Cost-effectiveness of stereotactic large-core needle biopsy for nonpalpable breast lesions compared to open-breast biopsy.

This paper demonstrates that the introduction of large-core needle biopsy (LCNB) replacing needle-localised breast biopsy (NLBB) for nonpalpable (screen-detected) breast lesions could result in substantial cost savings at the expense of a possible slight increase in breast cancer mortality. The cost-effectiveness of LCNB and NLBB was estimated using a microsimulation model. The sensitivity of LCNB (0.97) and resource use and costs of LCNB and NLBB were derived from a multicentre consecutive cohort study among 973 women who consented in getting LCNB and NLBB, if LCNB was negative. Sensitivity analyses were performed. Replacing NLBB with LCNB would result in approximately six more breast cancer deaths per year (in a target population of 2.1 million women), or in 1000 extra life-years lost from breast cancer (effect over 100 years). The total costs of management of breast cancer (3% discounted) are estimated at pound 4676 million with NLBB; introducing LCNB would save pound 13 million. The incremental cost-effectiveness ratio of continued NLBB vs LCNB would be pound 12 482 per additional life-year gained (3% discounted); incremental costs range from pound -21 687 (low threshold for breast biopsy) to pound 74 378 (high sensitivity of LCNB).

Cost comparison between stereotactic large-core-needle biopsy versus surgical excision biopsy in The Netherlands.

Yearly, approximately 7200 Dutch women with non-palpable breast lesions are referred for a diagnostic surgical excision biopsy. Recently, less invasive alternatives such as stereotactic large-core-needle biopsy have emerged. The aim of this study was to compare the costs of surgical excision biopsy and large-core-needle biopsy. As stereotactic equipment is expensive, the costs of large-core-needle biopsy depend on the extent of centralisation of this facility. Therefore, we assessed the extent of economies of scale in four different scenarios of (de)centralisation. We collected cost data in five Dutch hospitals. The cost of surgical excision biopsy amounted to 1184 Euros. In cases where large-core-needle biopsy would be employed decentralised in all 114 hospitals in The Netherlands, the average costs were estimated to be 1186 Euros compared with 572 Euros in a centralised scenario with involvement of 10 hospitals. Therefore, centralisation of stereotactic equipment for core-needle biopsies would be advisable from an economic perspective.

Cost effectiveness of stent implantation versus PTCA: the BENESTENT experience.

The aim of this paper is to assess the costs and effects of stent implantation versus percutaneous transluminal coronary angioplasty (PTCA). Data have been taken from both the BENESTENT-I and BENESTENT-II pilot study. Effects are expressed in terms of event-free survival and costs include those of the initial hospitalization and those during follow-up. The costs per additional event-free survivor after 7 months are estimated at Dfl 88,315, Dfl 28,127 and Dfl 6747 using respectively the results from the BENSTENT-I study, the BENESTENT-II pilot study and phase IV of the BENESTENT-II pilot study. Significant decreases in complications and ischaemic events have made stent implantation not only the most favourable in terms of event-free survival but also in terms of cost effectiveness.

GABA receptors in the region of the dorsomedial hypothalamus of rats are implicated in the control of melatonin and corticosterone release.

Recently, anatomical evidence was presented that the mammalian circadian clock located in the suprachiasmatic nuclei (SCN) may utilize GABA to transmit diurnal information to the dorsomedial hypothalamus (DMH). The present study provides further physiological evidence for the involvement of this GABAergic projection in the regulation of diurnal rhythms. Infusion of the GABA agonist muscimol in the region of the DMH completely blocked the daily increase of plasma melatonin during darkness and reduced sympathetic output in the pineal gland resulting in lower pineal melatonin production, as measured with transpineal microdialysis. Further experiments in SCN-lesioned animals indicated that the origin of this inhibitory input to the DMH is indeed the SCN. The results of this study imply that the SCN can influence the sympathetic outflow of the hypothalamus through its GABA-containing projection. Furthermore, the present results probably explain the previously reported strong inhibitory effect of benzodiazepines on plasma melatonin in both animals and humans.

Lesions of the suprachiasmatic nucleus do not disturb sexual orientation of the adult male rat.

An enlarged suprachiasmatic nucleus (SCN) has been found earlier in a group of homosexual men, as compared to heterosexual controls. In order to assess a possible relationship between the SCN and sexual orientation, the present study was undertaken to investigate whether the rat SCN might play a role with respect to the expression of sexual orientation. Sexual orientation was measured in partner preference tests as the percentage of time spent in the vicinity of sexually active male and female incentives, that were separated from the experimental animal by a wire mesh. The results show that established patterns of sexual orientation towards female incentives by the adult male rat are not influenced by SCN-lesions. Disturbances in circadian rhythmicity of activity in SCN-lesioned animals did not affect this conclusion.

Suprachiasmatic nucleus lesion increases corticosterone secretion.

The diurnal rhythm of corticosteroid secretion is controlled by the suprachiasmatic nucleus (SCN). In rats, plasma corticosteroid levels rise just before the onset of the activity period during the dark phase. Our previous results indicated that vasopressin as a neurotransmitter from the SCN inhibited corticosteroid secretion in the area of the paraventricular/dorsomedial nucleus of the hypothalamus. We hypothesized that during the day the SCN may serve as an inhibitory system for corticosteroid secretion. To investigate this possibility, intact and SCN-lesioned animals were exposed to mild stress in the morning and evening and their plasma corticosteroid levels were monitored. The results indicate that SCN-lesioned animals have higher morning corticosteroid levels and respond both in the morning and evening with higher corticosteroid levels after stress than do intact control animals. We conclude, therefore, that these results indicate an inhibitory role of the SCN on corticosteroid secretion. The apparent discrepancy with the reported stimulatory role of the SCN on adrenocorticotropic hormone secretion is discussed.

Functional development of fetal suprachiasmatic nucleus grafts in suprachiasmatic nucleus-lesioned rats.

Recovery of circadian drinking rhythms in suprachiasmatic nucleus (SCN)-lesioned rats after fetal SCN grafting was related to the immunocytochemical appearance and fiber outgrowth of vasopressin (VP)-, vasoactive intestinal polypeptide (VIP)-, and somatostatin (SOM)-containing neurons in the implants. At 4 weeks postgrafting, the first recovered animal was found. After longer survival times, 38% of the animals showed recovery. Immunocytochemical evaluation indicated that full maturation of the SCN grafts was not reached until 4 weeks postgrafting. Grafted VP and VIP cells were always located together, whereas SOM cells were clustered nearby but separate. Neuropeptide Y fibers were observed with an increasing fiber density between 2 and 5 weeks posttransplantation and were clustered particularly at the level of the SOM cells. In all rhythm-recovered animals transplants of VP and VIP fibers had grown laterally into the hypothalamus. A few nonrecovered animals also showed ingrowth of such fibers, though more caudally to the lesioned SCN. Many of the nonrecovered rats showed similar stainings but without these efferent outgrowth to the host. We conclude that neither a humoral factor nor the presence of VP and VIP efferents in the host brain alone are enough for the restoration of circadian drinking rhythms.

Vasopressin-containing neurons of the suprachiasmatic nuclei inhibit corticosterone release.

The suprachiasmatic nucleus (SCN) is the major pacemaker in the central nervous system responsible for generating circadian rhythmicity in mammals. Tracer studies show limited projections of the SCN, mainly to the paraventricular nucleus of the thalamus and paraventricular and dorsomedial nuclei of the hypothalamus, suggesting that the latter two areas may be the target areas of the SCN for controlling corticosterone release. The present results show that when infused in the paraventricular/dorsomedial nucleus of the hypothalamus femtomolar concentrations of vasopressin (VP), but not vasoactive intestinal peptide (VIP), are able to suppress elevated levels of corticosterone in SCN-lesioned animals to basal daytime values. On the other hand, infusion of the VP antagonist in the same hypothalamic area induced a sevenfold increase of basal corticosterone levels in intact animals. The SCN origin of this VP input was established in SCN-lesioned animals where no difference between the effect of infusing the antagonist or Ringer could be detected. These results imply that the SCN can influence the daily corticosterone rhythm through its VP-containing projection to the paraventricular/dorsomedial nucleus of the hypothalamus.

Vasopressin and oxytocin systems in the brain and upper spinal cord of Macaca fascicularis.

This paper describes the vasopressin (VP) and oxytocin (OXT) immunoreactive structures in the brain and upper spinal cord of the adult male and female Macaca fascicularis. Immunocytochemistry following intraventricular application of colchicine displayed VP neurons in the diagonal band of Broca (DBB), bed nucleus of the stria terminalis (BST), medial amygdaloid nucleus, dorsomedial hypothalamic nucleus, area of the locus coeruleus (LC), solitary tract nuclei (NTS), and the dorsal horn of the cervical spinal cord in addition to those known to exist in the paraventricular, supraoptic, and suprachiasmatic hypothalamic nuclei. Furthermore, a dense accumulation of VP fibers was observed in areas such as the DBB, medial septum, BST, amygdala, hippocampus, ventral tegmental area, periaquaductal gray, dorsal and ventral raphe, area of Forel, LC region, parabrachial nuclei, and NTS. The lateral septum and lateral habenula displayed no and very few VP fibers, respectively. No extrahypothalamic OXT neurons were found in the brain of this macaque monkey. Dense concentrations of OXT fibers were demonstrated in the amygdala, NTS, and marginal layer of the cervical spinal cord. No sexual dimorphism was found in this primate VP or OXT system. The results show a distribution of the central VP and OXT systems in this primate which is quite different from that in the rat. However, in various aspects it agrees with current data on the VP and OXT systems of the human brain. The present results suggest, therefore, that this monkey might serve as a better model for the human VP system than the rat.

Central vasopressin infusion prevents hibernation in the European hamster (Cricetus cricetus).

The amount of immunocytochemically detectable vasopressin in the brain of the European hamster (Cricetus cricetus) shows a seasonal variation; i.e., dense vasopressin immunoreactivity is present in the lateral septum during summer but is absent in autumn and winter [Buijs, R. M., Pévet, P., Masson-Pévet, M., Pool, C. W., De Vries, G. J., Canguilhem, B. & Vivien-Roels, B. (1986) Brain Res. 371, 193-196]. In the winter period the European hamster hibernates. Since vasopressin in the lateral septum is known to be involved in the control of body temperature, we investigated whether infusion of vasopressin in the lateral septum during autumn-winter could influence hypothermic patterns normally seen in hibernating animals. Hamsters whose lateral septum was infused with vasopressin showed almost no periods of hypothermia, whereas hamsters treated with control infusions displayed a normal hibernation pattern. The results indicate that persistence of vasopressin release in the lateral septum of the European hamster during winter can prevent hibernation.

Serotonergic denervation does not reduce brain uptake of n-isopropyl-p-[123I]iodoamphetamine in vivo.

The relation between brain uptake of radiolabeled n-isopropyl-p-iodoamphetamine [( 123I]IMP) and serotonin re-uptake sites was studied in vivo by lesioning serotonergic nerve endings. The reduction of brain serotonin demonstrated the effectiveness of the procedure. Accumulation of radioactivity/g brain tissue was higher in the lesioned than in the sham-operated rats. This was explained by the loss of body weight of the lesioned animals, allowing an increased distribution to the brain. These results demonstrate that the in vivo distribution and binding of [123I]IMP in the brain is not limited to the specific serotonin re-uptake sites on nerve endings.

Elevated serum oxytocin of the vasopressin-deficient Brattleboro rat is present throughout life and is not sensitive to treatment with vasopressin.

The postnatal developmental course of the enhanced OT serum level of the vasopressin-deficient (homozygous) Brattleboro rat was investigated radioimmunochemically together with the response to treatment with Pitressin tannate. Compared with heterozygous Brattleboro (control) pups, in which serum OT appeared to have an adult value from birth onwards (about 10 pmol/l), homozygous rats had approximately 2-fold enhanced OT serum level throughout early development. Between day 55 and adulthood the levels of OT rose further to 40-50 pmol/l. A 3-day treatment with Pitressin tannate both in the period before or after the age (day 16) at which the polyuria of the homozygous Brattleboro mutant can be revealed, failed to reduce the serum OT. It was therefore concluded that the high OT serum levels in the vasopressin-deficient Brattleboro rat are not induced by osmotic imbalance, but probably originates from functional teratological aspects of the mutation.

Effects of enhanced cerebrospinal fluid levels of vasopressin, vasopressin antagonist or vasoactive intestinal polypeptide on circadian sleep-wake rhythm in the rat.

Several endogenous peptides have been implicated in the regulation of sleep and wakefulness. The present study was carried out in order to determine whether the light-dark rhythm of vasopressin (VP) in the cerebrospinal fluid (CSF) had functional significance in relaying information from the circadian pacemaker, i.e. the suprachiasmatic nuclei (which synthesize VP as well as vasoactive intestinal polypeptide (VIP], to the centra regulating sleep. After constant delivery of VP in the CSF via an Accurel/collodion implant in the lateral ventricle, the VP CSF level was raised from 20-35 pg/ml to ca. 265 pg/ml whereby a VP rhythm in the CSF could no longer be detected. Under these conditions VP was found to increase the arousal state of the rat in the dark period, which resulted in a higher amplitude of the circadian sleep-wake rhythm. Application of the VP antagonist d(CH2)5[Tyr(Me)2]VP partly had opposite effects. A similar approach with central application of VIP resulted in an increase in rapid eye movement and quiet sleep but did not affect the amplitude of the circadian rhythm. It was concluded that although peptide levels in the CSF may show clear temporal variations with the light-dark cycle, this rhythmicity is not causally related to the circadian aspect of sleep-wakefulness. However, both VP and VIP contribute to the regulation of the amount of time spent in sleep and wakefulness and the level of VP in the CSF is correlated with the amplitude of the rhythm.

Immunocytochemically-stained vasopressin binding sites in rat brain. Ventricular application of vasopressin/Accurel in the Brattleboro rat.

An immunocytochemical procedure was developed to localize binding sites for vasopressin (VP) in the brain of Brattleboro (di/di) rats after 2 weeks of continuous ventricular administration of the peptide. Accurel-polypropylene tubing loaded with 0.15, 1.5 or 15 micrograms vasopressin was implanted into the lateral ventricle. Subsequently, bound VP was detected immunocytochemically in 2 distinct patterns: in perineuronal structures and dots between cells, in the lateral septum (dorsorostral part), striatum, cingulate cortex, granular cells of the dentate gyrus of the hippocampus, pyramidal cells of CA1 and CA3 hippocampal areas and around cerebellar Purkinje cells. The high dose (15 micrograms) loaded implants revealed the most intense staining; in the cytoplasm of neuronal cell bodies in the lateral and medial septum, striatum, cingulate cortex, bed nucleus of the stria terminalis, organum vasculosum of the laminae terminalis and locus coeruleus. The most intense staining in cell bodies was observed in brains which had low-loaded implants (0.15-1.5 microgram). A variety of controls, proved that no aspecific uptake was involved in the present procedure. The distribution of VP binding sites was only partly coincident with known sites of VP fiber innervation, and largely agrees with data obtained by autoradiographic techniques for [3H]VP binding. The present immunocytochemical technique gave a higher resolution than the currently used autoradiographic techniques. The differences in pattern and intensity of staining due to increasing the dosage rate of the in vivo vasopressin treatment, might mean that the current procedure retains preferentially either low or high affinity populations of binding sites depending on the implanted dose.

Immunocytochemically stained binding sites for oxytocin and alpha-melanocyte-stimulating hormone in rat brain following ventricular administration.

Binding sites for oxytocin (OXT) and alpha-melanocyte-stimulating hormone (alpha-MSH) in brain of homozygous Brattleboro rats were immunocytochemically visualized after ventricular administration of the peptides by Accurel implants. Two patterns were found: 'ring type' staining in perineuronal structures was observed in CA1 and CA3 areas of ventral hippocampus and in subiculum for OXT implanted brains and a very weak staining in striatum for alpha-MSH-implanted brains; cytoplasmic staining of intracellular binding sites was observed in the bed nucleus of the stria terminalis (BST) in brains with OXT implants and in the anterodorsal thalamic nucleus (AD) and postcingulate cortex in brains with alpha-MSH implants. These localizations are different from those described for vasopressin binding sites in the same rat strain.

Manipulation of vasopressin level in the cerebrospinal fluid of the rat by means of an easily interchangeable controlled-delivery Accurel mini-device.

The procedure described for the continuous release of vasopressin (VP) in the rat lateral ventricle via implantation of a VP-loaded Accurel/collodion mini-device has now been further developed, allowing the introduction, removal and exchange of the Accurel device through a polyethylene guide cannula. In this way, manipulation of the VP level in the cerebrospinal fluid can easily be accomplished. VP levels were measured by radioimmunoassay in liquor withdrawn from the cisterna magna.

Propressophysin is present in neurones at multiple sites in Wistar and homozygous Brattleboro rat brain.

Vasopressin (VP) is synthesized as propressophysin, containing also neurophysin (NP) and C-terminal glycopeptide (CPP), within the hypothalamo-neurohypophyseal system (HNS). Recently, VP and NP-immunoreactive cells were demonstrated in other rat brain nuclei. Here we report CPP immunoreactivity in perikarya in these nuclei. Within the homozygous Brattleboro rat, known to be deficient in neuronal VP production, no CPP immunoreactivity was seen in these nuclei. However, intense VP and CPP immunoreactivity was present in solitary cells (52.2 +/- 3.3 per rat) and fibres within the HNS.

Production of fimbrial adhesins K99 and F41 by enterotoxigenic Escherichia coli as a function of growth-rate domain.

The production of fimbrial adhesins K99 and F41 by enterotoxigenic Escherichia coli has been measured in steady-state chemostat experiments at various specific growth rates (microseconds) and in a recycling fermentor across a range of mu values falling to less than 0.004 h-1. It has been demonstrated that the production of K99 and F41 fimbriae is correlated with mu both in aerobic and anaerobic chemostat experiments. A significant production of fimbriae was only detected at mu values higher than 0.2 h-1. This behavior was further examined by culturing the bacteria in a recycling fermentor with complete biomass retention. It could be shown that the production of K99 and F41 fimbriae only occurred during balanced growth, with a high biomass yield at mu values higher than 0.04 h-1 corresponding to mass doubling times (td) of less than 17 h. The production of both fimbriae halted during balanced growth with a lower biomass yield (at mu values between 0.012 and 0.04 h-1 corresponding to td values between 17 and 58 h) and unbalanced stringent growth (at mu values lower than 0.012 h-1 or td values higher than 58 h). The external pH of the medium greatly influenced the production of both K99 and F41 fimbriae. At pH values lower than 7, the production of fimbriae was strongly inhibited. Also, at pH values higher than 7, a decrease in production was observed. The consequences of the observed phenomena for the pathogenic behavior of this E. coli strain are discussed.

Successful ventricular application of the miniaturized controlled-delivery Accurel technique for sustained enhancement of cerebrospinal fluid peptide levels in the rat.

A recently developed small controlled-delivery peptide device has now been further miniaturized (3.5 mm3 rod) and its action has been tested in vitro and in vivo using vasopressin (VP) as experimental substance. In vitro immersion showed a constant and lasting release of VP for weeks, as had been described for larger devices. By introducing the mini-device into the lateral ventricle of rat brain and by sampling CSF via a permanent cannula in the cisterna magna, a steadily enhanced level of VP could be attained for CSF. These increased levels persisted for one week, but most likely continue for longer periods.