Deep brain stimulation of the nucleus basalis of Meynert in Alzheimer's dementia.

Cholinergic neurons of the medial forebrain are considered important contributors to brain plasticity and neuromodulation. A reduction of cholinergic innervation can lead to pathophysiological changes of neurotransmission and is observed in Alzheimer's disease. Here we report on six patients with mild to moderate Alzheimer's disease (AD) treated with bilateral low-frequency deep brain stimulation (DBS) of the nucleus basalis of Meynert (NBM). During a four-week double-blind sham-controlled phase and a subsequent 11-month follow-up open label period, clinical outcome was assessed by neuropsychological examination using the Alzheimer's Disease Assessment Scale-cognitive subscale as the primary outcome measure. Electroencephalography and [(18)F]-fluoro-desoxyglucose positron emission tomography were, besides others, secondary endpoints. On the basis of stable or improved primary outcome parameters twelve months after surgery, four of the six patients were considered responders. No severe or non-transitional side effects related to the stimulation were observed. Taking into account all limitations of a pilot study, we conclude that DBS of the NBM is both technically feasible and well tolerated.

Do we have predictors of therapy responsiveness for a multimodal therapy concept and aerobic training in breast cancer survivors with chronic cancer-related fatigue?

Cancer-related fatigue (CRF) is a burdensome symptom for breast cancer (BC) patients. In this pilot study, we tested several questionnaires as predictors for treatment responsiveness, along with the implementation of a multimodal therapy concept consisting of sleep, psycho-education, eurythmy, painting therapy and standard aerobic training. At the Community Hospital Havelhöhe and the Hannover Medical School, 31 BC patients suffering from CRF could be evaluated in a 10-week intervention study. CRF was assessed by the Cancer Fatigue Scale (CFS-D). Further questionnaires were the Pittsburgh Sleep Quality Index, the autonomic regulation scale, Self-Regulation Scale (SRS), the Internal Coherence Scale (ICS) and the European Organization of Research and Treatment Health-Related Quality of Life Core Questionnaire scale. We estimated the regression coefficients of all scales on CFS-D by simple and multiple linear regression analyses and compared regression slopes and variances between the different questionnaires on CFS-D at the end of treatment. We found a significant impact of SRS and ICS at baseline on CFS-D at the end of the intervention [absolute standardised multiple regression coefficient values ranging from 0.319 (SRS) to 0.269 (ICS)] but not for the other questionnaires. In conclusion, this study supports the hypothesis that the SRS or ICS measuring adaptive capacities could be more appropriate as outcome predictors than classical questionnaire measures in complex interventions studies.

[Deep brain stimulation for addiction, anorexia and compulsion. Rationale, clinical results and ethical implications]. / Tiefe Hirnstimulation bei Sucht, Anorexie und Zwang. Rationale, klinische Ergebnisse und ethische Implikationen.

BACKGROUND: As an established treatment for movement disorders, the application of deep brain stimulation (DBS) for psychiatric indications has been investigated for almost 15 years. A CE label (also FDA approval) has recently been obtained for treatment of refractory obsessive-compulsive disorder (OCD). OBJECTIVES: This article aims at illustrating the current state of DBS in the treatment of refractory OCD. In addition, initial experimental approaches to investigate the potential use of DBS in substance addiction and anorexia nervosa (AN) will also be outlined as both disorders share some common features with OCD. MATERIALS AND METHODS: The present review is based on a keyword literature search (PubMed) while taking into account relevant references and own investigations RESULTS: Although the number of clinical trials for treatment of refractory OCD is limited and sample sizes are small, there is some evidence for a substantial improvement, a so-called full response of OCD symptoms under DBS. However, not all patients benefit from the intervention. Regarding substance addiction and AN, data are scarce and are only indicative of a potential benefit at most. DISCUSSION: Present data regarding the clinical benefits of DBS in OCD are encouraging and open up new avenues for the treatment of therapy refractory patients. However, several aspects, such as mechanisms of action, predictors and long-term side effect profiles, are incomplete or even unknown. In the case of addiction and AN, DBS remains purely experimental, at least for the moment. Hence, clinical trials should remain the gold standard for all three indications.

Management and outcome of pallidal deep brain stimulation in severe Huntington's disease.

Neurodegenerative movement disorders, such as Huntington's disease (HD), have become a promising field for Deep Brain Stimulation (DBS). This study aims to contribute to the establishment of a well-grounded database including both expected and unexpected effects of pallidal DBS in HD, and to discuss the ethical and legal restrictions of DBS in cognitively limited patients. Evaluation of the outcome data indicates that pallidal DBS exerted an independent effect on motor symptoms but probably also on the patient's cognitive and affective state. The cognitive decline, however, that characterizes the late stage of neurodegenerative disorders implicates ethical and legal problems given the patients' inability to give informed consent to DBS.

Four-year follow-up on fatigue and sleep quality of a three-armed partly randomized controlled study in breast cancer survivors with cancer-related fatigue.

Cancer-related fatigue (CRF) is a frequent long-term symptom in non-metastasized breast cancer patients (BC). This 4-year follow-up intended to compare the long-term effects of a 10-week multimodal therapy (MT: sleep education, psychoeducation, eurythmy- and painting therapy) and combination therapy [CT: MT plus aerobic training (AT)] to AT-control. BC-patients were randomized or allocated by preference to three arms in a comprehensive cohort study. Primary outcome was a composite score including Pittsburgh Sleep Quality Index (PSQI) and Cancer Fatigue Scale (CFS-D), captured at baseline, after 10 weeks of intervention (T1), 6 months later (T2), and after 4 years (T3). We exploratively tested for superiority of MT and CT versus AT after 4 years (T3) based on the statistical model of the main analysis. Of 126 (65 randomized) BC-patients included, 105 started treatments and 79 were re-assessed for long-term effects (T3). MT and CT were superior over AT after 4 years regarding PSQI/CFS-D and PSQI sum-score, respectively (all p < 0.05), but not for CFS-D. The multimodal and combination treatment for breast cancer patients with CRF indicates sustainable long-term superiority over aerobic training for the outcomes sleep quality and combined sleep quality/fatigue. A confirmative randomized controlled trial is warranted.

Neisseria gonorrhoeae epithelial cell interaction leads to the activation of the transcription factors nuclear factor kappaB and activator protein 1 and the induction of inflammatory cytokines.

We have studied the effect of human bacterial pathogen Neisseria gonorrhoeae (Ngo) on the activation of nuclear factor (NF)-kappaB and the transcriptional activation of inflammatory cytokine genes upon infection of epithelial cells. During the course of infection, Ngo, the etiologic agent of gonorrhea, adheres to and penetrates mucosal epithelial cells. In vivo, localized gonococcal infections are often associated with a massive inflammatory response. We observed upregulation of several inflammatory cytokine messenger RNAs (mRNAs) and the release of the proteins in Ngo-infected epithelial cells. Moreover, infection with Ngo induced the formation of a NF-kappaB DNA-protein complex and, with a delay in time, the activation of activator protein 1, whereas basic leucine zipper transcription factors binding to the cAMP-responsive element or CAAT/enhancer-binding protein DNA-binding sites were not activated. In supershift assays using NF-kappaB-specific antibodies, we identified a NF-kappaB p50/p65 heterodimer. The NF-kappaB complex was formed within 10 min after infection and decreased 90 min after infection. Synthesis of tumor necrosis factor alpha and interluekin (IL)-1beta occurred at later times and therefore did not account for NF-kappaB activation. An analysis of transiently transfected IL-6 promoter deletion constructs suggests that NF-kappaB plays a crucial role for the transcriptional activation of the IL-6 promoter upon Ngo infection. Inactivation of NF-kappaB conferred by the protease inhibitor N-tosyl--phenylalanine chloromethyl ketone inhibited mRNA upregulation of most, but not all, studied cyctokine genes. Activation of NF-kappaB and cytokine mRNA upregulation also occur in Ngo-infected epithelial cells that were treated with cytochalasin D, indicating an extracellular signaling induced before invasion.

Coordinate activation of activator protein 1 and inflammatory cytokines in response to Neisseria gonorrhoeae epithelial cell contact involves stress response kinases.

Neisseria gonorrhoeae (Ngo), the etiologic agent of gonorrhea, induce a number of proinflammatory cytokines by contact to epithelial cells. Cytokine genes and a variety of other immune response genes are activated as a result of the regulatory function of immediate early response transcription factors including activator protein 1 (AP-1). Since it is established that phosphorylation of c-Jun, the central component of AP-1, by the stress-activated c-Jun NH2-terminal kinase (JNK) increases the transcriptional activity of AP-1, we studied whether Ngo could induce stress response pathways involving JNK. We found that virulent Ngo strains induce phosphorylation and activation of JNK but not of p38 kinase. Analysis of a nonpathogenic Ngo strain revealed only weak JNK activation. In respect to the molecular components upstream of the JNK signaling cascade, we show that a dominant negative mutant of MAP kinase kinase 4 (MKK4) represses transcription of an AP-1-dependent reporter gene. Regarding upstream stress response factors involved in Ngo-induced MKK4/JNK/AP-1 activation, we identified p21-activated kinase (PAK) but not MAPK/ERK kinase kinase (MEKK1). Inhibition of small GTPases including Rac1 and Cdc42 by Toxin B prevented JNK and AP-1 activation. Our results indicate that Ngo induce the activation of proinflammatory cytokines via a cascade of cellular stress response kinases involving PAK, which directs the signal from the Rho family of small GTPases to JNK/AP-1 activation.

A comprehensive analysis of attempted and fatal suicide cases involving frequently used psychotropic medications.

OBJECTIVES: Self-poisoning is the most common suicide method in non-lethal suicide attempts and the third most frequent in fatal suicides. Psychoactive drugs are often used for intentional self-poisoning. While poisons centre data typically focus on survived suicide attempts and underrepresent fatal self-poisoning, medical examiner reports give insight into suicide deaths. To close this gap, we combined and compared data sets from both sources, assessing the mortality of psychotropic drugs used for self-poisoning. METHODS: Anonymized cases of self-poisoning with suicidal intention from 2000 to 2010 were extracted from the national poisons centre case database and compared with cases of suicide documented in the project "Suicides, a national survey". All cases with single substance exposure to a psychoactive drug (antidepressants, mood stabilizers, antipsychotics, sedatives) were included in the analyses. Opioids, over-the-counter- and illicit- drugs were excluded from the analysis. A mortality index was calculated by the ratio of the number of suicides and the sum of all (lethal and non-lethal) suicide attempts. RESULTS: Tricyclics had a higher mortality rate than other antidepressants. Among the sedatives, zolpidem was found to have a higher mortality index compared to benzodiazepines. Clozapine and levomepromazine were found to be the most lethal antipsychotics. Non-lethal suicide cases with single substance exposure (n = 4697) diminished as age increased, while the rate of suicide cases (n = 165) was higher in elderly subjects (>65 years of age, p < 0.001). CONCLUSION: In summary, our findings confirm previous study results on the relative toxicity of distinct classes of psychotropic drugs. In this comprehensive analysis of a national cohort lorazepam had a lower mortality rate compared to other sedatives.

Incommensurately modulated lanthanide coinage-metal diarsenides. II. GdCuAs2, GdAu(1-delta)As2 and TbAu(1-delta)As2--new distortion variants of the HfCuSi2 type with irregularly stacked zigzag chains of arsenic atoms.

GdCuAs2, GdAu(1-delta)As2 and TbAu(1-delta)As2 crystallize as incommensurately modulated variants of the HfCuSi2 type. Structure models have been developed in the monoclinic superspace group P12(1)/m1(alpha0gamma)00 (No. 11.1). The components of the modulation wavevectors q = alphaa* + 0b* + gammac* are alpha = 0.04 (1) and gamma = 0.48 (1) for GdCuAs2, alpha = 0.03 (1) and gamma = 0.48 (1) for GdAu(1-delta)As2 and alpha = 0.02 (1) and gamma = 0.46 (1) for TbAu(1-delta)As2. The predominant effect of the positional modulation is the distortion of a square net of arsenic atoms, which results in planar zigzag chains. Rod groups and layer groups of the respective structure motifs are identified and discussed.

Acute and chronic alcohol use correlated with methods of suicide in a Swiss national sample.

OBJECTIVES: Chronic and acute alcohol use are highly associated risk factors for suicides worldwide. Therefore, we examined suicide cases with and without alcohol use disorder (AUD) using data from the SNSF project "Suicide in Switzerland: A detailed national survey". Our investigations focus on correlations between acute and chronic alcohol use with reference to suicide and potential interactions with the methods of suicide. METHODS: We used data from the SNSF project in which all cases of registered completed suicide in Switzerland reported to any of the seven Swiss institutes of legal and forensic medicine between 2000 and 2010 were collected. We extracted cases that were tested for blood alcohol to use in our analysis. We compared clinical characteristics, blood alcohol concentrations, and methods of suicide in cases with and without AUD. RESULTS: Out of 6497 cases, 2946 subjects were tested for acute alcohol use and included in our analysis. Of the latter, 366 (12.4%) persons had a medical history of AUD. Subjects with AUD significantly had higher blood alcohol concentrations and were more often in medical treatment before suicide. Drug intoxication as method of suicide was more frequent in cases with AUD compared to NAUD. CONCLUSION: Overall, we found a high incidence of acute alcohol use at the time of death in chronic alcohol misusers (AUD). The five methods of suicide most commonly used in Switzerland differed considerably between individuals with and without AUD. Blood alcohol concentrations varied across different methods of suicide independently from the medical history in both groups.

The pregnancy hormone relaxin is a player in human heart failure.

Human congestive heart failure is characterized by complex neurohumoral activation associated with the up-regulation of vasoconstricting and salt-retaining mediators and the compensatory rise of counter-regulatory hormones. In the present study, we provide the first evidence that relaxin (RLX), known as a pregnancy hormone, represents a potential compensatory mediator in human heart failure: plasma concentrations of RLX and myocardial expression of the two RLX genes (H1 and H2) correlate with the severity of disease and RLX responds to therapy. The failing human heart is a relevant source of circulating RLX peptides, and myocytes as well as interstitial cells produce RLX. Elevation of ventricular filling pressure up-regulates RLX expression and the hormone acts as a potent inhibitor of endothelin 1, the most powerful vasoconstrictor in heart failure. Furthermore, RLX modulates effects of angiotensin II, another crucial mediator. Our data identify RLX as a new player in human heart failure with potential diagnostic and therapeutic relevance.

Hormonal factors from the mammalian pineal gland interfere with cell development in Hydra.

A partially purified, melatonin-free low-molecular-weight extract from the ovine pineal gland with antitumor activity (YC05R), interferes with terminal differentiation in the interstitial cell line of Hydra. Nematoblasts developed into defective nematocytes that were subject to cell death and the tentacles eventually became devoid of nematocytes. In an attempt to identify the causative components of the extract, several known potential constituents were assayed. Two factors were found to have similar effects, although only in rather high concentrations: 1alpha, 25 dihydroxyvitamin D3 (>150 nM) and pinoline (>5 microM), a natural tryptophan-derived beta-carboline. The proliferative activity in the interstitial cell line was only slightly reduced by these factors. Two other beta-carbolines that occur in the mammalian brain, harmine (10 microM) and n-butyl-beta-carboline-3-carboxylate (beta-CCB), caused the premature death of epithelial cells and thus the development of dwarfish animals which, however, continued to generate new animals by budding. The pineal extract probably contains some more, still unidentified components that interfere more potently with cell development, in Hydra as well as in mammals.

Low-molecular-weight hormonal factors that affect head formation in Hydra.

Support or inhibition of DAG-induced head formation: Hydra magnipapillata can be caused to form ectopic head structures by periodictreatmentwith PKC activators such as diacylglycerol (DAG). This ectopic head formation is supported by an extract from the ovine pineal gland that contains low-molecular-weight compounds. The frequency of ectopic head formation is also increased when DAG is paired with one of several lipophilic hormonal factors: (1) pinoline, a putative pineal hormone derived from tryptophan, (2) 12-S-HETE, a paracrine derivative of arachidonic acid, or (3) 1alpha, 25 dihydroxyvitamine D3, a hormonal factor also known as calcitriol. Dose-response curves were non-monotonic passing a maximum at low dosages. By contrast, DAG lost its capacity to induce ectopic head structures when it was paired with the provitamin D3, cholecalciferol. Patterning the head: one eicosanoid was found which influences patterning without being combined with DAG: 12-R-HETE caused growth-based elongation of the tentacles and an increase in the number of tentacles without affecting the longitudinal body pattern. Similar effects are brought about by substances that interfere with tyrosine phosphorylation, most potently bythe phosphotyrosine phosphatase inhibitor bisperoxo-(1,10-phenanthroline)-oxovanadate (V). The results speak for the existence of head-inducing hormonal factors, underline the significance of content protein kinases to pattern formation and point to a negative influence of the vitamin D3 content of the food on the capacity of the animals to develop head structures.

Molecular cytogenetic studies in three patients with partial trisomy 2p, including CGH from paraffin-embedded tissue.

We report on three cases of partial trisomy 2p in which the identification and exact localization of the duplicated chromosome segment was possible only by application of molecular cytogenetic techniques. These included fluorescence in situ hybridization by use of wcp2, N-myc, and subtelomeric 2p probes and comparative genomic hybridization with DNA isolated from blood samples, frozen fetal tendon, and formalin fixed, paraffin-embedded fetal lung tissue. Two of the cases concerned fetuses of gestational week 20 and 24 with duplication of nonoverlapping terminal (2pter-->p24) and more proximal (2p25-->p23) segments and with distinctly different phenotypes. The third case was due to a de novo inverted duplication of 2p25-->p23, with loss of the subtelomeric region of 2p. This 53-month-old girl was a Bloom syndrome carrier. The patient had prenatal growth failure, borderline microcephaly, dilated lateral horns of the cerebral ventricles, transient cortical blindness, myopia, muscle hypotonia, and dilatation of the left renal collecting system. Dermal cysts were found on the glabella, the soles of both feet, and the vocal cord, causing respiratory embarrassment. Previously reported cases of pure trisomy 2p are reviewed, in an attempt to correlate clinical findings to overlapping regions in 2p. These cases illustrate the effectiveness of molecular cytogenetic methods in resolving subtle chromosomal aberrations in order to coordinate more accurately a chromosome regionspecific phenotype.

Chronic exposure to a GSM-like signal (mobile phone) does not stimulate the development of DMBA-induced mammary tumors in rats: results of three consecutive studies.

Certain epidemiological and experimental studies raised concerns about the safety of radiofrequency (RF) electromagnetic fields because of a possible increased risk of leukemia and lymphoma. In this study, an RF field used in mobile telecommunication was tested using 7,12-dimethylbenz[a]anthracene (DMBA)-induced mammary tumors in female Sprague-Dawley rats as a model for human breast cancer. Three experiments were carried out under strictly standardized conditions and were started on the same day of three consecutive years. The field consisted of a GSM-like signal (900 MHz pulsed at 217 Hz, pulse width 577 micros) of relatively low power flux density (100 microW/cm(2) +/- 3 dB) and was applied continuously throughout each experiment to freely moving animals. The specific absorption rates averaged over the whole body were 17.5-70 mW/kg. The highest values in young animals were at or around the exposure limit permissible for the general public (i.e. 80 mW/kg). The animals were palpated weekly for the presence of mammary tumors and were killed humanely when tumors reached a diameter of 1-2 cm to allow a reliable histopathological classification and a distinction between malignant and benign subtypes. The overall results of the three studies are that there was no statistically significant effect of RF-field exposure on tumor latency and that the cumulative tumor incidence at the end of the experiment was unaffected as well. The risk ratios were 1.08 (95% CI: 0.91-1.29) and 0.96 (95% CI: 0.85-1.07) for benign and malignant tumors, respectively. These observations are in agreement with other published findings. In the first experiment, however, the median latency for the development of the first malignant tumor in each animal was statistically significantly extended for RF-field-exposed animals compared to controls (278 days compared to 145 days, P = 0.009). No such differences were detected in the two subsequent experiments. These results show that low-level RF radiation does not appear to possess carcinogenic or cancer-promoting effects on DMBA-induced mammary tumors. To explain the mechanisms underlying the different results obtained in the three experiments, a hypothesis is presented which is based upon the neuroendocrine control mechanisms involved in the promotion of DMBA-induced mammary tumors. Despite the apparent absence of stimulatory effects of low-level RF-field exposure on the development and growth of solid tumors, it will be necessary to verify these results for leukemias and lymphomas, which may have completely different biological control mechanisms.

Dexamethasone inhibits stimulation of pulmonary endothelins by proinflammatory cytokines: possible involvement of a nuclear factor kappa B dependent mechanism.

OBJECTIVES: Recent studies have indicated effectiveness of glucocorticoid (GC) treatment in late, fibroproliferative adult respiratory distress syndrome. There is furthermore growing evidence for a role of endothelin-1 (ET-1) in lung fibroproliferation, but the impact of GC on stimulated pulmonary ET-1 is not well defined. DESIGN AND SETTING: Prospective study in an experimental laboratory. SUBJECTS: Male Wistar rats. INTERVENTIONS: Isolated lungs were perfused over 120 min in recirculatory mode in presence of vehicle, interleukin-1 beta (IL-1 beta; 5 ng/ml) plus tumor necrosis factor-alpha (TNF-alpha; 5 ng/ml), dexamethasone (Dx; 1 nmol/l), Dx (10 nmol/l), IL-1 beta plus TNF alpha plus Dx 1, or IL-1 beta plus TNF alpha plus Dx 10 (n = 6 each). Pulmonary artery endothelial cells were stimulated over 30 min using a similar protocol. MEASUREMENTS AND RESULTS: Control lungs released 15.2 +/- 0.6 pg/ml big ET-1 and 0.46 +/- 0.06 pg/ml ET-1, and contained 0.73 +/- 0.05 ng/g wet weight (ww) big ET-1 and 3.06 +/- 0.22 ng/g ww ET-1. IL-1 beta plus TNF-alpha increased release of big ET-1 and ET-1, to 220% and 217%, and lung content of peptides, to 236% and 230%. Dx dose-dependently inhibited the cytokine-induced rise in peptide release and lung content and completely suppressed these effects at 10 nmol/l. Electrophoretic mobility shift assays with nuclear extracts of pulmonary artery endothelial cells demonstrated nuclear binding of the transcription factor nuclear factor kappa B in response to IL-1 beta plus TNF-alpha, which was decreased in presence of Dx 1 and Dx 10. CONCLUSIONS: GC inhibit the cytokine-induced upregulation of pulmonary vascular and tissue endothelins, possibly via nuclear factor kappa B dependent mechanisms. This finding may reinforce the therapeutic employment of GC in late ARDS.

Melatonin and 6-sulfatoxymelatonin circadian rhythms in serum and urine of primary prostate cancer patients: evidence for reduced pineal activity and relevance of urinary determinations.

The circadian rhythms of melatonin and 6-sulfatoxymelatonin (aMT6s) were analyzed in serum and urine of young men (YM, n = 8), of elderly patients with benign prostatic hyperplasia (BPH, n = 7) and of patients of similar age with primary prostate cancer (PC, n = 9). The data expressed as concentration and in urine also as hourly excreted quantity were analyzed chronobiologically by the single cosinor method and, subsequently submitted to linear regression analyses. Circadian rhythms were detected in all cases except for the excreted quantity of melatonin. The circadian patterns of melatonin and aMT6s in serum were very similar in the different groups and regression analyses showed close correlations between both variables. MESOR and amplitude were significantly depressed in PC (40-60%) as compared to BPH and YM indicating that the depression of serum melatonin in PC is due to a reduced pineal activity and is not caused by an enhanced metabolic degradation in the liver. Acrophases of serum melatonin occurred between 01:34 and 03:26 h and of serum aMT6s between 03:58 and 04:35 h. Circadian rhythms similar to those of serum melatonin and aMT6s were found in urine, particularly for aMT6s excretion as well as melatonin concentration; the determination of both parameters in overnight urine samples closely correlated with the nocturnal peak of circulating melatonin. These results imply that it is feasible to estimate changes in pineal function of prostate cancer patients by means of non-invasive determination using urinary melatonin and aMT6s.

Effect of melatonin and pineal extracts on human ovarian and mammary tumor cells in a chemosensitivity assay.

Pinealectomy enhances tumor growth and metastatic spread in experimental animals. This effect is only in part due to melatonin since melatonin-free pineal extracts containing yet unidentified pineal substances have also shown tumor inhibiting activity. Despite numerous reports suggesting melatonin as a potential anti-cancer agent there have not been sufficient clinical trials to define the actual therapeutic potential of melatonin for the treatment of human cancers. To help fill this gap, we used a chemosensitivity assay designed to test the sensitivity of tumors from individual patients towards chemotherapeutic drugs for assessing the effect of melatonin and pineal extracts on primary human tumor cells. Primary cell cultures from seven ovarian and six mammary tumors were incubated with melatonin, the pineal extract YC05R (containing substances between 500 and 1000 daltons) and chemotherapeutic drugs. The pineal extract YC05R inhibited growth of all tumors in a dose-dependent manner. Physiological concentrations of melatonin (10(-8)-10(-10) M) inhibited the growth of one out of six mammary carcinomas in a dose-dependent manner. Primary cell cultures from three ovarian tumors were affected by melatonin in different ways, i.e., two were inhibited and one was slightly stimulated. There was no correlation between sensitivity towards melatonin and sex steroid receptor status, stage or grade of the tumor. It is concluded that, 1), melatonin may be an inhibitor of human mammary and ovarian carcinoma in individual cases and, 2), the pineal gland contains very active anti-tumor substances inhibiting both, the mammary and ovarian tumors, tested. These substances require chemical and biological identification.

Influence of serum from healthy or breast tumor-bearing women on the growth of MCF-7 human breast cancer cells.

Sera from women healthy (HW) or with breast (BCW), ovarian or endometrial cancer, were added (10%) to the culture media of MCF-7 cells and cell proliferation assessed 4 days later to verify: a) whether sera from BCW, obtained before or 8 days after tumor ablaction, influence the proliferation of these cells, b) whether the effects of serum from BCW are specific for mammary tumor cells. Sera from BCW, but not sera from women with ovarian or endometrial cancer, increased MCF-7 cell proliferation in comparison with sera from HW. After surgical ablation of the breast tumors, serum's ability to increase MCF-7 cell proliferation decreased significantly. These effects cannot be explained by differences on serum levels of estradiol or melatonin. These results suggest the presence of growth-promoting substances of possible tumoral origin in serum of BCW, a fact that should be considered as support for the surgical treatment of tumor masses.