Reversible inhibition of spermatogenesis with an indenopyridine (20-438).

30 mg/kg/day 20-438, an Indenopyridine, induced a complete inhibition of spermatogenesis in male dogs within a few days. The dogs did not develop signs of general toxicity. Erection capability and ejaculation were not inhibited, although the sperm number fell to zero. Histologically the seminiferous tubuli were emptied of spermatides and spermatocytes. After drug withdrawal sperm number and histological appearance returned to normal within 8-11 weeks. In rats, single doses of 50 mg/kg or more induced also an arrest of spermatogenesis. The effect was easily detected by the decrease of testes weights. The weight of seminal vesicles remained unchanged. In chronically treated rats, serum-LH and FSH were slightly increased. The compound has similar effects as other substances acting on spermatocytes (AF 1312/TS, Silvestrini et al., 1975; Boris et al., 1974 or WIN 18446, Coulston et al., 1960). The exact mechanism of action (vascular?) has to be elucidated.


Effects of rapeseed oil compared to hydrogenated marine oil in rats. Histopathological effects of erucic acid and isomers on the heart.

In a recent review on the role of fats in human nutrition Vergroesen and Gottenbos (1975) emphasize, that the presence of erucic acid isomers in hydrogenated marine oils (HMO) may constitute a toxicological problem as serious as erucic acid in rapeseed oil (RSO). On the contrary Christophersen et al. (1976) stress, that these fatty acids in HMO represent a minor toxicological problem, and that conclusions drawn from HMO to RSO are questionable. Preliminary studies at our institute indicate lipidosis in the heart both in rats fed RSO and HMO, containing equivalent amounts of erucic acid and erucic acid isomers respectively. Further experiments of longer duration are performed with HMO and RSO in order to compare the effect on the heart, especially in relation to the formation of cell necrosis.


Food additives.

The use of additives to food fulfils many purposes, as shown by the index issued by the Codex Committee on Food Additives: Acids, bases and salts; Preservatives, Antioxidants and antioxidant synergists; Anticaking agents; Colours; Emulfifiers; Thickening agents; Flour-treatment agents; Extraction solvents; Carrier solvents; Flavours (synthetic); Flavour enhancers; Non-nutritive sweeteners; Processing aids; Enzyme preparations. Many additives occur naturally in foods, but this does not exclude toxicity at higher levels. Some food additives are nutrients, or even essential nutritents, e.g. NaCl. Examples are known of food additives causing toxicity in man even when used according to regulations, e.g. cobalt in beer. In other instances, poisoning has been due to carry-over, e.g. by nitrate in cheese whey - when used for artificial feed for infants. Poisonings also occur as the result of the permitted substance being added at too high levels, by accident or carelessness, e.g. nitrite in fish. Finally, there are examples of hypersensitivity to food additives, e.g. to tartrazine and other food colours. The toxicological evaluation, based on animal feeding studies, may be complicated by impurities, e.g. orthotoluene-sulfonamide in saccharin; by transformation or disappearance of the additive in food processing in storage, e.g. bisulfite in raisins; by reaction products with food constituents, e.g. formation of ethylurethane from diethyl pyrocarbonate; by metabolic transformation products, e.g. formation in the gut of cyclohexylamine from cyclamate. Metabolic end products may differ in experimental animals and in man: guanylic acid and inosinic acid are metabolized to allantoin in the rat but to uric acid in man. The magnitude of the safety margin in man of the Acceptable Daily Intake (ADI) is not identical to the "safety factor" used when calculating the ADI. The symptoms of Chinese Restaurant Syndrome, although not hazardous, furthermore illustrate that the whole ADI cannot always be ingested as a single dose on an empty stomach with impunity.


Drug metabolism in man: in vivo and in vitro correlations.

In man the liver drug metabolizing ability may be determined by assaying drug kinetics after its administration or by measuring activity of drug metabolizing enzymes from liver biopsies. Little is known about the relationship between these parameters. We investigated the problem by determining in vivo (antipyrine kinetics) and in vitro (cytochrome P-450) indices of drug metabolism in 150 consecutive patients with diagnostic liver biopsy. In patients with normal liver histology cytochrome P-450 content ranged 10.3 umole/g and the half-life 9.5 hrs. In general, alterations in liver histology were related to the changes in drug metabolism; the patients with severe changes had prolonged half-life and low cytochrome P-450, whereas the changes in those with slight parenchymal alterations were less pronounced. The relationship between in vivo and in vitro drug metabolism was non-linear in the whole material, and linear when comparing severe ill patients with controls or in subjects with closely equal liver histology. The results emphasize the importance of evaluating the liver histology when investigating in vivo and in vitro drug metabolism in man.


Pharmacokinetics of dextropropoxyphene in acute poisoning.

Dextropropoxyphene (DP) is a commonly used medicament for suicide attempts in Denmark. Death may occur from respiratory depression or cardiac arrest. Mechanical hyperventilation which induces hypocapnia seems to reduce the occurrence of cardiac complications. In an attempt to relate the clinical events to the plasma concentrations of DP and the major metabolite norpropoxyphene (NP) we studied patients with acute poisoning treated either for 48 h with induced hypocapnia by hyperventilation or under a conservative regime. Hypocapnia was found to lead to a significant increase in the plasma half-life of DP. Under conservative treatment the plasma half-life was 17.9 +/- 6.7 (S.D.) h (n = 6), while under induced hypocapnia the mean of values from 5 patients was 30.5 +/- 6.9 (S.D.) h. Maximum serum levels of DP and NP were, however, significantly higher in the intensively treated patients (n = 7) than in those treated conservatively (n = 9), though less marked for NP compared to DP (DP: 4.9 +/- 2.1/2.4 +/- 1.0 mumol/l, NP: 6.3 +/- 2.4/4.1 +/- 1.7 mumol/l). A concentration dependent renal clearance of NP was not demonstrable. Possible explanations are the following: 1) A change in disposition pattern blood/tissue of DP during hypocapnia. 2) A reduced metabolism DP to NP during hypocapnia. 3) A reduction in other routes of elimination.


Metabolism of L(+)-and D(-)-tartaric acids in different animal species.

L(+)-Tartaric acid, which is the naturally occurring form, is used as a food additive in a variety of foodstuffs. Recently, there has been an increasing interest in using synthetic (D,L)-tartaric acid as a substitute. Several toxicological studies have been published on L(+)-tartaric acid, but practically nothing concerning the racemic form. The metabolism of L(+)-tartaric acid has been investigated in a variety of species including man. Species differences have been noted in the ability to excrete the acid in the urine after oral administration. The decomposition of tartaric acid by the intestinal flora has been implicated as an important factor. (Underhill et al., 1931 a,b). In the present study the metabolic fate of L(+)- and D(-)-tartaric acids is compared in different species, in vivo after oral administration and in vitro after incubation with caecal extract.


Influence of diet and strain of rat on kidney damage observed in toxicity studies.

The laboratory animal is susceptible to biological variation due to a variety of causes. Thus genetic variation and nutrition have become recognized to influence the reaction of the animal to experimental procedures. Severe kidney injury was observed at our institute in preliminary studies with 1% butylated hydroxytoluene (BHT) incorporated in a semisynthetic diet fed to Wistar rats for one month. These lesions together with nephrocalcinosis, a common finding in rats fed a semisynthetic diet might suggest that the animals in our experiment were predisposed to kidney damage. In order to show the influence of the rat strain and the type of diet a study was performed with both Wistar and Sprague-Dawley rats fed a semisynthetic or commercial diet mixed with 1% BHT. It was observed that the semisynthetic diet had a marked effect on the severity of the kidney lesions and that the lesions were independent of the rat strain used. In addition, an apparent sex variation was found.


Influence of drugs on bile acid excretion.

The hydroxylation of bile acids in rat liver microsomes in cyt P-450 dependent (Björkhem et al., 1975). To find out possible interactions between drugs and bile acid hydroxylation and/or active transport mechanisms we investigated the influence of the microsomal inhibitor metyrapon, the microsomal inducer phenobarbital and the intrahepatic cholestasis producing agents chlorpromazine, phenylbutazone and progesteron on bile flow and bile acid excretion. The excretion in monohydroxy (MBA), dihydroxy (DBA) and trihydroxy (TBA) bile acids were estimated in bile-fistula rats in three one hour periods. MBA, DBA and TBA were separated with thinlayer-chromatography and estimated fluorimetrically. Bile flow, bile acid excretion and relation TBA/DBA were influenced by acute and subchronic administration of the above mentioned drugs in different ways.


Extrapolation of carcinogenicity data to low doses with a dose-response study of the binding of benzo(a)pyrene to rat liver DNA.

The binding of tritiated benzo(a)pyrene (BP) to liver DNA of 25 adult male rats (SIV 50) has been determined 50 h after a single intraperitoneal injection of doses between 40 ug/kg and 4 mg/kg. The dose-response relationship is linear up to 1 mg/kg, shows a sigmoid step towards 2 mg/kg and a shallow linear slope above that value. The observed binding ranges from 1.7 to 180 nmoles BP per mole DNA phosphate. The non-linearity between 1 and 2 mg/kg could be explained on the basis of an induction of metabolizing enzymes. A purely mathematical extrapolation of the tumour incidence from a carcinogenic dose (1 x 40 mg/kg for a 20% hepatoma incidence in newborn mice) to human exposure levels (about 0.1 ug/kg per day) would never have followed a step like the one found in our experiments. Our dose-effect study therefore shows how carcinogenicity data could be extrapolated in a biologically founded way to low doses.


A closed inhalation system for pharmacokinetic and metabolism studies of volatile compounds with small laboratory animals.

In the inhalation system described an animal can be kept in the same atmosphere of a 2-liter desiccator for up to 24 h. The expired carbon dioxide is adsorbed with soda lime and the resulting reduced pressure is balanced by a supply of oxygen also used for the inflow of the chemical to be investigated. Urine and faeces can be collected separately and the system allows a periodical control of the concentration of the chemical by sampling the air with needle and syringe.


Pesticides and heavy metals as food contaminants.

From the general pollution, contaminants spread along a variety of routes, many of which lead to our food. Pesticides and heavy metals as food contaminants have raised strong public concern and contributed to the general uneasiness associated with the pollution boom of the last two decades. Pesticides in food are predominantly residues from their application on growing crops, less often from post harvest use on stored agriculatural products, whereas heavy metals contaminate the food at various stages along the food production line. Both groups of contaminants exhibit in the number of their members a spectrum of health hazards. A few examples of these will be dealth with, and thought will be given to some features in the philosophies behind the current practices of risk assessment and management in this area. A widespread shortage of toxicological expertice maintain a level of ignorance sufficient to make risk evaluation very often a dilemma. This distressing shortcoming at least partly arises form a common neglect of toxicology as a university discipline. Some international efforts to control food contamination will also be touched upon.


Toxicokinetics.

The absorption, distribution and elimination of toxic compounds can be described by means of kinetic parameters such as used in pharmacology. Administration of toxic doses may lead to changes in some of the parameters. The toxic effect may further influence the known parameters of some test substances. Toxicokinetic parameters will be described using examples from two groups of compounds 1) naturally occurring toxic compounds and 2) synthetic compounds. Changes in elimination parameters caused by toxic substances will be demonstrated a.o. the effect of long term intake of ochratoxin A and methoxyethyl mercury on the kidney function in swine. In both examples are demonstrated a pronounced reduction in the clearances of inulin and para-amino-hippuric acid. Furthermore, an elucidation of concentration dependent change in enzyme activity and changes in metabolism of pesticides will be given. As examples alkylphosphates and dinitrophenols in domestic animals will be used.


Significance of induction phenomena.

A number of foreign compounds induce the proliferation of the hepatic smooth endoplasmatic reticulum and thereby increase the activity of monooxygenases that metabolize drugs and other foreign compound. With reference to the safety of food additives some antioxidants have been examined by various authors for their inducing capacity, in doses well above those ingested with treated food and above the stipulated accepted daily intake (ADI). Thus feeding of rats with the very high dose of 500 mg/kg body weight of butylated hydroxtoluene (BHT) resulted in an increase in its own oxidative metabolism. Also in monkeys BHT produces an inductive increase of microsomal enzyme activity, cytochrome p 450, and a proliferation of smooth endoplasmatic reticulum. The closely related antioxidant butylated hydroxyanisole (BHA) leads to similar effects in mice. Recent studies with ethoxyquin (EQ) have shown that this antioxidant stimulates the formation of a form of cytochrome P 450 which resembles the phenobarbital-inducible type. EQ itself is also an inhibitor of mixed function monooxygenase. The naturally occuring flavouring agents safrole and isosafrole in high doses also induce hepatic monooxygenations. Spectroscopic examination has revealed, however, that another type of cytochrome with characteristic binding of a suspected safrole metabolite is produced. This complex shows absorption maxima at 427 and 455 nm and can be dissociated by adding a number of different lipophilic agents, including safrole itself. In a time dependent displacement reaction the characteristic spectrum decreases and is replaced by a classical binding spectrum of the displacer itself. By these examples it can be shown that food additives exert a number of effects on hepatic drug inactivating systems. However, no risk of hepatic changes can be seen from the small amounts of antioxidants ingested in balanced human nutrition.


Chondroblastic osteosarcoma of the larynx.

Osteosarcoma of the larynx is a rare lesion. Acceptable cases in the literature are difficult to find. We report a case in which total laryngectomy was carried out for a large, obstructing mass that arose from the cricoid cartilage. We present the histologic criteria for the diagnosis of chondroblastic osteosarcoma.


Properties of a new carvable composite dental filling material.

The chemical principles and physical properties of a new composite system, which apparently cures in a two-step process to allow time for hand carving to the proper anatomic contours, are described. The new material appears to have better in vitro wear resistance than an older composite filling material.


A survey of causes of permanent tooth extractions in South Australia.

Reasons for permanent tooth extractions were studied in a survey in South Australia conducted over a two week period in which 154 dentists participated, a response rate of 43 per cent. Of 2,387 teeth extracted from 1,104 patients, caries accounted for 52 per cent, periodontal and orthodontic causes 25.6 and 11.1 per cent respectively, impacted teeth 6.5 percent, and prosthetic reasons 2.8 per cent. Caries was the most prevalent cause in the age  groups 20-40 and over 70 years. Between 40 and 70 years more than 50 per cent of the teeth were extracted for periodontal reasons.


A developmental defect of the mandibular symphysis. Case report.

A case in reported of coincidental abnormalities of development of both the premaxilla and anterior mandible. The defect in the mandible presented certain radiographic features frequently observed in cystic or neoplastic lesions. Histological examination revealed it to be of a developmental nature. The importance of adequate examination of tissue removed from lesions of the jaws is emphasized.


Recent developments in dental plaque disclosants.

The use of erythrosin and fluorescein for disclosing dental plaque in 81 children aged 11-14 years and in 17 young men is reported. Erythrosin stained all plaque. When fluroescein was used, plaque, whether mature or recently exposed to sugars was disclosed under ultra-violet light. In the children, the erythrosin stained approximately twice as extensively as fluorescein.


Incisal angle adhesive resins: a two-year clinical survey of three materials.

Three composite resin materials gave reasonable results in the short-term, provided that they were placed and finished correctly. This would be easier to do with the small incisal fractures. Although slightly more defects became apparent with time, most could be corrected without the replacement of the restorations.


Pulp testers and pulp testing with particular reference to the use of dry ice.

Pulp testing is mandatory before any operative procedures, invaluable in the diagnosis of pain and is an essential adjunct in the interpretation of radiolucent areas. Methods of pulp testing are reviewed and the use of dry ice for this purpose is discussed in detail. Limitations of pulp testing are considered. Vitality tests are of only limited use in traumatized teeth. The results are only qualitative and not quantitative.


A comparison of two methods of demonstrating an exercise in dental technology.

A comparison between conventional and live television methods of demonstrating an exercise in dental technology was carried out and indicated that they were equally effective as judged by grading of students' work. Students' comments suggested that the television method was received less favourably. Their comments form a basis for discussion regarding the use of material recorded on cassette or cartridge with immediate replay facilities rather than television demonstrations in real time.


The effects of commercial local anaesthetic solutions on the isolated rabbit ear artery.

The response of an isolated artery preparation to commercial local anaesthetic solutions containing either prilocaine or lignocaine in the presence of adrenaline or noradrenaline has been examined. In low doses, both local anaesthetics were found to augment the constrictor response to adrenaline, wheras at higher doses the effect of adrenaline was significantly depressed by them. In contrast, noradrenaline's vasoconstrictor response was not potentiated by low doses of lignocaine, although higher dose levels caused a significant reduction in its vasoconstrictor effect.


Dental dilemmas: can psychiatry help?

An overlap exists between dentsitry and psychiatry. The dentist, whose role is inevitably of considerable psychological significance, should be aware of the common psychiatric "disease entities", notably depressive illness, which can present through dental symptoms. Such disorders seldom respond to dental manoeuvers per se but often respond to psychiatric treatment. Some specific psychodental syndromes are described and illustrative case histories are given.


Provisional splinting in advanced periodontal disease. Case report.

This case report describes an approach to treatment for a patient with severe bone loss resulting from advanced periodontal diseae. A provisional splint was constructed in conjunction with suitable periodontal therapy. The purpose was to allow time for evaluation prior to deciding whether to commit the patient to permanent stabilization.


Further observations on mandibular anaesthesia.

Recent studies have emphasized that none of the accepted intraoral landmarks used in the conventional mandibular block technique is completely reliable, nor can they presage those instances in which the lingula presents an obstruction to the needle pathway. An answer to this problem is suggested by the use of extraoral landmarks to assist in estimating the height and expected depth of needle penetration. The importance of palpating for the anterior border of the medial pterygoid muscle deep in the pterygotemporal depression is reaffirmed.


Mid-face osteotomy in the adolescent cleft palate patient.

Retrognathia or retrusion of the maxilla and mid-face is present in about one-third of treated cleft palate patients. Surgical repositioning of either the dental segments, or the entire mid-face into a forward position, can greatly enhance appearance and at the same time provide for a more functional occlusion. Some surgical aspects of this work are presented together with an evaluation of soft tissue change.


The influence of the dentist upon dimensional change and creep of amalgam.

A laboratory study showed insignificant effect on dimensional change was brought about by the operator's skill, packing technique employed, and alloy. However, creep was significantly affected by the operator's skill and the type of alloy.


Histology of external and internal resorption.

Seven cases of resorption in teeth have been described. Three had large internal cavities penetrating the dentine to or from the exterior. One had internal resorption in two separate locations and another had internal resorption which may have been precipitated by carious involvement of the pulp. Two cases of external resoprtion were quite dissimilar, one possibly a reaction to canal infection, the other idiopathic. Various types of calcified material were found in the areas of resorption and odontoclasts were found in one case.


The traumatic bone cyst.

A case is reported of traumatic cyst lying in the molar region of the mandible. It extended to the inferior border of the mandible and extended the buccal alveolar bone. The cystic cavity contained the inferior neuro-vascular bundle yellow serous fluid, and a small amount of gas. The wall of the cavity was lined with loosely arranged connective tissue with numerous capillaries. Healing was uneventful and clinical and radiographic examinations revealed restoration of bone structure and normal contours.


Educational technology in the teaching of dentistry: the importance of objectives.

A description of educational technology is given and the importance of establishing clear teaching-learning objectives is related to curriculum, evaluation and teaching methods.


Characteristics of the Papua New Guinean dentition. I Shovel-shaped incisors and canines associated with lingual tubercles.

The prevalence of shovel-shaped and lingual tubercles in maxillary incisors and canines in four groups of people in Papua New Guinea is reported. The shovel shape was not common among the people of Highland New Guinea but its presence in Papuans was comparable with that in Mongoloid races.


The mucocele - floor of the mouth.

Three cases are reported to illustrate certain features related to swellings of the salivary glands. With a mucocele of the floor of the mouth difficulites may arise in the correct identification of the gland of origin, in elucidating the aetiological factors, and in obtaining adequate radiographic or sialographic views of the area. Surgical treatment follows the surgical removal of the involved gland.


Raynaud's disease: reduced hand blood flows with normal blood viscosity.

Hand blood flows and the blood and plasma viscosities were measured in patients with Raynaud's disease in an attempt to identify the mechanism of the episodic vascular insufficiency. Using venous occlusion plethysmography the following observations were made: (1) the hand blood flows were significantly less than in normals at 32 degrees, 27 degrees and 20 degrees C; (2) the percentage decrease in flow with cooling was greater in normals and (3) cooling of one hand from 32 degrees to 27 degrees C caused an abnormal decrease in flow through the contralateral hand. Using a rotational viscometer the blood and plasma viscosities were found to be normal at both high and low shear rates. The percentage increase in the blood viscosity with cooling from 35 degrees to 25 degrees was also normal. These studies demonstrate an increased constrictive response of the cutaneous vasculature of the hand to both local and reflex stimulation, and exclude a rheological abnormality, under conditions similar to those of the present study.


Brain atrophy and intellectual impairment in heavy drinkers--a clinical, psychometric and computerized tomography study.

The frequency of cerebral and cerebellar atrophy was assessed by computerized tomography (CT) in 26 heavy drinkers. Findings were correlated with clinical deficits, with the results of psychometric testing using the Wechsler Adult Intelligence Scale (WAIS), and with the alcoholic history and nutritional status. Cerebral atrophy was present in 19 cases (73%), 16 of whom also had cerebellar atrophy. There was a good correlation between the degree of cerebral hemisphere atrophy and age and length of drinking history, but a poor correlation between neurological deficits and atrophy. Impairment of visuo-spatial and visuo-motor functions with sparing of other non-dominant hemisphere functions and of verbal skills was the characteristic pattern found with the WAIS in 18 subjects; four showed a more global depression of intellectual function. The degree of cerebral hemisphere atrophy correlated significantly with the impairment of non-dominant hemisphere functions but not with total IQ.


Renal papillary necrosis associated with indomethacin and phenylbutazone treated rheumatoid arthritis.

A case of renal papillary necrosis is reported in a 55-year-old man with rheumatoid arthritis. He consumed 1.1 kg indomethacin and 5.5 kg phenylbutazone over the seven years prior to presentation.


The successful treatment of primary amyloidosis with intermittent chemotherapy.

A patient with primary amyloidosis is described with extensive vital organ involvement including infiltration of the liver, kidney and myocardium. Treatment with intermittent melphalan and prednisone resulted in improved hepatic and renal function, a reduction in liver size and arrested amyloid deposition in the myocardium. These observations suggest that chemotherapy can halt tissue amyloid deposition, and improve the prognosis of primary amyloidosis.


Compartmental shift of potassium--a result of sympathomimetic overdose.

A 17-year-old youth was admitted with a serum potassium concentration of 1.8 mmol/l after taking an overdose of pseudoephedrine and choline theophyllinate. Apart from tachycardia, tachypnoea and ankle clonus, examination was normal as was the initial electrocardiograph. The hypokalaemia resolved, but there was an overall positive potassium balance of only 13 mmol. This suggests that the sympathomimetics provoked a compartmental shift of potassium perhaps indirectly by inducing hyperglycaemia and hyperinsulinaemia, as well as directly. Other factors known to affect body potassium distribution were excluded. The fact that features commonly associated with hypokalaemia could not be demonstrated may be explained by a normal body potassium content. Severe hypokalaemia caused by a compartmental shift occurs with large doses of sympathomimetics as well as in periodic paralysis.


Concomitant IgA nephropathy and cyclical neutropaenia.

A case of concomitant cyclical neutropaenia and IgA nephropathy, a previously undescribed combination is reported. The patient has recurrent aphthous ulceration, and haematuria occurs with these episodes. The diagnosis of cyclical neutropaenia was based on the clinical features and serial peripheral blood studies, and a renal biopsy studied by light, electron and immunofluorescence microscopy in conjunction with the clinical features established the diagnosis of IgA nephropathy. Elevation of serum immunoglobulin, with a disproportionate elevation of IgA was found. The features of this case emphasise the importance of infection as an initiating event in the pathogenesis of IgA nephropathy, and they provide further evidence for the formation of poorly soluble immune complexes as a likely pathogenetic mechanism.


Early diagnosis of Addison's disease; pigmentation as sole symptom.

A diagnosis of primary adrenocortical insufficiency was made in a shapely, suntanned girl whose sole complaint was increasing pigmentation. Plasma cortisol was low in spite of markedly elevated levels of ACTH. Plasma cortisol, urinary 17-oxogenic steroids and urinary aldosterone did not respond to three days of ACTH stimulation. Addison's disease can be diagnosed and treated before development of anorexia, weight loss, weakness and other classical symptoms.


An evaluation of five years experience with a physicians workshop.

This paper reports five years experience with a new type of continuing education programme for practising physicians. The continued development and the organisation of the programme is described. A high proportion of the hospital's physicians have regularly attended and participated. Annual questionnaire surveys have shown a high degree of satisfaction with the the programme and the majority of physicians give it a high priority in their continuing educational activities. The features which appear to be responsible for the success of the programme include the variety of the format, the quality of the presentations, the active participation by all physicians and the fact that the activities are specifically aimed at the practising physician rather than physician trainees.


Philosophical aspects of "mental disease".

It is shown that the label "mental disease" derives from value judgements made by the labeller, and that science alone cannot determine the ultimate validity of these judgements. Hence, the term must be, in a genuine sense, based on social and moral convention. However, it is argued that this does not necessarily mean that the medical model, as contended by Szasz and his school, has no value. Rather, it is claimed here that only by returning to the medical model can we make best use of our psychiatric knowledge and best serve our patients.


Mental health services by and for Aborigines and Islanders: a follow-up report.

The indigenous behavioural health programme for Aborigine and Islander Community of the Townsville area was belatedly funded and has recently been expanded. An additional group of five behavioural health technicians have been trained to provide broadened services emphasizing alcoholism counselling and community based activities. Evaluation of the programme indicates a considerable increase in the utilization of mental health services by the community as compared to utilization prior to the behavioural health service. Self-referrals account for 40% of the cases. Referrals from the centre's physician and from family account for much of the others. Problems seen are multiple, often both of personal-emotional and of a social service nature. Alcoholism, family-material child-school problems, anxiety and depression were frequent emotional problems. Issues as to whether or not such indigenous programmes should rather deal with social problems or physical health are discussed.


A behavioural programme for the management of anorexia nervosa.

A treatment programme, based on the use of behavioural principles, is described. Important components of programme include the active participation of the patient in all phases of treatment planning, the use of contingent reinforcement for weight gain rather than eating behaviour, the provision of frequent feedback regarding progress and the lowering of the "response cost" for eating. In addition contracting, and the use of random scheduling of follow-up contacts, along with family therapy, are employed to maintain weight gain following discharge. The results achieved with an initial group of 5 female patients are briefly discussed.


Some age-related effects of the 1974 Brisbane floods.

Some age-related effects of the 1974 Brisbane floods are examined. The impact of the floods on health increased in those over 35 years of age probably because they were more likely to be householders. Women under 65 years of age had more psychiatric symptoms than men, but this sex difference disappeared in those over 65 years, perhaps because the working man is not constantly confronted with the damage to his home in the way that others are. The possibility that people over 75 years living in flood-affected suburbs experienced increased morbidity even though not themselves flooded cannot be excluded.


Interpersonal factors in suicide attempts: a pilot study in Christchurch.

Attempted suicide is a behavioural pattern with complex psychological and sociological determinants, many of which have been extensively studied in recent years. The basic facts of its changing incidence, its demography, and its place within a broader spectrum of self-destructive behaviour are well established but authorities are still divided on many issues related to its aetiology, its function in the individual and the kinds of services required for its clinical management. (Kessel 1965, Anderson 1974, Weissman 1974, Henderson and Williams 1974). The study reported here was designed partly to define the characteristics of a group of patients for whom clinical services were being planned and partly as a pilot study to develop a methodology for a more extensive controlled study which we hope to carry out next year. The preliminary findings are sufficiently interesting to report now.


Schizophrenia and season of birth: further southern hemisphere studies.

Studies in the northern hemisphere and an equatorial region have suggested that schizophrenics have a greater likelihood of being born in the coldest three months of the year. Two further southern hemisphere studies, performed in New Zealand and Tasmania, are reported in this paper. Results from these and other studies suggest that support for a link between schizophrenia and winter birth in the southern hemisphere is slight and inconsistent.


The season of birth of anxiety neurotics.

An association between spring birth and anxiety neurosis in New South Wales is confirmed. Two possible explanations, that the association might reflect a seasonal variation in conceiving or in giving birth among mothers of those with significant anxiety, or that spring birth selectively disposes to anxiety, were examined. Findings suggest that both effects may be operating.


Schizophrenia following withdrawal from chronic phenothiazine administration: a case report.

The chronic administration of phenothiazines has come under increasing scrutiny recently, and the uncritical use of this form of treatment has been criticized. A case is presented illustrating the development of schizophrenia in a young adult following withdrawal from phenothiazines. As far as could be ascertained ther was no evidence of schizophrenia prior to withdrawal of phenothiazines. The  possibility that withdrawal of phenothiazines  may have aetiological significance in this case is discussed.


[Cytogenetic examination of children with chronic granulocytic leukemia].

The most important marker chromosome in patients with CDL is small acrocentric chromosome which is due to the deletion one of the chromosome 22. Ph 1 can be found only in adult type of CDL. Dhe authors present their experiences in citogeneticaly examined children with CDL. The examinations were done in six patients in peripheral blood and bone marrow. Ph 1 was negative only in one case. In the other patients philadelphia chromosome was found in bone marrow and in the peripheral blood only when the illness go from bad to worse.


Brief family therapy for childhood tic syndrome.

This paper reports the success of brief analytically oriented outpatient family therapy exclusively in treating an eight-year old girl presenting with a short history of multiple tics involving facial, thoracic, and upper limb musculature, with associated hoarse coughing and grunting. Diagnostic features are reviewed. No medicines were used, and the patient remained asymptomatic nine months after ceasing family therapy. Tentative indications for family therapy for tiqueurs are proposed.


Dermatoglyphics in childhood leukaemia: a guide to prognosis and aetiology?

The results of analysis of the dermatoglyphics of 152 children with acute lymphoblastic leukaemia (ALL) (and the first-degree relatives of 54 of them) contrast with those of 31 children with acute myeloblastic leukaemia (AML) (and the first-degree relatives of 25 of them). In ALL our findings suggest that neither genetic susceptibility nor an environmental factor, effective during the early antenatal period, is of aetiological importance; but the response to treatment, assessed as length of first remission, was found to be related to the amount of fingertip pattern. This may have clinical application. In AML there is evidence of a genetically determined factor carrying a high risk of the development of the disease, in that a member of each of 5 different families of the 25 studied bore a rare hypothenar pattern, compared with none in 75 control families. No dermatoglyphic features were of prognostic significance in AML.


The rationale for the development of improved hypoxic cell radiosensitizers.

This paper outlines the chemical background to the selection of compounds likely to be clinically superior to the nitroimidazoles currently being evaluated in cancer therapy. The most important chemical properties to consider are electron affinity and lipophilicity, and the quantification and prediction of both these properties are considered. Examples are presented of the use of multiple regression analysis to evaluate the relative contribution of individual properties to the overall biological response.


Toxic and radiosensitizing effect of the 2-nitroimidazole misonidazole (Ro-07-0582) on murine CFU in vivo.

Spleen colony-forming stem cells of the bone marrow of mice (CFU) have been used as an in vivo test system for toxic and radiosensitizing effects of misonidazole. The cells were irradiated in vivo in the donors before they were suspended and injected i.v. into recipients. Hyoxic conditions were achieved by killing the donors 20 min before irradiation. A drug dose in donors of 1.0 mg/g body wt (ca 1200 microgram/ml in serum) was found to be weakly toxic over an exposure time of 50 min under hypoxic conditions. The radiosensitizing effect at this concentration was found to be about the same as the full effect of oxygen.


Effects of sensitizers on cell respiration: II. The effects of hypoxic cell sensitizers on oxygen utilization in cellular and chemical models.

The metabolic activity of nitroheterocyclic sensitizers could limit their usefulness in vivo. Biochemical mechanisms of drug metabolism, toxicity and effects on cell respiration have been studied in microsomes, and the kinetics of the simulated redox reactions determined by pulse radiolysis. Stimulated oxidation of coenzyme, glucose, ascorbate or glutathione substrate radicals by nitroheterocyclic sensitizers, with the concomitant appearance of the respective nitro radical anions, is observed. Under hypoxia, the nitro radical anions decay slowly by second order processes, forming reduced metabolites. In air, the nitro radical anions react with oxygen forming superoxide radical anions, peroxide and regenerating the drug. Nitro radical-anions also react with cytochrome-c indicating a possible interference with mitochondrial energy metabolism.


The nitroimidazoles as radiosensitizers and cytotoxic agents.

Using hamster cells in culture, the radiosensitizing and cytotoxic properties of 8 electron-affinic drugs have been compared. These include nitrofurans derivatives as well as 2 and 5-nitroimidazoles. Most work has been performed with misonidazole for which it appears that, at 37 degree C, the concentration of drug required to produce a given level of cell killing is inversely proportional to the square of the exposure time. Misonidazole was also compared with X-rays for its ability to produce neoplastic transformations in vitro, using the C3H 10T 1/2 cell line.


Some factors affecting the specific toxicity of misonidazole towards hypoxic mammalian cells.

The toxic action of misonidazole towards hypoxic mammalian cells has been shown to be a function of serum concentration, with higher serum concentrations enhancing the toxic effect. Added thiols protect cells against misonidazole toxicity. In addition, the action of misonidazole on hypoxic cells labelled with 5-BUdR has been examined. Cells with incroported 5-BUdR are no more sensitive to misonidazole toxicity than are cells without label.


Cytotoxic effect of 5-thio-D-glucose on chronically hypoxic cells in multicell spheroids.

The effect of 5-thio-D-glucose on chronically hypoxic cells in the multicell spheroids of Chinese hamster V79 cells was investigated. The radiation survival curves of spheroid cells indicated that most of the chronically hypoxic cells in the spheroids could be eliminated by incubating the spheroids with 5-20 mM of 5-thio-D-glucose or 17 hours. Histological studies also demonstrated that 5-thio-D-glucose preferentially kills the hypoxic cells located in the inner part of the spheroids.


Cell survival in V79 multicell spheroids treated with dehydroascorbate, 5-thio-D-glucose and 2-deoxy-D-glucose.

We found that dehydroascorbic acid (DHA), 5-thio-D-glucose (5TG) and 2-deoxy-D-glucose (2DG) were toxic to monolayers of V79 cells under hypoxic conditions at 37 degree C but not at 0 degree C. Very little toxicity was observed at either temperature under aerobic conditions. When spheroids (600 micrometer diameter) were treated with 7.5 mM of these chemicals for periods up to 3 days, the number of viable cells per spheroid dropped to 70% for DHA, 50% for 5TG and 25% for 2DG relative to controls. These survivals were reduced to much lower values when the experiments were repeated in glucose-free medium.


Effects of sensitizers on cell respiration: III. The effects of hypoxic cell radiosensitizers on oxidative metabolism and the radiation response of an in vitro tumour model.

Physiological factors are important when considering the effects of radiosensitizers on the radiation response of complex systems such as multicellular spheroids. In this system, under conditions of unlimited nutrient supply, cells are rendered hypoxic by metabolism. Thus, using the spheroid system as an in vitro model of the tumour-cell microenvironment, we have determined the relative contribution of radiosensitization and respiratory effects of a number of electron-affinic sensitizers having potential clinical use. These studies are indicative of physiological responses at the cellular level, and suggest optimal drug administration schemes for obtaining maximal radiation response in vivo hypoxic cell sensitizers.


Oxygen cathode measurements and radiation response in tumour-bearing mice treated with misonidazole.

Direct measurements using 200 micron oxygen cathode electordes have been made in tumour and subcutaneous tissues of anaesthetized C3H mice treated with misonidazole. In air-breathing animals a six-fold increase in tumour oxygen cathode readings was observed by 23 min after i.p. injection of misonidazole at 0.5 mg/g body weight. A similar rise, but of 2.5 times, was observed for the subcutaneous tissues. Comparison of tumour oxygen readings for drug-treated and control mice breathing 100% O2 at different pressures showed markedly increased levels for the drug-treated animals. Tumour response to radiation was measured for 250 kV X-rays and 15 MeV electrons. In each case, when a dose of radiation was combined with pre-treatement with misonidazole an increased radiation response was observed when compared with the same dose of radiation given alone. At the highest dose (40 Gy) there was a suggestion of an increased normal tissue reaction. The significance of the measurements is discussed.


Effect of anoxic radiosensitizers on cellular and mitochondrial oxygen consumption and respiration control ratio.

Misonidazole increased oxygen consumption of Ehrlich ascites cells and reversed the blockage of oxidative phosphorylation induced by amytal and KCN. It alos increased oxygen consumption of mitochondria in the presence of alpha-ketoglutarate substrate, but decreased the respiratory control ratio. Cellular oxygen consumption decreased, but mitochondrial consumption was increased by metronidazole, and the respiratory control ratio was not affected by this substance. It was concluded that misonidazole influences respiration in a similar way to uncouplers, and the interaction site for both substances is at the NADH level. These respiratory effects can be of importance in altering radiation response in multicellular tissues.


Metronidazole (Flagyl), misonidazole (Ro 07-0582), iron, zinc and sulphur compounds in cancer therapy.

The nitro radiosensitizers, metronidazole and misonidazole, have been shown to react rapidly with the sulphydryl compounds cysteine and cysteamine in the presence of ferrous ions. Similar reactions occur in the presence of copper ions but these are much slower. The initial interactions of the drugs and of oxygen with an iron-cysteine complex are extremely rapid: in the case of oxygen reaction half-lives of 27 ms have been measured. Misonidazole also reacts rapidly with glutathione in the presence of ferrous ions and is subsequently reduced: metronidazole is reduced only slowly if at all. These reactions, which have been found to be inhibited by high concentrations of zince ions, are discussed in the light of the known radiosensitizing and chemotherapeutic efficiencies of the nitro drugs and the side effect of peripheral neuropathy sometimes observed during their clinical use.


Respiration of mammalian cells at low concentrations of oxygen: I. Effect of hypoxic-cell radiosensitizing drugs.

Drugs which sensitize hypoxic mammalian cells to radiation damage in vitro can also affect the cellular respiration rate. This phenomenon was studied in detail to determine whether the changes in oxygen consumption occur at low oxygen concentrations and under optimal nutritional conditions. We have found that cells in tissue culture can undergo adaptive changes in respiration (electron flow) which make them insensitive to the effects of radiosensitizing drugs and even respiration uncouplers such as dinitrophenol, and the inhibitors rotenone and cyanide. At low cell densities, where nutrient depletion in the medium would be negligible, the drugs have reduced effects, particularly at low oxygen concentrations (below 40 mmHg oxygen partial pressure). Parallel cytotoxicity and growht inhibition studies indicate that most drugs are unlikely to have substantial effect on respiration at non-cytotoxic levels.


Cytotoxicity of radiosensitizers in multicell spheroids: combination treatment with hyperthermia.

Spheroids of EMT6 tumour cells were grown in spinner culture. As with V79 cell spheroids, the combination of 1.5mM misonidazole and hyperthermia at 42.5 degree C for 1 or 2 h cuased greater cytotoxicity than either heat or drug alone. Radioresistant hypoxic cells at the centre of the spheroids were eliminated but other cells were also killed.


The hyperthermic potentiation of the cytotoxic effect of misonidazole on the EMT6 mouse tumour: relevance of in vitro measurement of in vivo effect.

The effect of local hyperthermia combined with misonidazole and the influence of temperature monitoring on this effect in growth delay studies and in vitro colony assay are described.


Enhancement of local tumour control by misonidazole and hyperthermia.

Combination treatment of a C3H mammary carcinoma with misonidazole, hyperthermia and radiation resulted in greater local tumour control than with any of these agents singly or in pairs. Dose modification factors for the 3-fold combinations were 3.28 when tumours were immersed in a 42.5 degree C waterbath for 1h after irradiation, and 5.03 at 43.0 degrees C. Cytotoxicity of misonidazole alone was slight, as reflected histologically and in tumour growth. Hyperthermia had a marked effect on these two parameters. Foot damage by hyperthermia was greatest when feet were taped.


Hypoxic cell sensitizers and heavy charged-particle radiations.

Stationary-phase populations of Chinese hamster V-79 cells were irradiated with 250 kV X-rays and the Bragg peaks (spread to a width of 4 cm) of energetic He-, C-, Ne-, and A-ion beams produced at the 184-inch cyclotron and BEVALAC at Lawrence Berkeley Laboratory. Survival curves were generated with each radiation for cells suspended in air-saturated and nitrogen-saturated medium with and without sensitizer present. The oxygen enhancement ratios (OERs) measured for X-rays with 1mM metronidazole and 0.5 mM misonidazole were 2.0 and 1.6 respectively. The OERs without sensitizer for He-, C-, Ne-, and A-ion Bragg peaks were 2.4, 1.7, 1.6 and 1.4 respectively. For each type of radiation tested the presence of hypoxic-cell sensitizers resulted in an additional reduction in the measured OERs, indicating that these drugs should be of benefit in the radiotherapy planned with these and other high LET radiations.


A combination of sensitizers with high LET radiations.

Preliminary measurements of OER for pion beams in combination with a concentration of Misonidazole (0.4 mM) that is realistic in radiotherapeutic application are reported. These results indicate that 0.4 mM of misonidazole is as effective in reducing OER for negative pions as for X-rays. The application of high LET radiations in combination with hypoxic cell sensitizers is discussed.


An analysis of synergistic sensitization.

The molecular theory of cell survival predicts that a synergistic interaction on cell survival may be expected when DNA-damaging agents are used in combination with ionizing radiation. The synergism is expected to result from the interaction of DNA single-strand damage induced by the agent and single-stand breaks induced by the radiation. Mathematically this is expressed by an increase in the alpha coefficienty of the survival equation S = exp - (alpha D + beta D2), the beta coefficient remaining constant. Two examples of synergistic interaction with ionizing radiation are analysed, a chemical used in tumour therapy and ultra-violet light. The implication of this analysis for sensitization in radiation therapy are discussed.


Effect of radiation on cis-dichlorodiammineplatinum (II) and DNA in aqueous solution.

The radiolysis of cis-dichlorodiammineplatinum (II) (cis-PDD) was studied in order to better understand the mechanisms by which it acts as a radiation sensitizer. The Pt(I) intermediate formed by e- aq reduction of cis-PDD  loses both chlorides rapidly, interacts with O2 to form a Pt-oxygen adduct, reacts with the hydroxyl radical adduct of thymine and the peroxy radical of t-butanol, and disproportionates to platinum metal and trans-PDD. The Pt (III) intermediate formed by OH oxidation of cis-PDD likely disproportionates to cis-PDD and Pt(IV) complexes. In a biological model, radiation-induced 3H-thymine base residue release from DNA is found to be inhibited by cis-PDD.


Testing of hypoxic cell radiosensitizers in vivo.

Use has been made of the transplantable KHT sarcoma in C3H mice to test the in vivo effectiveness of some 2-, 4-, and 5-nitroimidazoles as hypoxic cell radiosensitizers. A comparison of the in vivo versus the in vitro sensitizing ability of misonidazole and metronidazole indicates some differences, probably due to drug delivery problems in vivo. The relative sensitizing abilities of eight 2-nitroimidazoles, two 4-nigroimidazoles and two 5-nitroimidazoles are compared on the basis of the amount of drug injected and the plasma levels obtained.


In vivo evaluation of the radiosensitizing and cytotoxic properties of newly synthesized electron-affinic drugs.

We are synthesizing and testing various 2-nitroimidazole analogs with different octanol/water partition coefficients for their radiosensitizing and cytototoxic properties. Our hypothesis is that, unlike the situation in vitro, lipophilicity will play a major role in determining the extent of radiosensitization of hypoxic tumour cells in vivo and also the degree of animal toxicity. The radiosensitivity testing involves determination of the surviving fraction of EMT6 tumour cells irradiated in vivo under different conditions following drug injection, and subsequent assay in vitro. Data obtained to date on eight 2-nitroimidazoles do not indicate any compound clearly superior to misonidazole (Ro-07-0582), although one or two are close and may prove better at the completion of testing. Cytotoxicity of the compounds is assayed by cell survival and histologically. Data obtained on the toxicity of misonidazole to the cells of EMT6 tumours suggest that a large proportion of the anoxic cells in these tumours are not near necrotic areas, but rather result from the temporary closure of blood vessels.


Cytotoxic and radiosensitizing effects  of hypoxic cell sensitizers on EMT6 mouse mammary tumour cells in vivo and in vitro.

The radiosensitizing activities and toxicities of misonidazole, metronidazole, 2-Methythio-3-nitropyrrole (3NPR), 2-amino-5-nitrothiazole (ANT) and 2,5-dinitroimidazole (KA121) were studied using EMT6 tumour cells and BALB/c KaRw mice. For 10(-4)M concentrations of the drugs, the DMF's for hypoxic cells were: Misonidazole, 1.6; 3NPR, 1.5, ANT, 1.5; KA121, 1.8. The OER was 3.2. In general, the drugs were toxic to hypoxic cells and were not toxic to aerobic cells at 10(-3)M for 24 h. The LD50's in BALB/c KaRw mice were: misonidazole, 1500 mg/kg; 3NPR, 350 mg/kg ANT, 420 mg/kg. In vivo, 1 mg/g misonidazole or metronidazole reduced the terminal slope of the tumour cell survival curve by a factor of 2.2 or 1.6 respectively.


Effect of combined metronidazole and DMSO on tumour control and skin tolerance in the rat.

A combination of the radiosensitizer, metronidazole, and the radioprotector, dimethyl sulfoxide (DMSO), was tested for its effects on the radiation tolerance of rat skin and on the radiosensitivity of the BA1112 rhabdomyosarcoma. The simplest interpretation of the effects of the combined treatment is that: metronidazole radiosensitizes BA1112 in one-fraction but not in five-fraction treatments; metronidazole slightly increases the radiosensitivity of skin in one-fraction treatments; metronidazole radiosensitization is independent of the radioprotection produced by DMSO.


Influence of tumour size on radiosensitization by misonidazole.

The administration of misonidazole shortly before irradiation increased the radiation response of the Lewis lung tumour growing either as approximately 500mm3 subcutaneous implants or as 15mm3 lung colonies. In the subcutaneous tumours, the dose enhancement ratio was approximately half the oxygen enhancement ratio. In the lung colonies the sensitization of hypoxic cells appeared to be complete. Similar studies on subcutaneous B16 melanoma showed that the drug increased radiosensitivity to a level comparable with that of cells in small pulmonary nodules, whose hypoxic fraction appears to be below 10(-3). The results indicate complete dose modification of hypoxic cells where their natural proportion is small with incomplete enhancement of radiosensitivity where the natural hypoxic fraction is larger.


The effect of misonidazole on the radiation response of clonogenic human pancreatic carcinoma cells.

An enhancing effect of misonidazole on the in vivo radiation response of clonogenic human tumour cells from a pancreatic carcinoma xenograft has been demonstrated using both a soft agar in vitro assay and an agar in diffusion chamber assay. Enhancement ratios of 1.8 and 1.3 were found when cells were assayed at 0 h and 18 h respectively after irradiation. No enhancement was seen with in vitro irradiation of oxygenated cells. The potential of these assay systems as a perclinical screening test for new radiosensitizers is discussed.


The demonstration of in vivo misonidazole tumour toxicity using post radiation hypoxia.

The cytotoxic effect of the radiosensitizer misonidazole on hypoxic tumour cells in vivo has been studied. Using standard procedures of large single doses of X-ray (30 Gy) followed by 1.0 mg/g misonidazole, no significant cytotoxicity (measured by tumour regrowth) could be observed. In contrast, when utilizing post radiation hypoxia (3 h of 7% oxygen breathing) in conjunction with post radiation misonidazole, an increased amount of direct drug toxicity was demonstrated. The use of this acute hypoxia treatment may prove to be a useful tool for measuring various in vivo radiobiological responses.


Sensitization of hypoxic normal tissue.

The radiosensitization by misonidazole of three normal tissues in the unanaeshtetized mouse (femoral marrow, intestinal crypts and the target tissue for tail necrosis) has been studied. At 1 mg/g body weight, no sensitization was observed for the former two tissues, and no cytotoxicity for marrow was demonstrated. Sensitization of fully anoxic marrow or tail shown, by a factor of 1.8--1.9, in comparison with normal tails (factor 1.5). Clamping experiments revealed the homogenous nature of the natural hypoxia in the tissue responsible for tail necrosis, and an effective increase in the oxygenation was seen at Day 7 after a large priming dose.


Dose-modifying effect of misonidazole on the radiation response of growing cartilage in mice.

Misonidazole administered before a single dose of 15 Gy X-rays enhances the radiation response of growing bone in mice by a factor 1.3. In combination with split-dose irradiation of twice 7.5 Gy the drug did not cause significant enhancement. These results are most likely due to the existence of hypoxic cells in growing cartilage as has been demonstrated already by other authors.


The effect of the radiosensitizer misonidazole on motor nerve conduction velocity in the mouse.

The clinical use of misonidazole as a hypoxic cell radiosensitizer is at present limited by its neurotoxicity at high doses (Urtasun et al., 1977; Dische et al., 1977). An in vivo neurological end point, viz. measurement of nerve conduction velocity, has been developed to examine sensitizer action. Conduction velocity in mice was measured as a function of time after a single dose of misonidazole and as a function of drug dose. Doses greater than 0.33 mg/g produced significant transient reductions in velocity. The time course of the reduction in velocity closely followed the uptake/excretion profile of misonidazole from blood serum.


Conjecture on the role of dry charges in radiosensitization.

A model of cellular radiation damage that involves dry electrons and holes is proposed and the implications of this model to hypoxic radiosenstization are discussed. The transport and reaction properties of dry charges in the structured water surrounding polar biomolecules are considered and a solvation time of 600 picoseconds in this medium is derived. Pre-solvation charge migration, attachment and recombination and the relevance of these processes to sensitization are discussed. DNA damage by physico-chemical interactions with dry holes is proposed and is shown to be modified by oxygen and other electron affinic sensitizers.


Misonidazole with small dose fractions in an experimental osteosarcoma.

The mouse osteosarcoma C22LR was irradiated with a single X-ray dose of 1000 or 1500 rad (to prevent rapid growth) and then with fractionated doses of 300 or 600 rad each. Half the mice were given 0.8 mg/g of misonidazole 1 h before irradiation. Tumour growth delay was determined. The radiosensitizer did enhance the effect of small (300 rad) doses per fraction, as well as that of 600 rad doses.


A comparison of the effects of tumour growth delay of fractionated and single dose irradiation when administered with misonidazole (Ro-07-0582).

A majority of previous studies have shown the effectiveness of nitroimidazole derivatives, metronidazole and Ro-07-0582, in specifically sensitizing the hypoxic cell componenet of solid tumours to single doses of irradiation. The present study investigated the effects of nitroimadazoel Ro-07-0582 (0.75 mg/g) on the growth of MNU fibrosarcoma when administered with fractionated radiation therapy. Delay of tumour regrowth was recorded and was compared to single dose experiments using the sensitizer. The results show that fractionated radiotherapy with the sensitizer has an advantage over fractionated therapy alone (delay factor 1.58), but not over single dose therapy with the sensitizer (delay factor 2.6). This difference may be due to the sublethal repair from re-oxygenation in fractionated radiotherapy.


The effect of misonidazole in combination with radiation dose fractionation.

Single doses or multiple fractions of 2, 3, 5 or 10 Gy were given daily to KHT Sarcomas, growing in C3H mice, in combination with a misonidazole dose of 0.5 mg/g body weight administered 30--40 min before each radiation dose. Cell survival assays were performed on groups of tumours after different total doses to determine tumour cell survival curves for each fractionation schedule. The results indicate that misonidazole is effective in sensitizing the tumours to single doses and to large dose fractions, but that the degree of sensitization declines with fraction size such that there is no difference between the survival curves obtained for 2 Gy fractions given with or without prior drug treatment. Comparison of iso-effect curves, derived from the data, with those for normal skin suggests that, even though misonidazole increases the effect of the radiation on the tumour when large dose fractions are used, the small dose fractions probably still give a better "therapeutic ratio".


Sensitization of mouse tumours using fractionated X-irradiation.

The response of 3 different tumours to single doses and fractionated irradiation with and without misonidazole was compared. The osteosarcoma BS2 showed no significant drop in sensitization for 2 fractions compared with a single dose. The rapidly shrinking carcinoma NT and the non-shrinking fibrosarcoma showed a significant drop in the SER as the radiation dose was fractionated. This is consistent with effective reoxygenation occurring in both tumours. No sensitizing effect was observed in the fibrosarcoma for 5 fractions each given with metronidazole. When only 2 out of 5 fractions were given with the drug misonidazole, they were slightly more effective with the first 2 than with the last 2 fractions.


Some aspects of the metabolism of misonidazole.

The metabolism of the 2-nitroimidazole hypoxic cell radiosensitizer, misonidazole, has been studied in patients receiving radiotherapy. Results are presented which show that the compound reaches adequate levels in tumour  tissue and that, in animal systems, reduction products of the nitro group may also be present. Ah h.p.l.c method is described which has been used to quantify unchanged misonidazole and its nitroimidazole metabolites.


The hypoxic cell sensitizer programme in the United States.

The initial results of a Phase I evaluation of misonidazole in the U.S.A. are described, as well as the U.S. National Cancer Institute programme for radiosensitizer development. A total of 12 patients have been given 1--6 doses of 1--2 g/m2. Serum levels ranged from 25--87 microgram/ml at 4--6 h. One patient has developed mild peripheral neuropathy. Urinary excretion was chiefly of a demethylated metabolite as measured by HPLC assay.


Clinical studies with misonidazole.

The preliminary details of a randomized clinical trial of misonidazole for the radiotherapy of Grades 3 and 4 cerebral astrocytoma are described. Plasma concentrations of misonidazole and its O-demethylated metabolite, determined by high-pressure liquid chromatography analysis, are reported for 8 patients with astrocytoma, 1 with carcinoma of the bronchus and 1 with carcinoma of the breast. In the latter case, tumour concentrations are also presented.


The response of human tumour metastases to radiation and misonidazole.

In an attempt to investigate the radiosensitivity effect of the nitroimidazole misonidazole in man, sequential tumour volume measurements have been performed in 4 patients with metastatic malignant disease in order to compare the growth delay induced by radiation given before of 4 hours after the oral administration of the drug. One study was not completed, and there was no evidence of radiation sensitization in 2 patients. The results in the fourth patient were consistent with a small enhancement of radiation effect. Drug blood levels were followed on 9 occasions and tumour drug concentration measured in 1 patient.


Penetration of misonidazole after intravesical administration in cases of carcinoma of the bilharzial bladder.

The penetration of misonidazole was studied by a semiquantitative T.L.C. method after intravesical administration 2 h before total cystectomy in cases of carcinoma of the Bilharzial bladder. In 5 out of 7 cases misonidazole was found at a concentration of the order of 0.4 mg/g in the superficial and deep parts of the tumour, but not in normal bladder tissues.


Prolonged metronidazole administration with protracted radiotherapy: a pilot study on response of advanced tumours.

In a pilot study, 2.5 g of metronidazole was administered in 3 divided daily doses for prolonged periods with protracted fractionated conventional radiotherapy. Total cumulative metronidazole dose was 94 g in 31 patients with head and neck carcinoma. In some others, lower dosage was used. Radiotherapy dose varied form 3000 rad in 5 patients to 7600 rad in 31 patients. Preliminary results with a minimum follow-up period of 6 months suggest enhanced tumour response without evident toxicity. The improved results, if sustained, may be speculatively explained by the combined or individual enhancement of effect due to the hypoxic radiosensitizer or by the high dose precision radiotherapy or by the specific elimination of the hypoxic tumour cells by cytotoxic effect of prolonged metronidazole administration. Controlled trials are now needed.


Definitive evidence for hypoxic cells influencing cure in cancer therapy.

From an analysis of 2803 patients with carcinoma of the cervix treated by radiation therapy, a 62% cure rate can be shown. In those patients with Stage IIb and III disease, a haemoglobin level during treatment of below 12 g% was associated with a significantly higher pelvic recurrence rate, and also lower  cure rate, than for those with a haemoglobin level 12g% or more. A prospective study shows that the correction of anaemia is associated with a decreased pelvic recurrence rate and an increased cure rate consistent with tumour hypoxia being greater in anaemic patients than in those with a normal haemoglobin level. It is also consistent with the thesis that hypoxia controls the radiation local control rate in patients with advanced carcinoma of the cervix.


Unconventional fractionation in clinical radiotherapy.

Radiotherapy with decreasing individual tumour doses has been used in treatment of lung metastases and carcinomas. Treatment given with this unconventional schedule is more effective than conventional radiotherapy based upon equal doses and equal intervals. Tumours could be classified into 2 groups according to the shrinkage rate. In the group shrinking more rapidly, tumours totally disappeared in most instances; furthermore in most instances, tumours in this more responsive group could be identified because in the week after the first fraction they had already started to shrink.


Clinical experience with misonidazole.

A total of 62 patients with advanced tumours have now been treated by a fractionated course of radiotherapy, with misonidazole. The prime purpose of the administration of the drug to these patients was to determine safe dosage and suitable regimes for use in clinical radiotherapy. The reaction of normal tissues did not seem enhanced but there was an impression of increased tumour response.


A preliminary clinical study in the use of misonidazole in cancer of the head and neck.

The value of misonidazole in advanced head and neck cancer was examined in 3 ways and the preliminary results are reported in a randomized study with large fractions of irradiation, when misonidazole appeared to confer no advantage; whereas in previously (partially) treated patients misonidazole was possibly useful. The combination of hyperbaric oxygen and misonidazole did not appear to be toxic.


Rapid-mixing studies of the mechanisms of chemical radiosensitization and protection in mammalial cells.

A continuous flow, rapid-mixing system has been constructed to measure the degree of radiosensitization or protection observable after incubation of Chinese hamster ovary cells at room temperature for periods from about 5 to 1000 ms with a number of radiation modifiers. In agreement with Adams et al. (1975) full sensitization by oxygen is obtained in only a few tens of milliseconds. Misonidazole (10 mM) sensitizes at very nearly the steady-state level (E.R.  approximately 2.3) in about 300 ms. Similarly near maximum sensitization by 10 mM metronidazole is seen within the same period. For large effects to be observed in such short times makes unlikely the involvement of any biochemical modification of either the drug or cells. Radioprotection by 1 M dimethyl suplhoxide reaches about 80% of the equilibrium control value within 850 ms. However, if its mode of action involves scavenging of hydroxyl radicals in competition with cellular components, the necessity for very high concentrations in the immediate region of the cellular target would be expected to require longer diffusion times. Cysteamine (10 mM) shows no evidence of its substantial protective ability even after 850 ms incubation. This molecule, which alone in this group exists as an ion in neutral solution, may encounter considerable difficulty in entering the cells.


Radiation damage to DNA in aqueous solution: effects of radiosensitizers.

Systems are described for examining the molecular mode of action of anoxic radiosensitisers with DNA-OH radicals. Pulse radiolysis showed that NPPN reacts with these radicals even in the presence of 0.5 mM oxygen. Analysis of low molecular weight products  liberated from DNA by irradiation showed that NPPN does not act in an oxygen-like way but that misonidazole does. Thus a molecular rationale exists for the use of combinations of radiosensitizers.


Chemical aspects of radiosensitization. Reaction of sensitizers with radicals produced in the radiolysis of aqueous solutions of nucleic acid components.

The effects of oxidants (sensitizers) in the radiolysis of aqueous solutions of pyrimidine and purine bases have been investigated. Their influence on the nature of the permanent radiolysis products and on the kinetics of disappearance of transient intermediates is reported. Particular attention has been paid to the chemical fates of carbocationic intermediates which can be produced from radical-sensitizer interaction.


A quantitative determination of free radicals and strand breaks in pure and radiosensitized DNA.

The yields of free radicals and of single strand breaks were studied quantitatively after gamma-irradiation at 77 K of solid calf thymus DNA without and with incorporated misonidazole. At 77 K the rate of formation of the free radicals (the nature of which had been previously elucidated in oriented DNA samples) was found to be 1.7 x 10 (-12) and 2.4 x 10 (-12) per rad per dalton for DNA without and with misonidazole, respectively. The corresponding yield of single strand breaks in samples thawed and dissolved before alkaline sucrose gradient ultracentrifugation was found to be 1.2 x 10(-13)  per rad per dalton, not significantly (within 30%) different for DNA without and with misonidazole. The significant quantitative difference between induction of free radicals and single strand breaks shows that there is no simple relation between the appearance of the two types of lesions.


Cytotoxicity of misonidazole and DNA damage in hypoxic mammalian cells.

The loss of colony-forming ability and the yield of DNA single strand breaks were studied following exposure of various mammalian cell types to misonidazole. A correlation was observed between cell inactivation and DNA damage. If, after exposure, the cells were washed free of the drug and then incubated at 37 degree C in growth medium, it was observed that surviving cells repaired their DNA to the point that sedimentation profiles were identical to those of unexposed cells. In nonsurviving cells, however, the DNA was found to be further degraded with post-exposure incubation.


Nitropyrrole radiosensitizers: structure function relationships.

Nitropyrrole derivatives have been tested as hypoxic cell radiosensitizers in vitro and in vivo. Radiosensitizing potential generally increases with nitropyrrole electron affinity. N-hydroxyethyl substitution decreases toxicity relative to N--CH3, N--CH2 CH3 and N--CH2 CH2 CH3 substitution. The most effective nitropyrrole tested in vivo is N-hydroxyethyl-2-cyano-5-nitropyrrole (NP-1).


Studies on cis-dichlorodiammineplatinum (II) as a radiosensitizer.

Cis-dichlorodiammineplatinum (II) (cisDDP) has been extensively studied as an antitumour agent; its binding to DNA has been proved but the radiosensitizing action has scarcely been tested. We report here that on TC.SV -40 mammalian cells cisDPP acts as a dose-modifying factor for ionizing radiation. The radiosensitizing action can be induced by two different mechanisms: reaction with non protein-SH groups and inhibition of repair processes. The cisDDP-DNA complex was studied against increasing radiation doses by analytical centrifugation and by spectrophotometrical measurements. The native complex seems to be more radiation resistant than the denatured one.


Polyfunctional radiosensitizers IV. The effect of contact time and temperature on sensitization of hypoxic Chinese hamster cells in vitro by bifunctional nitroxyl compounds.

Three biradical nitroxyl compounds have been shown to modify the slope and shoulder region of the hypoxic cell survival curve of V79 cells to different degrees. The amount of sensitization produced by these compounds is dependent on the cell-drug contact time at both 20 degree and 37 degree C whereas sensitization by the monoradical nitroxyl, NPPN, is independent of these factors. The results suggest that biradicals may modify cellular biochemistry in such a way as to change the repair capacity of the cells. This could be responsible for changes in the shape of survival curves when cell-drug contact times are increased.


Some examples of anomalous radiosensitizing behaviour of electron-affinic compounds in vitro.

Studies using V79 379A cells on about 50 nitroaromatic and nitroheterocyclic radisosensitizers have confirmed the relationship between sensitizing efficiency and electron affinity. Almost all the compounds studied behaved similarly by sensitizing hypoxic cells to X-irradiation in a dose-modifying manner whilst having no sensitizing effect on oxygenated cells. However, a small number of the radiosensitizers studied exhibited additional or atypical properties. A 4-nitroimidazole ring substituted with chlorine sensitized hypoxic cells much more efficiently than predicted from its redox potential. A 2-nitroimidazole substituted with a carboxylic acid side chain showed a low but constant level of sensitization over 5 decades of concentration. A 5-nitrofuran, in addition to sensitizing hypoxic cells by dose modification, sensitized oxygenated cells by a reduction in extrapolation number.


Interaction between electron-affinic sensitizers.

Measurements of effect of pairs of the sensitizers PNAP, misonidazole and oxygen have shown that if one sensitizer is giving an enhancement ratio (ER) of about 1.6 or less and the other is giving a larger ER, the combination behaves as if only the latter is present. There is only an additive effect of the two if they both give ERs less than 1.6 or greater than 1.6. These results show that at low concentrations sensitizers only act on damage associated with the "fast component" of the oxygen effect. This could result from interaction with two distinct species, or there could be only one critical species formed initially but more than one step by which it could be converted to a lethal form.


Copper as a hypoxic cell sensitizer of mammalian cells.

The sensitizing effect of copper solutions has been studied on mammalian cells. A non-toxic concentration of cupric chloride was reduced under anoxia by irradiation to cuprous chloride, added to anoxic murine leukaemic L5178Y cells and irradiated either under aerobic or anoxic conditions. Sensitization (dose modification factor 1.54) was  observed when the cells were irradiated in anoxia (oxygen-free nitrogen gassing). Sensitization was not observed when the cells were irradiated under aerobic conditions (air gassing). Electron spin resonance studies indicated that the conversion Cu II vector Cu I could be brought about by cells incubated under anoxic conditions at room temperature without irradiation.


Platinum complexes as radiosensitizers of hypoxic mammalian cells.

Cis-dichlorodiammineplatinum (II), or cis-PDD,  has recently been shown to be a potent radiosensitizer of bacteria, particularly under conditions of acute hypoxia. This study extends this observation to include the radiosensitization of mammalian cell (V-79) by low concentrations of cis-PDD, cis-dichlorobis(aziridine) platinum (II), and the trans-isomer of PDD as measured from survival curve analysis. This radiosensitization was obtained at concentrations of 10 micrometer, 60 micrometer, and 100 micrometer for the cis-PDD, aziridine-platinum, and trans-isomer respectively. The corresponding drug toxicity survival levels were 8, 40 and 50%. Dose modification factors of around 1.3 to 1.4 were observed.


Safety and efficacy of jet anesthesia for bone marrow aspirations.

Aspirations or Jamshidi needle biopsies (n = 287) of bone marrow were performed on children and adolescents with acute leukemia or other malignant disease following the use of a spring-loaded instrument that delivered local anesthetic in a jet spray; 89% of the patients were receiving chemotherapy, 12% were thrombocytopenic, and 23% of the 269 patients who were afebrile at the time of the procedure were severely neutropenic. None of these patients had an infection or a hemorrhage as a complication of the procedure. We conclude that not only is this procedure safe, but it is also much less painful than the traditional method of local anesthetic infiltration using a syringe and needle.


Proliferative state of blast cell progenitors in acute myeloblastic leukemia (AML).

Peripheral blood from patients with acute myeloblastic leukemia (AML) contains cells capable of giving rise to colonies in culture when stimulated by media conditioned by leukocytes (LCM) in the presence of phytohemagglutinin (PHA). Two types of colonies are recognized with high frequency: The first grows in the presence of low concentrations of PHA LCM, have a blast-like morphology, and are numerically correlated with morphologically identified blast cells. The second requires either high PHA LCM concentrations or PHA alone with or without 2-mercaptoethanol and consists of cells capable of forming rossettes with sheep erythrocytes and resembles. T-lymphocyte colonies from normal blood. Precursors of blast cell colonies from 15 leukemic patients were tested for cycle state, using either the 3H-thymidine or hydroxyurea techniques. All were found to have a high proportion of cells in the S phase of the cycle. In contrast, T lymphocyte precursors from three normal individual were quiescent. The data are consistent with the maintenance of the leukemic blast cell populations by the proliferative activity of a small subpopulation of blasts.


Lymphoblast cell size and prognosis in acute lymphoblastic leukemia in childhood.

The significance of cell size as a prognostic indicator in acute lymphoblastic leukemia (ALL) is controversial. Accuracy in measurement of cell size can be improved by determination of cell areas instead of single cell diameters. In the present study cell areas of 200 cells were determined in pretreatment bone marrows of 35 children with ALL. For better comparison with other studies which had used cell diameters only, the measured area was expressed as circle area from which the circle diameter was calculated. Cells with a diameter of greater than 12 micron were defined as macrolymphoblasts (MLB). Several clinical characteristics considered to be risk factors in ALL were ascertained for each patient. The duration of first complete remission was used to assess the prognostic significance of cell size and of number of risk factors. In contrast to previous reports patients with more than 25% MLB had longer remissions. However, nearly all patients of this group had no or one risk factor only. When patients with more than one risk factor were excluded from statistical analysis, the group with more than 25% MLB had no longer a better prognosis compared to the group with 25% MLB or less. Thus, in this study the percentage of MLB was not an independent prognostic indicator for risk of relapse in ALL.


Metabolic and endocrine alterations in osteosarcoma patients.

Eighteen patients with primary osteosarcoma were studied for abnormal endocrinologic functions. Oral glucose tolerance tests revealed abnormal glucose, insulin, or growth hormone response curves in 78% of the study population. Elevated somatomedin values were noted in 72% of the patients tested. No significant deviations were observed in serum cortisol, estradiol, testosterone, follicle stimulating hormone, and luteinizing hormone levels. Likewise, lipid screening and 24 hour 17-hydroxy and 17-keto steroid excretion levels were normal. Statistically these derangements were unrelated, leading to the hypothesis that some additional factor or factors are present and responsible for the abnormalities noted. These deviations, found in association with primary osteosarcoma, constitute a new "paraneoplastic syndrome."


The central nervous system in childhood leukemia. III. Mineralizing microangiopathy and dystrophic calcification.

We determined the prevalence, histopathologic features, and clinical correlations of a distinctive vascular lesion within the central nervous system (CNS) of children who died with acute lymphoblastic leukemia (ALL). Of 163 brains examined at autopsy, 28 (17%) had a noninflammatory mineralizing microangiopathy, usually accompanied by varying amounts of necrosis and calcification in adjacent neural tissue. The lesion always involved the lenticular nucleus with or without additional involvement of cerebral cortex. It was not the cause of death in any patient. An analysis of clinical features common to patients with microangiopathy indicated that cranial irradiation, in doses as low as 1500 rad, had induced the degenerative process. Survival beyond 10 months from the time of irradiation and multiple postirradiation CNS leukemic relapses, both had significant influences on the development of the lesion. Chemotherapy, particularly systemic or intrathecal methotrexate, might have contributed to the disease process, but apparently was not the instigating factor. Patients at greatest risk for developing microangiopathy are those under 10 years of age at the time of cranial irradiation, who then live more than 10 months and develop multiple CNS leukemic relapses.


Early deaths in newly diagnosed cases of pediatric acute leukemia: a Southwest Oncology Group Study.

A reanalysis of all ten clinical trials conducted by the Southwest Oncology Group from 1958 thorugh 1976 in newly diagnosed pediatric acute leukemia was carried out to quantify the "early death" rate (i.e., rate of deaths during the first four weeks of remission induction) and to determine factors related to these deaths. Out of 1,964 patients registered, there were 126 (6.4%) early deaths. For the 1,375 acute lymphocytic leukemia (ALL) patients only, there were 75 (5.5%) early deaths. During the last eleven years on this study (1965 through 1976), the death rate for ALL patients appears to have remained stable at five deaths per 100 patients, despite the general improvement in overall survival. The most important prognostic factor was the initial platelet count: patients with a platelet count below 25,000 had a death rate over three times higher than that of patients with a platelet count over 75,000. Infants under one year of age also had a very high early death rate (6 of 41, 15%).


Sister chromatid exchange in Philadelphia chromosome (Ph1)-positive leukemia.

The sister chromatid exchange (SCE) frequency was studied in the leukemic cells of 12 patients, 10 with Philadelphia chromosome (Ph1)-positive chronic myelocytic leukemia (CML), 1 with Ph1-negative CML, and 1 with acute myeloblastic leukemia. Except for two patients in the blastic phase of CML, the SCE values were within the normal range [3.8 +/- 6.4 (S.D.) SCE/cell; normal is 3.3 +/- 2.2 SCE/cell]. In the two cases with the blastic phase of CML, the values were 7.6 +/- 3.2 and 8.9 +/- 4.7 SCE/cell, a statistically significant difference from the control values. However, in the patient with acute myeoblastic leukemia, the SCE incidence increased from 3.6 to 24.4 SCE per cell when therapy was changed to daunorubicin and vincristine and the disease became progressive. Further studies on SCE and leukemia may prove the usefulness of this determination for therapeutic and clinical purposes.


Site of action of methyldopa in lowering the blood pressure in man.

1. Methyldopa was administered to hypertensive patients in association with two different inhibitors of dopa decarboxylase, one of which, carbidopa, scarcely penetrates the central nervous system while the other, benserazide, penetrates the central nervous system when given in high doses. 2. The evidence suggests that in man, as in animals, the predominant action of methyldopa is mediated by the formation of methyldopamine and methyl-nor-adrenaline within the brain.


The definition of transcription units for mRNA.

The detailed analysis of TUs with purified Ad2 DNA and the analysis of TU size for the bulk HeLa cell hnRNA compared to the size of mRNA of infected and uninfected cells supports the conclusion that mRNA in mammalian cells is generally derived by the processing of primary transcripts. In the context of this volume, these results indicate that the RNA transcription products of chromatin which are related to mRNA are longer than the mRNA itself. Proper functioning of chromatin in vitro must eventually take these results into account.


Reducing interpersonal stress in dental practice.

Inherent in the dental situation is the potential for a great deal of interpersonal stress. While the particular areas of stressful interaction are as numerous and varied as are the approaches to deal with such situations, what may be of ultimate importance is what an individual tells himself or herself about such situations. Stresses become distressful when we interpret them as terrible, unfair, or catastrophic, rather than an unfortunate or undersirable, perhaps the inevitable result of the general nature of the human condition. We may not have the power or ability to control many external stress-producing events, but we do indeed have the ability to alter how we feel about such events by becoming aware of our self-defeating beliefs and negative self-talk, and subsequently by finding more appropriate and positive messages to tell ourselves about such occurrences. In addition, the quality of the emotional environment established in  the dental office can be altered to reduce the interpersonal stresses resulting from poor communication between dentist, staff, and patient. The end result will hopefully be a longer and happier relationship for all persons involved in dentistry and better realization of everyone's stated goal-improved dental health.


Stresses and self-destructive behaviors of dentists.

The practice of dentistry is both a rewarding and a demanding profession, and the dentist's well-being may depend largely on how successfully he learns to keep the rewards and demands of his job in proper prospective. In order to achieve a desirable balance, he needs to identify the causal factors of stress and strain and take measures to eliminate, or at least lessen, their negative impact on his emotional health. This may involve a reevaluation of life style, health habits, and personal goals.


Dentist, "heal thyself": modification of life style.

In the late 1960's, preventive health care began to gain in popularity in the United States and the movement carried over into the 1970's. During this time, sizable decreases in deaths from heart disease, strokes, and accidents have been noted. As a result, the lowest death rate in the history of this country (8.9 per 1000) occurred in both 1975 and 1976. Since 1970, an increase in longevity has been documented and it can be said that Americans are living longer--not just longer but hopefully better! People are beginning to learn that "it is not so much that we die, we kill ourselves!" With proper weight, diet, and exercise, avoiding tobacco, early detection and treatment of high blood pressure, use of seat belts, and control of stimulants and drugs, thousands of lives are being saved annually. In today's busy and demanding society, success in any field requires more than just education and hard work. It requires good health, both mental and physical. Pursue these goals vigorously and remember, "It is always cheaper and much easier to maintain good health than it is to regain it once it is lost!"


The patient's greatest hazard.

To reduce the patient's hazard in the dental office, the dentist must take a medical history, perform a limited medical examination, order and interpret laboratory tests when indicated, initiate medical consultation when necessary, and evaluate the data obtained in order to make appropriate treatment modifications for high risk patients. The current status of health which our population enjoys must not be confused with a status of robustness. An apparently well patient may be in great jeopardy while you are delivering the most skillful dental care unless adequate precautions are taken.


Light and lighting in the dental office.

For any task, the eye can respond effectively if there is enough light, if that light is properly distributed, if the appropriate color correction is provided, and if visual contrasts are balanced. Dental offices differ in the types of work performed, the number of people engaged in various tasks, and the types of patients treated. Each office and each room can be planned according to the guidelines herein suggested as long as a rational analysis is applied to the result desired and the tasks being accomplished. The authors suggest that all concerned with office design, the architect, the contractors, and even other illuminating engineers be asked to read this article before integrating their efforts, for the dental office presents some variations not frequently encountered by these people. The need for conservation of our energy sources mandates wise use of all our energy expenditures. There is another resource conservation need that is sometimes overlooked--the effective use of talented people such as the dentist and his staff. The employment of adequate illumination design heeds both demands while giving a rewarding pleasantness and enjoyment of the work environment.


Mercury hygiene.

Dentists have a moral and legal responsibility to protect themselves and their employees from high amounts of mercury vapor in the dental office. Time should be taken to train both new and existing office personnel on the nature of the problem, improved housekeeping methods, the importance of reporting problems as they occur and proper clean-up procedures.


Biological effects and radiation protection in the dental office.

In conclusion, it is important to point out that dentistry's contribution to the United States population's radiation exposure is small. Significant improvements have been made, but since dentistry is only one of the contributors to the population's total exposure to radiation, it is important that we make every effort to keep our contribution as low as is practical. Unnecessary exposure should be reduced whenever possible but this should not be used to deter the practitioner from obtaining radiographs when they are clinically indicated. It is very likely that the risk to the United States population resulting from failure to obtain adequate diagnostic information when radiographs are indicated is considerably greater than any risk resulting from their use.


[Possible vertebrate use of a mechanism of chromatin reduction to fuse the V and C genes of immunoglobulins].

Diminution of a chromatin fragment separating V- and C-immunoglobulin genes is suggested as possible mechanism of fusion of V- and C-genes into one functionally active cisrtron. During the early stage of immunodifferentiation of lymphocytes, the chromatin fibrills unfold, and V- and C-genes bring together by DNA-DNA and DNA-protein interaction. The endonucleases excise the chromatin fragment interlocated between V- and C-genes, then the repair enzymes restore the intactness of chromating structure by fusion of V- and C-genes. A number of human pathologic syndromes, the elimination of nucleus during erythrocyte differentiation in mammals indicate the possibility of manifestation on diminution mechanism in vertebrates. Fusion of V- and C-genes by chromatin diminution fits the number of immunologic phenomena, and it may display for different paths of V-gene coding and may be experimentally verified.


High terminal deoxynucleotidyl transferase activity in pediatric patients with acute lymphocytic and acute myelocytic leukemias.

Specificity of TdT5 as a marker for ALL was evaluated by determining its activity in cells from normal control subjects and from 35 pediatric patients with ALL, AML, Hodgkin's disease and disseminated Burkitt's lymphoma. We evaluated the DNA polymerase activity, cell surface phenotypes (E rosettes, EAC rosettes, Smlg and la-like, HTLA and cALL antigens), and hematological and cytochemical characteristics in both the normal and patient groups. DNA polymerase alpha + beta and DNA polymerase gamma activity were indiscriminately high in all immature cells as found in ALL, AML, Burkitt's lymphoma and phytohemagglutinin-stimulated normal lymphocytes, when compared to mature leukocytes found in normal individuals or in patients whose cancer was in remission. High TdT activity was found in 24 of 26 T and non-T/non-B ALL patients in active phase as well as in two of three AML patients one of whom had Auer rods. Thus, TdT, although valuable for monitoring ALL patients, may have limitations in separating AML from ALL.


Influence of age and cortisone treatment on two intestinal lysosomal hydrolases in young rats.

The effects of cortisone acetate injected i.p. on acid phosphatase and beta-glucuronidase in the small intestine mucosa of two groups of rats aging 12-14 and 20-22 days are reported. The following results are obtained: a) Total and free activities of the two enzymes show age-dependent differences. b) Cortisone acetate causes a very marked decrease of the enzymic activities only in the younger rats while being ineffective on the older ones. c) The kinetics of the enzyme release at 37 degrees C appear independent either of age or of cortisone injection. d) The "in vitro" lysosome labilizing treatments are ineffective.


Parosteal (juxtacortical) osteogenic sarcoma. A roentgenological study of 30 patients.

Detailed analysis of the roentgen findings in 30 well-documented cases of parosteal osteogenic sarcoma (POS) was made. The supposedly characteristic periosteal lucency (cleavage plane) was found in only 30% of the patients. While most tumors were densely ossified, the radiodensity was uniform in only 27%. The surface of the tumor was usually irregular and a truly smooth surface was seen in only 24%. Four patients underwent arteriography; there was vessel displacement by the tumors but all were avascular. No correlation between the histologic grade of tumor and roentgen signs was found.


Pyridoxal phosphate catalyzed alpha-beta elimination of selenahomolysine.

In the presence of pyridoxal phosphate selenahomolysine undergoes alpha-beta elimination with production of pyruvate, ammonia and selenohomocysteamine. If the reaction occurs in anaerobic conditions the coupling of pyridoxal phosphate with selenohomocysteamine in a tetrahydro-selenazine ring may be detected by the appearance of an absorption band at 320 nm. In the presence of air the autoxidation rate of selenohomocysteamine is too high to allow the detection of the selenazine derivative. The results obtained add to the previously reported ones indicating that selenium- and sulfur-containing aminoacids react in quite the same way in the non enzymic model studied.


Differential denaturation of a crystalline Bence-Jones type cryoprotein as monitored by fluorescence.

1) A Bence-Jones type protein (Cryo-Ver) showing the cold precipitation phenomenon has an extremely low intrinsic fluorescence when excited at 280-295 nm. 2) This fluorescence increases considerably upon denaturation of the molecule by heat or guanidine hydrochloride. Guanidine is about twice as effective as heat in terms of fluorescence yield. 3) The heat-denatured protein is still reactive with anti-cryoVer antibodies, at variance with the guanidine-treated samples. 4) Since the protein contains two tryptophans per mole, one in the constant portion of the molecule, the other in the variable region, it is proposed that heat treatment affects only the variable region, which seems involved in the cryoprecipitation phenomenon.