niacin. Subjective discomfort caused by nausea and hot, pruritic skin has been described in patients after ingestion of therapeutic dosages of niacin is shown by this study to be alleviated by propranolol HC1. A dosage of 2 mg, I.V., given incrementally, in a clinical trial of six patients is described. The peripheral vasodilator effects of niacin were attenuated in some subjects but not in others. However, all subjects reported relief of unpleasant symptoms. Serial vital signs were taken and no significant changes were found. It is postulated that propranolol HC1 exerts a calmative effect at the CNS level. In a series that utilized doses of 40 and 80 mg of propranolol HC1 taken orally 30 min prior to the ingestion of 500 or 1000 mg of niacin, a progressive increase in the onset of the niacin flush was observed. It is proposed that as the available plasma level of propranolol HC1 falls, the ratio of niacin to propranolol HC1 increases, exceeding the threshold at which the flush occurs. Both these studies suggest that further work is indicated to establish the possible therapeutic efficacy of propranolol HC1.


Analysis of caries clinical trial data in the presence of study group imbalance. Imbalance of any important factor in caries clinical trials can bias group means, and make decisions based on such means of questionable value. Six hypothetical trials are presented which have varying degrees of imbalance in baseline DMFS. The crude group means for these trials vary radically, from one extreme in which the treated group has significantly less decay than the control group, to the opposite extreme in which the control group has significantly less decay than the treated group. Two methods for adjustment to correct for the imbalances, the analyses of covariance and blocking analysis, are discussed and applied to each trial. For these data sets the blocking analysis appears superior to the analysis of covariance in terms of maintaining the essential character of the data. An appendix explaining in detail how the blocking analysis is performed can be obtained on request to the author.


Estimation of gastro-intestinal blood loss in volunteers treated with non-steroidal anti-inflammatory agents. In a double-blind study of 24 healthy volunteers treated with daily doses of 150 mg flurbiprofen, 600 mg phenylbutazone, 2.1 g aspirin, or placebo for 7 days, assessments were made of faecal blood loss before, during and after treatment. Measurementl body showed that aspirin produced the greatest degree of blood loss. Although both flurbiprofen and phenylbutazone produced greater blood loss than did placebo, the difference from pre-treatment values was not significant, and the levels returned almost to normal in the post-treatment period.


Endoscopic study of gastro-intestinal injury with non-steroidal anti-inflammatory drugs. A double-blind placebo controlled study was carried out in 24 healthy male volunteers to assess the nature and extent of any gastro-intestinal damage caused by the short-term administration of flurbiprofen (300 mg/day), aspirin (2.1 g/day), and phenylbutazone (600 mg/day). Fibre-optic endoscopic examinations were made before and after 7-days' treatment by 3 observers. The results showed that aspirin produced severe and extensive damage. The changes seen with phenylbutazone were less severe than with aspirin but more marked than with flurbiprofen. Flurbiprofen was found to have produced minor changes which tended to be localized. The histopathological findings correlated well with the endoscopic observations.


Steroid-sparing action of flurbiprofen: use of an additional parameter of joint scans with 99m technetium. A double-blind placebo controlled trial was carried out in 14 steroid-dependent patients with rheumatoid arthritis to assess the effectiveness and steroid-sparing action of flurbiprofen over a 4-week period. During the first week, the patients' steroid dosage was stabilized at the minimum necessary to control symptoms. They were then treated with either 100 mg flurbiprofen or placebo 3-times daily for 3 weeks. Steroid dosage was initially reduced to 50% of the stabilized dose and reduced further if practicable, depending on therapeutic response. Clinical assessments were made, at weekly intervals, of pain, swelling, tenderness, erythema, range of movement, grip strength, walking time, and duration of morning stiffness. Joint scanning of 99mTc uptake was also measured before and after treatment in 11 patients. The results showed that whereas 3 out of 6 patients on placebo has distinct inflammatory flare-up, this did not occur in any of the 8 patients on flurbiprofen. Moreover, 3 of the flurbiprofen group showed improvement and a further reduction in steriod dosage was possible in 3 patients. Improvements in joint scans correlated well with the clinical findings in 6 of 11 patients.


A comparative study of flurbiprofen and indomethacin in rheumatoid arthritis. A double-blind, crossover study was carried out in 30 patients with active, classical or definite rheumatoid arthritis to compare the effect of 200 mg flurbiprofen per day with that of 100 mg indomethacin per day. Patients received, at random, each drug for a period of 2 weeks separated by a weeks' wash-out period on placebo. Assessments were made before the start of the trial and at weekly intervals of pain, morning stiffness, grip strength, articular index, walking time, and finger joint size. Patients' preference for any particular treatment period was recorded at the end of the trial. Laboratory investigations were carried out before and during the trial. Both drugs shows statistically significant improvement over baseline assessments, although there was little difference between the two active treatment periods. More patients preferred the treatment period with flurbiprofen, and this was probably related to the fewer side-effects which were reported with this drug.


A comparative study of the long-term efficacy of flurbiprofen and indomethacin in the treatment of rheumatoid arthritis, with special reference to iron metabolism. Preliminary results are reported for the first 23 rheumatoid arthritis patients entered in a long-term, double-blind trial to compare the efficacy of flurbiprofen and indomethacin. It was planned that, unless withdrawn, patients from matched pairs received either flurbiprofen (150 mg to 300 mg daily) or indomethacin (75 mg to 150 mg daily) over a minimum period of 6 months, dosage being adjusted to suit exacerbations and remission of disease. In addition to clinical assessments of severity of pain, duration and severity of morning stiffness, joint size and joint score, routine laboratory measurements were carried out, including estimates of serum iron and total iron binding capacity, rheumatoid factor and immunoglobulin levels. This interim report gives the statistical analysis of results from the 17 patients completing from 2 to 4 months of treatment and shows that both drugs were equally effective in controlling disease activity. Withdrawals due to side-effects or exacerbations of disease were similar for both drugs.


Controlled clinical trial comparing flurbiprofen and phenylbutazone in patients with rheumatoid arthritis. Preliminary results in 12 patients with rheumatoid arthritis are presented from an on-going double-blind, between patient comparison of flurbiprofen and phenylbutazone. Patients received either 300 mg flurbiprofen daily or 400 mg phenylbutazone daily over a 2-week treatment period. Two patients treated with phenylbutazone developed a rash, and treatment was discontinued in 1 of them after Day 2.


Flurbiprofen and indomethacin in the treatment of rheumatoid arthritis: a double-blind crossover study. A double-blind crossover study was carried out in 30 patients with rheumatoid arthritis to compare the effectiveness of 300 mg flurbiprofen daily with that of 150 mg indomethacin daily. Each drug was given in random order for 2 weeks, each period being preceded by a wash-out period of 2 weeks during which patients received paracetamol. With the exception of joint size and erythrocyte sedimentation rate, both drugs showed a statistically significant improvement when compared individually to baseline in all of the parameters assessed. There were no statistically significant differences between the two drugs when both treatments were compared. Three patients reported side-effects with flubiprofen and 3 with indomethacin, 1 of whom had to be withdrawn from the trial.


A double-blind comparative study of 150 mg flurbiprofen daily and 75 mg indomethacin daily in the treatment of osteoarthrosis of the hip joint. Thirty patients with osteoarthrosis of the hip were studied in a double-blind crossover comparison of 150 mg flurbiprofen daily and 75 mg indomethacin daily, each drug being given for 2 weeks separated by a wash-out period of 1 week on placebo. Statistical analysis of the results from 26 patients with complete records showed that both drugs produced statistically significant improvements over baseline after 1 and 2 weeks in assessments of severity of pain, night pain, duration of morning stiffness, and intermalleolar straddle. No statistical differences, however, were found between the two drugs. There were no reports of side-effects with flurbiprofen, but 6 reports from 3 patients whilst receiving indomethacin.


Sarcoidosis in hypersensitivity pneumonitis. An abnormal chest x-ray film showing hilar adenopathy, diffuse interstitial pulmonary infiltrations, or both, combined with a tissue biopsy revealing noncaseating granuloma, are suggestive of sarcoidosis; however, non-caseating granuloma may also be found in other forms of pulmonary disease. Immunologic and environmental evaluation of three patients with the diagnosis of sarcoidosis made by the above criteria, revealed hypersensitivity pneumonitis in all. Since therapeutic considerations in these two diseases are different (avoidance being the mainstay in hypersensitivity pneumonitis), all methods to ensure a correct diagnosis should be employed.