Circadian rhythms and the suprachiasmatic nucleus in perinatal development, aging and Alzheimer's disease. Circadian rhythms are already present in the fetus. At a certain stage of pre-natal hypothalamic development (around 30 weeks of gestation) the fetus becomes responsive to maternal circadian signals. Moreover, recent studies showed that the fetal biological clock is able to generate circadian rhythms, as exemplified by the rhythms of body temperature and heart rate of pre-term babies in the absence of maternal or environmental entrainment factors. Pre-term babies that are deprived of maternal entrainment and kept under constant environmental conditions (e.g., continuous light) in the neonatal intensive care unit run the risk of developing a biological clock dysfunctioning. However, the fact should be acknowledged that at least in mice the development of the circadian pacemaker (i.e., SCN) does not depend on environmental influences (Davis and Menaker, 1981), although other data suggest that severe disruption of the maternal circadian rhythm indeed abolishes the circadian rhythm of the fetal SCN (Shibata and Moore, 1988). During aging and in particular in AD circadian rhythms are disturbed. These disturbances include phase advance and reduced period and amplitude, as well as an increased intradaily variability and a decreased interdaily stability of the rhythm. Among the factors underlying these changes the loss of SCN neurons seems to play a central role. Other contributory factors may be reduced amount of light, degenerative changes in the visual system and the level of activity and decreased melatonin.


The human hypothalamus: comparative morphometry and photoperiodic influences. The concept of the hypothalamus as a distinct neurological entity concerned with a variety of regulatory processes dates back to the end of the 19th century. Before 1900 there were only vague intimations of the function of the brain surrounding the third ventricle and these were based primarily on various pathological and assorted clinical observations. Since then a large body of evidence has been derived implicating that the hypothalamus contains the control systems which are critically involved in many physiological, endocrine and behavioral processes. Among these are feeding and drinking, reproduction and the regulation of the sleep-wake cycle and temperature. Although the human hypothalamus accounts for only 4 cm3, or 0.3% of the adult brain volume, it contains the integrative systems critical for all these processes. A comparative morphometric analysis of the hypothalamus among mammals revealed that the volume of this part of the brain is highly correlated with brain size, irrespective of the ecological strategy or evolutionary history of the species considered. It appears that the human hypothalamus has just the size we may expect of such a large-brained mammal, but it is considerably larger than would be predicted from its body size. In mammals the preoptic region of the hypothalamus is implicated in the neural control of endocrine functions and in the temporal organization of a wide spectrum of biological rhythms. In recent years, the pivotal role of two hypothalamic cell groups have been considered in this context: the sexually dimorphic nucleus (SDN-POA) as part of the neural circuitry underlying masculine sexual behavior and reproductive functions and the suprachiasmatic nucleus (SCN) as the principal component of the central clock mechanism. Consistent with its role in the temporal organization of circadian processes, investigations in rodents and non-human primates suggest that the SCN is also involved in the seasonal control of reproductive and metabolic phenomena. Since the environmental light-dark cycle is the main Zeitgeber for circadian and seasonal rhythms in most species, including man, photic information could have substantial effects, not only on the neural activity of the biological clock, but also on its underlying structure. Our observations on the human SCN in relation to photoperiod indeed revealed a marked seasonal variation in the morphology of the human SCN. The volume of the SCN was, on average, twice as large in the autumn as in the summer and contained more than twice as many vasopressin immunoreactive neurons.(ABSTRACT TRUNCATED AT 400 WORDS)


LHRH neurons: functions and development. Examination of the properties of developing LHRH neurons, by in situ hybridization procedures or LHRH immunocytochemistry, showed that these cells (1) are unique among neuroendocrine cells in their origin from the epithelium of the medial olfactory pit, and (2) express LHRH mRNA. LHRH neurons, visualized by either method, tended to be clustered when seen along the migration route in the nasal mesenchyme. Neural cell adhesion molecule (NCAM) is present on the central processes of the olfactory, vomeronasal and terminalis nerves, which form the scaffold along which LHRH neurons migrate into the brain. Injection of a small amount (1 microliter) of antiserum to NCAM into the olfactory pits of 10-day-old embryonic mice, while not sufficient to break up the NCAM scaffolding, appeared to decrease the number of LHRH-immunoreactive cells in the epithelium of the medial olfactory pit, and retarded their migration in the nasal mesenchyme. This suggest that NCAM is important for LHRH cell migration. Never found actually colocalized with LHRH in the same neurons, NCAM nevertheless may be required for the migration of LHRH-expressing cells.


The human hypothalamo-neurohypophyseal system in relation to development, aging and Alzheimer's disease. The research reviewed in the present paper indicates that vasopressin and oxytocin cells in the human HNS constitute an extremely stable population of neurons throughout the human life span. Increases in the activity of these cells, which are probably related to maturation of the system were observed during fetal development and probably extend well beyond term. During senescence an increase in the activity of the vasopressin cells in the human HNS was observed which is probably a compensation for age-related changes in kidney function. These data do not support a role of declining vasopressin secretion in age-related memory decline. Although there is some evidence for an impairment of vasopressin synthesis and release in Alzheimer patients, vasopressin cell numbers in Alzheimer's disease do not fall below values observed in young controls. Furthermore, peripheral administration of vasopressin or vasopressin analogues to AD patients have not yielded consistent results.


Animal models for osmoregulatory disturbances. For the various types of di in humans, animal models are available. However, their value for explaining human di is for the major part an indirect one; by studying cellular mechanisms in these animal models, fundamental aspects of the cellular processes become available, which will help to understand similar processes in human di and subsequently lead to the molecular cause(s) of the various types of human di. Finally, it is to be expected that in the very near future transgenic animals will be raised in which very specific genetic information is overexpressed (or knocked out by homologous recombination; McMahon and Bradley, 1990). Recently hypervasopressinemia could be shown in transgenic mice, providing an animal model for the syndrome of the inappropriate VP secretion (Bartter and Schwartz, 1967), which is often observed in patients with lung cancers that ectopically express the VP gene (Habener et al., 1989). Furthermore it will be possible to study the exact cause(s) of human di by performing in vitro mutagenesis and to express the RNA constructs within a cell-free translation system and in oocytes (e.g., Schmale et al., 1989) and subsequently study the pattern of precursor synthesis, packaging and processing.


Anatomy of the human hypothalamus (chiasmatic and tuberal region). The hypothalamus sensu stricto consists of the chiasmatic, the tuberal and the mamillary region. The present study is confined to the poorly myelinated chiasmatic and tuberal region. Both regions harbor many nuclear grays with relatively clear-cut boundaries embedded in an ill-defined nerve cell assembly referred to as the hypothalamic gray. Prominent components of the chiasmatic region are the magnocellular neurosecretory complex (supraoptic nucleus, paraventricular nucleus, accessory neurosecretory nucleus), the sexually dimorphic intermediate nucleus, the suprachiasmatic and retrochiasmatic nuclei. The dominating structure of the tuberal region is the complex of the ventromedial, posteromedial and dorsomedial nuclei supplemented by the periventricular and infundibular nuclei. Lateral portions of the tuber cinereum harbor the lateral tuberal nucleus and the tuberomamillary nucleus. The lateral tuberal nucleus exhibits pronounced cell loss in Huntington's chorea and is also severely involved in cases of dementia with argyrophilic grains. The large nerve cells of the tuberomamillary nucleus show particularly severe affection in both Alzheimer's (intraneuronal neurofibrillary changes) and Parkinson's disease (Lewy bodies).


Neurologic manifestations of hypothalamic disease. The hypothalamus, in addition to regulating the anterior and posterior pituitary, controls water balance through thirst, regulates food ingestion and body temperature, influences consciousness, sleep, emotion and other behaviors. Much has been learned of these effects in human disease through the clinical manifestations that occur with hypothalamic lesions. This study reviews the clinical pathologic correlations that have been made in recent years showing that regions of the hypothalamus exert functions in humans that are similar to those identified in experimental animals. Clinical pathologic correlations have not always provided precise analysis of hypothalamic function. The hypothalamus is small and often lesions that come to clinical attention achieve considerable size before their recognition, making local anatomic dissections of the effects of the lesions difficult. Nevertheless, the use of modern non-invasive techniques including CT scans and magnetic resonance imaging (MRI) have provided new information not previously available. This paper reviews several cases of hypothalamic disorder recognized recently. (1) A 33-year-old black man with hypothalamic sarcoidosis. Manifestations of hypothalamic dysfunction included panhypopituitarism, aggressive hyperphagia, polydipsia (partially due to hyperglycemia secondary to diabetes mellitus), drowsiness, depression, and irritability. (2) A 37-year-old woman with a large intrahypothalamic tumor (biopsy showed pituitary adenoma), with drowsiness, poikilothermia, lack of satiety, confusion, and memory loss. She becomes depressed when she is transiently more alert (as after hypertonic contrast-dye infusion). (3) A 60-year-old man with hypothalamic compression by a pituitary tumor, associated with syndrome of inappropriate ADH (SIADH), severe anorexia, memory loss, but preserved thirst. After surgical decompression of the tumor his appetite acutely recovered, but he developed severe hypo(poikilo)thermia. (4) A 45-year-old woman with a suprasellar craniopharyngioma presented with severe drowsiness, hyperphagia, depression, and memory loss post-operatively, which responded to antidepressants (except for the memory loss). She had extremely labile blood pressures and serum Na for about 1 week post-operatively.


Genetic, hypothalamic and endocrine features of clinical and experimental obesity. Obesity occurs in both clinical and animal forms in a variety of specific models which allow study of its underlining endocrine and mechanistic features. Among the neuroendocrine varieties of obesity, polycystic ovaries are probably the most common. The importance of the gonadal feedback system for regulation of food intake and obesity is indicated by the effects of castration in experimental animals which is a widely used mechanism for producing experimental obesity. Cushing syndrome and hypothalamic obesity are rare clinical syndromes. The current evidence suggests that there are two types of hypothalamic obesity from a mechanistic point of view--one associated with hyperphagia as a necessary and sufficient cause and a disturbance of the autonomic nervous system without hyperphagia as a second mechanism. Although genetic factors underlie most types of human obesity, there are several dymorphic forms of obesity including the Prader-Willy syndrome, Cohen's syndrome, Carpenter's syndrome, Ahlstrom's syndrome and the Bardet-Biedel syndrome. The Prader-Willi syndrome is characterized by obesity hypotonia hypogonadism and mental retardation. In animals, a dominant form of inheritance of obesity is seen in the yellow mouse. Current evidence suggests that this syndrome can be explained by reduced acetylation of MSH in the pituitary and/or hypothalamus. Several recessively inherited forms of obesity exist including the obese mouse, the diabetes mouse, fatty rat, the fat mouse, tubby mouse and the corpulent rat. In addition, there are a number of polygenic types of experimental obesity. The final mechanistic classification of obesity are those due to dietary manipulation. For both human beings and animals, a highly fat diet appears to be particularly problematic for the development of obesity.(ABSTRACT TRUNCATED AT 250 WORDS)


Hypothalamic involvement in sexuality and hostility: comparative psychological aspects. Evidence presented in this article shows the representation of sexual and aggressive behaviors at the level of the hypothalamus to be more prominent than in all other brain areas involved. Indeed, there are good arguments to attribute a central position to the hypothalamus within larger structural systems encompassing the limbic system, where aspects of the behaviors involved can be influenced. So far, however, the arguments are purely descriptive and factual and do not contribute much to answering questions about hypothalamic function: the grounds for and consequences of this massive representation of apparently almost all emotionally relevant social behavioral complexes, so universally established in a diversity of species, still has to be detected. A second and equally important aspect of hypothalamic function obviously has to be related to its central position within various hormonal systems. The present article concentrated on the acute dynamics and behavioral significance of activation of the pituitary-adrenocortical and pituitary-gonadal axes. Evidence indicates that the unconditioned behavioral stimuli or the consequences of behavior, but also stimuli conditioned to emotionally relevant events, may drastically alter hypothalamic hormonal regulation. Most importantly, these hormonal consequences in themselves again seem to determine further behavior and responses in relevant situations. The evidence presented with respect to reward and aversion, associated with alterations of specific hormones of the gonadal axis, may add a new dimension to our understanding of psychoendocrine functions of the hypothalamus (see also Gary, 1975; Leshner et al., 1981; Carey, 1987). Psychologically, such data can be taken as an argument for a more thorough study of the relation between memory processes and emotion (Bower et al., 1981). However fragmentary and incomplete this review may be, it will be clear that hypothalamic substrates and directly related areas, as well as affiliated hormonal mechanisms, play a central role in many of the most complex motivational and emotional syndromes and disorders. The prime idea in this is that the psychological concomitants of hypothalamic (dys)function are as much output as input, and as much the consequences as the cause within related syndromes. Such a view places the hypothalamus at the core of psychological theories of emotion and motivation, which from their most early origin have been heavily set towards hormonal and humoral changes and their relationships with psychological experience.(ABSTRACT TRUNCATED AT 400 WORDS)


Endogenous pyrogens in the CNS: role in the febrile response. The febrile reaction is an integrated endocrine, autonomic and behavioral response, coordinated by the hypothalamus, that includes certain components of the stress response, such as elevated corticosteroid secretion. It is produced by the actions of circulating cytokines, such as interleukin-1 (IL-1) and tumor necrosis factor (TNF), on the organum vasculosum of the lamina terminalis (OVLT), resulting in the secretion of prostaglandin E2, which initiates a variety of responses, including elevation of body temperature and corticosteroid secretion. Although circulating cytokines apparently do not enter the brain, injections of IL-1 or TNF well within the blood-brain barrier produce identical effects. We have examined the localization of possible central sources of cytokines and prostaglandins, using immunohistochemistry, immunoblotting and enzyme assay. Our data indicate that in the brain cyclooxygenase, the key enzyme in the synthesis of prostaglandins, is found in neurons in the OVLT, but is also made by neurons in many sensory and visceral regulatory systems. We present evidence also that IL-1 beta in the human brain and TNF alpha in the mouse may be present in the central nervous system as neuromodulators that are important for producing the autonomic, endocrine and behavioral components of the febrile reaction. We propose a sequence of events in the febrile reaction involving: (1) action of circulating cytokines on cyclooxygenase containing neurons within the OVLT to produce local prostaglandin secretion; (2) local diffusion of prostaglandin E2 into the preoptic and anterior hypothalamic areas; (3) action of prostaglandin E2 on cytokine containing neurons in the preoptic and anterior hypothalamic areas; and (4) release of cytokines from neuronal terminals at distal sites involved in producing the autonomic, endocrine and behavioral components of the febrile reaction.


In situ hybridization histochemistry in the human hypothalamus. We have seen that mRNA for several neuropeptides can be visualized at the microscopic level in human post-mortem brain tissues using in situ hybridization histochemistry and oligonucleotides as probes. The specificity of the hybridization signal detected in each case is supported by several criteria such as Northern blot analysis, use of at least two oligonucleotides complementary to different regions of the same target mRNA, cohybridization of labeled and excess unlabeled oligonucleotide probes, and melting curve analysis of the formed hybrids. Furthermore, factors such as age, post-mortem delay or gender did not show a significant effect in the levels of hybridization in the control population studied. Hybridization signals comparable to those found in the control population were obtained in frozen tissues, stored for up to 6 years before analysis. The results obtained for the different neuropeptides examined are, in general, in good agreement with the available information on their distribution and cellular localization as determined by radioimmunoassay or immunohistochemistry. The use of in situ hybridization histochemistry has clearly revealed the location of neurons synthesizing these neuropeptides, adding important information to that provided by radioimmunoassay or immunohistochemistry. A typical example is the identification of peptide synthesizing neuronal cell bodies by immunohistochemistry. This requires, in some cases, the use of treatments such as colchicine, obviously impossible with human brain tissues. The abundance of mRNA could be further related to transcriptional activity and, when compared with peptide levels, can provide some clues on peptide turnover rates. Thus in the hypothalamus, the paraventricular and supraoptic nuclei were found to contain cells expressing arginine-vasopressin and oxytocin mRNAs. Their distribution was in good agreement with that determined by immunohistochemistry (Dierickx and Vandesande, 1977). We have also found that these nuclei contain transcripts for neuropeptide genes such as preproenkephalin A, neuropeptide Y and somatostatin, in agreement with previously reported immunohistochemical data (Agid and Javoy-Agid, 1985; Emson et al., 1986). In the basal ganglia, numerous cells heterogeneously distributed throughout the caudate and putamen nuclei were found to contain preproenkephalin A mRNA.(ABSTRACT TRUNCATED AT 400 WORDS)


Brain banking and the human hypothalamus--factors to match for, pitfalls and potentials. The study of an increasing number of processes occurring in the human brain can be carried out on autopsy material. The availability of this material, whether fresh, frozen or fixed, makes it possible to develop methodologies for studying the neuroanatomical and neurochemical aspects of the human brain. It has also become possible in recent years to correlate functional changes with neurochemical changes and with neuroanatomical abnormalities in disease states. Some compounds and structures are damaged irreversibly within minutes after death and some brain components are known to disintegrate within seconds. This led to the widespread idea that autopsy material would not be suitable for basic research purposes and would not supply the necessary answers on the various fundamental questions regarding processes occurring in normal or diseased brain. However, from data published in recent years in which autopsy material has been routinely used, it becomes more and more evident that this is a misconception. There is an increasing number of reports based on the use of normal and pathological human brain tissue obtained by autopsies in spite of the fact that there is a worrying continuous decline in autopsy rate which causes serious concern among scientists world-wide (Anderson and Hill, 1989). It also became evident that when using the proper fixation procedures, sufficient structural integrity is retained in the tissue to allow morphological and morphometrical studies (Swaab and Uylings, 1988). Electron microscopic examination of synaptosomal preparations from post-mortem human brain showed them to be only slightly less pure than preparations from fresh tissue although there was some degree of damage (Hardy et al., 1982). Agonal state effects the stability of brain compounds and causes brain hypoxia. This again forms a tremendous difficulty for the study of human neurological and psychiatric diseases as one of the frequent causes of death is bronchopneumonia which leads to brain hypoxia and results in pronounced lactic acidosis. The Netherlands Brain Bank has succeeded to partly circumvent some of the serious problems encountered in providing human tissue for research by performing rapid autopsies with an average post-mortem delay of 2-4 h. This has become possible by a close collaboration of numerous nursing homes in Amsterdam and its vicinity and with the neuropathologists of the Free University in Amsterdam. We also measure the pH of the tissue as indicator of agonal state in order to reveal unsuitable specimens. The human hypothalamus contains various nuclei manifesting a wide variety of changes in different conditions.(ABSTRACT TRUNCATED AT 400 WORDS)


The fourth C.U. Ariëns Kappers lecture. The organization of the human circadian timing system. The mammalian circadian timing system has three principal components; (1) photoreceptors and visual pathways mediating entrainment; (2) a pacemaker, the suprachiasmatic nucleus of the hypothalamus; and (3) efferent pathways coupling the suprachiasmatic nucleus to effector systems exhibiting circadian function. In most mammals there are two visual entraining pathways, a direct retinohypothalamic pathway terminating in the suprachiasmatic nucleus, for which the transmitter is unknown, and a secondary visual pathway, the geniculohypothalamic tract, from the intergeniculate leaflet of the lateral geniculate to the suprachiasmatic nucleus that is neuropeptide Y-producing. These pathways end in a distinct subdivision of the suprachiasmatic nucleus characterized by the presence of vasoactive intestinal polypeptide neurons. A second suprachiasmatic nucleus division does not receive visual afferents and is characterized by vasopressin neurons. The efferent projections of the suprachiasmatic nucleus are very restricted, predominantly to the hypothalamus. Although we have much less information on the human circadian timing system than on that of other animals, it seems clear that the human conforms to the general animal pattern in most features. There are, however, two significant differences. First, the largest neural component of the human suprachiasmatic nucleus is a population of neurotensin neurons found throughout the nucleus. Few, if any, neurotensin neurons are found in monkey or other mammals. Second, the human suprachiasmatic nucleus contains a large number of neuropeptide Y neurons located where the plexus arising from geniculate neuropeptide Y neurons is found in other mammals. This is unique and suggests that the geniculohypothalamic projection may be bypassed in the human. It also may imply that the functional organization of the human SCN is fundamentally different from that of other mammals. The function of the circadian timing system is to coordinate the activities of a series of homeostatic regulatory mechanisms with the control of behavioral state in a temporal pattern that facilitates adaptive behavior, including reproduction (Fig. 9). The function of this system, then, is to provide the appropriate physiological and behavioral background to facilitate adaptation and survival.


Hyperfractionation versus conventional fractionation in oropharyngeal carcinoma: final analysis of a randomized trial of the EORTC cooperative group of radiotherapy. EORTC protocol 22791 compared once daily fractionation (CF) of 70 Gy in 35-40 fractions in 7-8 weeks, to pure hyperfractionation (HF) of 80.5 Gy in 70 fractions in 7 weeks using 2 fractions of 1.15 Gy per day, in T2-T3 oropharyngeal carcinoma (excluding base of tongue), N0,N1 of less than 3 cm. From 1980 to 1987, 356 patients were entered. In the final analysis (June 1990), the local control was significantly higher (p = 0.02 log-rank) after HF compared with CF. At 5 years, 59% of patients are local disease-free in the HF arm compared to 40% in the CF arm. The superiority of HF was demonstrated in patients staged T3N0,T3N1 but not in T2. The Cox model confirmed that the treatment regimen was an independent significant prognostic factor for locoregional control (p = 0.007 log-rank). This improvement of locoregional control was responsible for a trend to an improved survival (p = 0.08 log-rank). There was no difference in late normal tissue damage between the two treatment modalities.


Assessment of dose inhomogeneity at target level by in vivo dosimetry: can the recommended 5% accuracy in the dose delivered to the target volume be fulfilled in daily practice? The inhomogeneity of the dose delivered to the target volume due to irregular body surface and tissue densities remains in many cases unknown, since the dose distribution is calculated for most radiation treatments in only one transverse section and assuming the patient to be water equivalent. In the present study, the transmission and the target absorbed dose homogeneity is assessed for 11 head-and-neck cancer treatments by in vivo measurements with silicon diodes. Besides the dose to the specification point, the dose delivered to 2-4 off-axis points in the midline sagittal plane is estimated from entrance and exit dose measurements. Simultaneously made portal films allow to identify the anatomical structures passed by the beam before reaching the exit diode. The mean deviation from the expected transmission is -6.8% for bone, +6% for air cavities and -2.5% for soft tissue. At the midplane, the mean deviations from the expected target dose are respectively -3.5%, +2.3% and -1.9%. The deviations from the prescribed dose are larger than 5% in 12 out of the 39 target points. The accuracy requirement in target dose delivery of plus or minus 5%, as proposed by ICRU, cannot be fulfilled in 7 out of the 11 patients and is mostly due to irregular body contour and tissue densities. As only a limited number of points are considered, the inhomogeneity in the dose delivered throughout the whole irradiated volume is underestimated as is illustrated from the exit dose profiles obtained from the portal image.(ABSTRACT TRUNCATED AT 250 WORDS)


Clinical implications of heterogeneity of tumor response to radiation therapy. Heterogeneity of response of tumor tissue to radiation clearly exists. Major parameters include histopathologic type, size (number of tumor rescue units (TRUs)), hemoglobin concentration, cell proliferation kinetics and immune rejection reaction by host. Further, normal and presumably tumor tissue response is altered in certain genetic diseases, e.g. ataxia telangiectasia. Any assessment of response of tumor tissue to a new treatment method or the testing of a new clinical response predictor is optimally based upon a narrow strata, viz., uniform with respect to known parameters of response, e.g. size, histological type. Even among tumors of such a clinically defined narrow strata, there will be residual heterogeneity with respect to inherent cellular radiation sensitivity, distributions of pO2, (SH), cell proliferation etc. The value of a response predictor of an individual tumor will be determined by the heterogeneity of values for these and or other characteristics and by the coefficient of variation (CV) of the measured values of the individual parameters. Heterogeneity of one or more parameters of response is reflected in the slope of the dose response curve for local control, viz. the greater the heterogeneity the less steep the slope. To examine for this effect, the slope of dose response curves for control of model tumors of 10(8) tumor rescue units (TRU) and the SF2 = 0.5 (survival fraction after a single dose of 2 Gy) has been used to assess the impact of inter- and intra-tumoral variation of SF2 on slope, defined as gamma 50 values. The gamma 50 is the increase in local control expressed in percent points for a one percentage increment in dose, at the mid-point on the dose-response curve. The gamma 50 was 6.5 for CV = 0.0. For inter-tumoral CVs of 10%, 20% and 40%, the gamma 50 rapidly decreased to 2.4, 1.3 and 0.7. Intra-tumoral variation was less important, viz., for CVs of 10%, 20%, and 40% the gamma 50 values were reduced to 5.3, 3.8 and 2.2. Combining inter- and intra-tumoral variation reduced the gamma 50 only slightly below that for inter-tumoral variation alone. For example, were the CV 10% for inter- and intra-tumoral variation, the gamma 50 would be 2.1 as compared to 2.4 for inter-tumoral variation alone. The number of TRUs also affects slope, viz. gamma 50 increased from 1 to 9.7 as the TRU number increased from 10(1) to 10(12).(ABSTRACT TRUNCATED AT 400 WORDS)


Accelerated versus conventional fractionation in the postoperative irradiation of locally advanced head and neck cancer: influence of tumour proliferation. Fifty-six patients with locally advanced head and neck squamous cell carcinoma were subjected to adjuvant radiotherapy after radical surgery with randomisation to either conventional fractionation (CF), comprising 50 Gy/25 F/5 weeks, or to accelerated hyperfractionation (AHF) to a dose of 42 Gy/30 F/11 days (3 F/day), a dose/F of 1.4 Gy and an interfraction interval of 4 h. The in vitro [3H]thymidine labelling index (TLI) was determined as an indicator of tumour proliferation. Early mucosal reactions were somewhat more severe after AHF than after CF and the peak was attained earlier. The actuarial 3-year complication rate was significantly lower in the AHF (64%) than in the CF group (87%). This is probably related to a smaller fraction size and a lower total dose. The overall 3-year disease-free survival amounted to 46 +/- 7%. Sex, the anatomical site, the nodal status, the performance status and TLI have been shown to be significant prognostic factors, but only the latter two proved to be independent covariates. Overall, the type of fractionation did not seem to influence survival. However, AHF seemed to offer higher survival probabilities in fast growing tumours and this attained a significant level for tumours with TLI > 10.4% (Tpot < 4.5 days). However, CF and AHF were associated with similar survival rates in slowly growing tumours. The relative effectiveness of the CF and AHF schedules is predictable on the basis of the linear-quadratic system. In the case of tumour response, a time factor has to be included assuming that accelerated repopulation of microscopic residues occurs from the outset.(ABSTRACT TRUNCATED AT 250 WORDS)


Time factors in breast carcinoma: influence of delay between external irradiation and brachytherapy. From 1971 to 1983, 398 (33 T1, 309 T2, 56 T3) biopsy-proven breast adenocarcinomas were treated conservatively at Hôpital Henri Mondor by an initial course of external irradiation (45 Gy, 25 fractions, 5 weeks) followed by interstitial iridium-192 implant for a further 37 Gy to the tumor. The mean interval between external irradiation and brachytherapy was 5.9 weeks (S.D. 1.7, range 1-18). Seventy-seven local failures were observed at 10-148 months (median 34.5). The actuarial probabilities (S.E.) of local control at 5 and 10 years were 0.86 (0.02) and 0.74 (0.03), respectively. The follow-up for patients free of local recurrence was 4-205 months (median 95). Multivariate analysis showed an increasing probability of local failure with longer interval between external irradiation and brachytherapy (Relative Risk [R.R.] 1.23 [95% confidence limits: 1.07, 1.41] per week, p = 0.005), and a lower risk of failure in case of complete tumor regression after external irradiation (R.R. 0.47 [0.25, 0.90], p = 0.022), and higher brachytherapy dose rate (R.R. 0.13 [0.02, 1.02] per Gy/h, p = 0.053). No influence of tumor size and total dose (possibly because only limited variations in total dose were observed), or histological grading (not performed in 140 [35%] patients) was found. Because of the lack of dose-control relationship, quantification of the effects of delay between external irradiation and brachytherapy (in terms of compensatory dose) and of dose rate (Incomplete Repair Model) was not possible.(ABSTRACT TRUNCATED AT 250 WORDS)


The effect of treatment duration in the local control of cervix cancer. A significant effect of treatment duration on pelvic control was found in 830 patients with cervix cancer treated by radical radiation therapy. Using three methods of analysis, the loss of control consistently approximated 1% per day of treatment prolongation beyond 30 days, although analysis of stage subgroups showed that this effect was predominantly manifested in Stages III/IV compared with Stages I/II. In multivariate analyses using both a logistic regression and a Cox regression model, stage (p = 0.0001 for Stage I/IIA and 0.0036 for Stage IIB relative to Stage III/IV) treatment time (p = 0.0001), and age (p = 0.0067) were independently correlated with pelvic control. Exclusion from analysis of patients with delays due to tumour or treatment related complications, intercurrent illness or manifestations of poor tumour response did not significantly change the magnitude of the time effect nor the ranking of the significant covariates. These results are consistent with the occurrence of accelerated repopulation and warrant further investigation, preferably in a randomized trial of accelerated versus conventionally fractionated radiation therapy.


Is the experience with CHART compatible with experimental data? A new model of repair kinetics and computer simulations. A new incomplete repair model is introduced that differs from previous models of this type by not assuming that repair is complete during long intervals, e.g. "overnight" intervals of 12-24 h. The model was used to assess the risk of myelopathy resulting from continuous hyperfractionated accelerated radiotherapy treatment (CHART) in light of recent experimental data on the rat spinal cord. Model calculations employing biexponential repair kinetics showed that CHART treatments might result in a higher myelopathy risk than an equal dose given in conventional 2-Gy fractions if the parameters obtained from the animal data hold. The probability of observing what has been reported for CHART was determined in computer simulations for different variance scenarios. The chance to observe four myelopathies in the 74 cervical cord patients was estimated to range between 25 and 62%, while the probability to see 0 in 68 thoracic cord patients ranged from 48 to 27%. These numbers were derived from reasonable assumptions about the repair kinetics (e.g. 60% of damage repaired with a half-time of 8 h) so that the over-all probability to observe 4/74 and 0/68 was maximized, and depending on the scenario fell in the range 12-17%. Finally, from these simulations a myelopathy risk of approximately 0.3-1.2% is predicted for the currently employed maximal CHART dose to the spinal cord, i.e. 42 Gy. We conclude that the CHART experience is not compatible with the new experimental data (p < 5%). Incomplete repair is unlikely to be the sole reason for the unexpected toxicity of CHART (p < or = 17%).(ABSTRACT TRUNCATED AT 250 WORDS)


Impact of spinal cord repair kinetics on the practice of altered fractionation schedules. The kinetics of repair of sublethal lesions in the spinal cord was assessed in detail using a rodent model. Experiments were designed to obtain the fractionation sensitivity, alpha/beta, and to quantify the kinetics of repair after a clinically relevant fraction size. Pairs of 2-Gy fractions at intervals ranging from 0 to 24 h were given from Monday through Friday, to cumulative doses of 40-84 Gy. In addition, two groups of animals received 1.5 or 1.2 Gy twice a day at 8-h intervals, 5 days a week, to total doses of 66-90 Gy and 67.2-98.4 Gy, respectively. All irradiations were followed by a top-up dose of 16 Gy. Analysis of the experimental data revealed that a bi-exponential repair model fit the experimental data significantly better than did the mono-exponential model (p = 0.002). The repair half times obtained were 0.7 (0.2-1.3) h and 3.8 (2.6-4.9) h, respectively. The proportion of injury repaired by the longer half time was estimated to be 0.62 (0.37-0.86). The data showed that delivering 2 fractions per day at 6- or 8-h intervals instead of one per day led to a 16.5% (11.8-21.1%) and 13.5% (9.1-17.8%) reduction in the tolerance, respectively. Finally, the results indicated that when incomplete repair between fractions was accounted for, the linear-quadratic (LQ) model was valid in describing fractionation response down to 1.2 Gy per fraction.


Fractionation sensitivity of the rat cervical spinal cord during radiation retreatment. Data concerning the fractionation sensitivity of normal tissues during radiation retreatment are limited. Experiments were performed to investigate whether the fractionation sensitivity of the rat cervical spinal cord is changed during retreatment 6 months after a first dose of 15 Gy, representing about half the biologically effective dose for induction of paresis. After a 6 months interval, the long-term recovery from the first treatment was about 45%. The fractionation sensitivity of the rat cervical spinal cord during reirradiation was not significantly different from the fractionation sensitivity of not previously irradiated control rats, with an alpha/beta ratio of 2.3 Gy in control rats and 1.9 Gy during reirradiation of the spinal cord. An additional observation from these experiments was the presence of incomplete repair after fractionated treatment with 2 fractions of 3 Gy per day with 10-h intervals.


Fractionation sensitivity and latency of late radiation injury to the mouse urinary bladder. Transurethral bladder filling is a functional, non-invasive, in vivo assay of early and late radiation injury to the mouse bladder. Fractionated irradiations using single doses or 2, 3, 5, or 10 dose fractions in an overall time of 4 or 4.5 days, with a range of total doses, were given to the bladder of 12-14 week-old C3D2F1/Bom mice. In 372 mice, bladder volume at an intravesical pressure of 20 mmHg was measured before irradiation and at regular intervals thereafter. The endpoint for late bladder injury was a volume of less than 50% of the median pretreatment volume in all animals, occurring more than 30 days after irradiation. This endpoint was reached after a latent period ranging between 35 and 401 days. Fractionation and latency parameters were estimated using a mixture model. There was a highly statistically significant dose-dependency of the latent period (p < 10(-8)). The alpha/beta ratio was estimated at 5.8 Gy [95% confidence limits (3.6; 8.8) Gy] for 250 kVp X-rays. Thus late radiation injury in the mouse urinary bladder is one of the least sensitive late endpoints with respect to change in dose per fraction. Introducing early bladder injury as a variable in the model improved the fit significantly (p = 0.03), but the alpha/beta ratio remained unchanged. Thus the hypothesis that late bladder injury may be, at least in part, consequent upon early injury did not explain the relatively high alpha/beta ratio for this late endpoint.


Treatment acceleration in radiotherapy: the relative time factors and dose-response slopes for tumours and normal tissues. A published collation of data for control of head and neck cancer in over 4500 patients has been subjected to direct analysis to deduce dose-response, fractionation, and time parameters. The analysis confirms the presence of a significant time factor of the order of 0.5-0.6 Gy/day, deduced previously using various assumptions and normalisation procedures. In addition, the dose-response curve was characterised by Da = 29 Gy which contributed to long "effective" doubling times being deduced for tumour clonogens in the patient population as a whole. Some late-reacting normal tissues also show significant time factors, and furthermore, their dose-response curves are in general steeper than for tumours. Hence, care should be taken in accelerating treatments to improve local control, if the treatments are truly at tolerance regarding late-appearing major complications.


Dose-time factors in head and neck data. This paper discusses two points regarding the interpretation of dose-time effects on tumor control in head and neck data. It is shown that the sample size in many clinical series will be too small to be able to statistically detect a dose-response relationship. The results from a non-parametric regression technique applied to control rate data from a large number of institutions suggest an influence of both dose and time on the control rate and qualitatively agree with a previous analysis of these data.


[Dental status and dental preventive behavior in Flanders]. Socio-economic factors are important parameters for dental health status and preventive behavior. In an epidemiologic survey of +/- 8000 5- and 12-year old schoolchildren in Flanders significant differences in dental attendance, brushing habits and caries prevalence were found between 12-year old boys and girls. Ethnic differences were pronounced. Dental attendance and brushing frequency were lower in non-West-European children. These children showed a higher caries attack rate at the age of 5 but in 12-year olds the opposite was noted. Interprovincial differences should probably be attributed to differences in social levels.


[Dental caries in a Belgian school population of 5-to-21-year-olds]. During the last 20 years, existing data show that caries activity has decreased in some industrialized countries, while marked increases have occurred, often rapidly, in developing countries. Changes in the prevalence of a multifactorial disease like dental caries are difficult to explain but seem to coincide either with increased intake of refined sugar-containing feeding or with the widespread availability of fluorides from many sources, more particularly in the tooth-pastes. The combination of fluorides with different other factors must be considered to explain the reduction in caries prevalence in the 1970's, but only the cariostatic effect of fluorides can be measured significantly. In spite of few studies in Belgium, a trend to a reduction of caries prevalence has been observed in temporary and permanent dentition. The aims of this study are to assess: 1. the oral health in a population of 5 to 21 old schoolchildren 2. and the effect of water naturally fluoridation on the dental caries prevalence. The dental caries prevalence is determined in each age group using the dft, dfs, D (2-4) MFT and D (2-4) MFS indices. The situation in this population is not satisfactory and there is a marked need for better oral health. The D (2-4) MFT increases from 1.67 to 11.29 between 6 and 20 years of age. In each age group, the numbers of carious and untreated surfaces in temporary and permanent dentition are more important than the number of filled surfaces. The percentage of children with caries-free teeth decreases from 27.0 to 0% between 5 and 20 years of age. A relation is recorded between the caries indices and the socio-economic category of the father, with the lowest indices among the higher educational group. The results show that the prevalence of dental caries is significantly lower in lifetime residents of the fluoridated community (Mouscron). Fluoridation reduces but does not eliminate social inequalities. The benefits of water fluoridation have been demonstrated in most countries but fluoridation alone is not sufficient to achieve total prevention.


[From epidemiology to social epidemiology in dentistry. The example of caries]. Today, we know the caries aetiology and prevention rather well. We also know that caries-related levels of dental health are inequitably distributed among social classes: on the average, disadvantaged people experience higher DMFS then privileged people. This difference can be explained by a differential access to health care, which can be shown by the study of components of the DMFS index: proportion of filled surfaces (F/DMFS), proportion of missing surfaces (M/DMFS), and proportion of recurrent caries (secondary caries/filled surfaces). Though we are able to describe the social distribution of levels of dental care, we cannot "explain" the differences we observe. The explanation of those differences defines the field of social epidemiology. This consists in determining the social aetiology of diseases, starting from social determinants of attitudes and behaviors influencing health.


[Dental hygiene in 10-to-18-year-old youths in Flanders. Results of a school survey]. This study is part of the cross-national Survey on Health and Lifestyles in School-aged children--a WHO collaborative study (HELENA). The aim of this report was to describe the oral health habits (oral hygiene, use of dental floss and fluoride, consumption of sugar snacks) in schoolchildren aged 10 to 18 in the Flemish-speaking community of Belgium. Toothbrushing was consistently less frequent among boys than among girls. There is a negative correlation between the frequency of toothbrushing and the consumption of soft drinks in both sexes, and between toothbrushing and sweets consumption in girls. The use of dental floss is still very rare. Efforts must be continued to reduce the consumption of sweets and soft drinks. No differences in oral health habits were noted among children from different school types. Parental profession did not influence oral health habits in this study.


[Which dentist for which campaign?].

[Which dentist for which campaign?]. Some dentists took part in the Red Cross dental health campaign "Teeth 2000". It was an opportunity to analyze their participation in a campaign, to compare them with the profile of the average Belgian french-speaking dentist and finally, to put forward certain criteria to target these dentists.


[Meta-analysis: a structured bibliographic protocol]. Meta-analysis is a way of reviewing literature in a structured and systematic format. A formalized protocol for selection of the reviewed papers and a qualitative as well as quantitative evaluation are essential. Mathematical pooling of the results of the individual studies can be part of the process. A number of pitfalls are possible. However, when performed in a correct way and evaluated critically by the reader, a meta-analysis can add consistently to the medical knowledge concerning a specific subject.


[Epidemiological study of caries prevalence in 5-and-12-year-old school children in Flanders]. A caries prevalence survey was carried out among twelve and five-year-old school children in Flanders (Belgium). The aim of the study was an evaluation of the education, prevention and treatment programme organised by the Flemish Working Group on Oral Prevention. The survey covered 3600 5-year old children and as many 12-year old adolescents, selected at random in the five Dutch-speaking provinces of Belgium. Concerning the caries experience of 5-year old children, we noticed a small dmft of 1.65 and a percentage of caries-free of 60%. Regarding the results for the 12-year olds, we recorded a DMFT of 2.72 and 25% caries-free adolescents. Children from non West-European origin scored much higher in dmft but showed a remarkably lower DMFT-index. We can suggest that an increased attention remains necessary for risk groups such as children with a high caries susceptibility, young immigrants and low income families. The dental health education in schools should be kept on-going and even be extended towards adolescents. Because we remarked a very low dental attendance pattern among young children, we really need to convince parents of the importance of early visits to the dentist. We believe that epidemiology is the only basis for a sound and evident prevention strategy.


The effect of neglecting correlations when propagating uncertainty and estimating the population distribution of risk. Interest in examining both the uncertainty and variability in environmental health risk assessments has led to increased use of methods for propagating uncertainty. While a variety of approaches have been described, the advent of both powerful personal computers and commercially available simulation software have led to increased use of Monte Carlo simulation. Although most analysts and regulators are encouraged by these developments, some are concerned that Monte Carlo analysis is being applied uncritically. The validity of any analysis is contingent on the validity of the inputs to the analysis. In the propagation of uncertainty or variability, it is essential that the statistical distribution of input variables are properly specified. Furthermore, any dependencies among the input variables must be considered in the analysis. In light of the potential difficulty in specifying dependencies among input variables, it is useful to consider whether there exist rules of thumb as to when correlations can be safely ignored (i.e., when little overall precision is gained by an additional effort to improve upon an estimation of correlation). We make use of well-known error propagation formulas to develop expressions intended to aid the analyst in situations wherein normally and lognormally distributed variables are linearly correlated.


Modeling the modification of the risk of radon-induced lung cancer by environmental tobacco smoke. The presence of environmental tobacco smoke (ETS) in homes has been implicated in the causation of lung cancer. While of interest in its own right, ETS also influences the risk imposed by radon and its decay products. The interaction between radon progeny and ETS alters the exposure, intake, uptake, biokinetics, dosimetry, and radiobiology of those progeny. The present paper details model predictions of the various influences of ETS on these factors in the U.S. population and provides estimates of the resulting change in the risk from average levels of radon progeny. It is predicted that the presence of ETS produces a very small (perhaps unmeasurable) increase in the risk of radiation-induced tracheobronchial cancer in homes with initially very high particle concentrations for both active and never-smokers, but significantly lowers the risk in homes with initially lower particle concentrations for both groups when generation 4 of the lung is considered the target site. For generation 16, the presence of ETS generally increases the radon-induced risk of lung cancer, although the increase should be unmeasurable at high initial particle concentrations. The net effect of ETS on human health is suggested to be a complicated function of the initial housing conditions, the concentration of particles introduced by smoking, the target generation considered, and the smoking status of exposed populations. This situation precludes any simple statements concerning the role of ETS in governing the incidence of lung cancer in a population.


Risk perception and the value of safety. This paper examines the relationship between perceived risk and willingness-to-pay (WTP) for increased safety from technological hazards in both conceptual and empirical terms. A conceptual model is developed in which a given household's WTP for risk reductions is a function of traditional socioeconomic variables (i.e., income and base level of risk) and perceived characteristics of the hazards (i.e., dread, knowledge, and exposure). Data to estimate the model are obtained through a combined contingent valuation and risk perception survey that considers 10 technological hazards, five of which are well-defined (e.g., death rates are known and the risks are relatively common) and five are less well-defined. Econometric results, using TOBIT estimation procedures, support the importance of both types of variables in explaining WTP across all 10 hazards. When the risks are split into two groups, the results show that WTP for well-defined hazards is most influenced by perceived personal exposure, while WTP for less well-defined risks is most influenced by levels of dread and severity.


Comparison of the dependence of the TD50 on maximum tolerated dose for mutagens and nonmutagens. The relationship between the minimum TD50 (i.e., the TD50 measured at the most sensitive site) and the maximum dose administered (maxD) in rodent carcinogenicity bioassays was investigated separately for mice and rats. The relationship between log(1/TD50) and log(1/maxD) was analyzed as a function of (1) mutagenicity and (2) the statistical significance cutoff for selecting the minimum TD50 values. For rat bioassays, the variance of log(1/TD50) is larger and the correlation of log(1/TD50) with log(1/maxD) is weaker for mutagens than for nonmutagens, suggesting that the relationship between minimum TD50 and MTD is, in general, stronger for nonmutagens than for mutagens. The difference in correlation does not depend on the TD50 statistical significance cutoff, but the difference in variance is not significant for the most stringently selected dataset. For mouse bioassays, no significant mutagen/nonmutagen differences in log(1/TD50) variance are found. A significantly weaker correlation of log(1/TD50) with log(1/maxD) for mutagens in comparison to nonmutagens occurs only for the dataset with minimum TD50 chosen at the least stringent level, suggesting that this difference may be due to chance variation. We also looked for changes in correlation and regression parameters as a function of mutagenic potency in Salmonella; the variance of log(1/TD50) and its correlation with log(1/maxD) are not found to vary in a consistent manner. Taken as a whole, our results indicate that (1) mutagenicity is a determinant of the TD50/maxD relationship in rats and (2) any effect that mutagenicity may exert on the TD50/maxD relationship in mice is unimportant.(ABSTRACT TRUNCATED AT 250 WORDS)


Probabilistic connotations of carcinogen hazard classifications: analysis of survey data for anchoring effects. A study was undertaken to test for anchoring effects when numerical probabilities were elicited for carcinogen hazard designations. Subjects were asked to assign probabilities to both probable and possible. The sequence was randomly varied so that half of the subjects evaluated probable first and half evaluated possible first. While there was no consensus on the numerical probabilistic meanings assigned to these verbal expressions, in general, probable was assigned a higher probability than possible and there were specific values that were assigned frequently, indicating some consistency in interpretation. There appeared to be a fairly constant scaling factor between the probabilities assigned to the designations. Anchoring was manifested in two ways: a smaller difference between the designations when they were evaluated in sequence than when they were evaluated in isolation, and assignment of readily accessible "benchmark" values such as 50% and 75%.


Estimating dermal uptake of nonionic organic chemicals from water and soil: I. Unified fugacity-based models for risk assessments. Contamination of water and soil that might eventually contact human skin makes it imperative to include the dermal uptake route in efforts to assess potential environmental health risks. Direct measurements of dermal uptake from either water or soil are only available for a small number of the thousands of chemicals likely to be found in the environment. We propose here a mass-transfer model for estimating skin permeability and dermal uptake for organic chemicals that contaminate soil and water. Statistical relationships between measured permeabilities and chemical properties reveal that permeability varies primarily with the octanol-water partition coefficient (Kow) and secondarily with the molecular weight. From these results, we derive a fugacity-based model for skin permeability that addresses the inherent permeability of the skin, the interaction of the skin with the environmental medium on skin (water or soil), and retains a relatively simple algebraic form. Model predictions are compared to measured human skin permeabilities for some 50 compounds in water and four compounds in soil. The model is adjusted to account for dermal uptake during both short-term (10-20 min) and long-term (several hour) exposures. This model is recommended for compounds with molecular weight less than or equal to 280 g.


Cancer risk assessment with intermittent exposure. Applications of methods for carcinogenic risk assessment often focus on estimating lifetime cancer risk. With intermittent or time-dependent exposures, lifetime risk is often approximated on the basis of a lifetime average daily dose (LADD). In this article, we show that there exists a lifetime equivalent constant dose (LECD) which leads to the same lifetime risk as the actual time-dependent exposure pattern. The ratio C = LECD/LADD then provides a measure of accuracy of risk estimates based on the LADD, as well as a basis for correcting such estimates. Theoretical results derived under the classical multistage model and the two-stage birth-death-mutation model suggest that the maximum value of C, which represents the factor by which the LADD may lead to underestimates of risk, will often lie in the range of 2- to 5-fold. The practical application of these results is illustrated in the case of astronauts subjected to relatively short-term exposure to volatile organics in a closed space station environment, and in the case of the ingestion of pesticide residues in food where consumption patterns vary with age.


Extrapolation of carcinogenicity between species: qualitative and quantitative factors. Prediction of human cancer risk from the results of rodent bioassays requires two types of extrapolation: a qualitative extrapolation from short-lived rodent species to long-lived humans, and a quantitative extrapolation from near-toxic doses in the bioassay to low-level human exposures. Experimental evidence on the accuracy of prediction between closely related species tested under similar experimental conditions (rats, mice, and hamsters) indicates that: (1) if a chemical is positive in one species, it will be positive in the second species about 75% of the time; however, since about 50% of test chemicals are positive in each species, by chance alone one would expect a predictive value between species of about 50%. (2) If a chemical induces tumors in a particular target organ in one species, it will induce tumors in the same organ in the second species about 50% of the time. Similar predictive values are obtained in an analysis of prediction from humans to rats or from humans to mice for known human carcinogens. Limitations of bioassay data for use in quantitative extrapolation are discussed, including constraints on both estimates of carcinogenic potency and of the dose-response in experiments with only two doses and a control. Quantitative extrapolation should be based on an understanding of mechanisms of carcinogenesis, particularly mitogenic effects that are present at high and not low doses.


[Anti-influenza vaccination for active persons (25-64 years): a cost-benefit study]. This paper is a specific cost-benefit study concerning 25-64 years people flu vaccination. For this active population the vaccination rate is only 12% and the cost of absenteeism is potentially high. To make the balance between prevention costs and (direct and indirect) avoided costs by the vaccine, we use a basic case with mean value parameters as: efficacy rate of vaccine, impact of epidemics, size of vaccinated population, immunization length and compensation rate of the so-called production losses. These parameters are then supposed to vary in a sensitivity analysis. In any case net benefit of vaccination appears, which size varies mainly in relation to epidemics and vaccinated population extents. But improvements are to be achieved for giving more precise values to "real" efficacy rate of vaccination and effective economic impact of absenteeism on production.


[Determination of cost-effective strategies in colorectal cancer screening]. The object of the article is to implement particular methodologies in order to determine which strategies are cost-effective in the mass screening of colorectal cancer after a positive Hemoccult test. The first approach to be presented consists in proposing a method which enables all the admissible diagnostic strategies to be determined. The second approach enables a minimal cost function to be estimated using an adaptation of "Data Envelopment Analysis". This method proves to be particularly successful in cost-efficiency analysis, when the performance indicators are numerous and hard to aggregate. The results show that there are two cost-effective strategies after a positive Hemoccult test: coloscopy and sigmoidoscopy; they put into question the relevance of double contrast barium enema in the diagnosis of colo-rectal lesions.


[Comparative efficacy of annual and semi-annual doses of ivermectin or diethylcarbamazine for the prevention of lymphatic filariasis]. A double blind randomized trial was performed on 58 healthy Polynesian Wuchereria bancrofti carriers, they were randomly allocated to treatments with repeated annual or semi-annual doses of ivermectin 100 mcg/kg or diethylcarbamazine (DEC) 3 mg/kg, or with repeated annual doses of DEC 6 mg/kg. After the 12-month treatment, the clearance of microfilaremia was complete in 7 of the 23 carriers treated with ivermectin and in 3 of the 35 treated with DEC. Nine months after that treatment, the lowest mean microfilaremia was observed in the carriers treated with 3 successive semi-annual doses of DEC 3 mg/kg. Adverse reactions were comparable in carriers treated with ivermectin and in those treated with DEC, and did not interfere with daily activities of treated subjects.


Studies of exclusion in individuals with severe mental retardation. Exclusion performances in matching to sample are demonstrated when subjects select experimentally undefined comparison stimuli in the presence of undefined sample stimuli, apparently by rejecting defined comparison stimuli. Several studies have documented exclusion performances in a small number of individuals with severe mental retardation. These studies also demonstrated the potential of exclusion procedures for establishing prerequisites for emergent naming performances. The present study examined exclusion in a larger cohort of subjects. Initial experiments asked two questions. First, how reliably would exclusion performances be demonstrated? Second, would those performances be followed by emergent naming, and, if so, how reliably? Follow-up experiments examined the stimulus control basis for exclusion performances. Our findings and conclusions can be summarized as follows: First, reliable exclusion was demonstrated in nearly all subjects. Second, naming performances typically emerged. These performances were seen in the context of a recent experimental history of matching to sample and of naming baseline stimuli in the experimental format. Third, apparent exclusion may sometimes result from relating undefined sample and comparison stimuli. Together, our findings suggest potentially effective strategies for teaching people with mental retardation and point to variables that should be considered when designing exclusion-based teaching interventions.


How much benefit could be obtained from cardiovascular disease intervention programs? To estimate the potential benefits of cardiovascular disease intervention programs in Spain, we have computed cardiovascular population mortality fractions and deaths attributable to the main risk factors by using relative risks from international studies and Spanish prevalence and mortality data (subjects of both sexes, aged 25-64). As many as 71% of the cardiovascular deaths studied in men and 44% in women might be delayed every year in Spain if it were possible to eliminate the current exposure of the population to smoking, obesity, sedentariness, hypertension and hypercholesterolemia. With the eradication of tobacco exposure 31% of coronary deaths and 16% of stroke deaths in men (7% in both cases for women) might be avoided. Similar actions on sedentariness, hypertension and hypercholesterolemia might delay 17% and 29%, 13% and 13%, and 9% and 11% of deaths, respectively, in males (figures generally somewhat higher in females). These figures would be moderately lower if reductions in the prevalence of these factors are considered realistically. These results may encourage the implementation of strategies against cardiovascular diseases in countries with risk factor prevalence similar to that of Spain.


Hearing abilities of Down syndrome and other mentally handicapped adolescents. Down syndrome (DS) individuals are prone to auditory processing difficulties in a variety of audiological, short-term memory, and language tasks. The present study explored: (a) the hearing capabilities of DS adolescents and young adults relative to a sample of non-DS mentally handicapped (MH) individuals, and (b) the relationship between hearing ability and performance on several cognitive tasks. Samples of 26 DS and 26 MH trainable mentally handicapped individuals were matched on IQ and chronological age (CA). Audiometric data revealed greater hearing losses in DS than in MH individuals at five of the six tested frequencies, more DS conductive and mixed hearing losses, and particularly high DS losses in the high-frequency range. Measurement of the speech reception threshold revealed poorer reception of speech by the DS than the MH group. Classification of tympanograms indicated fewer normal ears and twice as many DS ears with middle ear problems reflecting no mobility or retraction of the tympanic membrane. Presence of DS middle ear difficulties was also confirmed by poorer elicitation of the acoustic (stapedius) reflex in DS subjects. Correlation of hearing variables with seven cognitive tasks administered on the same day revealed only one significant relationship after the statistical removal of the effects of CA and IQ: DS subjects with poorer hearing identified fewer words in a task in which a masking noise quickly followed a spoken word. This result suggests that group findings of DS auditory-verbal processing difficulties stem, in part, from subjects with hearing difficulties needing more time to identify spoken words.


[Epidemiology of acute lymphoid leukemia]. Acute lymphocytic leukaemia (ALL) has a bimodal age incidence. It constitutes the majority of leukaemias diagnosed in childhood but less than 5% of adult leukaemia. Distinction between lymphocytic and myeloid forms of acute leukaemia in routine statistics has only been possible since 1968. There is no adequate study on the aetiology of acute lymphocytic leukaemia in adults. Apart from ionizing radiation and certain genetic conditions, risk factors for ALL are poorly understood. While Greaves' biological hypothesis offers some insight into childhood ALL, the causes of adult ALL are obscure. An epidemiological study of adult ALL is proposed, with particular emphasis on environmental risk factors and recent biological markers of ALL, in order to advance understanding of this leukaemia.


[Development in health status of a group of retired subjects in the Paris region according to their practice of physical activity]. The relation between physical activity and health among retired people aged 65 and over was studied in a sample of 993 subjects, men and women, living at home in the Paris area and randomly selected from a pension fund roll. In 1982-1983 (T1), 627 subjects were interviewed. Five years later (T2), 464 subjects participated in the survey. Health was measured by the number and types of impairments and disability. The incidence of cardiorespiratory impairment and the incidence of disability were weaker among subjects with physical activity in T1 than among subjects without physical activity. These findings were unchanged after adjustment for age, sex, socioeconomic status, cigarette smoking, body mass index, uncomfortable housing, living alone and hard physical conditions during working life. This result suggests the beneficial effect of physical activity in promoting health among retired people aged 65 and over.


Hospital admission profiles of Spanish immigrants in Paris. Assistance publique hôpitaux de Paris. France. The aim of this study was to try to determine the hospital admission profiles of Spanish immigrants in France and whether differences exist between the admission patterns in this population and the autochthus French population. The study was carried out between 1984 and 1985 in all the hospitals of the "Assistance Publique-Hôpitaux de Paris". In-patients were codified by using the OTARIE system (Organisation du Traitement Automatisé de Recherche Intéressant l'Epidémiologie) based on the I.C.D. 9R. (International Classification of Diseases). Observation of the proportional morbidity rates and the standardized rates showed differences between the two populations for tuberculosis, congenital pathology, poisoning and symptoms (multi-etiological processes, poorly defined conditions and symptoms "per se"). The Spanish sample showed a greater diagnosis for tuberculosis and symptoms (psychiatric and neurological) than the French population. However, poisoning and congenital pathologies were more frequent in the latter.


[Vaccination against influenza in nursing homes in Brussels]. The aims is to measure the immunization rate against influenza in nursing homes in Brussels, to identify the methodologic problems of a survey in this type of population, to analyse the predictors of vaccine administration and to make recommendations for increasing vaccine coverage. On February 1, 1989, there were 339 nursing homes (14,095 beds) in Brussels. These nursing homes were stratified according to their size and administrative status. One home in eight was selected at random as well as two residents in three in each home. The study population included 1,165 residents in 44 nursing homes; their mean age was 81 years. The determinants of vaccine administration were analysed by logistic regression according to Donabedian's model of supply and demand. Vaccine coverage was estimated at 69%; an optimistic estimate since 20 of the homes contacted refused to participate and there are reasons to believe that the immunization rate was low in this group. Among the 781 residents able to respond, only 10% had requested to be immunized. The vaccine had been offered to 67% of that group. Factors predicting vaccine administration were the legal status of the nursing homes, the ambulatory status of the resident, knowledge of the vaccine, a history of prior vaccination, a favorable opinion about the vaccine effectiveness, safety and usefulness. Neither age nor the existence of a chronic condition were significant predictors.


Influence of different methods of vagotomies on the secretion of cholecystokinin in dogs. In six dogs, a selective proximal vagotomy, gastric vagotomy, and truncal vagotomy were performed successively. Basal and postprandial cholecystokinin (CCK) concentrations in the peripheral blood were measured by radioimmunoassay. After all the different types of vagotomy, especially after truncal vagotomy, an increased postprandial secretion of CCK was found compared with the healthy animal. Possible causes discussed are the cutting of vagal fibers, which might inhibit the secretion of CCK cells, and the changed gastric and pancreatic secretion.


Preserved mitochondrial function by allopurinol despite deteriorated hemodynamics in warm ischemia-damaged canine liver. To investigate the pathophysiology of warm ischemia (WI) of the liver, the changes in hemodynamics and energy metabolism were studied during and after 60-min complete WI induced by total hepatic vascular exclusion (HVE) in the canine model. Hepatic arterial blood flow after WI was maintained at 76% of the pre-ischemic level, while portal blood flow was only 27% of the pre-ischemic level associated with increased portal vein pressure, which was twice the pre-ischemic level, resulting in a decrease of total hepatic blood flow to 46% of the pre-ischemic level. Concentration of tissue lipid peroxide increased after WI. Arterial blood ketone body ratio (AKBR), which reflects the hepatic mitochondrial redox state, could not recover to the pre-ischemic level after termination of WI. However, when 100 mg/kg of allopurinol (xanthine oxidase inhibitor) was administered intravenously 10 min prior to initiating WI, AKBR was restored to the pre-ischemic level at 30 min after WI in spite of the fact that allopurinol administration to one group produced no remarkable changes in the hepatic hemodynamics compared with the group without allopurinol treatment. Concentration of adenine nucleotides was significantly higher for the treated group at the end of and after WI than for the group without allopurinol treatment and was maintained at a higher level even after WI. Lipid peroxide production was suppressed. Electron microscopic examination revealed that allopurinol treatment could not prevent mitochondrial swelling. It is suggested that WI causes injury primarily to the portal sinusoidal circulation, resulting in portal congestion concomitant with high portal pressure after the release of WI. Allopurinol could prevent the deterioration of mitochondrial ATP metabolism, and was able to inhibit lipid peroxide production, resulting in the rapid recovery of mitochondrial redox state in spite of the fact that it produced no amelioration of hepatic hemodynamics and morphological alterations.


Effectivity and safety of mannitol treatment for acute hepatic failure in rats. In rats with D-galactosamine-induced hepatic failure, 14C-D-mannitol transport into the brain was accelerated through an increase of vesicular transport via the blood-brain barrier and thus brain mannitol contents increased. However, the osmolarity of the brain tissue changed little and the mortality was decreased by mannitol infusion to acute hepatic-failure rats. Experimental data indicate the effectivity and safety of hypertonic mannitol therapy for cerebral edema in acute hepatic failure.


Concentrations of D-lactate and its related metabolic intermediates in liver, blood, and muscle of diabetic and starved rats. This is a report investigating the methylglyoxal (MG) bypass in animals, by which D-lactate is produced from triosephosphate via MG. Rats were made diabetic using streptozotocin or starved for 72 h. D-Lactate and various metabolites related to it, such as L-lactate, pyruvate, methylglyoxal, glucose, and inorganic phosphate, were measured in the blood plasma, liver, and skeletal muscle of the rats. Diabetic and starved rats had significantly higher levels of D-lactate in plasma, liver, and skeletal muscle compared with the control group. In contrast, pyruvate levels in plasma, liver, and skeletal muscle was markedly lower than normal in diabetic and starved rats. L-Lactate level lowered markedly in plasma, liver, and skeletal muscle of starved rats and elevated in liver of diabetic rats. Differences between plasma L-lactate level for diabetes and control were not significant. MG level was significantly elevated in plasma and depressed in livers and muscles of starved rats as well as livers of diabetic rats. Hepatic glycerol content was markedly increased in those states. Enzyme activities related to D- and L-lactate, such as pyruvate kinase, phosphofructokinase, aldolase, and glyoxalase I, were measured in the livers of these rats. Pyruvate kinase activity decreased in these states, but other enzyme activities showed no significant changes. D-Lactate was much more excreted than L-lactate in the urine of diabetic and fasted rats compared with normal rats.


Effects of lipoxygenase and cyclooxygenase inhibitors on murine antibody-dependent cellular cytotoxicity (ADCC). The purpose of this study was to determine the effects that specific inhibition of arachidonic acid (AA) metabolism has on the antibody-dependent cellular cytotoxicity (ADCC) of murine spleen cells. The action of three inhibitors of the lipoxygenase (LO) pathway--nordihydroguaiaretic acid (NDGA), esculetin (Es), and phenanthroline (Phe)--was compared with that of three inhibitors of the cyclooxygenase (CO) pathway--indomethacin (INDO), acetyl salicylic acid (ASA), and imidazole (IMI). All the LO inhibitors suppressed ADCC function in a dose-dependent manner, but NDGA was the most potent inhibitor of this cytolytic activity. In fact, NDGA inhibited the ADCC function with 97% inhibition at 100 microM, while Phe and Es, at the same concentration, inhibited ADCC by 21% and 19%, respectively. However, CO inhibitors did not markedly affect ADCC function and only some doses of them had a slight, but significant, depressing effect (8-11% inhibition at 0.01-0.1 microM of INDO, 7% inhibition at 400 microM of ASA, and 13% inhibition at 800-1000 microM of IMI). These results suggest the LO pathway of the arachidonic acid metabolism plays an important role in regulating ADCC activity of murine spleen cells and the products of the CO pathway have little effect on ADCC lysis.


An experimental model for simultaneous quantitative analysis of pulmonary micro- and macrocirculation during unilateral hypoxia in vivo. An experimental model was developed for quantitative analysis of pulmonary microcirculation using in vivo fluorescence videomicroscopy during unilateral hypoxia induced by one-lung ventilation (1 LV). In five white New Zealand rabbits, pulmonary arterioles on the surface of the right lung were visualized by means of intra-arterial injection of FITC-labeled erythrocytes and FITC-Dextran. During 1 LV of the left lung, the mean airway pressure in the right lung was kept at the level of two-lung ventilation (2 LV) by means of N2-CPAP. Arteriolar diameters as well as parameters of macrocirculation (AP, CVP, PAP, LAP, CO) and gas exchange (paO2, Qs/Qt) were measured simultaneously during 2 LV and 1 LV. FiO2 was kept constant at 1.0 during both experimental phases. Macrohemodynamic parameters during 1 LV did not differ from those measured during 2 LV. 1 LV induced a significant decrease in paO2 (213 +/- 105 versus 427 +/- 22 mm Hg, P < 0.05) and a significant increase in Qs/Qt (22 +/- 7 versus 13 +/- 2%, P < 0.05). During 2 LV (baseline), the pulmonary arteriolar diameters ranged from 15-120 microns. 1 LV resulted in a significant decrease of arteriolar diameters to 89.0 +/- 9.3% of baseline (P < 0.05). Relative changes in arteriolar diameters were similar for vessels with baseline diameters of 0-40, 40-60, and 60-120 microns (88.4 +/- 9.9%, 89.6 +/- 9.4%, and 88.4 +/- 8.7%, respectively). The present model is the first one allowing in-vivo investigation of HPV during 1 LV and 2 LV on the basis of simultaneous measurement of pulmonary arteriolar diameters and macrocirculatory parameters in vivo. Although PAP and PVR did not change significantly, a reduction of pulmonary arteriolar diameters was proven in response to alveolar hypoxia during 1 LV. We suggest the model to be useful in studying the physiological effects of HPV on macro- and microcirculation as well as investigating pathophysiological and pharmacological influences on HPV.


Effect of centrally administered enkephalins on carrageenin-induced paw oedema in rats. Intracerebroventricularly (icv) administered met-enkephalin, leu-enkephalin, and morphine induced dose-related attenuation of carrageenin-induced acute paw oedema in rats. Naloxone (10 micrograms, icv) antagonized the anti-inflammatory effects of the enkephalins (20 micrograms) and morphine (20 micrograms), but itself induced an anti-inflammatory effect at a higher dose (50 micrograms, icv). The anti-inflammatory effects of the enkephalins, morphine, and the higher dose of naloxone were significantly inhibited by metyrapone, an inhibitor of endogenous corticoid synthesis. The icv-administered doses of the enkephalins and morphine induced insignificant inflammation-attenuating effects when administered i.p. Results suggest that the anti-inflammatory effects of the enkephalins and morphine are exerted through central opiate receptors. Furthermore, the inflammation-attenuating effects of these drugs and the higher dose of naloxone appear to be dependent upon endogenous corticoids, suggesting that activation of the hypothalamo-pituitary-adrenocortical axis may be involved.


Morphology of phages of a general Salmonella typing set. The typing set includes 27 tailed phages belonging to three families, the Myoviridae (contractile tails, 4 phages), Siphoviridae (long, non-contractile tails, 21 phages) and Podoviridae (short tails, 2 phages). Heads are isometric or elongated. The phages fall into 10 morphological groups, seven of which correspond to known enterobacterial phage species (Jersey, N4, T5, T7, ZG/3a, chi, 16-19) and one to a Rhizobium phage species (CM1). T5-type and T7-type phages are for the first time reported in salmonellae. Two phages produce large amounts of abnormal mottled heads.


In vitro infection of human placental trophoblast by wild-type vaccinia virus and recombinant virus expressing HIV envelope glycoprotein. Short-time (< or = 7 days) cultures of trophoblast mononuclear cells isolated from term placentae were challenged with vaccinia virus. Cytopathic effects were induced in crude placental cell preparations as well as in cultures established after negative immunosorting of major histocompatibility complex class I epitope-expressing cells, i.e. cultures exclusively derived from villous cytotrophoblast according to our present state of knowledge. The trophoblast in vitro supported a full replicative cycle of both wild-type viruses and a recombinant clone serving as a vector for the human immunodeficiency virus type 1 envelope gene. Results may shed light on mechanisms involved in the rarely observed foetal damage caused by smallpox vaccination during pregnancy.


Processing of the minor capsid protein of the cauliflower mosaic virus requires a cysteine proteinase. The major capsid protein of the cauliflower mosaic virus (CaMV) is processed in vivo. The viral aspartic proteinase that catalyses this maturation has been characterized previously and is coded by the CaMV gene V. This virus has a second capsid protein, a minor component, encoded by gene III. This protein, P3, is also processed at its C-terminus in vivo. To determine whether P3 is matured by the CaMV proteinase P5, we expressed, in Saccharomyces cerevisiae, P3, P5 and a fusion protein P7-P4, containing potential sites of cleavage. P5 was found to be involved in maturation of P7-P4 but did not cleave P3. The latter result was confirmed by experiments carried out with an in vitro translation system (the reticulocyte lysate) and with preparations of replication complexes purified from infected plants. Moreover, [N-(L-3-trans-carboxyoxiran-2-carbonyl)-L-leu cyl]-amido(4-guanido)butane, a specific inhibitor of cysteine proteinases, inhibited the maturation of P3, suggesting that the two CaMV capsid proteins are not processed by the same proteolytic event.


Inhibition of HIV by an anti-HIV protease synthetic peptide blocks an early step of viral replication. The processing of the human immunodeficiency virus (HIV) gag and gag-pol precursor proteins by the virus-encoded protease is an essential step in maturation of infectious virus particles. Like most retroviral proteases, the HIV protease belongs to the aspartyl-protease family and can be inhibited by specific inhibitors. Twenty-four synthetic peptides known to be inhibitors of human renin were tested for inhibition of HIV replication in tissue cultures. One of them, a synthetic peptide analogue, SR41476, which has been shown to be a specific inhibitor of purified recombinant HIV1 protease in vitro, totally blocked infection with different isolates including the HIV1 LAV prototype, the highly cytopathic Zairian isolate HIV1 NDK, and HIV2 ROD, both in primary blood lymphocytes (PBL) and in the lymphoid cell lines MT4 and CEM, for at least 3 weeks. It also significantly reduced virus replication in chronically infected CEM cells, without any effect on cell proliferation. Radioimmunoprecipitation assay revealed that the inhibitor blocked processing of polyprotein precursors p55 gag and p40 gag into a mature form of gag proteins, p25 and p18. Synthetic peptide analogue SR 41476, when added before infection, efficiently inhibited formation of HIV DNA provirus and successfully suppressed synthesis of HIV-specific proteins. These results imply that the HIV protease inhibitor not only inhibited virus maturation in the late phase of the HIV replication cycle, but also interfered in the early phase, before the provirus was formed. This mechanism of antiviral activity provides new possibilities and strategies for AIDS chemotherapy.


[Left ventricular aneurysm with normal coronary arteriogram after myocardial infarction]. Left ventricular aneurysms after myocardial infarction are generally considered one of the complications of severe coronary artery disease. Postinfarction ventricular aneurysms with normal coronary arteriogram are rare. Only a few cases have been reported previously in Japan. We examined the incidence and the clinical characteristics of postinfarction ventricular aneurysms without coronary obstruction. Among the consecutive 1800 patients studied in our laboratory with selective coronary cineangiography and left ventriography, we found 5 (4 male, 1 female) patients with left ventricular aneurysms with no or minimal coronary arterial obstruction. The patient's ages ranged from 34 to 83 with a mean of 59. Interestingly, no patient had prior anginal history, and every case occurred with a first sudden attack of chest pain. The likely mechanisms causing the development of myocardial infarction were coronary spasm and/or thromboembolic accident. One patient, in whom a coronary induction test was performed, showed positive findings. It is possible that poor collateral circulation and well preserved contraction of viable myocardium in these patients bring about the formation of left ventricular aneurysm after myocardial infarction with normal coronary arteriogram.


[Electrophysiologic study of cibenzoline in patients with paroxysmal atrial fibrillation with special reference to atrial fibrillation threshold]. Electrophysiologic effects of cibenzoline were studied in 7 patients (6 males and one female) aged from 40 to 69 years (mean +/- SD; 52 +/- 10) with paroxysmal atrial fibrillation which was documented by 12 leads ECG or by 24 hours Holter monitoring. No organic heart diseases were found except in one patient with dilated cardiomyopathy and sick sinus syndrome (SSS). Cibenzoline (200mg) given orally increased P wave duration, PR interval and QRS duration significantly. The duration of P wave was gradually increased as the pacing frequency was increased. Neither sinus cycle length, nor sinus node recovery time (SRT), nor Wenkebach cycle length, nor atrial effective refractory period, nor QT interval was changed by the drug. One patient with SSS showed increase in SRT from 2,303 msec to 5,150 msec. The minimum current which was required to induce atrial fibrillation by rapid atrial stimulation (50 Hz, 1 sec) lasting more than 30 sec was defined as atrial fibrillation threshold (AFT). The AFT was 4.0 +/- 2.2 mA at the baseline state in 7 patients. After the oral administration of cibenzoline, 5 patients showed increase in AFT, while 1 patient showed decrease and another patient showed no change in AFT. Statistically, AFT was significantly increased to 7.3 +/- 3.4 mA in 7 patients. The results suggest that cibenzoline might be effective to prevent paroxysmal atrial fibrillation in patients without organic heart diseases.


[Autonomic function and severity of hypertrophic cardiomyopathy by power spectrum analysis on heart rate variability]. To examine the relation of autonomic function and severity of hypertrophic cardiomyopathy (HCM) with and without ventricular tachycardia (VT) and poor blood pressure response on Treadmill exercise, 30 patients with HCM and 10 healthy controls were selected. Autonomic function was assessed by heart rate variability (HRV) on 24hr-Holter monitoring. The power spectrum analysis was classified into LF component, HF component and ratio of LF/HF. (1) Night time HF and LF decreased, and LF/HF increased in HCM compared with healthy controls. (2) HF decreased more in HCM with VT. (3) LF/HF also decreased in HCM with poor blood pressure response on exercise. These results suggest that autonomic function may be altered in HCM, and severity of HCM proved to be able to be assessed by power spectrum analysis of HRV.


[A 62-year-old survivor with Ebstein's anomaly without right ventricular failure]. A 62-year-old woman was admitted our hospital because of concussion of the brain. The level of consciousness improved within several days. Cardiac examination was performed because the patient had experienced feelings of fainting since one year previously, and heart murmur also was heard. The electrocardiogram showed WPW configuration. At the same time that she complained of feelings of fainting, the electrocardiogram showed supraventricular tachycardia. The echocardiogram showed displacement of the septal tricuspid leaflet and mild tricuspid valve, regurgitation. Cardiac catheterization was performed and, using the intracardiac electrocardiogram, we confirmed atrialized right ventricle. We diagnosed this patient as having Ebstein's anomaly with WPW syndrome. The clinical manifestations of this anomaly are quite variable, depending upon the spectrum of pathology and the presence of associated malformations. It is well documented that a considerable proportion of these patients are able to survive into adult life. However, the patient who survives into the sixth decade without a sign of heart failure is extremely rare. We speculate that this patient had not developed right ventricular failure until her 60's because she had a milder form of Ebstein's anomaly and did not have any other congenital heart disease.


[Histological evidence of prolonged coronary artery spasm in a necropsy case of recurrent myocardial infarction]. A 69-year-old male had acute inferior infarction during an operation of an aneurysm of the abdominal aorta and died from multiple organ failure 3 weeks after the operation. His initial coronary angiogram (CAG) showed no significant stenosis, but repeated CAG showed that the patients had developed a prolonged spasm in the mid-portion of the right coronary artery. Histologically, we observed eccentric luminal narrowing with atheromatous plaque where the spasms had been demonstrated, and a "waving form" of elastic fibers accompanied by intimal thickening in the opposite site of the atheromatous plaque. These findings suggest that organic stenosis may be underestimated angiographically because of compensatory enlargement of the non-atheromatous site in some patients with coronary artery spasm, and prolonged spasms may augment organic stenosis by following intimal thickening.


[A case of spontaneous mediastinal emphysema developed by numbness of the left arm, dysphagia and chest pain]. A 20-year-old female developed dysphagia, chest pain and numbness of the left arm after dinner on August 22, 1990. She consulted a doctor, who diagnosed tachycardia and prescribed propranolol. On August 23, she hadn't improved. On the same day, she visited our hospital. Chest X-ray films revealed lucent band and distinct line running parallel to the border of the heart and we suspected mediastinal emphysema. Immediately we took chest CT scan, which demonstrated free air surrounding the trachea, thoracic aorta and heart. We diagnosed spontaneous mediastinal emphysema. She was treated with bed rest and mediastinal emphysema subsided within 8 days. The numbness in the patient's arm is an unusual symptom in mediastinal emphysema. We suggest that the numbness of the arm may be due to interference with the circulation to the arm by distention of the mediastinal tissue.


Stress-strain characteristics of normal and emphysematous hamster lung strips. A simple mathematical model of the one dimensional, stress-strain behavior of hamster lung tissue based on strain energy considerations was tested in degassed, uniaxially stretched strips obtained from normal and emphysematous hamster lungs cycled in saline. The relationship between Eulerian stress (sigma) and extension ratio (lambda) was found to take the form sigma = (lambda 2-1/lambda) x f(lambda) where the function f(lambda) was experimentally determined. Stress in six normal and five emphysematous strips was calculated by dividing the tension at each stretch increment by the strip cross-sectional area. Plotting sigma lambda/(lambda 2-1) versus a function of the form e eta lambda yielded a linear expression for f(lambda), me eta lambda + b, where n = 2. The complete stress-strain behavior of hamster lung strip tissue could then be expressed as a simple function of lambda over a range of lambda = 1.0-2.0: sigma = (lambda 2-1/lambda)(me2 lambda+b) The values of the constants m and b depend solely upon the mechanical properties of the elastic and collagen fiber networks in these atelectatic, saline cycled lung strips. The slope m = 0.151, and the intercept b = 0.416 in normal strips (r = 0.98). In emphysematous strips m = 0.016 and b = -0.199 (r = 0.82). Given the smaller m found for emphysematous strips, less strain energy accumulated with increasing stretch and did not even begin in these strips until lambda = 1.3. Further, the fit of the equation to the data was not as good for emphysematous as for normal strips. We conclude that the above equation adequately describes the stress-strain properties of normal hamster lung strips tissue but is not as good in emphysematous strips where the disease is patchy.


Changes in inspired gas composition and experimental bronchospasm in the rabbit. In clinical practice, bronchospasm could be facilitated by hypoxia and by hypercapnia. In this study we assessed the influence of breathing a hypoxic (FIO2 = 0.10) or a hypercapnic (FICO2 = 0.08) gas mixture on the response to nebulized histamine (2% solution for 5 min) in anesthetized, tracheotomized, paralyzed and mechanically ventilated rabbits. Total respiratory resistance (Rrs) and elastance (Ers) were derived by least-square analysis from the relationship between tracheal pressure and flow. Control values of Rrs were larger during hypoxia and hypercapnia than in air while the values of Ers were similar. The absolute change in Rrs after histamine was similar in air and hypoxia, and larger in hypercapnia. The relative change, however, was smaller in hypoxia than in the two other conditions. Ers was also substantially increased by histamine and, contrary to Rrs, remained high 60 min after the aerosol. The results suggest: (1) that both hypoxia and hypercapnia increase airway resistance but do not change tissue properties; (2) that the response to histamine is depressed by hypoxia; (3) that a substantial part of the immediate response, and most, if not all, of the residual response after 60 min is due to changes in lung tissue viscoelastic properties.


Viscoelastic properties of the visceral pleura and its contribution to lung impedance. The mechanical impedances of 10 dog lung lobes (ZL) and circular pleura samples 1.6 cm in diameter (Zpl) were measured with small-amplitude forced oscillations between 0.2 and 4.2 Hz. Two to four samples were ablated from each lobe after their in situ tension had been fixed at 5 cmH2O transpulmonary pressure with plastic rings. Lobe resistance was inversely proportional to frequency (f) and lobe elastance increased linearly with the logarithm of f by 23%/decade. The real part of Zpl (Rpl) decreased hyperbolically with f. Pleural elastance (Epl) showed only a 5%/decade increase with log f. The regional variability of Epl was large and the data allowed the lumping of Epl into only two groups. The variability of Epl was higher in the group of Epl values from the coastal surfaces than in the group of Epl values from any other surfaces (3105 +/- 2741 (SD) vs 2263 +/- 1152 cm H2O/L). The mean intraindividual variation of Epl corresponding to costal and to other surfaces was 38 +/- 25 and 32 +/- 23%, respectively. The hysteresivity index (Fredberg and Stamenovic, J. Appl. Physiol., 67: 2408-2419, 1989) of the pleura was significantly smaller than that of the lobes (0.025 vs 0.148). Extrapolation of Zpl to the entire lobe surface predicted pleural/lobar resistance and elastance ratios of 2.7 +/- 0.4 and 16.8 +/- 10.6%, respectively, at 0.2 Hz, and 0.4 +/- 0.4 and 15.5 +/- 10.6%, respectively, at 4.2 Hz. This suggests that for small deformations and medium lung volumes the pleural contribution to ZL is almost ideally elastic and only slightly frequency-dependent.