Melatonin, cortisol and prolactin response to acute nocturnal light exposure in healthy volunteers.

An investigation of the cortisol and prolactin responses accompanying acute melatonin suppression by light (600 lux) in humans is described. Light given from midnight to 0300h suppressed nocturnal plasma melatonin concentrations by 65%. Despite this significant suppression of melatonin, no significant effect on plasma cortisol or prolactin concentrations was observed. These data support recent studies which argue that, if there is a relationship between melatonin, the hypothalamo-pituitary, and the hypothalamo-pituitary-adrenal axis in humans, it is neither direct nor simple.


Effects of thyroid hormones on central nervous system in aging.

Support for the many relationships between thyroid hormones and brain function comes from both laboratory and clinical studies. Studies in laboratory animals provide convincing evidence for a neuroregulatory role of thyroid hormones in the brain, suggesting that they may affect behavior. This notion is supported by human studies which have revealed that the effects of thyroid hormones on brain function are most important during the development and maturation of the brain; thereafter, age does not seem to critically affect brain-thyroid hormone relationships.


Major depression and subclinical (grade 2) hypothyroidism.

Subclinical hypothyroidism (SCH) has been reported to occur in patients with a variety of affective syndromes. However, the clinical correlates of SCH in patients with major depression have received limited attention. We therefore examined demographic, clinical and treatment response variables in a cohort of patients with unipolar, nonpsychotic major depression with and without SCH. Of 139 subjects, 19 had SCH defined as an elevated basal TSH with normal circulating levels of T3 and T4. Major depression with SCH differed from that without SCH by the presence of a concurrent panic disorder and a poorer antidepressant response.


Effects of peripheral hormones on memory and ingestive behaviors.

This article explores the mechanisms by which peripheral gastrointestinal hormones produce central nervous system effects on memory and feeding. Cholecystokinin produces its satiety effects and memory-enhancing effects by stimulating ascending vagal fibers. Hyperglycemia has been demonstrated to be a cause of memory dysfunction in persons with diabetes mellitus. A number of other hormones, such as amylin and bombesin, modulate both memory processing and feeding. The causes of the anorexia of aging are briefly reviewed.


Adrenal activity does not mediate alarm substance reaction in the forced swim test.

Rats tested in the forced swim test were more immobile in fresh water than in water soiled by other rats, which presumably contained an alarm substance. Adrenalectomy did not affect the behavior of the rats in fresh or soiled water, nor did it affect production of or response to the putative alarm substance. The results of this study indicate that the adrenals do not mediate the response to, or production of the alarm substance.


Failure to stimulate melatonin synthesis in the rat pineal gland with an adenosine analog.

Recent studies indicate the presence of adenosine binding sites in rat pinealocytes and an effect of their activation on pineal serotonin metabolism. However, controversial data exist, and reports suggest that the role of adenosine in pineal physiology is complex. On this basis, we evaluated the effects of an adenosine analog (N-ethyl-carboxamido-adenosine: NECA) on in vitro and in vivo melatonin production in the rat pineal gland. In the in vitro protocol, pineals were incubated with NECA (0.5 mM, 1 mM, or 2.5 mM) or isoproterenol (ISO: 10(-6)M) for 4 hr. In the in vivo experiments, animals were given NECA (1 mg/kg IP), ISO (0.5 mg/kg IP) or 1 ml saline diluent and sacrificed 2 hr later. The samples were assayed for pineal N-acetyltransferase (NAT) activity and melatonin concentrations. ISO caused the expected marked rise in NAT activity and melatonin levels in both protocols. NECA was ineffective in causing any modification of the parameters measured. We conclude that the adenosine analog NECA may not be involved in the activation of melatonin production. These data contrast with others in which NECA administration resulted in an increase in melatonin levels. The participation, if any, of the purinergic system in the physiology of the pineal gland is still far from being characterized.


Clinical evidence for thyroid dysfunction in patients with seasonal affective disorder.

Of 49 consecutive patients over a 21-mo period satisfying conservative criteria for seasonal affective disorder (SAD), a well-characterized syndrome involving seasonal neurovegetative dysregulation, 17 (35%) were found to have elevated serum TSH compatible with mild primary hypothyroidism (TSH > 4.6 microIU/ml). An additional eight patients (16%) met criteria for "conjectural" hypothyroidism (TSH > 3.5 microIU/ml or exaggerated TSH response to TRH). The frequency of cases with supranormal TSH within the SAD group, both with and without inclusion of the "conjectural" cases, proved statistically significant when compared to that within psychiatric patients not satisfying criteria for SAD (N = 381) or to that within the population at large. The author suggests that SAD may in part represent a reformulation in modern neuropsychiatric terms of a previously noted fall-winter decrement, both biochemical and clinical, among hypothyroid patients.


Oxytocin and vasopressin hexapeptide fragments have opposing influences on conditioned freezing behavior.

We investigated the influence of C-terminal fragments of oxytocin (OT) and arginine vasopressin (AVP) on conditioned freezing behavior. Subcutaneous injections of 0.3 microgram AVP(4-9) or OT(4-9) given to rats after shock training or before behavioral observation significantly altered fear-induced freezing behavior. Animals treated with OT hexapeptide froze less than controls, while animals treated with AVP hexapeptide froze more. These results support the concept that the hexapeptide metabolites of oxytocin and vasopressin can selectively modulate certain behavioral processes, and that these peptides have opposite effects on performance in behavioral tests designed to evaluate memory consolidation and retrieval.


The birthday: lifeline or deadline?

This study of deaths from natural causes examined adult mortality around the birthday for two samples, totalling 2,745,149 people. Women are more likely to die in the week following their birthdays than in any other week of the year. In addition, the frequency of female deaths dips below normal just before the birthday. The results do not seem to be due to seasonal fluctuations, misreporting on the death certificate, deferment of life-threatening surgery, or behavioral changes associated with the birthday. At present, the best available explanation of these findings is that females are able to prolong life briefly until they have reached a positive, symbolically meaningful occasion. Thus, the birthday seems to function as a 'lifeline' for some females. In contrast, male mortality peaks shortly before the birthday, suggesting that the birthday functions as a 'deadline' for males.


Bronchoscopy and tuberculostearic acid assay in the diagnosis of sputum smear-negative pulmonary tuberculosis: a prospective study with the addition of transbronchial biopsy.

A prospective study of the efficacy of bronchoscopy and tuberculostearic acid assay in the diagnosis of sputum smear-negative pulmonary tuberculosis (TB) was carried out in 39 patients with symptoms and radiographic changes suggestive of active pulmonary TB. The diagnosis of TB was confirmed in 15 patients, probable TB was diagnosed in eight and 16 patients did not have TB. An early diagnosis of TB was made by bronchoscopy in six patients (40 per cent). Culture of sputum obtained before bronchoscopy was positive in nine patients (60 per cent) while combined with bronchoscopy specimens, a positive mycobacterial culture was obtained in 12 patients (80 per cent). Mycobacteria were cultured from transbronchial biopsy specimens from five patients (33 per cent) but none of these was exclusively positive. Histological examination of transbronchial biopsy tissue was diagnostic of TB in four patients and it was the exclusive means of early diagnosis in two. Transbronchial biopsy also provided an alternative diagnosis in four other patients. Tuberculostearic acid assay had a sensitivity of 0.40 in bronchial aspirate, 0.80 in bronchoalveolar lavage fluid, and 0.27 in transbronchial biopsy specimens: the combined result was 0.87. In nine patients with pulmonary TB in whom an early diagnosis could not be made, the tuberculostearic acid assay was positive in seven (78 per cent). We conclude that bronchoscopy with bronchoalveolar lavage and transbronchial biopsy is helpful in providing early diagnosis and positive culture results. Assay of tuberculostearic acid in bronchoalveolar lavage fluid is a useful adjunct to early diagnosis. However, mycobacterial culture and assay of tuberculostearic acid in transbronchial biopsy specimens have little diagnostic value.


The presentation and outcome of HIV-related disease in Nairobi.

The range of clinical presentations of HIV-related disease in Africa has not been adequately described, despite the fact that many hospitals have to rely heavily on clinical diagnosis. Six hundred adult medical patients seen in the Casualty Department of the main Government hospital in Nairobi were enrolled in a study of the presentation and outcome of HIV-related disease: 506 of these patients were admitted, of whom 19 per cent (95) were HIV seropositive. The remaining 94 were dealt with as outpatients: 11 percent (10) of these were seropositive. A history of prior treatment for sexually transmitted disease and, if male, being uncircumcised, were associated with being seropositive. Three presentations were strongly associated with HIV infection: acute fever with no focus except the gastrointestinal tract (enteric fever-like illness), acute cough with fever (community-acquired pneumonia) and chronic diarrhoea with wasting. The WHO clinical case definition (CCD) for AIDS missed a substantial amount of HIV-related morbidity (sensitivity 39 per cent) and misidentified many seronegative patients (positive predictive value 59 per cent). In comparison with the Centers for Disease Control surveillance definition for AIDS, the CCD was specific (91 per cent) and sensitive (79 per cent) but only had a positive predictive values of 30 per cent: the CCD may therefore be a poor surveillance tool for AIDS. Seropositive patients were much more likely to die than were seronegative patients (39 per cent vs. 15 per cent mortality). Enteric fever-like illness was the presentation which most commonly proved fatal. A wider spectrum of disease is associated with underlying HIV immunosuppression than has previously been described in Africa.


Culture and somatic experience: the social course of illness in neurasthenia and chronic fatigue syndrome.

An anthropological view of culture and somatic experience is presented through elaboration of the notion that illness has a social course. Contemporary anthropology locates culture in local worlds of interpersonal experience. The flow of events and processes in these local worlds influences the waxing and waning of symptoms in a dialetic involving body and society over time. Conversely, symptoms serve as a medium for the negotiation of interpersonal experience, forming a series of illness-related changes in sufferers' local worlds. Thus, somatic experience is both created by and creates culture throughout the social course of illness. Findings from empirical research on neurasthenia in China, and chronic fatigue syndrome (CFS) in the United States, corroborate this formulation. Attributions of illness onset to social sources, the symbolic linking of symptoms to life context, and the alleviation of distress with improvement in circumstances point to the sociosomatic mediation of sickness. Transformations occasioned by illness in the lives of neurasthenic and CFS patients confirm the significance of bodily distress as a vehicle for the negotiation of change in interpersonal worlds. An indication of some of the challenges anthropological thinking poses for psychosomatic medicine concludes the discussion.


Prevalence of psychiatric disorders in early stages of HIV infection.

As part of a military universal HIV screening program, 442 men were assessed for the presence of DSM-III-R defined psychiatric disorders and symptoms of anxiety and depression after notification of HIV seroconversion. Of them, 84.4% were in the earliest, asymptomatic stages of disease at the time of interview (96% did not have AIDS). The Structured Clinical Interview for DSM-III-R and Structured Interview Guide for the Hamilton Anxiety and Depression Scales were used. Relevant comparisons were made to Epidemiologic Catchment Area prevalence data. HIV seropositive men were more likely than age-matched men in the community to have current diagnoses of major depression (ages 18-44) and anxiety disorders (ages 25-44). Higher lifetime rates of major depression and alcohol use disorder, and high current prevalence of sexual dysfunction (21.7%) were noted. We conclude that men who become HIV seropositive have high rates of mood and substance use disorders prior to knowledge of seroconversion, and that early in the course of HIV infection men are at risk for developing major depression, anxiety disorders, and disorders of sexual desire.


Creutzfeldt-Jakob disease in recipients of human growth hormone in the United Kingdom: a clinical and radiographic study.

In the past 3 years there have been five further cases, in addition to one case reported in 1985, of Creutzfeldt-Jakob disease in recipients of human growth hormone in the United Kingdom. The clinical findings of two of these cases are described, demonstrating a typical presentation with a predominantly cerebellar syndrome at onset which is not commonly a presenting feature of sporadic Creutzfeldt-Jakob disease. In one case a 99mTc hexamethylpropylenamine single photon emission tomographic scan showed marked impairment of tracer uptake in the basal ganglia and cerebral cortex at a time when the clinical picture was predominantly cerebellar. This technique may be useful in early diagnosis. In the other case post mortem examination of the brain showed prominent amyloid deposition in the cerebellum, which has not been described previously in pituitary-hormone related Creutzfeldt-Jakob disease. The previously published cases of growth hormone-related Creutzfeldt-Jakob disease are reviewed and reasons for the particular clinical pattern seen are discussed.


The relationship between long-term glycaemic control and diabetic nephropathy.

Urine albumin excretion was studied by two widely accepted methods in 210 patients with insulin-dependent diabetes mellitus and related to the mean of serial glycosylated haemoglobin (HbA1) measurements made every 3 months during the previous 6 years. Microalbuminuria (albumin excretion rate > 20 micrograms/min) was present in 9.5 per cent of patients when defined by a 24-hour collection and 8.1 per cent of patients when defined by a timed overnight urine sample. Those with microalbuminuria, as estimated from a timed overnight urine sample, had a longer duration of diabetes but otherwise did not differ in age, duration of diabetes or arterial blood pressure from patients whose albumin excretion rate was 20 micrograms/min or less irrespective of the method of urine collection. The mean and the most recent HbA1 levels differed significantly between the normal and the microalbuminuric groups when defined by the 24-hour albumin excretion rate (p < 0.001, p < 0.01), but no significant difference between these groups was found when albumin excretion rates were calculated from the timed overnight urine sample. Albumin excretion rate, examined in relation to mean HbA1, increased significantly with worsening glycaemic control whether measured over 24 hours or overnight (p < 0.05, p < 0.01). These findings support an association between glycaemic control and microalbuminuria, but the correlation is weak, dependent on the method of urine collection and is just as good for a relatively short-term as for a long-term measure of average blood glucose.


Similarity of depression in diabetic and psychiatric patients.

Diabetic and psychiatric out-patients were studied to determine whether the symptom profile of depression was similar in medically ill and medically well subjects. The diagnosis of major depression was determined using psychiatric interviews and DSM-IIIR criteria. The 21-item Beck Depression Inventory (BDI) was used to characterize the prevalence and severity of depression symptoms, and the measure was divided into cognitive (13 symptoms) and somatic (eight symptoms) subsets. Seventeen (81%) of 21 symptoms (including 12/13 cognitive and 5/8 somatic symptoms) were not statistically different in prevalence or severity between the depressed diabetic patients (N = 41) and the depressed psychiatric patients (N = 68). Both of these depressed groups were significantly different from a nondepressed diabetic comparison group (N = 58) in the prevalence and severity of every BDI symptom except weight loss. These data show that the symptom profile of depression in diabetic patients (in particular the cognitive symptoms) is similar to that in depressed psychiatric patients and is readily differentiated from the symptom profile in nondepressed diabetic patients. Our observations support the diagnostic validity of the DSM-IIIR criteria for major depression in this medically-ill outpatient sample.


Effects of stress and blood type on cortisol and VLDL toxicity preventing activity.

Past research has associated ABO blood type and mental stress with cardiovascular risk. We studied the effects of blood type (A vs. O) coupled with a mirror drawing stressor on very low density lipoprotein toxicity-preventing activity (TxPA) and plasma cortisol levels. Exposure to the stressor significantly decreased TxPA and increased cortisol for the total group of 25 older adult males. However, the stress response patterns of the 15 blood type A males were different from those of the 10 type O subjects. The blood type A group had higher initial levels of TxPA and cortisol as well as quicker stress recovery rates than the type O group. ABO blood type may be an important behavioral hematologic variable to assess in studies concerning biochemical stress response or cardiovascular risk.


Bilateral paramedian thalamic infarction: a distinct but poorly recognized stroke syndrome.

Six patients with bilateral paramedian thalamic infarction were seen in a general hospital over a 4 year period. This distinct stroke syndrome was recognized by the features of disturbed vigilance, often episodic, with vertical gaze disorder. Other signs included an amnesic syndrome, convergence difficulty, third nerve palsies, eyelid retraction, dysarthria, ataxia and involuntary limb movements. Diagnosis was confirmed by CT brain scan or magnetic resonance imaging. A variety of risk factors for stroke were present. All patients improved but two had significant residual disabilities.


Mechanisms of abnormal glucose metabolism during the treatment of acute severe asthma.

Twenty-five patients with acute severe asthma were treated with oxygen, corticosteroids and either salbutamol or aminophylline by intravenous infusion. Blood glucose, plasma insulin and glucagon were measured during the first 24 hours of treatment. Salbutamol and aminophylline rapidly caused hyperglycaemia, accompanied by a rise in insulin and a fall in plasma glucagon. At first the increase in plasma insulin was insufficient to restore normoglycaemia, but by 24 hours homeostasis was restored. The early submaximal insulin response was attributed to the fasting caused by breathlessness. There was no evidence of an increase in hormone secretion caused by direct beta 2-adrenergic stimulation of the pancreatic islets. The effect of corticosteroids on blood glucose over the period of study was considerably less than the contribution of either salbutamol, or aminophylline.


The spectrum of chronic liver disease in renal transplant recipients.

Chronic liver disease has been reported to be an important cause of late morbidity and mortality in renal transplant recipients. We have examined the prevalence and nature of chronic liver disease among 538 patients with functioning renal allografts managed at the Western Infirmary, Glasgow, between 1980 and 1989. Thirty-seven patients (7 per cent) satisfied biochemical criteria for chronic liver dysfunction. Liver biopsies were obtained from 24 of these, and autopsy tissue was available from three other patients. Chronic hepatitis of variable severity was present in 15 patients, haemosiderosis in 12 patients and nodular regenerative hyperplasia in five patients. Nineteen patients (51 per cent) had serological evidence of infection with the hepatitis C virus, and one of these developed chronic hepatitis B and D infection as well. Although a variety of chronic liver diseases occurred in our transplant population, the frequency of serious sequelae from liver dysfunction was much lower than that reported from transplant centres in other countries.


Laboratory investigation in the diagnosis of pulmonary thromboembolism.

Laboratory findings were compared with lung scans in a prospective study of 260 patients undergoing ventilation-perfusion (V/Q) lung scanning for suspected pulmonary thromboembolism. The best discrimination between different lung scan results was obtained from the level of plasma cross-linked fibrin degradation products, every patient with a scan indicating a high probability of thromboembolism having detectable levels. An acute phase response was demonstrated in patients with pulmonary thromboembolism by a raised neutrophil count and elevated levels of plasma fibrinogen and serum C-reactive protein. A normal level of serum C-reactive protein and/or plasma cross-linked fibrin degradation productions in blood taken within 4 days of onset of symptoms virtually excluded the diagnosis of pulmonary thromboembolism. Detection of free plasma DNA was not helpful in discriminating between groups with different lung scan results. Discriminant analysis was used to assess the variables examined and to derive diagnostic models. An accuracy of 78 per cent was obtained with one model for classifying test patients according to the three lung scan classes of low, intermediate and high probability. A second model, for distinguishing patients with a low and a high probability of pulmonary thromboembolism on the basis of lung scans, and a third for predicting those with a low probability on lung scan, were accurate in 94.6 per cent and 83.5 per cent of patients respectively. Discriminant models could be used in the diagnosis of pulmonary thromboembolism, especially when diagnostic imaging is not available.


Fulminant community acquired infections admitted to an intensive care unit.

Disease progression, support required, prognostic indicators and survival in hospital and after discharge were studied in 53 patients with community acquired infections who required admission to the intensive care unit from the Department of Infectious Diseases between January, 1985 and August, 1991. The median age was 37 years and over two-thirds of patients were previously fully fit; 38 per cent of patients required intensive care within 6 hours of admission with rapidly progressive disease. Both APACHE II scores and number of organ systems failed were good indicators of prognosis: mortality was 85 per cent in those with three or more organ failures and 86 per cent in those with APACHE II scores of > or = 25. No deaths were observed in those with scores of < 10. Some organ failures (cardiovascular, renal and respiratory) occurred more frequently in those who died. Mechanical ventilation was required by 60 per cent of patients, inotropic drugs by 42 per cent and renal dialysis by 17 per cent. Mortality in hospital was 25 per cent with no further deaths at 6 months to 2 years. As a group these patients were young and previously fit. Deterioration was rapid, necessitating admission to the intensive care unit at short notice. Our results highlight the importance of having intensive care facilities in close proximity to infectious disease units. In contrast to many other groups of patients admitted to the intensive care unit, the overall outlook for patients with community acquired life-threatening infections is good, and long-term monitoring suggests that these patients remain well once recovery has occurred.


Clinical features, complications and mortality in type 1 (insulin-dependent) diabetic patients in Addis Ababa, Ethiopia, 1976-1990.

Clinical features, complications and prognosis of 431 consecutively registered Ethiopian Type 1 (insulin-dependent) diabetic patients seen in the Diabetic Clinic in Yekatit 12 Hospital in Addis Ababa, Ethiopia, from 1976-1990 are reported. Male:female ratio was 1.4:1; mean age at diagnosis was 18.1 years (confidence interval (CI) 1.6) in women and 21.4 (CI 1.2) in men. A history of ketoacidosis at some time was present in 38 per cent, in 11 per cent at diagnosis of diabetes. Tuberculosis was the most common complicating illness, occurring at some time in 16.5 per cent of patients. In addition, 9.5 per cent (CI 4 per cent) were known to have diabetic retinopathy, 6.0 per cent (CI 2 per cent) nephropathy and 7.9 per cent (CI 2 per cent) neuropathy at their last clinic visit. During the 15 years of the study, 9.7 per cent of the patients have died, with a mean duration of diabetes at death of 9.2 years (CI 1.8), and an overall mortality rate of 15.5/1000 person-years of diabetes. Five-year survival was 96 per cent (CI 3 per cent), 15-year survival 82 per cent (CI 9 per cent), and 20-year survival 63 per cent (CI 17 per cent), calculated using the Cox proportional hazards model; prognosis was better in those diagnosed at a younger age (p = 0.029) and in those with a body mass index of > 19 kg/m2 on treatment (p = 0.096).


Spontaneous peritonitis in cirrhotic hospital in-patients: retrospective analysis of 101 cases.

One hundred and one patients with cirrhosis resulting from alcohol abuse, admitted to Broussais University Hospital, Paris, between January, 1986 and December, 1989 were assessed for infection of the ascitic fluid using clinical and cytobacteriological criteria. All of 46 patients (45.5%) with clinical signs and symptoms of peritonitis had an ascitic fluid polymorphonuclear (PMN) count > 250 cells/mm3. Bacteria could be isolated from the ascitic fluid of 23 patients (50%). Twenty-six bacterial strains were isolated (there was more than one strain in two samples). Escherichia coli was found in 14 cases. It is noteworthy that no anaerobes were grown. Mortality, biochemical parameters and clinical features correlated significantly with an ascitic fluid PMN count > 250 cells/mm3. High mortality correlated with a PMN count > 1000 cells/mm3 (70% vs. 33%).


Primary glomerulonephritis and hydrocarbon exposure: a case-control study and literature review.

A case-control study was undertaken to investigate the possible role of chronic hydrocarbon exposure and tobacco and alcohol consumption in the causation of primary glomerulonephritis. Exposure to hydrocarbons and the consumption of tobacco and alcohol were assessed blindly by telephone interview and questionnaire in 55 patients with end-stage renal disease due to biopsy-proven primary glomerulonephritis in whom there had been no evidence of systemic disease. This was compared with 55 normal subjects matched for age, sex, social class and residential area and a comparable internal control group of 45 patients with end-stage renal disease secondary to systemic disease, diabetic nephropathy or chronic pyelonephritis. Hydrocarbon exposure scores derived from the results of the questionnaires were significantly higher (p < 0.001) in the patients with primary glomerulonephritis than in the normal subjects and the internal control group. Moreover, more detailed assessment of the type of hydrocarbon exposure showed significantly greater exposure of patients with glomerulonephritis to petroleum products (p < 0.001), greasing/degreasing agents (p < 0.01) and paints/glue (p < 0.05), and a resulting estimated relative risk of developing glomerulonephritis with each type of hydrocarbon exposure of 15.5, 5.3 and 2.0. Those patients with heavy hydrocarbon exposure (hydrocarbon score > 25,000) had a significantly higher serum creatinine at presentation than those with mild to moderate exposure, suggestive of more advanced renal disease. However, there was no significant difference in tobacco and alcohol consumption among subjects in different groups. We conclude that occupational exposure to hydrocarbon is likely to play a role in the pathogenesis of primary glomerulonephritis and that the risk of developing glomerulonephritis is greatest in those subjects exposed to petroleum products.


Damage to cellular DNA from particulate radiations, the efficacy of its processing and the radiosensitivity of mammalian cells. Emphasis on DNA double strand breaks and chromatin breaks.

For several years, it has been evident that cellular radiation biology is in a necessary period of consolidation and transition (Lett 1987, 1990; Lett et al. 1986, 1987). Both changes are moving apace, and have been stimulated by studies with heavy charged particles. From the standpoint of radiation chemistry, there is now a consensus of opinion that the DNA hydration shell must be distinguished from bulk water in the cell nucleus and treated as an integral part of DNA (chromatin) (Lett 1987). Concomitantly, sentiment is strengthening for the abandonment of the classical notions of "direct" and "indirect" action (Fielden and O'Neill 1991; O'Neill 1991; O'Neill et al. 1991; Schulte-Frohlinde and Bothe 1991 and references therein). A layer of water molecules outside, or in the outer edge of, the DNA (chromatin) hydration shell influences cellular radiosensitivity in ways not fully understood. Charge and energy transfer processes facilitated by, or involving, DNA hydration must be considered in rigorous theories of radiation action on cells. The induction and processing of double stand breaks (DSBs) in DNA (chromatin) seem to be the predominant determinants of the radiotoxicity of normally radioresistant mammalian cells, the survival curves of which reflect the patterns of damage induced and the damage present after processing ceases, and can be modelled in formal terms by the use of reaction (enzyme) kinetics. Incongruities such as sublethal damage are neither scientifically sound nor relevant to cellular radiation biology (Calkins 1991; Lett 1990; Lett et al. 1987a). Increases in linear energy transfer (LET infinity) up to 100-200 keV micron-1 cause increases in the extents of neighboring chemical and physical damage in DNA denoted by the general term DSB. Those changes are accompanied by decreasing abilities of cells normally radioresistant to sparsely ionizing radiations to process DSBs in DNA and chromatin and to recover from radiation exposure, so they make significant contributions to the relative biological effectiveness (RBE) of a given radiation.(ABSTRACT TRUNCATED AT 400 WORDS)


Heavy ion effects on cells: chromosomal aberrations, mutations and neoplastic transformations.

The quantification of chromosomal aberrations, mutations and neoplastic transformations induced by heavy charged particles meets with considerable experimental and conceptual difficulties which are related to the specific pattern of energy deposition. These problems are discussed on the background of current ideas on track structure, and some new experimental results are analysed.


Protection of early cellular damage in 1 Gy-irradiated mice by the elevation of extracellular adenosine.

In whole-body 1Gy-irradiated mice a modification of early cellular damage by means of preirradiation dipyridamole and adenosine monophosphate (AMP) treatment was investigated. Both drugs were given either alone or in combination, AMP being administered i.p. at doses of 5, 10 and 15 mg, dipyridamole s.c. at the dose of 2 mg, 20 min before AMP. The thymidine level in plasma and the amount of free polynucleotides in the thymus and spleen, both estimated at the interval of 4 h after irradiation, were used as indices of early cellular damage in vivo. The elevated level of thymidine observed in the plasma of irradiated controls decreased significantly after the administration of AMP (5 mg) alone to 71%, after the combination of dipyridamole and AMP a still deeper significant fall to 60% was observed. Such a protective effect was observed when injecting AMP 15 min before irradiation. Using the interval of 65 min between AMP administration and irradiation, no protection was detected. The higher doses of AMP (10, 15 mg) enhanced the protective effect manifested in plasma thymidine level only moderately. The amount of free polynucleotides, elevated in the thymus and spleen of irradiated mice, was significantly decreased in the thymus of mice pretreated with the combination of dipyridamole and AMP. The results suggest that the treatment used decreases the radiation damage of the sensitive thymocyte population. It is proposed that the joint use of AMP, an adenosine prodrug, and dipyridamole, a drug inhibiting adenosine uptake by cells, leads to an elevation in extracellular adenosine which activates cell surface adenosine receptors.(ABSTRACT TRUNCATED AT 250 WORDS)


Damage at two levels of DNA folding measured by fluorescent halo technique in X-irradiated L5178Y-R and L5178Y-S cells. I. Initial lesions.

We examined, by the fluorescent halo assay, alterations in the nucleoid structure (structure formed from cells under mild lysis conditions: in non-ionic detergent Triton X-100, 0.0005% and 1.5 mol/l NaCl) of L5178Y (LY) cell sublines which had been untreated, treated with reducing/chelating agents (beta-mercaptoethanol or sodium diethyl dithiocarbamate (DDTC(Na))) or X-irradiated. These sublines differ in radiation sensitivity: LY-R is more resistant (D0 = 1.1 Gy) and LY-S more sensitive (D0 = 0.5 Gy). Halo diameters were measured after cell lysis in the presence of propidium iodide (PI) (0.5 to 50 micrograms/ml) at pH 6.9 or 9. The maximal DNA unwinding in PI was obtained at 7.5 micrograms/ml PI, at both pH 6.9 and 9 in both sublines; the maximal halo diameter was larger in LY-S than in LY-R cells. In nucleoids from both sublines DNA could be rewound at higher (10-50 micrograms/ml) PI concentrations both at pH 6.9 and 9. This ability was impaired by mercaptoethanol or DDTC(Na) (at pH 9) or by X-irradiation, indicating damage and/or alteration in the DNA superhelical structure. The susceptibility to reducing/chelating agents was greater in LY-S than in LY-R nucleoids, pointing to differences in chromatin structure between these sublines. The amount of X-ray-inflicted damage was higher, when measured at pH 9 than at pH 6.9 and was about twice larger in LY-S than in LY-R nucleoids, when the cells were irradiated with the same X-ray dose.(ABSTRACT TRUNCATED AT 250 WORDS)


Thermosensitization, heat shock protein synthesis and development of thermotolerance in M-14 human tumor cells subjected to step-down heating.

M-14 human tumor cells have been subjected to two regimens of step-down heating (SDH) consisting of a conditioning treatment at 42 degrees C for 1 h or at 44.5 degrees C for 20 min, immediately followed by heating at 40 degrees C. Both conditioning treatments thermosensitize the cells towards the subsequent heating at 40 degrees C; the thermosensitization ratio is 6.4 for cells conditioned at 42 degrees C for 1 h and 32.3 for cells conditioned at 44.5 degrees C for 20 min. The overall protein synthetic activity is reduced to 32.7% or 18.4% of control values following 1 h at 42 degrees C and 20 min at 44.5 degrees C, respectively; this inhibition is followed by a full recovery of the synthetic activity during the subsequent exposure at 40 degrees C. SDH-treated cells synthetize four heat shock proteins, with approximate molecular weights of 28, 64, 70 and 90 kDa. The pattern of HSPs induction observed in SDH-treated cells is similar to that found in cells subjected to single hyperthermic exposures. Cells subjected to the SDH sequence 42 degrees C/1 h-->40 degrees C/4 h develop thermotolerance, as indicated by a reduced sensitivity to further hyperthermic challenges.


Induction of SOS repair by ionizing radiation. Results from experiments at accelerators.

beta-galactosidase and alkaline phosphatase activities of Escherichia coli strain PQ37 carrying the fusion gene of sulA and lacZ treated with different types of ionizing radiation were examined. The induction factor (ratio of beta-galactosidase to alkaline phosphatase activity), reflecting the SOS-induction potency, increases significantly with radiation dose. Maximum effectiveness to induce SOS-response has been found for deuterium and helium ions in comparison to gamma-rays, carbon or krypton ions. Increased energy of helium ions leads to greater SOS-induction potency of radiation.


Assessment of ideal neutron beams for neutron capture therapy.

The discrete-ordinates transport computer code DORT has been used to develop a two-dimensional cylindrical phantom model for use as a tool to assess beam design and dose distributions for boron neutron capture therapy. The model uses an S8 approximation for angular fluxes and a P3 Legendre approximation for scattering cross sections. A one-dimensional discrete-ordinates model utilizing the computer code ANISN was used to validate the energy-group structure used in the two-dimensional calculations. In the two-dimensional model the effects of varying basic parameters such as aperture width, neutron source energy, and tissue composition have been studied. Identical results were obtained when comparing narrow beam calculations to fine-mesh higher-order Sn treatments (up to S32), and with P5 cross sections. It is shown that, when the correct assessment volume is used, narrow beams will give little or no advantage for therapy even with an optimum-energy ideal neutron beam.


Dosimetry of 252Cf sources for neutron radiotherapy with and without augmentation by boron neutron capture therapy.

Interstitial and intracavity 252Cf sources have been used to treat a number of tumor types with encouraging results. In particular these tumors include a variety of cervical, head-and-neck, and oral-cavity cancers and possible malignant gliomas. As a neutron source, 252Cf offers certain theoretical advantages over photon therapy (i.e., in treating tumors with significant hypoxic or necrotic components). With the recent availability of 10B-labeled tumor-seeking compounds, the usefulness of 252Cf may be further improved by augmenting the 252Cf dose to the tumor with an additional dose due to the fission (following thermal neutron capture) of 10B located in the tumor itself. While the high mean neutron energy permits 252Cf to deliver a high-LET, low-OER dose to the tumor on a macroscopic scale, thermalization of neutrons followed by 10B capture may augment this dose at the cellular level if adequate loading of tumor cells with 10B is possible. This paper presents results of a Monte Carlo simulation study investigating the dosimetric characteristics of linear 252Cf sources both with and without the quantitative increase in tumor dose possible with the addition of 10B. Results are displayed in the form of "along and away" tables and dose profiles in a water phantom. Comparisons of Monte Carlo results with experimental and analytical dosimetry data available in the literature are also presented.


5-Nitro-4-(N,N-dimethylaminopropylamino)quinoline (5-nitraquine), a new DNA-affinic hypoxic cell radiosensitizer and bioreductive agent: comparison with nitracrine.

Targeting of electron-affinic radiosensitizers to DNA via noncovalent binding (e.g., intercalation) may offer the potential for increasing sensitizing efficiency. However, it has been suggested that high-affinity DNA binding may compromise sensitization by restricting the mobility of sensitizers along the DNA, and by decreasing rates of extravascular diffusion in tumors. The weak DNA intercalator nitracrine (1-NC) is a more efficient radiosensitizer than related nitroacridines with higher DNA-binding affinities (Roberts et al., Radiat. Res. 123, 153-164, 1990). The present study investigates whether electron-affinic agents of even lower DNA-binding affinity may be superior to nitroacridines. The quinoline analog of 1-NC, 5-nitraquine (5-NO), was shown to have an intrinsic association constant for calf thymus DNA in 20 mM phosphate buffer which was 12-fold lower than that of 1-NC. 5-Nitraquine was not accumulated as efficiently as 1-NC by AA8 cells, but, despite a similar one-electron reduction potential, was 2- to 3-fold more potent than 1-NC as a hypoxia-selective radiosensitizer in vitro when compared on the basis of average intracellular concentration. Thus the radiosensitizing potency of 5-NQ appears not to be compromised by its low DNA-binding affinity. The cytotoxic mechanisms of 5-NQ and 1-NC appear to be similar (hypoxia-selective formation of DNA monoadducts), but 5-NQ is 1200-fold less potent than 1-NC as a cytotoxin. Despite this advantage, 5-NQ was not active in vivo as a radiosensitizer in SCCVII tumors. This lack of activity appears to be due to its relatively high toxicity in vivo (intraperitoneal LD50 of 105 mumol kg-1 in C3H/HeN mice), high one-electron reduction potential (-286 mV), and rapid metabolism to the corresponding amine in mice. The in vitro therapeutic index (hypoxic radiosensitizing potency/aerobic cytotoxic potency) of this weak DNA binder was lower than that of the non-DNA targeted radiosensitizer misonidazole, suggesting that DNA targeting enhances cytotoxicity more than radiosensitization. Development of useful DNA-targeted radiosensitizers may require the exploitation of DNA binding modes different from those of the nitroacridines and nitroquinolines.


High resistance of cultured Mongolian gerbil cells to X-ray-induced killing and chromosome aberrations.

The Mongolian gerbil (Meriones unguiculatus) is known to be one of the most radioresistant animals. We have examined the X-ray sensitivity of normal diploid fibroblasts from Mongolian gerbil embryos compared with those of cultured embryo cells obtained from various laboratory animals and a normal human. There was a wide difference in X-ray sensitivity for cell killing among different mammalian species. The D0 values for Mongolian gerbil cells ranged from 2.08 to 2.28 Gy, values which are twice as high as those for human cells. The mean D0 value for human cells was 1.06 Gy. Mouse, rat, Chinese hamster, and Syrian/golden hamster cells showed similar D0 values ranging from 1.30 to 1.56 Gy. When cells were irradiated with X rays, ten times more chromosome aberrations were detected in human cells than in Mongolian gerbil cells. The frequencies of chromosome aberrations in other rodent cells were between the values for cells from humans and those from gerbils. These data indicate that the Mongolian gerbil cells are resistant to X-ray-induced cell killing and chromosome aberrations, and that the radiation sensitivity of mammalian cells in primary culture may be reflected by their radioresistance in vivo.


Amplification of the c-myc oncogene in radiation-induced rat skin tumors as a function of linear energy transfer and dose.

The c-myc oncogene was previously shown to be amplified in large, later-stage carcinomas of the rat skin induced by 0.8-MeV electrons. In a panel of 70 tumors induced by neon ions (45 keV/microns), c-myc amplification was rare, and in contrast to the data for tumors induced by low-linear-energy transfer (LET) (0.3 keV/microns) radiation, showed no correlation with tumor size, growth period, or time, but was associated with radiation dose. The tissue specificity for c-myc amplification seen in tumors induced by electrons was not seen in tumors induced by neon ions. These results suggest that quite distinct molecular mechanisms operate even in late stages of carcinogenesis that depend on the LET of the inducing radiation. Furthermore, the results suggest that c-myc amplification observed in tumors induced by low-LET radiation is not a general property of rat skin carcinomas, but is linked mechanistically to the inducing radiation, even though it is not detectable until many months after exposure and tumor appearance.


The effects of graded doses of 1 MeV fission neutrons or X rays on the murine hematopoietic stroma.

The acute radiosensitivity in vivo of the murine hematopoietic stroma for 1 MeV fission neutrons or 300 kVp X rays was determined. Two different assays were used: (1) an in vitro clonogenic assay for fibroblast precursor cells (CFU-F) and (2) subcutaneous grafting of femora or spleens. The number of stem cells (CFU-S) or precursor cells (CFU-C), which repopulated the subcutaneous implants, was used to measure the ability of the stroma to support hemopoiesis. The CFU-F were the most radiosensitive, and the survival curves after neutron and X irradiation were characterized by D0 values of 0.75 and 2.45 Gy, respectively. For regeneration of CFU-S and CFU-C in subcutaneously implanted femora, D0 values of 0.92 and 0.84 Gy after neutron irradiation and 2.78 and 2.61 Gy after X irradiation were found. The regeneration of CFU-S and CFU-C in subcutaneously implanted spleens was highly radioresistant as evidenced by D0 values of 2.29 and 1.49 Gy for survival curves obtained after neutron irradiation, and D0 values of 6.34 and 4.85 Gy after X irradiation. The fission-neutron RBE for all the cell populations was close to 3 and varied from 2.77 to 3.28. The higher RBE values observed for stromal cells, compared to the RBE of 2.1 reported previously for hemopoietic stem cells, indicate that stromal cells are relatively more sensitive than hemopoietic cells to neutron irradiation.


A fourth complementation group among ionizing radiation-sensitive Chinese hamster cell mutants defective in DNA double-strand break repair.

The XR-V9B mutant of Chinese hamster V79 cells which exhibits hypersensitivity to ionizing radiation was isolated by the replica plating technique. The increased sensitivity of XR-V9B cells to X rays (approximately 4-fold, as judged by the D10) was accompanied by increased sensitivity to other DNA-damaging agents such as bleomycin (approximately 17-fold), VP16 (approximately 6-fold), and adriamycin (approximately 5-fold). Only a slightly increased sensitivity was observed after exposure to UV radiation, MMS, or mitomycin C (1.4-, 1.7-, and 2-fold, respectively). As measured by neutral elution after exposure to X rays, XR-V9B cells showed a defect in the rejoining of double-strand breaks (DSBs); after 4 h of repair more than 50% of DSBs remained in comparison to 5% in wild-type cells. No difference was observed in the kinetics of single-strand break rejoining between XR-V9B and wild-type cells, as measured by alkaline elution. To determine whether XR-V9B represents a new complementation group among ionizing radiation-sensitive Chinese hamster cell mutants defective in DSB repair, XR-V9B cells were fused with XR-V15B, XR-1, and V-3 cells, which have impaired DSB rejoining and belong to three different complementation groups. In all cases, the derived hybrids regained the sensitivity of wild-type cells when exposed to X rays, indicating that the XR-V9B mutant represents a new fourth complementation group among X-ray-sensitive Chinese hamster cell mutants defective in DSB repair.


Radiation-related ophthalmological changes and aging among Hiroshima and Nagasaki A-bomb survivors: a reanalysis.

The relationship of ionizing radiation to the age-related ophthalmological findings of the 1978-1980 ophthalmological examination of A-bomb survivors of Hiroshima and Nagasaki has been reanalyzed using DS86 eye organ dose estimates. The main purpose of this reevaluation was to determine whether age and radiation exposure, as measured using the recently revised dosimetry information (DS86), have an additive, synergistic, or antagonistic effect. The data in this study are limited to axial opacities and posterior subcapsular changes, for which a definite radiation-induced effect has been observed in Hiroshima and Nagasaki A-bomb survivors. The best model fitting for axial opacities gives a significant positive effect for both linear dose and linear age-related regression coefficients and a significant negative effect for an interaction between radiation dose and age. Such a negative interaction implies an antagonistic effect in that the relative risks in relation to radiation exposure doses become smaller with an increase in age. On the other hand, the best-fitting relationship for posterior subcapsular changes suggested a linear-quadratic dose and linear age-related effect. The estimate of the quadratic dose coefficient shows a highly negative correlation with age, but the negative quadratic dose term is extremely small and is of little biological significance.


Replication of nuclear and mitochondrial DNA in X-ray-damaged cells: evidence for a nuclear-specific mechanism that down-regulates replication.

The mechanism by which X rays inhibit DNA replication has been investigated in three distinct populations of DNA molecules in human cells: (a) large chromosomal DNA, (b) a population of 50-100 10.3-kb nuclear episomal plasmids per cell, and (c) a population of about 500 16-kb cytoplasmic mitochondrial DNA molecules per cell. DNA replication was inhibited by X rays in nuclear chromosomal and plasmid DNA, but not in mitochondrial DNA. The mechanism by which ionizing radiation inhibits DNA replication must therefore be nuclear-specific and is unlikely to involve diffusible low-molecular-weight substances. Since mitochondrial DNA exists in the cell as independent 16-kb circular molecules and responds to radiation as would be expected for small targets, the implication for nuclear plasmids is that their replication is regulated by a large target. A current model for DNA replication involves the movement of DNA through replication centers made up of polymerases, helicases, and associated replication enzymes that are attached to a matrix. The difference in the response to X rays between mitochondrial DNA and nuclear plasmid DNA can be explained if nuclear plasmids are tightly associated with chromosomal DNA and attached to the matrix, and are coordinately replicated.


Failla Memorial Lecture. Redox, radiation, and reductive bioactivation.

A brief review is presented of the background to, and the principles involved in, the development of redox-sensitive drugs for use in cancer therapy. The role of redox processes in the action of various types of radiosensitizers and in the activation of bioreductive drugs is described. The mechanisms by which many simple hypoxic cell radiosensitizers act are believed to involve fast electron transfer processes involving DNA. Some of these agents can also function as hypoxic cell cytotoxins, although the mechanisms involved are different. These "bioreductive drugs" are activated by intracellular metabolic reduction mediated through various cellular reductases. Usually, though not always, bioreduction is favored under hypoxic conditions, and this is why many of these compounds display differential cytotoxicity to hypoxic cells. This is one of the rationales for selectivity in solid tumors. The potencies of both hypoxic cell radiosensitizers and bioreductive drugs are strongly correlated with their electron affinities. Classes of bioreductive agents of current interest are described briefly. These include simple and dual-function nitroheterocycles including the highly potent compound RB-6145, quinone-based drugs including analogues of mitomycin C, and heterocyclic compounds containing N-oxide functions. The study of bioreductive agents for potential use as adjuncts for various approaches to cancer treatment is described.


Dual cell cycle checkpoints sensitive to chromosome replication and DNA damage in the budding yeast Saccharomyces cerevisiae.

In eucaryotic cells chromosomes must be fully replicated and repaired before mitosis begins. Genetic studies indicate that this dependence of mitosis on completion of DNA replication and DNA repair derives from a negative control called a checkpoint which somehow checks for replication and DNA damage and blocks cell entry into mitosis. Here we summarize our current understanding of the genetic components of the cell cycle checkpoint in budding yeast. Mutants were identified and their phase and signal specificity tested primarily through interactions of the arrest-defective mutants with cell division cycle mutants. The results indicate that dual checkpoint controls exist in budding yeast, one control sensitive to inhibition of DNA replication (S-phase checkpoint), and a distinct but overlapping control sensitive to DNA repair (G2 checkpoint). Six genes are required for arrest in G2 phase after DNA damage (RAD9, RAD17, RAD24, MEC1, MEC2, and MEC3), and two of these are also essential for arrest in S phase when DNA replication is blocked (MEC1 and MEC2).


Radiation-induced mitotic delay: a genetic characterization in the fission yeast.

Radiation-induced mitotic delay is under investigation in the fission yeast, Schizosaccharomyces pombe. A large range of cell cycle- and radiation-sensitive mutants of this yeast is available to facilitate this effort. Through an examination of such mutants it has been shown that the X-ray transition point and the p34cdc2 execution point are coincident; wee1- strains are not delayed by irradiation; and the radiation-sensitive mutants rad1-1, rad3-136, rad9-192, and rad17-W are not delayed by radiation or by inhibitors of DNA synthesis, including hydroxyurea. A model is proposed: Damaged DNA generates a signal to delay mitosis which is carried by the products of the rad genes to activate the tyrosine kinase p110wee1. This in turn inactivates the serine/threonine kinase p34cdc2, thereby blocking entry to mitosis. Unreplicated DNA also initiates a signal to delay mitosis which is carried by these same rad genes but, as indicated in the literature, transmission to p34cdc2 does not require p110wee1. The delay-deficient rad mutants may possess some properties of tumor suppressor genes, with implications for mutagenesis and oncogenesis.


Effects of ionizing radiation on cyclin expression in HeLa cells.

The levels of cyclin B mRNA and protein rise rapidly in G2 + M phase, and fall at the end of mitosis. The studies described here were initiated to determine the effects of ionizing radiation on the level of cyclin B bearing in mind that the division delay induced by ionizing radiation might be influenced by the expression of cyclin B. After irradiation in S phase, the cyclin B mRNA in HeLa cells was measured as the cells proceeded through the cell cycle. Instead of the usual rise, after irradiation cyclin B mRNA levels remained low during the G2 delay. After irradiation in G2 phase, cyclin B mRNA was readily detectable although at slightly lower levels than in the controls. However, cyclin B protein was markedly decreased in amount.


A radiation-induced inhibitor of chromosome condensation and nuclear envelope breakdown in HeLa cells.

An in vitro microscopic assay for mitosis-inducing activity in mitotic HeLa cells was developed and used to demonstrate that cells irradiated and arrested in G2 phase of the cell cycle contain an inhibitor of mitosis. This assay system has a number of advantages over other assays including the use of autologous components (HeLa nuclei and mitotic cell extracts) in contrast to the microinjection method with Xenopus oocytes and without the requirements for microinjection expertise and Xenopus oocytes. The radiation-inducible inhibitor was detected at the lowest radiation dose tested (2 Gy) with maximal activity achieved within 30 min after radiation. Inhibitor activity decayed with time after radiation (2 Gy) with no activity detected at 6 h even though the cells remained in G2 phase, suggesting that either synthesis or activation of additional components is necessary for recovery from G2 arrest. The inhibitor activity was not detected in irradiated cells treated with caffeine to induce premature recovery from G2 arrest.


Diffusion of low-energy electrons in tissue-like liquids.

The spatial-energetic distribution of low-energy electrons was studied for a source located in a liquid medium simulating biological tissue. A time-independent Boltzmann equation was used to model this distribution microscopically. Ionization was treated as a perturbation to a quasi-elastic collision process between the electron and the medium. A diffusion limit was obtained by using a scale parameter, leading to a sequence of recursive partial differential equations whose solutions, associated with a macroscopic scale, were obtained by numerical approximations. As an application, electron ranges were estimated based on these solutions and then compared with values reported in the open literature based on experimental results and on Monte Carlo calculation. Local dosimetry, i.e., the energy imparted to a volume of a sphere with radius equal to the range of low-energy electrons, of low-energy electrons from internal emitters can benefit by the knowledge of the ranges estimated for biological tissue. Auger electron emitters, for example, have been the object of a number of investigations because of their radiobiological significance.


Compound dual radiation action. I. General aspects.

The theory of dual radiation action (A. M. Kellerer and H. H. Rossi, Curr. Top. Radiat. Res. Q. 8, 85-158, 1972) has attributed the effects of ionizing radiation on eukaryotes to the production of molecular changes (sublesions) that combine pairwise to produce injury (lesions) responsible for radiation effects. If the yield of sublesions is independent of radiation quality (as is currently assumed), dual radiation action results in the well-known proportionality between the average yield of lesions and alpha D+beta D2, where beta is a radiation-independent quantity. It has, however, been observed that beta changes with radiation type. In this paper we propose an explanation of this discrepancy. Specifically, we suggest that dual radiation action-type processes where beta is variable are the result of a mechanism--termed compound dual radiation action--which consists of a sequence of simple dual radiation action processes, each process being the causative agent for the next one. The sequence, single-strand DNA breaks, double-strand DNA breaks (chromosome breaks), and exchange-type chromosomal aberrations, is one such example examined in the paper.


The RBE-LET relationship for rodent intestinal crypt cell survival, testes weight loss, and multicellular spheroid cell survival after heavy-ion irradiation.

This report presents data for survival of mouse intestinal crypt cells, mouse testes weight loss as an indicator of survival of spermatogonial stem cells, and survival of rat 9L spheroid cells after irradiation in the plateau region of unmodified particle beams ranging in mass from 4He to 139La. The LET values range from 1.6 to 953 keV/microns. These studies examine the RBE-LET relationship for two normal tissues and for an in vitro tissue model, multicellular spheroids. When the RBE values are plotted as a function of LET, the resulting curve is characterized by a region in which RBE increases with LET, a peak RBE at an LET value of 100 keV/microns, and a region of decreasing RBE at LETs greater than 100 keV/microns. Inactivation cross sections (sigma) for these three biological systems have been calculated from the exponential terminal slope of the dose-response relationship for each ion. For this determination the dose is expressed as particle fluence and the parameter sigma indicates effect per particle. A plot of sigma versus LET shows that the curve for testes weight loss is shifted to the left, indicating greater radiosensitivity at lower LETs than for crypt cell and spheroid cell survival. The curves for cross section versus LET for all three model systems show similar characteristics with a relatively linear portion below 100 keV/microns and a region of lessened slope in the LET range above 100 keV/microns for testes and spheroids. The data indicate that the effectiveness per particle increases as a function of LET and, to a limited extent, Z, at LET values greater than 100 keV/microns. Previously published results for spread Bragg peaks are also summarized, and they suggest that RBE is dependent on both the LET and the Z of the particle.


Oncogene amplification detected by in situ hybridization in radiation-induced skin cancers in rats.

Amplification of the c-myc oncogene has been detected by Southern blotting in the DNA of radiation-induced skin cancers in the rat. In the current work the localization of oncogene amplification within specific cells in the different cancers and in multiple biopsies of the same cancer was studied by in situ hybridization. The amount of amplification was measured by counting grains on tissue sections hybridized in situ to biotin-labeled human c-myc third exon, rat v-H-ras, and rat v-Ki-ras probes. The in situ estimates of c-myc amplification were generally correlated with previous findings using the Southern blot method, but within each cancer only a fraction of cells exhibited amplification. Multiple biopsies of a squamous carcinoma showed amplification of v-H-ras and c-myc but not v-Ki-ras during tumor growth, but none of these oncogenes were amplified during tumor regression. The c-myc-positive cells were distributed uniformly within the cancers and exhibited a more uniform nuclear structure in comparison to the more vacuolated c-myc-negative cells. A high [3H]thymidine labeling index was found in irradiated epidermal cells on Day 7 after exposure, and yet no evidence of c-myc oncogene amplification was found in situ. No c-myc amplification was found in unirradiated normal epidermis or in irradiated epidermal cells in the vicinity of radiation-induced cancers. The data indicate that c-myc amplification is cell-specific within radiation-induced carcinomas and does not occur in epidermal cells proliferating in response to radiation exposure.


Radiation-induced DNA single-strand breaks in freshly isolated human leukocytes.

Single-strand breaks are a major form of DNA damage caused by ionizing radiation, and measurement of strand breaks has long been used as an index of overall cellular DNA damage. Most assays for DNA single-strand breaks in cells rely on measuring fractionated DNA samples following alkali denaturation. Quantification is usually achieved by prelabeling cells with radioactive DNA precursors; however, this is not possible in the situation of nondividing cells or freshly isolated tissue. It has previously been demonstrated that the alkali unwinding assay of DNA strand breaks can be quantified by blotting the recovered DNA on nylon membranes and hybridizing with radiolabeled sequence-specific probes. We report here improvements to the technique, which include hot alkali denaturation of DNA samples prior to blotting and the use of carrier DNA that is non-complementary to the radiolabeled probe. Our method allows both single- and double-stranded DNA to be quantified with the same efficiency, thereby improving the sensitivity and reproducibility of the assay, and allows calibration for determination of absolute levels of DNA strand breaks in cells. We also used this method to assay radiation-induced DNA strand breaks in freshly isolated human leukocytes and found them to have a strand break induction rate of 1815 strand breaks/cell/Gy.


Fitting the Armitage-Doll model to radiation-exposed cohorts and implications for population cancer risks.

The Armitage-Doll model of carcinogenesis is fitted to Japanese bomb survivors with the DS86 dosimetry and to three other radiation-exposed cohorts. The model is found to provide an adequate description of solid cancer incidence and also, to a lesser extent, of that of leukemia as a function of radiation dose when up to two radiation-affected stages are assumed. For non-leukemias the optimal model is one in which there are two radiation-affected stages separated by two additional stages. In the case of leukemia one radiation-affected stage or two adjacent stages provide suitable fits. There appear to be significant differences between the optimal models fitted to each cohort, although there is no heterogeneity within the Japanese data set by sex, by cancer type, or by age at exposure. Low-dose and low-dose-rate population risks for a population having the cancer and overall mortality rates of the current UK population are calculated on the basis of the optimal models fitted to the Japanese data to be about 8.3 x 10(-2) excess cancer deaths person-1 Sv-1, 10.1 x 10(-2) radiation-induced cancer deaths person-1 Sv-1, or 1.40 years of life lost person-1 Sv-1. Risks for a population having the mortality rates of the current Japanese population are about 6.5 x 10(-2) excess cancer deaths person-1 Sv-1, 7.8 x 10(-2) radiation-induced cancer deaths person-1 Sv-1, or 0.89 years of life lost person-1 Sv-1. It is a feature of the Armitage-Doll model, and other multistage models of carcinogenesis, that if radiation acts at more than one stage then (inverse) dose-rate effects may arise as a result of interactions between the effects of a protracted dose at the various radiation-affected stages. However, it is shown in this paper that these three measures of cancer risk in general display fairly slight dependence on administered dose in the range 0.001 to 1.0 Sv and on the length of the time over which the dose is administered in the range 1 to 100 years. Dose-rate effects resulting from the protraction of a radiation exposure over many years acting on (the same) cells at various stages of a multistep process of carcinogenesis are therefore expected to be slight. Dose-rate effects which have been observed in epidemiological studies and cellular radiobiology may thus find their explanation in other phenomena such as short-term intracellular repair.


Low pH does not affect the dose response for 5'-amino-5'-deoxythymidine modulation of IdUrd DNA incorporation and radiosensitization in a human bladder cancer cell line.

We report that coincubation of 647V cells for one cell cycle with low concentrations (30 microM) of 5'-amino-5'-deoxythymidine increased IdUrd DNA incorporation and radiosensitivity at low extracellular pH (pHe 6.8) in a fashion similar to treatment at normal pHe. IdUrd DNA incorporation is inhibited by high (300 microM) 5'-AdThd concentrations at both normal and low pHe (7.4 and 6.8), resulting in no significant radiosensitization. These results at low pHe were not anticipated based on previously published studies of 5'-AdThd modulation of thymidine kinase (TK) activity and nucleoside cellular uptake. Our results suggest that regulation of intracellular pH (pHi) during the course of one cell cycle negates the 5'-AdThd dose-dependent modulation of TK activity demonstrated previously. Flow cytometric measurement of pHi in 647V cells showed that normal pHi (pH 7.4) was maintained in 647V cells over a 12- to 24-h exposure to low pHe (pH 6.8). Thus the concomitant use of IdUrd and high concentrations of 5'-AdThd (> 30 microM) is unlikely to result in selective in vivo radiosensitization of human tumors under conditions which are intermittently or chronically acidic. However, low concentrations of 5'-AdThd may prove to be an effective in vivo modulator of IdUrd radiosensitization of human tumors under both normal and acidic conditions.


Developmental changes induced by gamma irradiation in Ipomoea batatas L. Lam (sweet potato).

Storage roots of Ipomoea batatas L. Lam were exposed to gamma irradiation at 90, 180, and 240 Gy. The two highest doses caused a delay in the initiation of rooting and especially of shooting; they also caused formation of rosette-like, stemless shoots without apical meristems. The storage roots irradiated with 90 Gy did form stems, but 50% of them had no apical meristem. The irradiated storage roots produced absorbent roots which developed shoots after 70 days of growth. Nonirradiated storage roots did not differentiate shoots from the absorbent roots. When grown in vitro, phytomers, stem segments with leaves and an axillary meristem, separated from the shoots of irradiated storage roots and exhibited growth aberrations, very intense rooting, and a delay in shooting. Phytomers from nonirradiated normal plants were irradiated with 10, 20, 30, 40, and 90 Gy and grown in a hormone-free medium. The 40- and 90-Gy doses delayed shooting as well as rooting. Only phytomers exposed to 40 and 90 Gy differentiated shoots from the absorbent roots. A stimulation of growth revealed in the accumulation of dry mass was found in the shoots of phytomers irradiated with 10 to 30 Gy. The long after-effects of irradiation as well as possible causes of growth stimulation are discussed.


Neutral filter elution detects differences in chromatin organization which can influence cellular radiosensitivity.

We have shown previously that the neutral filter elution assay is dependent not only on the number of DNA double-strand breaks present in a mammalian cell but also on the way in which DNA expands on the filter following lysis. Results in this study indicate that the rate of DNA elution appears to be dependent upon the proximity of the DNA in relation to the replication complex. The rate of elution for DNA analyzed immediately after a 30-min labeling period with [14C]thymidine was about five times slower than the rate of elution for bulk-labeled DNA. However, the rate was increased a few hours later when the recently replicated DNA had matured and was likely to be farther from replication-associated attachment sites on the nuclear protein matrix. About one cell cycle after pulse labeling, when the labeled DNA was replicated again, DNA underwent similar changes in elution rate. For the four cell lines examined here, the elution rate 3-4 h after pulse labeling correlated with cellular radiosensitivity. Changes in rate of elution caused by altering EDTA concentration or pH may also be explained by DNA structural changes which occur during lysis. We conclude that the neutral filter elution method is sensitive to differences in chromatin organization which may also play a role in cell sensitivity to ionizing radiation.


Killing of EMT-6 cells by decays from isotopes incorporated on sensitizer adducts.

EMT-6 tumor cell killing by decays from 3H and 125I incorporated by adduct formation of radiolabeled sensitizers was studied in vitro. Hypoxic radiosensitizers become covalently bound to cellular molecules after metabolic reduction, and EMT-6 tumor cells can tolerate over 10(9) adducts/cell of misonidazole without loss of colony-forming ability. Cells were incubated under hypoxic conditions in the presence of [3H]misonidazole or [125I]iodoazomycinriboside for various times and the amounts of bound 3H and 125I were determined. Cells were stored as monolayers at 22 degrees C, in suspension culture at 4 degrees C, and frozen in complete medium plus 8% DMSO at -196 degrees C for various times to facilitate the accumulation of radioactive decays before plating in vitro for colony-forming assays at 37 degrees C. At 22 degrees C in monolayer culture, EMT-6 tumor cells tolerated 950 and 1720 decays/cell of 3H and 125I, respectively, without evidence of radiotoxicity. This number of decays/cell over the exposure times used represents 1.54 x 10(6) 3H/cell and 8.4 x 10(4) 125I/cell, respectively. Significant cell killing was detected after similar amounts of isotope decay when cells were held at 4 degrees C. When cells were frozen in the presence of 8% DMSO, they were more resistant to inactivation by isotope decays or by gamma rays than cells in liquid phase at 4 degrees C. These data suggest that selective hypoxic tumor cell suicide by 3H or 125I decays from bound sensitizer at 37 degrees C will be an inefficient process, at least for drugs with specific activities as tested. These data are consistent with data on cell inactivation by isotopes incorporated into cells by other procedures.


Decreased repair of radiation-induced DNA double-strand breaks with cellular differentiation.

Although the majority of mammalian cells in situ are terminally differentiated, most DNA repair studies have used proliferating cells. In an attempt to understand better the relationship between differentiation and DNA repair, we have used the murine 3T3-T proadipocyte cell line. In this model system, proliferating (stem) cells undergo growth arrest (GD cells) and subsequently terminally differentiate into adipocytes when exposed to media containing platelet-depleted human plasma. Pulsed-field gel electrophoresis was used to evaluate the induction and repair of DNA double-strand breaks (DSBs) after ionizing radiation. The levels of radiation-induced DSBs in GD and terminally differentiated cells were similar, but in both cases greater than those found in stem cells at each radiation dose tested (0 to 40 Gy); these differences appear to be due to growth arrest in G1 phase. DNA DSBs were repaired with biphasic kinetics for each cell type. For terminally differentiated cells 25% of DNA DSBs remained unrejoined compared with < 10% for GD and stem cells after a repair time of 4 h. These data indicate that terminal differentiation of 3T3-T cells is associated with a reduction in the repair of ionizing radiation-induced DNA DSBs.


Protection against metastasis of radiation-induced thymic lymphosarcoma and weight loss in C57Bl/6NCr1BR mice by an autoclave-resistant factor present in soybeans.

We have investigated the ability of Bowman-Birk inhibitor, a protease (trypsin and chymotrypsin) inhibitor, to protect against radiation-induced thymic lymphosarcoma in C57Bl/6NCr1BR mice. Fifty-five 7-week-old male mice were randomized into 11 groups and gavaged 5 days per week with purified Bowman-Birk inhibitor, Bowman-Birk inhibitor concentrate, and autoclaved Bowman-Birk inhibitor concentrate. Following 7 days of gavage, those mice undergoing total-body or sham total-body irradiation received 1.7 Gy weekly for 4 weeks. At 6 months following the radiation exposure, all mice were sacrificed and examined histopathologically. Samples of Bowman-Birk inhibitor concentrate, purified Bowman-Birk inhibitor, and autoclaved Bowman-Birk inhibitor concentrate were evaluated with thin-layer chromatography. The mice treated with total-body irradiation and autoclaved Bowman-Birk inhibitor had significantly (P < 0.05) fewer deaths, lower average grade of lymphosarcoma, and larger fat stores compared to those treated with total-body irradiation and water gavage. The results for the total-body-irradiated mice receiving Bowman-Birk inhibitor concentrate suggested an effect midway between these two groups. Thin-layer chromatography analysis indicated that sterols and the phospholipids varied in the three different samples in a way that approximately corresponded with the observed effects. We have observed that an autoclave-resistant factor in soybeans is capable of reducing metastasis of radiation-induced lymphosarcoma and weight loss in C57Bl/6NCr1BR mice, presumably by preventing the extension and metastasis of cancer cells. Thus, in addition to the anticarcinogenic Bowman-Birk inhibitor, there appears to be another anticarcinogenic agent in soybeans which is capable of inhibiting the later stages of cancer cell development.


Effects of partial hepatectomy on the growth characteristics and hypoxic fractions of xenografted DLD-2 human colon cancers.

A recent publication by Leith et al. (Cancer Res. 51, 4111-4113, 1991) showed that administration of epidermal growth factor (EGF) (0.25 mg/kg; q.i.d. x 7) to mice bearing xenografted A431 human epidermoid cancers produced increased tumor growth and a reduction of the percentage of hypoxic cells within neoplasms. In contrast, sialoadenectomy, which removes the majority of circulating EGF in the mouse, resulted in slower tumor growth and increased hypoxic percentages. To investigate such homeostatic mechanisms further, we investigated the growth characteristics and hypoxic fractions of xenografted DLD-2 human colon tumors when tumor-bearing mice received partial hepatectomy (about 65%), unilateral nephrectomy, or nonspecific surgical trauma (laparotomy). Surgical procedures were performed when tumor volumes were about 375 mm3, and hypoxic percentages within tumors were measured by clonogenic excision assay procedures 72 h later. We found that partial hepatectomy increased the growth rates of the transplanted DLD-2 cancers by about a factor of 2.4. This increased growth rate was accompanied by an increase in the mitotic index from about 1.5 to 3.0%. Also, hypoxic fractions were decreased from 0.561 in control tumors to 0.235 in tumors from mice receiving partial hepatectomies. Unilateral nephrectomy and nonspecific surgery manipulations did not alter tumor growth rates, mitotic indices, or hypoxic percentages. These results indicate that partial hepatectomy produces significant alterations in tumor physiology. Results are consistent with a growth factor-mediated mechanism.


[The importance of bone marrow examination for hemoblastoses].

Morphological bone marrow evaluation is an integral component in staging patients with hematological malignancies. In acute leukemias or myelodysplastic syndromes cytologic examination is crucial since it allows precise analysis on the individual cell level. Histological examination of an iliac crest trephine biopsy is mandatory in malignant lymphomas because of the frequent nodular involvement of bone marrow in these diseases. In recent years magnetic resonance tomography (MRT) has been shown to be a sensitive method for detecting marrow infiltration in a variety of marrow diseases. In malignancies with focal marrow involvement, such as malignant lymphoma, MRT is today a useful complement to morphological bone marrow evaluation.


Technique to improve lateral cervico-thoracic radiographs.

Lateral radiographs taken during radiotherapy simulation of the upper thoracic and lower cervical region are often of poor quality because of the difference in separation seen by the incident beam. A simple method of compensating for this is the application of a thin foil of lead on the simulator that obscures the light field in the superior portion of the field. This technique has the advantage of being simple, fast and easily reproducible.


[Bone marrow scintigraphy. Principles, clinical results and indications].

After consideration of the anatomical and physiological principles, the radiopharmaceuticals for scintigraphy of the erythropoietic, reticuloendothelial and-as a new development-of the granulopoietic bone marrow are introduced and compared. The data on performing and evaluating bone marrow scans are followed by the presentation of the clinical results. Staging and re-staging of malignant lymphomas, multiple myeloma, breast and lung cancer are considered to be the main indications. 99mTc-labelled monoclonal anti-NCA-95-antibodies are regarded as the radiopharmaceutical of choice.


Radiotherapy technique integrates MRI into CT.

The 1970s saw the introduction of computed tomography, which enabled soft tissue anatomy to be seen. Today simulation of therapeutic fields by x-ray is augmented by radiotherapy treatment planning using CT data. The 1980s brought magnetic resonance imaging with superior soft tissue contrast. This article describes a technique correlating three-dimensional MRI/CT data sets used routinely in treatment planning of tumors in the head.


[MR tomography of the bone marrow in malignant systemic diseases. Diagnosis and therapeutic follow-up control].

This paper presents a short survey of the current status of bone marrow diagnosis in systemic neoplastic disease by means of MR imaging. The different patterns of bone marrow infiltration from lymphomas and leukaemias are presented and the differential diagnoses are discussed. Apart from the primary diagnosis the relevance of conventional MRI and chemical shift imaging for therapy follow up and after-care is discussed.


[Bone marrow edema in MRT].

Like other vascularized organs, bone can react with increasing interstitial fluid to disturbances in permeability caused by various noxae. Signs of bone marrow edema recognizable in magnetic resonance imaging are described for conditions such as trauma, stress, reflex sympathetic dystrophy, ischemia, and infection. A bone marrow edema may be an early or the only sign of a disease entity visible solely on MR images. We made a retrospective study of musculoskeletal MR examinations conducted over a period of 3 months to estimate the incidence of bone marrow edema.


[Bone marrow changes following radiotherapy. Results of MR tomography].

Magnetic resonance imaging (MRI) offers a new approach in the morphologic evaluation of the bone marrow. Physiologic and pathologic changes can be assessed with very high sensitivity. Radiotherapy induces acute depletion of the hematopoietic bone marrow, resulting in fatty degeneration. With MRI it is possible to evaluate the changes during irradiation and it also discloses the long-term fatty degeneration after radiotherapy. The irradiated bone marrow mostly exhibits a homogeneous hyperintense pattern on T1-weighted images. This allows clear recognition of the former target volumes. Our quantitative studies based on chemical shift imaging data reveal a lack of recovery of hematopoiesis after radiotherapy with 30 Gy or more. These results are independent of patients' age and of the interval after radiotherapy.


[Diagnosis of pneumatosis intestinalis coli in CT].

Pneumatosis intestinalis coli seldom causes symptoms of an acute abdomen and is rarely diagnosed in CT. The origin of the gas collections in the wall of the bowel often remains unclear. As shown in our case, pneumatosis may involve any portion of the bowel, but usually spares the rectum. Due to extreme meteorism and coprostasis it can be difficult to recognize pneumatosis radiographically. In CT the gas collections beneath the serosa are well defined, discrete, oval or round.


Identification of stressors in radiologic technology.

Much is written about stress in the workplace, but until the causes of stress are identified, little can be done to address the problem. This article reports results of a survey of 198 randomly selected radiologic technologists who were asked to assess the relative stressfulness of 35 stressors. Disrespectful physicians, inadequate pay, unnecessary exams and lack of staff topped the list.


[Digitization of conventional x-ray films].

The diagnostic value of a digitization system for analogue films based on a charge-coupled-device (CCD) scanner with adjustable resolution of 2.5 or 5 lp/mm was assessed. Some 110 skeletal radiographs, 50 contrast studies, including 25 of patients with Crohn's disease, and 70 abdominal plain films before and after successful lithotripsy for renal stones were digitized. Receiver operating characteristic (ROC) studies showed improved detection of cortical and trabecular defects with contrast-optimized digitized films. Edge enhancement algorithms yielded no additional information. Inflammatory lesions of Crohn's disease were detected equally well by conventional films and digitized images. A statistically significant improvement (p less than 0.05) in the recognition of disintegration after lithotripsy was found for the processed digitized images. On the basis of this initial investigation, the digitization system tested appears to be useful for diagnostic purposes, especially when contrast resolution plays an important part, as with stone fragmentation or cortical defects.


[New developments in the computer-assisted diagnosis of focal bone lesions].

Since the 1960s there have been numerous reports in the literature about computer-aided medical diagnosis and therapy. However, so far computer-aided diagnosis has not become important in the clinical routine or in the field of radiology. This paper describes the hitherto existing proposals for expert systems to evaluate focal bone lesions and presents a new concept. The basic ideas of this program are: (1) a PC-based interactive dialogue along on the basis of a defined questionnaire; (2) the use of certainty factors to handle uncertainty and vagueness in evaluating the different radiological findings and their correlation with diagnoses; (3) the link between visual information and the questionnaire. The aims of such expert systems are (a) a complete and systematic analysis of the films, (b) independency of association with previously diagnosed cases in reporting the films, (c) the procurement and use of radiological descriptive terms, and (d) aid in the radiological evaluation of focal bone lesions.


[Product of the month: scientific text processing using the MS-DOS computer].

A new German word processing system, "Starwriter 6.0" for MS-DOS computers is introduced and important functions are described. The possibility of using different fonts, creating complex formulas, footnotes and endnotes, and using various functions for importing and exporting text and data files make this program highly suitable for scientific texts.


[Recurrence paralysis: computed tomographic analysis of intrathoracic findings].

The long and singular course of the inferior (recurrent) laryngeal nerve makes it very vulnerable to infiltration by tumors of various locations. In particular, mediastinal and pulmonary lesions must be considered in the case of left vocal chord palsy. Recurrent nerve paralysis caused by a tumor indicates advanced disease. We retrospectively reviewed the computed tomography (CT) findings in 29 patients with bronchogenic carcinoma or mediastinal tumors and recurrent nerve paralysis with respect to the site, size and extent of the tumor and the lymph node status. The review revealed a marked predominance of left upper lobe tumors with extensive lymph node metastases to the anterior mediastinum and the aortopulmonary window. The extent of mediastinal involvement exceeded the average involvement in a control group of 30 randomly selected patients with bronchogenic carcinoma at the time of presentation. In all patients CT demonstrated tumor tissue which could have caused the paralysis at one or more sites along the anatomical course of the recurrent nerve. In most cases the tumor was located at the aortic arch. The left paratracheal region, right paratracheal region and right pulmonary apex were affected in one case each. We conclude that in patients with cancer, CT is a suitable method for localizing a recurrent nerve lesion.


[Measurements and variations in the region of the optic canal. CT and anatomy].

This investigation of the optic canal is based on measurements of 60 macerated adult European skulls from the Alexander-Ecker Collection at the Anatomy Department of the University of Freiburg. An indian skull is also described, in which the cranial end of the left optic canal is closed by a bony plate. Computer tomographical and anatomical measurements were compared in order to assess the correlation of the two methods of investigation and the accuracy of the CT representation of osseous structures. The coronal projection of the optic canal proved to be optimal for CT examination--the sections meet the optic canal at an angle of 85.5 degrees. The measurements of transverse diameters correlate poorly, whereas vertical diameters and distances correlate well. The extent to which anatomical variations can be assessed by CT was also investigated. All anatomical variants could be observed in coronal sections, except the bony lamina in the Indian skull, which could not be seen until a contrast medium was used. The so-called "keyhole anomaly" appeared in 3.3% in our material, the "figure-of-eight" variant in 2.5%, and a carotid clinoid canal in 13.3%.


[An unusual bone scintigram in osteomyelitis. A case report].

Despite hyperemia in the blood-pool phase of bone scintigraphy with 99mTc-MDP there was an decreased concentration of the nuclide in a 7-year-old boy with acute osteomyelitis of the femur. In addition to inflammatory destruction of the bone tissue, the other reason for this surprising scintigraphic finding might be a reduced blood flow because of thrombotic occlusion or compression of bone-supplying vessels.


["Metastasizing" Echinococcus alveolar of the liver].

We report a case of metastatic alveolar echinococcosis of the liver. There were calcifications of the liver parenchyma, and a large tumour adjacent to the porta hepatis infiltrated neighbouring structures. In addition, haematogenous metastases to the spine and foot were found. This extensive haematogenous "metastasis" is rare and may complicate diagnosis, but the typical findings in the liver should permit the correct conclusion.


Patient monitoring during clinical MR imaging.

The impressive growth in the number of patients imaged with magnetic resonance (MR) technology has been accompanied by technical advances that have permitted more acutely ill patients to be studied with this diagnostic tool. Such patients, however, might require monitoring of vital functions during the examination. Unfortunately, the present construction of most MR imaging systems makes direct visualization of the patient difficult, if not impossible. Furthermore, the static and time-varying magnetic (and electric) fields associated with MR imaging systems may be incompatible with most physiologic monitoring devices, either because of safety or function. The authors review herein the data regarding presently available monitoring devices for various physiologic parameters and provide recommendations regarding what--and whom--to monitor during clinical MR examinations.


Brain parenchyma motion: measurement with cine echo-planar MR imaging.

With echo-planar magnetic resonance (MR) imaging, the authors measured the intrinsic pulsatile motion of brain parenchyma. Phase-sensitive, electrocardiography-gated, two-dimensional cine images were acquired throughout the cardiac cycle by using a spin-echo, blipped echo-planar MR pulse sequence. Transverse and coronal planes were obtained in 14 healthy volunteers. Corrections were made for gross head motion. Brain motion consisted of a rapid displacement in systole, with a slow diastolic recovery. The motion occurred chiefly in the cephalocaudal and lateral directions; the anteroposterior motions were relatively small. Cephalocaudal velocities increase with proximity to the foramen magnum. The lateral motion is mainly a compressive motion of the thalami. Brain parenchymal velocities were as high as 2 mm/sec caudally in the brain stem and 1.5 mm/sec medially in the thalami. Net parenchymal excursions were at most 0.5 mm. Phase-based echo-planar velocity measurements agreed well with echo-planar Fourier velocity zeugmatography measurements and were consistent with reported values. Velocity mapping with echo-planar imaging offers a rapid and flexible method of assessing the pulsation velocities of the human brain.


Brain motion: measurement with phase-contrast MR imaging.

Brain motion during the cardiac cycle was measured prospectively in 10 healthy volunteers by using a phase-contrast cine magnetic resonance (MR) pulse sequence. The major cerebral lobes, diencephalon, brain stem, cerebellum, cerebellar tonsils, and spinal cord were studied. The overall pattern of brain motion showed caudal motion of the central structures (diencephalon, brain stem, and cerebellar tonsils) shortly after carotid systole, with concurrent cephalic motion of the major cerebral lobes and posterior cerebellar hemisphere. Peak brain displacement was in the range of 0.1-0.5 mm for all the structures except the cerebellar tonsils, which had greater displacement (0.4 mm +/- 0.16 [mean +/- standard error of mean]). Caudal motion of the central structures did not occur simultaneously but progressed in a caudal-to-rostral and posterior-to-anterior sequence, being seen first in the cerebellar tonsils and then later in the diencephalon (hypothalamus). Caudal motion of the low brain stem and cerebellar tonsil was simultaneous with caudal motion of cerebrospinal fluid in the cervical subarachnoid space. Oscillatory flow in the aqueduct was delayed compared with brain stem motion.


Intracerebral lesion contrast with spin-echo and fast spin-echo pulse sequences.

Fast spin-echo (FSE) magnetic resonance (MR) imaging was compared with conventional, peripherally gated T2-weighted spin-echo (SE) imaging in the detection of high- and low-signal-intensity lesions in the central nervous system. Lesion detectability was determined with percentage of contrast measurements and contrast-to-noise ratios with two different measurements for noise. All three measures of lesion detectability were similar. FSE and SE sequences were quantitatively equivalent in the detection of high-signal-intensity lesions. The SE sequence, however, was superior to the FSE sequence in the detection of small, low-signal-intensity lesions in the central nervous system caused by magnetic susceptibility effects.


Intracranial vascular stenosis and occlusion: evaluation with three-dimensional time-of-flight MR angiography.

To assess the usefulness of magnetic resonance (MR) angiography in the characterization of intracranial arterial stenosis and occlusion, a three-dimensional time-of-flight method was compared with conventional angiography in 214 vessels in 29 patients. Studies were independently interpreted by two neuroradiologists who scored each vessel as normal, narrowed, or occluded. Overall, 97% of normal vessels and 100% of occlusions were correctly graded. Sixty-one percent of stenoses were graded correctly; the remainder were graded as normal. The portions of the intracranial vessels near the skull base and especially the paracavernous and supraclinoid segments of the internal carotid arteries were areas of frequent over- and underestimation of stenosis due to the presence of dephasing artifacts. In patients with stenosis or occlusion, MR angiography also provided information regarding the presence of collateral flow in the circle of Willis. When used in conjunction with MR imaging of the brain and MR angiography of the extracranial carotid arteries, intracranial MR angiography allows a more complete evaluation of the patient with symptoms of cerebral ischemia or infarction.


Mapping of brain tumor metabolites with proton MR spectroscopic imaging: clinical relevance.

Brain tumor metabolism was studied with hydrogen-1 magnetic resonance spectroscopy and positron emission tomography with fluorine-18 fluorodeoxyglucose in 50 patients. N-acetylaspartate (NAA) was generally decreased in tumors and radiation necrosis but was somewhat preserved at neoplasm margins. Choline was increased in most solid tumors. Solid high-grade gliomas had higher normalized choline values than did solid low-grade gliomas (P < .02), but the normalized choline value was not a discriminator of tumor grade, since necrotic high-grade lesions had reduced choline values. Serial studies in one case showed an increase in choline as the glioma underwent malignant degeneration. Choline values were lower in chronic radiation necrosis than in solid anaplastic tumors (P < .001). In two cases studied before and after treatment, clinical improvement and a reduction in choline followed therapy. Lactate is more likely to be found in high-grade gliomas, but its presence is not a reliable indicator of malignancy.


Cytotoxic brain edema: assessment with diffusion-weighted MR imaging.

To determine whether cytotoxic brain edema is associated with a decrease in diffusion, it was induced in rats, in the absence of ischemia, with an established model of acute hyponatremic encephalopathy. Cytotoxic brain edema secondary to acute hyponatremia was induced with intraperitoneal injections of 2.5% dextrose in water and subcutaneous injection of arginine-vasopressin. Coronal spin-echo magnetic resonance (MR) images were obtained with and without strong diffusion-sensitizing gradients before and after induction of acute hyponatremia. The apparent diffusion coefficient (ADC) was measured at two coronal section locations. In hyponatremic rats, the brain ADC was significantly reduced (P = .0153 and .0001) and was positively correlated with increased total brain water content (P = .0011). Plots of ADC versus total brain water showed a statistically significant inverse linear relationship between ADC and increasing brain water at the anterior coronal section location. The results indicate that the ADC may be a sensitive indicator of cytotoxic brain edema and thus may enable quantitative evaluation of such edema with diffusion-weighted MR imaging.


Malignant parotid tumors: clinical use of MR imaging and histologic correlation.

Magnetic resonance (MR) imaging was performed in 116 patients in whom a parotid mass lesion was clinically suspected. Eighty-six patients had benign disease. The 30 patients in whom a malignant tumor was found were further evaluated. To determine which features are characteristic of malignant parotid tumors, spin-echo T1- and T2-weighted images of malignant lesions in the parotid gland were compared with those of benign disease. In our series, tumor margins, homogeneity, or signal intensity were not discriminative factors to correctly predict benign or malignant disease. Infiltration into deep structures (eg, the parapharyngeal space, muscles, and bone) was observed only in malignant tumors. Infiltration into subcutaneous fat was noticed in malignant as well as in inflammatory disease. No statistically significant correlation was found between tumor grade and MR imaging features in malignant disease. MR imaging is useful in delineating malignant tumors but is unreliable in correctly predicting the histologic nature of a mass lesion in the parotid gland.