Use of t-butyldimethylchlorosilane/imidazole reagent for identification of molecular species of phospholipids by gas-liquid chromatography mass spectrometry.

The t-butyldimethylsilyl derivatives of 1,2-diakyl, 1-alk-1'-enyl-2-acyl, 1-alkyl-2-acyl and 1,2-diacyl glycerols were analysed with a gas chromatograph mass spectrometer system. The characteristic fragment ions were as follows. The molecular weight determining ion was [M-57]+, which was formed by cleavage of the t-butyl radical from the molecular ion. The nature of the alk-1'-enyl residue could be determined by the presence of ions at [RCH-CH 56]+ and [RCH = CH + 130]+ (RCH = CH = alk-1'-enyl), and the alkyl residue by the ion at [R + 130]+(R = alkyl group). Ions giving information about the acyl group, [RCO]+, [RCO + 74]+ and [M-RCH = CHO, -RO or -RCOO]+ were also observed. The mass spectra of pairs of trimethylsilyl and t-butyldimethylsilyl derivatives showed differences in several respects. The t-butyldimethylsilyl derivatives gave more effective information for elucidating the structure of phosphoglycerides.


Controlled transcutaneous powering of a chronically implanted telemetry device.

Radiofrequency (RF) powered subcutaneous transmitter devices offer the unique possibility of very long-term measurements from sites within the body under a variety of normal living conditions without percutaneous connections and concomitant dangers such as local tissue infection. Disturbances in the energy transport across the cutaneous barrier may, however, give rise to output data signal fluctuations, which are perceived as transients or drift. A RF-powered implanted biotelemetry device is proposed where the energy transport is controlled by continually optimizing the emission frequency and the duration of energy transfer.


A portable smoking pattern recorder.

An instrument has been developed which can be used to record the smoking patterns of human smokers in almost any location. The smoker is required to smoke the cigarette through an orifice plate cigarette holder connected to the recorder. The smoking pattern data are recorded onto a standard audio cassette as pressure and flow signals together with timing impulses and speech. The instrument is battery powered and can be built into a small brief case. The four channels of data are decoded on a separate instrument, which uses the timing signals to synchronise a data logger, thus making the whole system independent of tape speed errors. The speech channel is used to identify the smoker, cigarette, location, etc. Comparisons have been made of the performance of the portable recorder and a laboratory smoking analyser and data logger. It was found that data decoded from the portable recorder are generally within 1% of the values recorded directly on the laboratory instrument.


Synchronization in biotelemetry systems with time division of channels.

In order to improve synchronization in biotelemetry systems, a relative pulse-width selector was designed. It employs a sawtooth generator, sample-and-hold and analogue comparator. The use of this selector creates a possibility of reducing the increase in the synchronizing pulse with respect to the channel pulses and eliminating tuning the transmitter's modulator and receiver's selector to each other. Two different selectors are described: a simple one for two different pulse widths and a more complicated one with a counter for any setting of pulse width in the system.


Destruction of noise in biotelemetry.

The difference in statistical characteristics between physiological signals and noise creates the possibility of designing a selective circuit to separate signals from noise. Analysis shows that by an extremely low signal-to-noise ratio before the pulse conditioner in a biotelemetry system, the mixture of normal and spurious pulses are present at the demodulator input. The system of noise destruction analyzes the sequential distances between two following pulses and blanks all spurious pulses using the criteria of high autocorrelation of physiological signals in short intervals. Evaluation of the circuit demonstrates a dramatic increase in accuracy in the presence of strong interference because the system of noise destruction performs a linear extrapolation of free-of-noise parts of pulse flow into destroyed spaces. The equations to calculate selective thresholds and output errors are delineated. The noise destructor is especially useful in long-term monitoring and automatic data analysis because it prevents a formation of sharp noisy spikes at the biotelemetry system's output.


Anxiety engendered by amniocentesis.

Anxiety was measured and compared in three groups of 12 pregnant couples undergoing amniocentesis for prenatal diagnosis of chromosomal disorders. Significant elevations in anxiety were found in all groups prior to counseling on the day of the procedure and prior to receiving test results. Women who had previously given birth to a child with a chromosomal disorder displayed higher anxiety levels prior to amniocentesis than women whose indication for the procedure was age. Fathers in the previous trisomy group had higher anxiety levels prior to the receipt of test results as well as before the amniocentesis when compared to fathers in the maternal-age group. An experimental group of couples in which the women were over 35, received weekly calls from the genetic counselor. This intervention did not reduce median anxiety scores significantly for either men or women but did lower anxiety among the minority of extremely anxious mothers. Parental anxiety levels were interpreted based on interview data. Conditions which promote anxiety were contrasted to those which diminish it. Suggestions were made for amniocentesis counseling earlier in pregnancy and for identifying parents who would benefit by extra attention from counselors.


Problems in counseling the epileptic mother.

Epileptics, medical colleagues, and the public must be educated regarding the teratogenicity of anticonvulsants to the developing fetus. To prevent the serious problems of the fetal hydantoin-barbiturate syndrome, epileptic mothers must be given counseling. There are numerous problems encountered in counseling any individual with genetic disorders and dull intellect. More than the usual time and effort and cooperation of many agencies is needed to achieve success in counseling.


Genetic counseling and parental self-concept change.

Twelve parents of children with genetic diseases (Klinefelter syndrome, trisomy 21, lactase deficiency, phenylketonemia, Noonan syndrome, ichthyosis, Prader-Willi syndrome, and trisomy 13) were tested with the Tennessee Self-Concept Scale prior to and immediately after genetic counseling. Total Positive Score, indicative of self-esteem level, changed significantly. The score increased due to positive changes in the subjects' family, social, moral, physical and psychologic identity, and affect and behavior. This change is interpreted as an improvement in self-concept. Two other changes were only marginally insignificant, however. The Total Conflict decreased and that is a sign of improvement; but the NDS increased. Of the two scores, the NDS is the more powerful indicator and an increase in it is a signal for caution. Self-concept improvement with genetic counseling of parents whose progeny had one of the described diseases has, therefore, been documented. Carefully designed investigations of the future will verify factors which induce psychologic change and effect the management of disease.


Ultrastructural features of mast cells in human omental veins.

Mast cells are relatively common in human omental veins where they generally occur in the tunica adventitia and among the peripheral smooth muscle cells of the tunica media. The distance between mast cells and adjacent muscle cells is often as short as 1 micrometer. The tunica intima does not contain mast cells. With few exceptions the typical mast cells were oval in shape, had numerous slender projections and contained granules (0.3-0.7 micrometer) with characteristic stacks of lamellae and scrolls. A few elongated cells with processes containing granules filled with dense homogeneous matrix material were also detected and could represent so-called chromaffin mast cells. Noradrenergic axons and terminals identified by their large (85 nm) and small (50 nm) dense-cored vesicles are present in the vicinity of many mast cells which could allow various interactions between the two cell types and their released amines and ATP. Electrical field stimulation which affects the nerve terminals does not change the ultrastrcutre of the mast cells unless the alpha-blocking agent phentolamine (7.5 X 10-7 M) is present during the stimulation, when degranulation results.


[Round cells of human sperm].

Many round cells are found whose number may become conspicuous. These cells may originate as well from germinal as from somatic lines. Electron microscopy is the only way to distinguish the two kinds of origin. In some specimens germinal cells predominate (spermattids, plurinuclear cells), in others there are many phagocytic cells which may ingest a great number of spermatozoa and this phenomeon may stimulate an azoospermy by failure of spermatogenesis. The study of human sperm (or testicular biopsies) by electron microscopy is needed to obtain the necessary information in order to orient diagnosis, prognosis and therapy.


[Changes in the fetal membranes of the rat after amniocentesis - preliminary observations].

With the aid of scanning electron microscopy the normal pattern of both faces of amnion and visceral yolk sac were described. The inner face of the amnion turned towards the amniotic cavity is overlaid by large pavimentous cells bearing numerous microvilli. The opposite face, which delimits the exocoelome, consists of flattened fibroblasts separated by a fundamental connective substance. The two faces of the visceral yolk sac also show very different patterns. The exocoelomic face is covered by pavimentous cells ; these are smaller and bear less microvilli than amniotic cells. The yolk sac endoderm appears built up with prismatic or cubic cells, whose apical part is bulging and possesses a dense covering of microvilli. Amniocentesis effects are then reported. This intervention seems to provoke fetal membrane modifications only after 15 hours. These modifications essentially concern the visceral yolk sac whose exocoelomic cells are covered by more numerous microvilli which may show an intensification of a secretory process.


[Growth and morphologic characteristics of normal human endometrial cells in primary culture].

Monolayer cultures of endometrium were established from 59 normal women after hysterectomy. The technical procedure is described, allowing cells in monolayer to grow satisfactorily for more than 60 days, showing a doubling-time of about 4-5 days. During early passages, two cell populations are characterized by microscopic examination : confluent areas of epithelial polygonal cells and scattered fusiform fibroblastic cells. After the 8th passage, epithelial cells are no longer recognized : the monolayer is homogeneous and all cells are fibroblast-like. These cells are an interesting model system for steroid sex hormone studies.


[Mortality of carcinoma of uterine cervix in France : 1950-1976, trends and geography (author's transl)].

A study of changes in mortality due to carcinomas of cervix uteri in France between 1950 and 1976 was undertaken. Rates increased slightly over the whole period (0.44% per year). However, from 1950 to 1968 there was an increase (1.9% per year) and from 1969 to 1976 a decrease (1.17%). This decrease may be due partly to improvements in diagnosis, screening and cure. The geographical distribution has not shown any regional particularity. There is a high significant correlation with geographical distribution of breast cancer mortality, a hitherto unknown finding in France.


[Evaluation of screening for uterine cervix cancer: from theory to practice (author's transl)].

In many regions, screening for cervical cancer activities by means of cytology have developed "on faith", without fulfilling sufficient quality criteria (identification--smear taking--staining--reading--nomenclature of ciagnosis--communication with the practitioner). Progress made in cytological diagnosis and better knowledge epidemiological data make, at present, such a situation inacceptable from the point of view of public health expenses, as well as for the population of women concerned. Thorough evaluation of this problem shows that inadequate programmes could be more harmful than useful. It is then indispensable to evaluate the needs, then to create technical structures of good quality, before starting any mass screening campaign.


[Natural history of the cervical precancerous lesions (author's transl)].

The histogenesis of precancerous lesions and of carcinoma in situ has undergone deep changes over the past ten years. In particular, concepts of re-epidermisation by indirect metaplasia has made it possible to understand the progressive process which results what are generally described as dysplasias. These lesions were previously considered as being made up of two groups : regular dysplasia with slight or moderate dyskaryosis, with a good prognosis, and irregular dysplasia with severe dyskaryosis; but they are now felt to be non-obligatory stages in the same process which may stop for a time, regress or on the contrary accelerate and become an invasive carcinoma. There is no clearly defined limit between dysplasias and carcinoma in situ. These concepts are confirmed by cytology, histology and other methods (histophotometry, cytogenesis, biochemistry, etc). The aetiology of these lesions is involved with the hormonal environment and vaginal pH which would appear to play a role in the epidermoid differentiation of undifferentiated or reserve cells which are the basis of the constitution of preneoplastic lesions. The penetration of mutagens into these cells is explained by the hypothesis of amoeboid movements of undifferentiated cells which bring the nuclear heterochromatin into contact with the external surroundings where carcinogenic histones are found.


[Precancerous lesions of the cervix. Diagnosis and treatment (author's transl)].

In gynaecological practice, the problem of precancerous lesions of the cervix arises under three different circumstances : --ectropion, --dysplasia, --in a young girl when the mother has taken Stilbestrol. The literature is reviewed in these three cases : --ectropion is an anatomical state which does not absolutely require treatment. According to the majority of authors it would not appear that its destruction is useful in the prophylaxis of carcinoma of the cervix; --dysplasia, although it does not always progress to a carcinoma, would seem to be a potentially malignant state, the diagnosis of which must be made by the combination of cytology, colposcopy and biopsy. Treatment is based upon the topography of the lesion, its severity and the age of the patient : either conservative if the patient is young and wishes to have children, or surgical (conisation or hysterectomy) if she is older, does not want any more children or has an additional gynaecological problem. --in the presence of a lesion in a young girl whose mother has taken Stilboestrol, precise diagnosis must be made by biopsy with surveillance and treatment of lesions of adenosis, either by progesterone pessaries or by excision.


[The role of colposcopy in the diagnosis and treatment of dysplasias and intra-epithelial carcinomas of the uterine cervix (author's transl)].

Colposcopy plays an essential role in the diagnosis and treatment of dysplasias of the uterine cervix. It may be used to assess the lesions recognising dysplasia, observing the degree of severity and indicating regions from which biopsies should be taken. It accurately defines the limits of the lesions by indicating the site of the squamo-columnar junction, on the ectocervix or in the cervical canal. In association with Schiller's test, it defines the peripheral limits of the lesions on the cervix or vagina and leads to the discovery of purely vaginal lesions. On the basis of such an assessment, it is possible to discuss appropriate method for reaching a histological diagnosis, perform selective biopsies or obtain surgical specimen, and the best form of treatment. Only colposcopy offers the possibility of determining the indications for local treatment and observing patients after treatment. Colposcopy must be accompanied by precise technique in the histological examination of biopsies and operative specimens. Colposcopy is not a routine method of examination. In order to be effective and reliable, it must be selective and performed by a specialised colposcopist.


[Study with serial sectioning of 312 preclinical cancers of the uterine cervix. Indications for selective treatment (author's transl)].

The authors have studied by step serial sectioning 312 cervix the most obtained by cold knife conization. They have studied too, the frequency of inadequate resection (i.e. non in sano conization) and clinically occult invasion according to the age of patients. Conization is adequate for the treatment of 70 per cent of women less than 30 years of age. But after 50 it is sufficient in only 22 per cent of the patients. Conization must be performed in most cases of grade III to V cervical smear (according to Papanicolaou's classification). The cervical cone must be studied by serial sectioning (every 500 microns). According to the result of this study the treatment must be selected : conization for in situ carcinoma resected in sano, simple hysterectomy for in situ carcinoma not resected in situ and Wertheim type operation for invasive carcinoma.


[Carcinoma in situ of the uterine cervix. Experience of the Centre Oscar Labret of Lille (author's transl)].

Forty cases of carcinoma in situ of the cervix were seen in the "Center Oscar Labret" of Lille between 1953 and 1978. The best treatment appears to be only simple total hysterectomy. Twenty patients underwent such an operation. seven In the course attended of follow-up, among 36 patients who regularly the out-patient clinic, there was one case of persistent progression and one early vaginal recurrence of the carcinoma in situ.


[Permanent survey in the cancerology. Evaluation of the first three years of application of an automated system for recording and analysis of cancer data. Information Unit of the National Federation of French Cancer Control Centers].

A general oncological file system has been perfected and used since 1975 for the recording and analysis of data from twenty French centres. By virtue of the use of common basic language, the structures for the collection of information which have been developed (basic card containing clinical and therapeutic data as well as information concerning the course of the disease) represent a normalised medical record which has proved to be a useful tool in establishing regular statistical reviews (more than 265,000 records have been analysed in 3 years). This automatized system for the collection and exploitation of data offers a method which is suitable for studies aimed at improving knowledge of many aspects of malignant disease and the conditions of treatment. It makes possible the rapid collection of large numbers (more than 65,000 carcinomas in 2 years, including almost 40,000 not yet treated). Thorough analysis aids in revealing valuable facts, carrying out epidemiological studies and in perfecting therapeutic orientations.


Medical hazards at sea.

With the advances in the conservative management of surgical emergencies over the last 20 years medical hazards at sea are relatively few and do not differ significantly from those experienced ashore. A modern luxury linear is a safe place in which to fall ill provided that adequate medical services are available. Most British shipping companies maintain comprehensive medical services both ashore and afloat which are concerned with not only treatment but also preventive medicine. It is essential that passengers discharged from hospital or under treatment are provided with full medical documentation and details of current medication so that the ship's physician or an overseas doctor is aware of the diagnosis and treatment. Many companies can arrange special facilities for invalid passengers provided adequate notice is given in advance. It is advisable to contact the medical services of the company concerned if medical problems are anticipated during the course of a sea voyage.


Different effects of current strength on inhibitory responses of the mouse vas deferens to methionine- and leucine-enkephalin.

The inhibitory potency of methionine (Met)-enkephalin on the field-stimulated mouse vas deferens was greatly increased by a reduction in current strength whilst that of leucine (Leu)-enkephalin increased only slightly. All currents were submaximal and all muscle twitches were neuronally evoked. These results suggest that inhibitory effects of Met- and Leu-enkephalin in the mouse vas deferens are not commonly mediated and provide a rapid method for ascertaining heterogeneity of enkephalin extracts.


Inhibition of guinea-pig lymphocyte activation by histamine and histamine analogues.

1 The incorporation of [3H]-thymidine into guinea-pig lymphocytes stimulated by a plant lectin (concanavalin A), soluble antigen (tuberculin (P.P.D.)) and syngeneic hepatoma cells, was partially inhibited (50%) by histamine in vitro. 2 The effect of histamine on both mitogen and antigen dose-response curves suggests a non-competitive, probably physiological antagonism. 3 The inhibitory dose range of histamine lay between 10 nM and 30 microM with an ID50 of approximately 400 nM. 4 The potency order for histamine analogues for the inhibition of lymphocyte activation was histamine greater than or equal to 4-methylhistamine greater than 2-methylhistamine greater than 3-methylhistamine. This is in accord with the mediation of the response through an H2-receptor. 5 H2-receptor antagonists reversed the inhibitory effect of histamine in a dose-related manner, but both metiamide and burimamide, in high concentrations, augmented lymphocyte activation in their own right. This precluded the determination of affinity constants and made it impossible to state with certainty that the inhibition of lymphocyte activation by histamine was mediated by an H2-receptor.


Naloxone inhibits the anti-diarrhoeal activity of loperamide.

1 Subcutaneous prostaglandin E2 (2.5 mg/kg) produces profuse diarrhoea in fed rats. 2 Pretreatment of rats with subcutaneous loperamide (1.0 mg/kg) completely prevents prostaglandin-induced diarrhoea. If naloxone is administered prior to loperamide injections the activity of the antidiarrhoeal compound is completely destroyed. 3 These data provide strong evidence that the antidiarrhoeal activity of loperamide is mediated via the opiate receptor.


Involvement of SRS-A in the Schultz-Dale response of the guinea-pig small intestine.

1 The anaphylactic reaction of the guinea-pig ileum, the so called Schultz-Dale reaction, shows a biphasic response: a short rapid contraction followed by a partial relaxation and a slow contractile response. 2 Dose-response curves with ovalbumin as an antigen were obtained for the quick and slow contraction of this anaphylactic reaction. 3 Mepyramine (1 microgram/ml) blocked the rapid first contraction, but failed to abolish the slow one in about 50% of the animals studied. 4 The SRS-A antagonist, FPL 55712, significantly depressed the slow sustained contraction during the Schultz-Dale reaction. Disodiumcromoglycate was without effect on both phases when it was added 5 min before addition of the antigen. However, when added simultaneously with the antigen it produced a 30% suppression of the slow phase in the highest concentration used.


Contractures elicited by tetraethylammonium in avian muscle treated with methohexitone.

1 The chick biventer cervicis muscle immersed in methohexitone (8.8 x 10(-5) M) responded to tetraethylammonium with contractures which were dose-related. The ED50 for tetraethylammonium was 2.1 x 10(-3) M. 2 In the absence of methohexitone, tetraethylammonium produced contractures only at much higher concentrations: these contractures were accompanied by fasciculations and neuromuscular block of the twitch fibres. 3 The contractures produced by tetraethylammonium in the presence of methohexitone were not reduced by exposure to botulinum toxin which eliminated all response of the muscle to indirect stimulation. 4 Tubocurarine (1.2 x 10(-6) M) displaced the dose-response curve for tetraethylammonium-methohexitone-induced contractures to the right. The dose-ratio was 15.63 +/- 1.98. 5 Physostigmine (1.8 x 10(-6) M) potentiated the activity of tetraethylammonium-methohexitone 3.26 or 3.84 fold, depending on the method of calculation used. 6 Physostigmine potentiated contractures elicited by indirect repetitive stimulation 4.8 to 6.0 fold more than it potentiated contractures due to tetraethylammonium-methohexitone. 7 It is concluded that in the presence of methohexitone, tetraethylammonium produces contractures of the chick muscle by releasing acetylcholine but also by a direct agonist action on the cholinoceptor.


Functional antagonism as a means of determining dissociation constants and relative efficacies of sympathomimetic amines in guinea-pig isolated atria.

1 The positive inotropic and chronotropic responses to sympathomimetic amines were examined in guinea-pig isolated atria. 2 The order of potency measured from EC50 values was isoprenaline greater than orciprenaline greater than salbutamol greater than or equal to fenoterol greater than terbutaline. Terbutaline and salbutamol were partial agonists on rate and together with orciprenaline and fenoterol also on tension responses. 3 Functional antagonism by carbachol caused a rightwards shift of the dose-response curve and depression of the maximum response. The rate maxima for orciprenaline, fenoterol and terbutaline were above that of isoprenaline. All the tension maxima were below isoprenaline. 4 Dissociation constants (KA) and relative efficacies (er) were determined by analogy with irreversible antagonism. 5 The relative orders of affinity (KA) were isoprenaline greater than orciprenaline greater than fenoterol greater than salbutamol greater than terbutaline. Affinities were identical on rate and tension. 6 The relative efficacies were all greater than isoprenaline for rate responses. On tension they were the same or less than isoprenaline. 7 The implications of these results are discussed, in particular the fact that a partial agonist has a greater efficacy than a full agonist.


Investigation of the mechanism of propranolol-induced bronchoconstriction.

1 Dose-related increases in airways resistance (Raw) and decreases in dynamic lung compliance (Cdyn) were recorded in guinea-pigs and rats following intravenous injection of propranolol and of the cardioselective beta-adrenoceptor blocking drugs, atenolol and practolol. 2 The bronchoconstriction reached a peak in 2 to 4 min and subsided within 15 min. Repeated injections caused identical responses in the airways. 3 The isomer (+)-propranolol, which has only weak beta-adrenoceptor blocking activity, produced identical responses when given alone or when given after a dose of the racemate, sufficient to cause measurable beta-adrenoceptor blockade in the lungs. 4 After the initial bronchospasm had subsided, the beta-adrenoceptor blocking drugs and the isomer, (+)-propranolol, produced potentiation of the bronchoconstrictor effects of 5-hydroxytryptamine and histamine. 5 Both the bronchospasm and the potentiation occurred in adrenal demedullated rats. 6 The results indicate that the bronchoconstrictor effects of these drugs are unrelated to beta-adrenoceptor blockade in the airway smooth muscle.


Perceptions of and reactions to stressful situations: the utility of a general anxiety trait.

In a number of studies Magnusson & Ekehammer (1975 a) have hypothesized three or four situationally specific anxiety factors. This paper replicates their work but reveals the presence of a general anxiety trait (independent of situational influences) which accounts for five times as much variance as situational factors. The influence of the situation on anxiety is considerably less than Magnusson & Ekehammer have supposed, and is minimal compared with the utility of a general anxiety trait.


The buddy system: a method for generalized reduction of inappropriate interpersonal behaviour of retarded-psychiatric patients.

Previous research has suggested a strategy for training social skills in chronic retarded-psychotic patients, but has not demonstrated extensive generalization or maintenance of gains. This study varied the standard training procedure (e.g. Bellack et al., 1976) in an attempt to improve generalization and maintenance. First, training involved instructions, modelling, role-playing, and feedback with daily problem situations rather than preselected, pre-written scenes. Second, each of the two patients treated served as a partner for the other; each patient monitored the other's behaviour and provided reinforcement, information and feedback to the 'buddy' (directly in the living environment). The procedure was effective in teaching appropriate social behaviours on the ward as well as in therapy sessions. Post-checks, taken 6 weeks after the conclusion of the treatment, indicated that improvements were maintained.


A survey of badminton injuries.

A Badminton Injury Questionnaire (BIQ) was developed to survey the type and frequency of injuries that are likely to occur from playing competitive badminton. Two hundred and thirty-one players, ranging from club players to international champions, completed the survey which indicated an injury incidence rate of .09 and .14 injuries per person per year for male and female badminton players respectively. Badminton participation resulted in relatively few injuries, most of which were cramps, blisters, strains and sprains of the lower extremities and a surprisingly low incidence of tennis elbow.


Effect of water-training in the maintenance of cardiorespiratory endurance of athletes.

The effectiveness of water-training in maintaining cardiorespiratory endurance was investigated in 16 cross country athletes, 18--24 years. Following a competitive season, subjects were stress-tested (T1) and divided into three equated groups based on VO2 max. Group I (n=5) continued training as it had during the competition season. Group II (n=5) underwent an experimental period of water-training, and Group III (n=6) let their training lapse. Subjects in the water-training group exercised in deep water for 40 minutes, 6 days/week for 3 weeks, supported by a flotation device which permitted them to engage in a running type activity, resembling their natural running form. All subjects were retested after 3 weeks (T2). A non-significant F ratio from an analysis of variance at T1 confirmed the equality of the three groups in terms of VO2 max. Analysis of covariance at T2 using T1 VO2 max values as covariates revealed a significant (p less than .05) F ratio reflecting a significant (p less than .05) difference between the regular training group and the group which let its training lapse. The water-training group did not differ significantly from the regular training group indicating that the water-training programme prevented a significant decline in VO2 max.


Blood lactate concentrations during incremental work before and after maximum exercise.

Five male subjects performed three successive incremental work tests on an electronically braked cycle ergometer. The first and second tests were separated by thirty minutes of rest, the second and third by three minutes of maximum work. During the third test, venous blood lactate concentrations were still decreasing at work rates where they were increasing during the first two tests. The work rate at which rapid increases in lactate concentrations occurred during the final test coincided with the work rate where rapid increases occurred in the two initial tests. It was concluded that this point represented a threshold where a balance existed between removal and release of lactate from and into the plasma compartment, and did not coincide with the anaerobic threshold. It is postulated that steady state work at levels above this threshold would result in a continuous increase in venous lactate concentration.


Performance of a constant torque pedal device.

A constant-torque oscillatory pedal-crank device using vertical movement of the feet is described and its performance compared to a conventional rotational cycle. Using a generator to measure the power output the constant-torque device produced 33% less power and thus has no practical value as an alternative to the conventional pedal-crank system.


Some physical efficiency tests on Bengalese football goalkeepers.

Simple anthropometric measurements and physical efficiency tests were conducted on 21 Football Goalkeepers from West Bengal, India. The age of the subjects varied between 18--24 years (av. 21.1). The Vital Capacity (total ml/cm of height, L/m2 of surface area) and the Peak Expiratory Flow Rate (total, L/cm of height, L/kg of body weight, L/m2 of surface area, L/age) were noted to be higher in the subjects of the present study than those reported for average healthy Indian population, but lower than values from top Indian athletes. The values of grip strength observed in this study could not be compared because of unavailability of Indian norms. The higher values of physical efficiency tests observed in these subjects in comparison to those of average Indian populations were probably due to training effects.


Combined force injury of the elbow joint--the mechanism clarified.

An unusual elbow injury occurring as a result of a poorly executed breakfall in judo is recorded. The treatment, possible mechanism and outcome are described. The poor prognosis of severe lesions is emphasised with reference to current literature.


Measuring radiographic bone density and irregularity in normal hands.

This paper describes a method of measuring the radiographic density of the proximal phalanges and metacarpals using a television image analyser. The site for measurement is highly definable and covers the majority of the middle 2/4ths of these bones. Measurements yield two figures; one for mean bone density and one for the density distribution factor (irregularity). Thirty pairs of normal female hands were radiographed and measured. Variations of density and irregularity bone by bone, with age and with dominance are described.


Desmoid tumour: an angiographic study of five cases.

Compared with the frequent reports on the angiographic features of fibrosarcomas only a few similar studies concerning desmoid tumours have been published. Five patients with desmoid tumours and investigated by angiography are reported. The findings were normal in two instances. The forearm tumours of two patients were supplied by unusually large branches of anterior interosseous arteries with normal courses within the tumour. Increased vascularity was seen in these two tumours as well as in a fifth tumour of the buttock. These three tumours behaved more aggressively than the two with entirely normal angiographic appearances. On the basis of the literature and the findings in these five cases there might well exist a positive correlation between the degree of agressiveness of a desmoid tumour and its angiographic features as already established in the case of fibrosarcomas.


Intravenous urography in neonates and infants. What dose of contrast should be used?

The dose of contrast to be used for IV urography in neonates and infants is discussed. Toxic levels are only just above the currently accepted doses of 2-4.4 ml contrast medium per kg bodyweight. The dangers of expressing the dose of contrast medium as a volume of contrast related to the patient's age are discussed. A case is presented who had a severe reaction following an acceptable dose expressed as volume for age, but probably excessive when expressed as ml per kg bodyweight. It is concluded that for IV urography in neonates and infants the dose of contrast must be related to weight of patient and not its age; no dehydration should be used; and the injection should be slow, taking about three minutes.


The accuracy of ultrasound in the detection of cirrhosis of the liver.

The association of high amplitude echoes returned from the liver and cirrhosis is well recognized. There have been no reports in the literature as to the overall incidence of this finding in the clinical situation. We report our experience in a series of 67 patients with proven cirrhosis who had liver biopsy and an ultrasound examination within three months of one another. In 43 patients cirrhosis was suggested by recognition of a bright liver echo pattern. In 23 patients the liver echo pattern was normal, although additional relevant information was shown in half of this group. The detailed pathology has been analysed in an attempt to account for the false negative examinations, revealing a strong trend for cases of micronodular cirrhosis to give positive ultrasound examinations and macronodular cirrhosis negative examinations.


Ultrasonic diffraction analysis in the investigation of liver disease.

An ultrasonic analytical method has been developed which is capable of remote, in vivo differentiation between various types of soft tissue on the basis of differences in their gross histological structure. The method is analogous to that employed in X-ray crystallography and is referred to as ultrasonic diffraction analysis. A clinical trial of this method in the investigation of liver disease in 70 patients is reported, in which a total of 416 ultrasonic diffraction patterns associated with various liver conditions have been analysed and related to independent follow-up information. The existance of a malignant condition of the liver has been identified in 95% of the cases involving focal metastatic deposits and in all of the 11 cases studied where the livers had diffuse malignant involvement. Cirrhosis and secondary involvement of the liver due to Hodgkin's disease have also been shown to exhibit specific tissue signatures which enable them to be differentiated from other hepatic disorders.


The absorbed dose in the vicinity of an interface between two media irradiated by a 60Co source.

Monte Carlo techniques are used to generate the distribution of absorbed dose in the vicinity of an interface between two media. Computer-generated distributions for absorbers comprising the media carbon-copper, water-aluminium and aluminium-water are presented. The features of the distributions in regions of electron equilibrium and non-equilibrium, in particular finite discontinuities at the boundaries and subsequent build up or build down, are discussed both qualitatively and quantitatively. The difficulties inherent in interpreting ionization measurements in the neighbourhood of interfaces are outlined.


A simplified method of monitoring muco-ciliary transport.

A radioactive powder, formed by drying 99Tcm sulphide colloid, was used as a tracer to determine both lung clearance and tracheal mucosal transport of inhaled particles simultaneously in normal and bronchiectatic subjects. No change in either parameter with posture was noted in normal subjects, but patients with bronchiectasis exhibited rapid lung clearance when supine and slow clearance when erect, demonstrating the inefficient muco-ciliary transport in these patients. The method seems of value in monitoring the progress of bronchiectatic patients.


Tumour regression during radiation treatment as a guide to prognosis.

The response to radiation treatment was studied in 110 patients with head and neck cancer with a minimum follow-up of two years. If the tumour had disappeared by the mid-point of treatment (3000 rad), a significantly more favourable prognosis was found in early (T1-2N0) tumours. On the other hand, whether these tumours had disappeared or were persisting at the end of treatment, there was no difference in the recurrence during the observation time of two years. In advanced tumours there was no significant relationship between disappearance by the mid-point of treatment and recurrence up to two years. But when an advanced tumour had disappeared at the end of treatment, the prognosis was significantly more favourable. The unpredictability and often impossibility of judging the prognosis in individual cases encourages the authors to stress the importance of executing the original individual surgical plan irrespective of radiation response.


Oral contraceptives and fatal subarachnoid haemorrhage.

A case-control study was conducted of the deaths from subarachnoid haemorrhage (SAH) in women aged 15-44 in England and Wales in 1976. There was a small excess of oral contraceptive use by the women who died from SAH compared with their generally healthy practice-matched controls; this was not, however, statistically significant. Out of 134 women who died from SAH, 34 had a history of hypertension compared with only six of their controls. Renal disease and pre-eclamptic toxaemia were more commonly associated with hypertension in the dead women than in controls. No change in the annual mortality from SAH has been observed in the past 20 years such as might have been expected if the risks were high. Although current or past use of oral contraceptives may have increased the blood pressure and risk of SAH in a few women, the most important factor in determining this risk was hypertension. SAH should thus probably not be regarded as serious cause for concern in healthy non-hypertensive women using oral contraceptives.


Improved combination chemotherapy in advanced gastric cancer.

Thirty-five patients with advanced-stage metastatic or unresectable gastric adenocarcinoma were given combination chemotherapy consisting of fluorouracil, doxorubicin, and 1,3-bis (2-chlorbethyl)-1-nitrosourea. Two patients achieved complete remission and 16 partial remission to give an overall response rate of 52%. Six further patients (17%) had stable disease, while in 11 (31%) the disease showed clear-cut progression despite treatment. The only pretreatment factors that suggested poor prognosis were poor initial patient performance and the stomach as the predominant site of disease. Patients responding to treatment had a significantly longer time to relapse (median 48 weeks) than patients with stable disease (median 16 weeks) and a significantly improved survival time (medians, 52 weeks with 30% of patients' living at 88 weeks and 32 weeks with all dead at 64 weeks respectively). Comparing these results with those in other reports indicated that the three-drug combination chemotherapy consisting of fluorouracil, doxorubicin, and either a nitrosourea or mitomycin was superior to single and two-drug regimens and currently represents the optimum treatment for advanced-stage gastric cancer. Gastric adenocarcinoma should now be considered to be a gastrointestinal malignancy that is relatively susceptible to chemotherapy, and studies of these improved chemotherapeutic regimens as post-surgical adjuvants may lead to further improvements in prognosis.


Resetting of osmoreceptor response as cause of hyponatraemia in acute idiopathic polyneuritis.

In a patient with hyponatraemia associated with acute idiopathic polyneuritis plasma concentrations of antidiuretic hormone increased when hypertonic saline was infused intravenously, and urine osmolality rose concomitantly. A water load was excreted normally, while the plasma remained extremely hypo-osmolal. It is concluded that osmoregulation was functioning normally but was set abnormally low, possibly owing to a disturbance of the peripheral volume receptors.


Prevalence of rectal and pharyngeal infection in women with gonorrhoea in Sheffield.

The prevalence of gonococcal infection of the rectum and pharynx in 239 consecutive women with gonorrhoea presenting as named contacts was 47% and 10% respectively. In 2% of all patients the rectum and pharynx were each the sole sites of infection. Treatment failure occurred in three patients given a single dose of aqueous procaine penicillin 2.4 megaunits intramuscularly, two of whom had rectal infections; no treatment failures occurred in patients with pharyngeal infections. The incidence of rectal gonorrhoea significantly increased with the duration of infection (P less than 0.001). This suggests that autoinoculation from infected vaginal material is of major importance in the transmission of gonococcal infection to the rectum.


Chlamydia trachomatis genital infections.

The prevalence and clinical features of Chlamydia trachomatis infection were studied in men with nongonococcal urethritis (NGU), in their female sexual partners, and in other women. Of 92 patients with NGU, 36 (39%) were chlamydia-positive; although all had symptoms of urethritis, fewer than half had evident discharge. Clinical features of chlamydia-positive and chlamydia-negative NGU were indistinguishable. Most female contacts of chlamydia-positive patients with NGU were infected with C. trachomatis; contacts of chlamydia-negative patients with NGU seldom harboured chlamydia. Inflammatory and erosive changes were equally common in the uterine cervix of chlamydia-positive and chlamydia-negative women, although almost half of infected cases had no clinical signs of infection and no specific symptoms. In such women the present unavailability of sensitive screening techniques is a major obstacle to the effective control of chlamydial infection.


Antichlamydial antibodies in pelvic inflammatory disease.

The role of Chlamydia trachomatis in pelvic inflammatory disease (PID) diagnosed without laparoscopy was assessed by measuring antichlamydial antibodies in the patient's serum and by comparing the results with those in patients with uncomplicated non-specific genital infection (NSGI) and gonorrhoea and in non-infected controls. A modified microimmunofluorescence test was used. Patients with severe PID had significantly more positive antichlamydial IgG and IgM results than did control subjects, patients with gonorrhoea, and patients with NSGI. Less severe PID was associated with significantly raised levels of antichlamydial IgG antibodies compared with NSGI and controls and with raised levels of IgM antibodies compared with controls. Two patients with PID had lower genital tract gonorrhoea, one of whom had raised antichlamydial antibody levels. These findings may indicate a mixed infection and therapy should be reviewed in such patients. A serological diagnosis of chlamydial infection is relatively easy and cheap and enables a rapid diagnosis of chlamydial infection to be made.


Chlamydia trachomatis infection of the Fallopian tubes. Histological findings in two patients.

In two patients with acute salpingitis, C. trachomatis was isolated from the cervix. In one of the patients, the organism was also recovered from the Fallopian tubes, and in the other, chlamydial inclusions were found in Giemsa-stained tubal epithelial cells. A significant change in micro-immunofluorescence antibodies to C. trachomatis occurred in both patients during the course of the disease. The Fallopian tubes of both patients were removed and studied by conventional histological techniques and, in the case of one of them, by transmission electron microscopy.


Rising incidence of chancroid in Rotterdam. Epidemiological, clinical, diagnostic, and therapeutic aspects.

The incidence of chancroid in Rotterdam has increased by more than five-fold during 1977-78. In a retrospective study of 53 patients with chancroid seen at this clinic during this period, the results of smears were positive in 82% and of cultures in 84% (of those for whom cultures had been performed). Symptoms were generally mild. Treatment with co-trimoxazole was highly effective clinically, as confirmed by in-vitro sensitivity studies.


Effect of injections of small doses of human fibroblast interferon into genital warts. A pilot study.

Eleven male patients with genital warts were given injections of fibroblast interferon (300 u) and placebo into the bases of two similar warts. The changes in size of the treated warts compared with that of the controls suggested that interferon did inhibit the growth of the warts. The dose given was probably insufficient for a dramatic effect. In one patient, however, a wart on the penile shaft was injected with interferon and did disappear within two weeks whereas an untreated meatal wart increased in size.


Perigenital cutaneous schistosomiasis.

Perigenital cutaneous schistosomiasis was diagnosed in a patient who had no previous genitourinary or gastrointestinal symptoms suggesting schistosomiasis; his only symptom was a pruritic papular rash in the perineum. Late cutaneous schistosomiasis due to deposition of ova in the dermis is rare but can affect the genital and periumbilical areas. This report highlights the difficulty in diagnosing cutaneous schistosomiasis and the need for biopsy of itchy cutaneous lesions in patients from localities where the infection is endemic.


Brain size and intelligence in man.

The relationship between brain size and intelligence was investigated in two ways. Cranial capacity was measured in people with known IQs. A very small correlation was found between cranial capacity and intelligence; but this was shown to be the result of the confounding effects of height. A large series of brains was also investigated, data being obtained on occupation from the case notes. When the effects of body height and weight were controlled for, it was possible to demonstrate a statistically significant, but very slight, relation between brain size and occupational group.


Involvement of the trigeminal motor system in brain stem self-stimulation and stimulation-induced behavior.

Anatomical and behavioral correlates of intracranial self-stimulation (ICSS) at sites in the pons suggest the involvement of the trigeminal motor system in brain stimulation reward. 90% of the electrodes terminating in or dorsal to the trigeminal motor nucleus supported ICSS. Stimulation through these ICSS electrodes was usually accompanied by a display of repetitive jaw movement in the period following brain stimulation. There appeared to be a close relation between post-stimulation jaw movement and ICSS. In the motor nucleus there was a positive linear relationship between current intensity and duration of jaw movement. Optimal current intensities for ICSS induced long periods of jaw movement. Extensive lesions of the dorsal pons which included the locus ceruleus had no effect on ICSS in the trigeminal motor system. Therefore it seems unlikely that ICSS in the trigeminal system is mediated by noradrenergic neurons located in the dorsal pontine area. These data suggest that a centripetal analysis of ICSS sites along pathways afferent to the trigeminal motor system may lead to a more complete description of the anatomical correlates of brain stimulation reward. The functional implications of a trigeminal reinforcement mechanism are discussed.


The nucleus mesencephalicus lateralis, pars dorsalis in neotropical passerines.

The volume of the nucleus mesencephalicus lateralis, pars dorsalis and the optic lobe were determined in 8 species of neotropical birds in the order Passeriformes: Pyrocephalus rubinus, Pitangus sulphuratus, Atticora fasciata, Molothrus bonariensis, Tangara nigrocincta, Ramphocelus dimidiatus, Euphonia xanthogaster and Spinus magellanicus. The ratio of the volume of the nucleus to the volume of the optic lobe was calculated for each species, and was found to be larger in all 8 species than in a series of nonpasserine species examined previously by Cobb. A possible relationship between the relative size of this nucleus and the auditory capabilities of birds is discussed.


Fever produced by intrahypothalamic pyrogen: effect of protein synthesis inhibition by anisomycin.

In the unrestrained cat, the inhibition of protein synthesis by anisomycin, given either subcutaneously (5.0--25.0 mg/kg) or directly into the anterior hypothalamic, preoptic area (1.0--25.0 micrograms) impaired the development of a bacterial fever. S. typhosa infused intravenously (1:10 dilution in 1 ml) or into AH/POA (1.0 microliter) evoked an intense fever which was either significantly delayed or prevented by anisomycin. Conversely, anisomycin failed to affect the typical hyperthermia evoked by 100 ng PGE2 or 1.0--7.0 micrograms 5-HT similarly infused into AH/POA. These data demonstrate that an intermediary humoral factor of unknown nature is required in the hyperthermic effector pathway underlying the febrile response.


The reactivity of the somesthetic S1 cortex during sleep and waking in the rat.

The reactivity of the somesthetic S1 cortex was studied in the rat, in the course of the seven principle stages of the sleep-waking cycle, in terms of the variation in amplitude of positive wave 4 of the evoked potential induced by stimulation of the thalamocortical radiations. The amplitude of positive wave 4 is minimal during waking with theta (attentive and/or active). It increases in the course of waking without theta, to reach its maximum during the stage of sleep with slow waves. The amplitude decreases with the deepening of slow sleep (spindles, intermediate stage) to a level near to waking without theta, during rapid sleep. No significant difference is observed during periods of eye movements bursts. The variability of the amplitude of intra-state responses is lowest in the phases of waking and paradoxical sleep. The recovery cycle of the S1 cortex responses is long (several hundreds of milliseconds). The rate of recovery is inversely proportional to the amplitude of the response to the conditioning stimulus. It is therefore higher during waking and rapid sleep than during the different stages of slow sleep. These results are integrated in the neurophysiological data of sleep in the rat.


Afferent connections of the hypothalamic retrochiasmatic area in the rat.

The afferent projections to the retrochiasmatic area (RCA) of the rat hypothalamus have been studied by means of retrograde axonal transport of horseradish peroxidase. Iontophoretic deposit of the marker was used in most animals, and consistent projections from the hypothalamic ventromedial nucleus, the lateral part of the substantia nigra and the parabigeminal nucleus (NPB) were observed. A comparison between NPB projections and projections from the neighboring tegmentum suggests that some neurons of the NPB project to both the RCA and the superior colliculus. Consequently, these NPB neurons might link visual information on its way toward the retrochiasmatic area which, in view of its strategic position, could play a role in neuroendocrine processes.


Effects of melatonin on spontaneous and evoked neuronal activity in the mesencephalic reticular formation.

The acute effects of melatonin on the spontaneous activity of single cells in the mesencephalic reticular formation were studied in 40 male rats unanesthetized and immobilized with Flaxedil. One hundred and ten neurons were explored. Only 64 modified their spontaneous activity after the intravenous administration of melatonin. This response consisted of an increase in neural firing (6 neurons), decrease (55 neurons) and biphasic response of decrease and increase (3 neurons). When the effect of melatonin on the evoked activity in the mesencephalic neurons by peripheral stimulation (sciatic and photic) was checked an increase of the number of neurons that showed inhibitory responses to photic stimulation was found. No changes in blood pressure and EEG were observed at the doses of melatonin used (200, 400 and 600 micrograms/100 g of body weight). However, with doses of 600 micrograms a tendency toward synchronization was seen in the EEG. The present observations indicate an inhibitory effect of melatonin on the spontaneous neuronal activity of the mesencephalic reticular formation. This effect may contribute to the changes in the sleep-wakefulness cycle and anticonvulsant action attributed to this hormone.


Quantification of synaptic vesicles in hippocampus of aging rats and initial studies of possible relations to neurophysiology.

Synaptic vesicle populations were quantified in Schaffer-commissural synapses which terminate on CA1 pyramidal cell apical dendrites, in aging and young-mature rats. Vesicles were found to be reduced with age, and this effect was most pronounced in the oldest animals (e.g., 28 months) within the aged group. Numerical density of synaptic vesicles in aged rat hippocampus was reduced whether expressed as vesicles per terminal, vesicles per mu 2 of terminal, or vesicles per mu2 of terminal corrected for shrinkage or swelling as assessed by mitochondrial cross-sectional diameters. Counted synaptic terminal areas were not significantly different in the aged animals, although a trend toward reduced terminal size with aging was seen. The latter observation apparently rules out increased terminal swelling in aged rat synapses as a basis for reduced vesicle density. In some rats, neurophysiological studies were concomitantly performed. A significant correlation was found between the amplitude of the monosynaptic population spike after 20 min of 4 Hz stimulation of the Schaffer-commissural fibers and synaptic vesicle populations in terminals of these stimulated pathways. However, because of a low n this result must be viewed as preliminary.


Rat brain melanin at different ages and after various treatments.

Melanin was measured by a spectrophotofluorometric method in the brains of albino rats from birth to 20 months of age. The concentration of brain melanin increased from Day 1 until adult levels were reached at 1 month. Between 1 and 20 months of age no significant differences were found in brain melanin. Daily injections of alpha-MSH, MIF-I, melatonin, or diluent did not consistently alter the concentration of brain melanin and a high (40%) protein diet did not appear to increase it. After concurrent injections of alpha-MSH and theophylline, an initial elevation of the level of melanin in the brain of newborn rats was found beginning at Day 8 but by age 1 month the values had returned to control levels. The results show that the largest changes in the concentrations of melanin in the brains of rats occur with age during the first month after birth.


Failure to detect radioimmunoassayable arginine vasotocin in mammalian pineals.

The presence of arginine vasopressin (AVP) and arginine vasotocin (AVT) in pineal and neural lobes of a variety of species was evaluated by radioimmunoassay using two antisera. One antiserum recognizes only AVP, while the other cross-reacts 100% with both AVP and AVT. Only traces of AVP were detected in toad and chicken pituitaries and chicken pineals, tissues found to contain abundant AVT. On the other hand, pineals from rats and rabbits, while containing measurable quantities of AVP, did not contain detectable levels (less than 6 pg) of AVT. These results fail to demonstrate the presence of AVT in rat and rabbit pineals and strongly question the role of AVT as a physiological pineal hormone in mammals.


The cardiovascular effects of ketamine used for induction of anaesthesia in patients with valvular heart disease.

The effects of induction of anaesthesia by ketamine 2 mg.kg-1 were studied in six patients with valvular heart disease before tracheal intubation and operation. Cardiac index was unaffected because a mean decrease in stroke index was compensated for a mean increase in heart rate. A significant increase was found in mean arterial pressure, pulmonary arterial mean pressure, pulmonary capillary wedge pressure and central venous pressure. Systemic vascular resistance increased, but not significantly, whereas pulmonary vascular resistance increased significantly by more than 150 per cent. Right ventricular minute work index increased in all patients, and the increase was as much as 400 per cent. Left ventricular minute work index increased in four of the six patients, but the magnitude of the increase was not so marked. It is therefore concluded that ketamine causes pronounced pulmonary vasoconstriction and an undesirable strain on the myocardium. Such effects could prove deleterious in patients with limited functional reserve of the right ventricle.


Cardiovascular haemodynamics after induction of anaesthesia with althesin in patients with valvular heart disease.

The haemodynamic effects of the induction of anaesthesia with Althesin 0.1 ml.kg-1 were studied in eight patients with valvular heart disease before tracheal intubation and surgery. A 20 per cent reduction in stroke index was compensated for by an increase in heart rate of similar magnitude. Cardiac index, mean arterial, pulmonary arterial, central venous and pulmonary capillary wedge pressures and systemic vascular resistance were unaffected. Pulmonary vascular resistance declined by nearly 30 per cent. It is therefore conclude that Althesin causes only minimal cardiovascular depression in patients with valvular heart disease.


Effect of chlorobutanol on Limulus ventral photoreceptor latency: a model of a two component latent period.

Chlorobutanol (1,1,1-trichlor-2-methyl-2-propanol) decreases the duration of the latent period of Limulus ventral eye receptor potentials. This effect is both concentration and intensity dependent. Between 0.05 and 1 mM chlorobutanol in sea water the extent of latency shortening effect of chlorobutanol linear function of the logarithm of the chlorobutanol concentration. The latency shortening effect of chlorobutanol diminishes with decreasing intensity of stimulation and virtually disappears at intensities just exceeding threshold. These results are explained by postulating that the latent period is composed of two processes only one of which is sensitive to chlorobutanol and, further, that the duration of the chlorobutanol-sensitive process is not appreciably affected by the stimulating intensity. This model of a two component latent period may be tested experimentally. In several experiments prolonged exposure of ventral photoreceptor cells to chlorobutanol coupled with a short exposure to calcium deficient sea water produced a collapse of the receptor potential followed by a slow recovery after returning to perfusion with normal sea water. During the recovery a slow, low amplitude positive wave exists which has been tentatively called a prepotential.


Effect of pancuronium on intraocular pressure changes induced by succinylcholine.

The study was undertaken to evaluate the influence of pretreatment with a small dose of pancuronium on intraocular pressure changes associated with administration of succinylcholine and tracheal intubation. Thirty patients divided into control and study groups were anaesthetized with sodium thiopentone (3-5 mg mg.kg-1) and intubation with the aid of succinylcholine (1 mg.kg-1). The control group received saline pretreatment while the study group received pancuronium 1 mg three minutes before succinylcholine. Anaesthesia was maintained with nitrous oxide and oxygen (70:30). A Schiotz tonometer was used to measure intraocular pressure before induction of anaesthesia, one minute after succinylcholine and immediately after intubation. Patients in the control group demonstrated significant elevation of intraocular pressure at one minute after succinylcholine and immediately after intubation, while the study group showed no significant change at the same observation periods. These findings indicate that pretreatment with pancuronium 1 mg three minutes before succinylcholine may be beneficial in patients with high intraocular pressure and penetrating injuries of the eye.


Quantitative demonstration of somatic synapse sprouting following dendritic deafferentation in neonatal rat interpeduncular nucleus.

Neonatal habenular lesions deafferent the dendrites of interpeduncular nucleus (IPN) neurons by preventing formation of S and crest synapses. The small number of synapses normally contacting IPN neuronal perikarya are of unknown, but non-habenular, origin. The number of synapses on IPN perikarya is significantly increased (p less than 0.001) when 10 control animals are compared to 7 animals with unilateral habenular lesions and 7 animals with bilateral lesions. The increases with bilateral lesions are approximately twice those resulting from unilateral lesions (p less than 0.01). This phenomenon involves sprouting of both the somatic synapses which contain spherical vesicles and those with flattened vesicle endings, and is greater when the latter are considered alone (p less than 0.001). Only the small group of somatic synapses with asymmetrical contacts failed to show a change. The increases suggest a postsynaptic control mechanism which acts in the direction of preserving synaptic input, but permits displacement of the site of input from dendrites to soma. Factors which may be important in determining this outcome are the production of the lesions prior to synaptogenesis, and the presumed shrinkage of the dendrites of the IPN neurons.


The effect of lidocaine on succinylcholine-induced rise in intraocular pressure.

The effect of lidocaine on the increase of intraocular pressure induced by succinylcholine was studied in patients 6 to 85 years of age. Three groups of patients were studied. One group of eight patients received lidocaine 1 mg.kg-1 before succinylcholine and a control group of ten patients did not have lidocaine. Anaesthesia was induced with thiopentone 5 mg.kg-1 and maintained with nitrous oxide 50 per cent with oxygen and halothane 1.0-1.5 per cent. The tracheae of all patients were intubated. Lidocaine in doses of 1.0 to 2.0 mg.kg-1 did not prevent transient rise in intraocular pressure following administration of succinylcholine and tracheal intubation.


Choline acetyltransferase activity in the cerebellum and in centers of lateral line system of teleosts.

Using choline acetyltransferase as a marker of cholinergic activity, different cerebellar areas and brainstem nuclei were assayed in the goldfish and the catfish. Enzyme activity resulted remarkedly higher in archicerebellum than in paleocerebellum. In addition three brainstem nuclei related to lateral line system, showed high or very high levels of choline acetyltransferase. The results suggest that cholinergic transmission would play an important role in central circuits of lateral line system, including the projection towards archicerebellar areas.


Removable, conforming device for cooling the cortical surface.

A technique for cooling the cerebral cortex is described. It makes use of a neoprene bladder through which cold fluids is circulated. The flexible bladder is contained within a cylinder permanently attached to the skull. The bladder itself can be quickly installed and removed and conforms to the cortical surface with minimal pressure.


Partial voltage clamping of Limulus ventral photoreceptor potentials: evidence of programmed conductance changes.

Light-initiated currents elicited by brief light stimuli from Limulus ventral photoreceptors bathed in normal sea water generally exhibit a smooth contour, although the unclamped receptor potential elicited by an identical light stimulus usually exhibits distinct C1 and C2 components. However, light-initiated currents obtained from cells exposed to chlorobutanol often exhibit two components. Data from such experiments indicate that peak C2 current is more strongly voltage dependent than peak C1 current, as in Limulus lateral eye retinular cells. The results of partial voltage clamp experiments with ventral photoreceptors in which the clamping episode terminated at different times during the receptor potential reveal relatively minor perturbations of the rebound receptor potential when compared with the unclamped control response. These findings suggest that the temporal pattern of the membrane conductance changes which underlie the receptor potential is determined prior to the occurrence of the receptor potential. It is likely that the program for these conductance changes is developed during the latent period of the receptor potential.


Does prior dantrolene affect the in vitro diagnosis of malignant hyperthermia susceptibility?

A therapeutic and prophylactic dose of dantrolene administered to malignant hyperthermia-susceptible pigs had no effect on the abnormal in vitro contracture response of subsequent muscle biopsies. The in vitro contracture response of MHS pig muscle to halothane and to caffeine was not altered by prior dantrolene treatment. It is concluded that prior dantrolene administration has no effect on the discrimination of porcine MSH by in vitro pharmacological testing.


Identification and distribution of alpha-melanotropin in discrete regions of the cat brain.

The distribution of alpha-melantropin-like material (alpha-MSH) was demonstrated in rat brain using a microdissection technique combined with radioimmunoassay. Highest concentrations of alpha-MSH were noted in the hypothalamus and preoptic area. Particularly high concentrations were observed in the arcuate nucleus, median eminence, suprachiasmatic nucleus, periventricular nucleus and the medial preoptic nucleus. The thalamic paraventricular nucleus also contained high alpha-MSH concentrations. Moderate to low concentrations were noted in other thalamic, septal, amygdaloid and midbrain nuclei. Low concentrations were observed in cortical and striatal regions.


Pancuronium for rapid induction technique for tracheal intubation.

Suxamethonium in a dose of 2 mg.kg-1 was compared to pancuronium in three different dosages (0.1 mg.kg-1, 0.15 mg.kg-1, 0.2 mg. kg-1) for a rapid induction (crash) technique for tracheal intubation. Pancuronium 0.1 mg.kg-1 was inferior to suxamethonium, but the larger doses of pancuronium were equally satisfactory. In those instances where suxamethonium is either contraindicated or undesirable, pancuronium in a dose of 0.15 mg.kg-1 is a suitable alternative for rapid induction for tracheal intubation.


A new aspect of the collision test principle: cell body distance from recording site.

A theoretical method is described for estimating the distance between a spike recording-site, possibly axonal, and the corresponding cell body of unknown location. The method requires that an orthodromic spike be recorded following an antidromic spike, with estimation of a collision interval analogous to that used for establishing antidromicity. To calculate the distance between recording-site and cell body, values are needed for the collision interval between antidromic and succeeding orthodromic spikes, the refractory period of the spike, and the antidromic conduction speed. Problems may arise in determining the last value. The method is illustrated with antidromic spikes recorded in the medial thalamus of the cat upon stimulating the caudate nucleus.


Preservation of auditory-evoked brainstem responses in anaesthetized children.

In a series of six anaesthetized children we have been unable to demonstrate any effect of anaesthetic concentrations of halothane or thiopentone on the brainstem auditory-evoked response. The results imply preservation of brain stem function during anaesthesia with these drugs and suggest future application of anaesthesia to the testing of hearing disabilities in children, as well as application of evoked response audiometry to neurological critical care.


Cardiac response of Nigerian hypertensives to anaesthesia and surgery.

This study was undertaken to determine the cardiac response of Nigerian hypertensives to anaesthesia and surgery, using systolic time intervals as an indication of ventricular function. Nine hypertensive and eight normotensive patients who were admitted for various operations had carotidogram, phonocardiogram and electrocardiogram recorded simultaneously before induction of anaesthesia, after induction and during operation. The pre-ejection phase, (PEP) and the left ventricular ejection time (LVET) were measured from the tracings and the ratio PEP/LVET was calculated. The results showed that for both normotensive patients and hypertensive patients there was a mean increase of the PEP/LVET ratio under anaesthesia and surgery, indicating deterioration of ventricular function. Hypertensive patients showed a much greater deviation from normal, approaching heart failure values. It is concluded that hypertensive patients seemed to be at greater risk during anaesthesia and surgery. The implication is that hypertensive patients should be adequately treated before operation.


Posterior laryngeal cleft - anaesthetic experiences.

Two cases of congenital posterior laryngeal cleft are reported which typify the anaesthetic techniques used for operation on this defect at The Hospital for Sick Children, Toronto. Although this anomaly of the airway is rare, it is potentially curable by surgery and should be included in the differential diagnosis of neonatal respiratory distress aggravated by feeding. The anaesthetic technique used for microlaryngeal surgery consisted of topical lidocaine, insufflation of oxygen and halothane with supplementary methoxyflurane and spontaneous ventilation. A nasotracheal tube is left in situ postoperatively until laryngeal oedema has subsided. The literature is reviewed and the relevant anaesthetic experience over a ten-year period at The Hospital for Sick Children, Toronto, is summarized.


[Accidental hypothermia: treatment of a case using peritoneal irrigation].

A case of accidental hypothermia is reported. This patient was rewarmed by using a peritoneal irrigation. Rewarming was rapid and without complication. The patient was discharged from the hospital free from any sequellae. Peritoneal irrigation constitutes a fast and effective technique of core body rewarming in cases of moderate or severe hypothermia. Another advantage of this method is that it can be accomplished without complicated equipment and that it can be used even in small community hospitals.


Safety modifications to mobile hypothermia units.

Major safety deficiencies of older mobile hypothermia units are described. Problems include absence of high or low temperature output limitation or of visual warning of abnormal operating temperatures. Modifications described provide two high temperature thermostats and one low temperature thermostat, which shut the unit down if the temperature limits are exceeded. Visual and auditory alarms were also added. Operators of mobile thermal units should be aware of the major safety deficiencies of some older models, and should insist on either modification, where appropriate, or replacement.


Laryngoscope blade with suction unit.

A laryngoscope blade incorporating a suction tube is described. Blood or secretions are automatically aspirated from the pharynx when the blade is inserted.


Analysis of dose-response patterns in mutation research.

Mutation induction data in unicellular systems can be described mathematically within the framework of single-event Poisson statistics. This formal description can be linked to various mechanistic models for mutation and killing. Such mathematical links between formalism and mechanism enable one to make use of the quantitative details of dose-response relations in drawing general inferences regarding the macromolecular processes involved in mutation and killing. Mutation yields, and in particular the position and magnitude of maximum yields, should be measured as carefully as possible as a means of verifying the apparent pattern of mutation induction kinetics suggested by double-logarithmic plots of mutation frequencies. For purely linear processes of mutation induction and exponential survival the maximum mutant yield is known to occur at the LD37 dose; however for non-linear kinetic patterns, the position and magnitude of the maximum yield shifts away from the LD37 in mathematically predictable ways. For any given pattern of killing and mutation, the ratio of the maximum mutant yields plotted over lethal hit units for two mutagens is a convenient measure of their relative mutagenic efficiencies.


Soil populations of Rhizoctonia solani from areas of health and diseased beets within four sugarbeet fields differing in soil texture.

Both debris isolation and beet seed colonization methods were used to ascertain Rhizoctonia solani populations in areas of healthy (AH) and rhizoctonia crown rot diseased (DA) sugarbeets within four fields differing in soil texture over a 1-year period (August 1976 to July 1977). Inoculum densities were initially (August-October) higher in DA than in AH, but declined over the winter to levels similar to AH by June. As ascertained by the debris isolation method, AH populations remained low (mostly less than 30 colonies/50 g soil) throughout the year. High (90-422 colonies/50 g soil) DA inoculum densities were apparently sustained by active parasitism. Seasonal R. solani populations were postulated to consist of groupings of propagules differing in capacities for survival. Inoculum densities in AH and DA were similar in June indicating that factors other than inoculum density per se may initiate DA within beet fields. Soil textural differences did not adversely affect R. solani populations. Assays based on debris isolation depicted populations more accurately than did beet seed colonization assays. Most colonies developing in debris isolation plates originated from sclerotia.


The fate of aflatoxin in naturally contaminated corn during the ethanol fermentation.

Corn naturally contaminated with aflatoxin was used as a substrate in the ethanol fermentation. Distribution of toxin in several process and recovery fractions was identified. Although little degradation of the mycotoxin occurred during fermentation, no toxin appeared in the distilled alcohol. As accumulation of toxin in spent grains represents a potential problem in use of the material as animal feed, several decontamination procedures were tested. Sodium hydroxide, ammonium hydroxide, sodium hypochlorite, and hydrogen peroxide were identified as efficient agents of toxin degradation.


Silver-resistant Enterobacteriaceae from hospital patients.

The inclusion of agar medium containing 0.5 mM AgNO3 in the hospital laboratory replicating system for routine antibiotic-susceptibility determinations resulted in identification of species of Enterobacteriaceae (Escherichia coli, Enterobacter cloacae, Klebsiella pneumoniae, Proteus mirabilis, and Citrobacter freundii) with silver resistance. Since the study began in October, 1975, 11 in-hospital patients receiving silver sulfadiazine for burn wound prophylaxis have yielded silver-resistant bacteria from their infected burns. During this treatment routine burn-site cultures from these patients yielded 230 isolates of Enterobacteriaceae, including 211 which were sulfonamide-resistant, 97 of which were also silver-resistant, and 38 of which were untested for silver resistance. Seven silver-resistant but sulfonamide-sensitive isolates were incidentally recovered from respiratory specimens from four nonburn patients with silver tracheostomy tubes, one silver-resistant sulfonamide-sensitive isolate was recovered from a small infected burn on the foot of an Emergency Room patient. Previous treatment of this burn was unknown. Representative AgNO3-resistant E. coli isolates from four patients were serologically untypable. Serotyping of representative isolates of K. pneumoniae showed a diversity of types except from two patients who had been in the same ward at the same time.


Identification of clinical isolates of selected species of Bacteroides: production of phenylacetic acid.

A total of 132 human clinical isolates were identified and tested for the production of phenylacetic acid. With the exception of B. vulgatus, B. melaninogenicus ss. melaninogenicus, and B. melaninogenicus ss. intermedius, all other species under study produced phenylacetic acid. This property can thus serve as a basis for faster characterization of the strains in clinical laboratories.


Production of alkaline phosphatase by epithelial cells and adherent bacteria of the bovine rumen and abomasum.

Three distinct bacterial populations have been defined in the bovine rumen: the rumen fluid population; the population associated with food particles; and the population adherent to the rumen epithelium. Alkaline phosphatase activity has been reported in cells of the first two populations and here we report that assays of rumen epithelial samples containing both tissue and bacteria also contain the enzyme. The reaction product technique has localized the enzyme both in adherent bacteria and in cell of the stratified squamous rumen epithelium. The epithelium of the abomasum shows much lower levels of alkaline phosphatase activity.


Mycophenolic acid production by Penicillium brevicompactum in two media.

Penicillium brevicompactum produces mycophenolic acid as it grows vegetatively, not only on a simple medium where growth is slow but also on a richer medium where growth is less restricted. The implications of this finding on the association of fungal secondary metabolism with the idiophase in liquid and solid culture are discussed.


[Electron microscopic study of forest soil].

Scanning electron microscopy was used to evidence the aggregated structure of a forest soil as well as the presence of fungal hyphae external to soil aggregates. The supernatant of soil suspension in water mainly contained isolated bacteria, while ultrathin sections of aggregates frequently revealed groups of bacteria surrounded by a sheath of mucilage with adhering clay minerals on the outside. These results confirm the existence of two particular biotopes in the soil studied: one is located inside aggregates, and the other, in the inter-aggregate spaces.


A serological survey for Brucella canis in dogs in the Province of Quebec.

A serological survey for canine brucellosis has been conducted on 341 dogs from different regions of the province of Quebec. A significant titer was found in six sera (1.6%) with the 2-mercaptoethanol tube agglutination test. Only two dogs presented titers >/= 1:200 which is considered as indicative of active infection.


Polioencephalomalacia in white-tailed deer (Odocoileus virginianus) in Saskatchewan.

Polioencephalomalacia similar to that in domestic ruminants was diagnosed in two wild white-tailed deer (Odocoileus virginianus) with abnormal behaviour in Saskatchewan.


The use of plastic plates for fixation of spinal fractures in the dog.

Plastic plates are a rapid and easy method to realign and stabilize the spinal column following a traumatic injury and may give greater bone-to-plate contact than metal plates. They distribute the pressure on the spinous processes over a larger surface area although plate slippage and spinous process fractures can occur as with any plate. Laminectomies should not be a routine procedure with plating but each patient should be evaluated individually and autogenous bone grafts may be used to advantage to promote fusion of vertebral bodies. In the two cases presented, the plastic plates achieved their purpose. However, it is essential that fusion of the vertebrae occurs before the plates slip or the spinous processes fracture.


Randomized phase II trial of rubidazone and adriamycin in women with advanced breast cancer.

Thirty-eight females with advanced breast cancer who had failed prior chemotherapy were entered in a randomized study of rubidazone (150 mg/m2 iv over 1 hour) versus Adriamycin (60 mg/m2 iv over 5 minutes), both given every 4 weeks. The two treatment groups each contained 19 patients and were similar with respect to age, menopausal status, dominant disease status, Eastern Cooperative Oncology Group performance score, and prior hormonal therapy and chemotherapy exposure. No regressions (complete or partial) were observed with rubidazone, but four (21%) patients achieved regressions (one complete and three partial) with Adriamycin. Considering all cycles, hematologic toxicity included leukopenia (wbc count nadir of less than 4000/mm3) in 88% of patients receiving rubidazone and in 89% of those receiving Adriamycin. Three of eight patients treated with Adriamycin after rubidazone failure achieved a regression. Rubidazone appears to be of little value in the treatment of patients with advanced breast cancer who have failed prior chemotherapy.


Analysis and interpretation of response rates for anticancer drugs.

A statistical method for interpreting data on the efficacy of anticancer agents is proposed. Tables were prepared for the retrospective analysis of studies evaluating the activity of anticancer agents against individual tumor types. The number of responding patients and the number of patients entered in the study were used to more objectively and formally determine the future disposition of the drug. Several examples of clinical studies show that use of our tables allows a more satisfactory and reliable classification than is often currently reported.


Two-stage plans for patient accrual in phase II cancer clinical trials.

This paper considers two-stage patient-accrual plans for phase II trials of anticancer drugs. The purpose is to identify the therapeutic level of drugs as either above or below a reference response rate. Using such a plan, decisions concerning the future disposition of drugs can be made more formally and objectively. The tables used to implement the plan are prepared for a 20% reference response rate, due to its wide acceptance in the design of phase II clinical trials.


A mathematic model for relating the drug sensitivity of tumors to their spontaneous mutation rate.

A mathematic model has been developed relating the drug sensitivity of a tumor to its own spontaneous mutation rate towards phenotypic drug resistance. The proportion as well as the absolute numbers of resistant cells will increase with time and the fraction of resistant cells within tumor colonies of the same size with vary depending on whether mutation occurs as an early or late event. Analysis of the model indicates that the probability of the appearance of a resistant phenotype increases with the mutation rate. Furthermore, for any population of tumors with a non-zero mutation rate the likelihood of there being at least one resistant cell will go from a condition of low to high probability over a very short interval in the tumor's biologic history.


Sorbent removal of adriamycin in vitro and in vivo.

Adriamycin adsorption to four sorbents, uncoated activated charcoal, acrylic hydrogel-coated activated charcoal, a polystyrene non-ionic resin, and a pyrolized resin, was determined in vitro in aqueous and plasma solutions. Uncoated charcoal and pyrolized resin were most efficient in removing Adriamycin from these solutions. Four hours after an iv bolus of Adriamycin (2.5 mg/kg) to beagle dogs, acrylic hydrogel-coated activated charcoal hemoperfusion was performed. Extraction of Adriamycin averaged 43% throughout the 3-hour hemoperfusion period and resulted in a 20-fold increase in total body elimination of Adriamycin but plasma drug concentrations returned towards control values following hemoperfusion. Pharmacokinetic analysis of plasma Adriamycin profiles suggested that reduction of tissue concentrations of Adriamycin could be attained if hemoperfusion periods were extended. It is suggested that hemoperfusion may be useful in reducing blood levels of Adriamycin in patients with hepatic disease or accidental overdosage, but that reduction of tissue levels of Adriamycin would require extended or repeated hemoperfusion treatments.


Enhancement by thymidine of 5-fluorouracil's inhibition of thymidylate synthetase in human tumors.

The effects of thymidine (TdR) on the conversion of 5-fluorouracil (5-FU) to 5-fluoro-2'-deoxyuridine-5'-monophosphate and the resulting inhibition of thymidylate synthetase was determined in crude, human tissue extracts. TdR alone has no effect but it augmented the inhibition of thymidylate synthetase produced by 5-FU. TdR augmentation was probably mediated either by increasing 5-FU conversion to 5-fluoro-2'-deoxyuridine-5'-monophosphate or by inhibiting 5-FU catabolism.


Initial clinical studies with bruceantin.

A phase I clinical study of bruceantin was conducted in 66 patients with various types of advanced solid tumors to evaluate its toxicity and efficacy. The initial dose of 0.2 mg/m2/day x 5 days repeated at 2-week intervals was progressively increased to a maximum dose of 4.5 mg/m2/day. Hypotension was the dose-limiting toxic effect; it was delayed, cumulative, and occurred more often in patients with abnormal pretreatment liver function. Nausea, vomiting, and fever were common at higher doses, and diarrhea, stomatitis, alopecia, paresthesia, and rash were observed in some patients. The hematologic toxicity of bruceantin was moderate at high doses and was manifested mainly as thrombocytopenia; it was more severe in patients with abnormal hepatic and renal functions. No objective tumor regressions were observed. The recommended dose of bruceantin is 3.5 mg/m2/day x 5 days for phase II studies.


Acute cardiovascular alterations induced by low doses of adriamycin, rubidazone, and daunorubicin in the anesthetized beagle dog.

Iv injections of Adriamycin (0.375-3.0 mg/kg), rubidazone (0.75-6.0 mg/kg), or daunorubicin (0.75-6.0 mg/kg) given within 1 minute produced immediate hypotension in anesthetized beagle dogs. The threshold hypotensive dose for Adriamycin (0.375 mg/kg, 7.5 mg/m2) was lower than that for either rubidazone (0.75 mg/kg) or daunorubicin (1.5 mg/kg). Recovery from hypotension was more rapid after administration of rubidazone or daunorubicin than after Adriamycin. Adriamycin (1.5-3.0 mg/kg) caused respiratory distress and depressed mean arterial pressure an average of 54%-82% for up to 30 minutes. The hypotension was almost eliminated when the Adriamycin (1.5 mg/kg) infusion period was extended to 15 minutes. Significant increases in plasma histamine concentrations, coinciding with the peak hypotensive response, were detected within 1 minute after infusion of either Adriamycin (1.5 mg/kg) or rubidazone (1.5 mg/kg). Similar effects were noted after 6.0 mg/kg of daunorubicin. It appears that the acute cardiovascular effects of the three anthracycline compounds are mediated through release of histamine.


1-year followup of cardiac status after adriamycin therapy.

To study the natural history of the alterations in cardiac function produced by Adriamycin therapy, serial M-mode echocardiograms, electrocardiograms, and systolic time intervals were obtained in 15 patients prior to Adriamycin therapy and at 3-month intervals during and 1 year after cessation of therapy. The echocardiographic E-point septal separation increased from a median 0 dose value of 0.40 cm to 0.70 cm (P less than 0.003) at the time of the maximum dose of Adriamycin. The electrocardiographic frontal plane voltage decreased 13% (P less than 0.008) and the pre-ejection period/left ventricular ejection time ratio increased from a median value of 0.37 to 0.40 (P less than 0.01) during this same period. During the first year after Adriamycin was discontinued, no significant change was noted in any of these values. Thus, as a group, the slight deterioration of ventricular function that occurred during Adriamycin therapy remained unimproved during the 1-year followup period.


Ocular assessment of patients treated with tamoxifen.

Tamoxifen is a specific estrogen antagonist used in the treatment of breast cancer. In a previous study, corneal and retinal changes were reported in four patients receiving high-dose tamoxifen therapy for greater than 1 year. Nineteen patients treated with tamoxifen for periods of 3 months to 4 years at normal dose levels have been studied and no ocular changes attributable to the drug were observed.


Phase I clinical evaluation of 2,3-dihydro-1H-imidazo[1,2-b]pyrazole.

2,3-Dihydro-1H-imidazo[1,2-b]pyrazole, a DNA synthesis inhibitor, was given to 25 patients in a phase I study. The drug was administered by rapid iv infusion daily x 5 days at 3-week intervals at doses ranging from 150 to 1500 mg/m2/day. Side effects were observed with doses of greater than or equal to 1000 mg/m2/day and included nausea and vomiting, diarrhea, dark urine, and anemia. At doses of 1500 mg/m2, three patients had evidence of hemolysis (two had hemoglobinuria and one had acute intravascular hemolysis). The hemolysis was severe enough to cause death in one patient and necessitated abandoning further dose escalation. There was minimal or no myelosuppression at any dose level. No objective tumor regression was observed in any of the 16 patients evaluable for response. Further studies are recommended to carefully evaluate the etiology of the hemolysis before proceeding to a phase II trial. It is unlikely that this drug will prove to be useful unless methods for circumventing hemolysis are developed.


Schedule-dependent synergism of methotrexate and vincristine against murine L1210 leukemia.

BD2F1 mice were inoculated with 10(6) L1210 murine lymphocytic leukemia cells and treated simultaneously with methotrexate and vincristine or with methotrexate followed by vincristine greater than or equal to 24 hours later. Four to six doses of methotrexate, 48 mg/kg ip, administered every 4 days beginning on Day 1 resulted in a 168%-228% increase in lifespan, while vincristine, at 0.5 mg/kg ip, given on the same schedule until death (two or three doses) gave only a 37% increase in lifespan. Simultaneous administration of both agents resulted in a therapeutic effect which was approximately additive. When vincristine was given 24 hours or 24 and 72 hours after the methotrexate, a further increase (70%-100%) in lifespan over that expected from an additive effect and long-term survivors (greater than 90 days) were obtained. Synergism between the two agents and long-term survivors were also seen with higher methotrexate concentrations (72 or 96 mg/kg) given in four or five courses. If therapy was initiated on Day 2 when the peritoneal tumor burden was approximately 2 x 10(7) cells, the combination of methotrexate with delayed vincristine still resulted in an increased therapeutic effect over that obtained with either drug alone, or that expected on an additive basis.


Quantitative experimental evaluation of adriamycin cardiotoxicity in the mouse.

Adriamycin cardiotoxicity was morphologically evaluated in mice treated iv ten times at three dose levels which were equal to fixed fractions of the LD50. Good correlation between the degenerative heart lesions, scored according to a nonparametric scoring system, and the doses was found and allowed calculation of a median cumulative cardiotoxic dose of 36.4 mg/kg of body weight (121.5 mg/m2). The method is suitable for quantitative screening of the potential cardiotoxicity of new anthracycline analogs under standardized conditions.


Phase II study of 4'-(9-acridinylamino)methanesulfon-m-anisidide (AMSA) in metastatic breast cancer.

A phase II study of 4'-(9-acridinylamino)methanesulfon-m-anisidide (AMSA) was carried out in previously treated patients with metastatic breast cancer. Four of 26 evaluable patients achieved partial responses and four showed minor responses. The maximum tolerated dose of AMSA was 30 mg/m2/day x 3 days and the dose-limiting toxic effect was myelosuppression. Two of the AMSA responders had not responded to initial therapy with an Adriamycin-containing regimen, indicating a lack of cross-resistance between these two DNA binders.


Phase I study of N-(phosphonacetyl)-L-aspartic acid (PALA).

N-(Phosphonacetyl)-L-aspartic acid, an inhibitor of aspartate transcarbamylase, was administered to 25 patients with advanced cancer by 10-minute infusion daily x 5 consecutive days to determine the toxicity and to look for evidence of therapeutic effect. Planned dose escalations ranged from 100 to 1250 mg/m2 (daily dose). Nausea, vomiting, and diarrhea were the most frequent toxic effects, with three of six patients treated at a daily dose of 1250 mg/m2 having severe diarrhea. Other toxic effects were encountered rarely and were not dose-limiting; these included mild leukopenia, thrombocytopenia, rash, stomatitis, and increases in SGOT. One patient with a widely metastatic carcinoid of unknown origin had an objective response lasting 6 weeks.


The delta and epsilon errors in the assessment of cancer clinical trials.

The error probabilities alpha and beta are widely used to compute sample sizes and to analyze results of clinical trials. These errors are, however, not the only probabilities to consider when assessing results of clinical studies. The rate of false positive (delta) and false negative (epsilon) results allows one to determine if an experimental finding is likely to reflect the true situation in the population of interest. The delta error is generally high in randomized phase III and in early phase II clinical trials in cancer patients, whereas the epsilon error is relatively low in these settings. This is essentially due to the small probability of detecting a more effective treatment or a new chemotherapeutic agent active in cancer. The delta error could be considerably reduced by increasing the sample sizes and by restricting the allowance made for the alpha error, which should be set at a 1% level as a minimum requirement.


Phase I-II trial of methyl-GAG: a Southwest Oncology Group Pilot Study.

One hundred and nine patients with advanced malignancy, refractory to conventional therapy, were treated with a weekly schedule of methyl-GAG. Ninety-one patients (83%) were less than fully ambulatory. Sixty-five patients were fully evaluable for response. There were two complete and nine partial responses. An additional nine patients had objective tumor regressions and were classified as improved. The median duration of response was 5 months. Toxic effects were primarily mucositis (17 patients) and nausea and vomiting (14 patients). Sixty-seven patients had no manifestations of drug toxicity. Responses observed in a wide variety of solid tumors warrant further clinical trials.