Circadian Phase in Adults of Contrasting Ages

There is evidence that aging may impair phase‐shifting responses to light synchronizers, which could lead to disturbed or malsynchronized circadian rhythms. To explore this hypothesis, 62 elder participants (age, 58 to 84 years) and 25 young adults (age, 19 to 40 years) were studied, first with baseline 1‐wk wrist actigraphy at home and then by 72 h in‐laboratory study using an ultra‐short sleep‐wake cycle. Subjects were awake for 60 minutes in 50 lux followed by 30 minutes of darkness for sleep. Saliva samples were collected for melatonin, and urine samples were collected for aMT6s (a urinary metabolite of melatonin) and free cortisol every 90 minutes. Oral temperatures were also measured every 90 minutes. The timing of the circadian rhythms was not significantly more variable among the elders. The times of lights‐out and wake‐up at home and urinary free cortisol occurred earlier among elders, but the acrophases (cosinor analysis‐derived peak time) of the circadian rhythm of salivary melatonin, urinary aMT6s, and oral temperature were not significantly phase‐advanced among elders. The estimated duration of melatonin secretion was 9.9 h among elders and 8.4 h among young adults (p<0.025), though the estimated half‐life of blood melatonin was shorter among elders (p<0.025), and young adults had higher saliva melatonin and urinary aMT6s levels. In summary, there was no evidence for circadian desynchronization associated with aging, but there was evidence of some rearrangement of the internal phase‐angles among the studied circadian rhythms.     

Phase Typing of Patients with Seasonal Affective Disorder: A Test for the Phase Shift Hypothesis

The study evaluates the phase-shift hypothesis for seasonal affective disorder (Lewy et al., 1987, 1988) in parallel-design comparison of effects of morning (800-1000) or afternoon (1600-1800) light treatment on mood and circadian phase. Subjective arousal, body temperature, melatonin and cortisol were measured at 800, 1200, 1600, 2000 and 2400 in 23 women with seasonal depression and 20 controls before and after a week of bright light (2 hours per day). The rates of clinical response to both treatments were similar. Comparison of circadian variations did not provide evidence for significant phase-delay in patients compared to controls. However, morning light produced significant phase advance in patients, but not in controls. Also we found that advance phase shifts in well-responded patients were more often than in patients with worse response and controls. Before light treatment phase concordance between different variables in patients was lower compared to either themselves after light treatment or controls before and after light treatment. Dependence of antidepressant response to light from pretreatment circadian phases was also observed. Those patients who responded worse to morning light tended to have advance circadian phases, while those who responded worse to afternoon light tended to have delay phases. Although some results are lending support for the phase-shift hypothesis, other explanations for mechanisms by which biological rhythms are implicated in winter depression and light treatment might be suggested.     

Phase Typing of Patients with Seasonal Affective Disorder: A Test for the Phase Shift Hypothesis

The study evaluates the phase-shift hypothesis for seasonal affective disorder (Lewy et al., 1987, 1988) in parallel-design comparison of effects of morning (800-1000) or afternoon (1600-1800) light treatment on mood and circadian phase. Subjective arousal, body temperature, melatonin and cortisol were measured at 800, 1200, 1600, 2000 and 2400 in 23 women with seasonal depression and 20 controls before and after a week of bright light (2 hours per day). The rates of clinical response to both treatments were similar. Comparison of circadian variations did not provide evidence for significant phase-delay in patients compared to controls. However, morning light produced significant phase advance in patients, but not in controls. Also we found that advance phase shifts in well-responded patients were more often than in patients with worse response and controls. Before light treatment phase concordance between different variables in patients was lower compared to either themselves after light treatment or controls before and after light treatment. Dependence of antidepressant response to light from pretreatment circadian phases was also observed. Those patients who responded worse to morning light tended to have advance circadian phases, while those who responded worse to afternoon light tended to have delay phases. Although some results are lending support for the phase-shift hypothesis, other explanations for mechanisms by which biological rhythms are implicated in winter depression and light treatment might be suggested.     

Effect of Melatonin Treatment on 24-hour Variations in Hypothalamic Serotonin and Dopamine Turnover During the Preclinical Phase of Freund's Adjuvant Arthritis in Rats

The effect of melatonin treatment on time-of-day variations in hypothalamic serotonin (5-HT) and dopamine (DA) turnover was studied in rats treated with Freund's complete adjuvant (FCA). Animals received s.c. injections of 30 æg of melatonin or vehicle 1 h before lights off for 11 days. On day 10 of treatment, FCA or its vehicle was s.c. injected, and 2 days later, the rats were killed at 6 different time intervals throughout a 24-hour cycle. Hypothalamic 5-HT, 5-hydroxyindole-3-acetic acid (5-HIAA), DA and 3,4-dihydroxyphenylacetic acid (DOPAC) levels were measured by HPLC. 5-HT and DA turnover were estimated from the 5-HIAA/5-HT and DOPAC/DA ratios, respectively. In the anterior hypothalamus, time-of-day variation in 5-HT turnover was suppressed by FCA, an effect counteracted by melatonin treatment. Melatonin also prevented FCA effect on medial hypothalamic 5-HT turnover, while in the posterior hypothalamus, similar daily variations of 5-HT turnover were found in all experimental groups. As far as DA turnover, FCA or melatonin administration suppressed its daily variations in the anterior hypothalamus. Time-of-day variations in medial hypothalamic DA turnover were similar in all groups while only rats treated with melatonin and FCA or its vehicle exhibited significant daily changes of DA turnover in the posterior hypothalamus. Results indicate that melatonin treatment affects partly the 24-hour pattern of variation of hypothalamic 5-HT and DA turnover at an early phase of FCA arthritis in rats.     

Phase equilibria of model milk membrane lipid systems

The phase behaviour of mixtures of recombined milk membrane lipids dioleoylphosphatidylcholine (DOPC), sphingomyelin (SM), dioleoylphosphatidylethanolamine (DOPE), phosphatidylinositol (PI) and dioleoylphosphatidylserine (DOPS) in 60% water was examined as a function of temperature between 5 and 90 degrees C. The aim was to examine under which lipid composition the average properties turn from balanced over to hydrophobic. The phase boundaries were determined by small angle X-ray diffraction (SAXD) and differential scanning calorimetry (DSC). The lamellar phase was dominating in the DOPC/SM/DOPE system. The phase boundary for the reversed hexagonal phase was only observed at high DOPE content within the examined temperature interval. The anionic phospholipids PI and DOPS induced a swollen lamellar phase, but no significant change of the transition between the lamellar phase and the reversed hexagonal phase was observed.     

Facts and fiction about sulfur metabolism in relation to plant-pathogen interactions

Sulfur deficiency developed into a widespread nutrient disorder in the 1980s because of the drastic decrease of SO(2) emissions in western Europe after Clean Air Acts came into force. It was observed that not only the yield and quality of agricultural crops were negatively affected by sulfur deficiency but also their health status. Since the mid 1990s the physiological background of this latter phenomenon in the sulfur metabolism has been studied by different researchers. From 2001 until 2006, field trials with different varieties of oilseed rape were conducted in Germany, and also from 2001 until 2003 in Scotland, to investigate the underlying mechanisms of sulfur-induced resistance and to develop fertiliser strategies which increase the health status of crops and minimise the requirement for chemical fungicides. A comprehensive disease assessment was conducted and a range of different sulfur-containing metabolites and enzymes were analysed in relation to sulfur nutrition and fungal diseases. H2S emissions from field-grown crops under different sulfur nutritional status were studied for the first time and a positive relationship was observed. Besides S fertilisation, fungal infection increased H2S emissions, too. The studies deliver new insight into the complex of sulfur-induced resistance but many questions still remain open. This contribution will show different possible strategies to solve some of the open questions.     

Isolation of viruses from drinking water at the Point-Viau water treatment plant

Viruses were isolated from every sample of raw (100 L) and treated (1000 L) water collected at a water treatment plant drawing sewage-contaminated river water. Few plaque-forming isolates were formed but cytopathogenic viruses were isolated as frequently in drinking water as in raw water. In drinking water some samples contained more than 1 cytopathogenic unit per litre, but most contained 1-10/100 L. These viruses had not been inactivated or removed by prechlorination, flocculation, filtration, ozonation, and postchlorination. There were no coliforms present and a residual chlorine level had been maintained. Poliovirus type 1 was a frequent isolate but many isolates were nonpoliovirus. The presence of these viruses in drinking water raises questions about the efficacy of some water treatment processes to remove viruses from polluted water.     

Female-specific dominant lethal effects in mice

For some chemicals, induction of presumed dominant lethal mutations has been observed only in female mice and not in males. In those cases, questions arise as to (1) whether the increased embryonic mortality is due to genetic effects of the chemicals in the oocyte or, (2) is caused indirectly through maternal toxicity, and, if genetic, (3) the basis for the sex difference. These questions were studied using the compounds adriamycin and platinol. Neither compound induces dominant lethals in male germ cells, but both increased early embryonic mortality when females were treated prior to mating (treatment of maturing oocytes). Reciprocal zygote transfer experiments rules out, either entirely or for the large part, maternal toxicit as the cause, and cytogenetic analysis of first-cleavage metaphases revealed high incidences of chromosomal aberrations. The results of both of these experiments thus provide evidence that the early embryonic mortality resulted from genetic effects induced in oocytes. Most interestingly, each compound produced unexpected types of chromosomal aberrations. Adriamycin produced deletions, rings, and presumed chromosome-type rearrangements. Platinol, on the other hand, produced a few chromatid-type aberrations, but the bulk of aberrations were characterized by disorganization of the chromatin, minute fragments, and thread-lik chromatin bridges between fragments and chromosomes or between two or more chromosomes. The latter type of cytogenetic damage was observed primarily in the compounds are associated with the diffused state of the maturing oocyte chromosomes.     

Outlook on sponge reproduction science in the last ten years: are we far from where we should be?

To comprehend the state of the art of sponge reproduction science (SRS), we quantified and analyzed the trends in SRS in the last decade, aiming to answer three questions: (i) Were there fewer SRS works presented during the last sponge conference? (ii) Did the number of SRS publications decline in the last decade? (iii) Does the number of abstracts at sponge conferences influence overall SRS publications? In addition, we checked whether the SRS community has answered Ereskovsky’s ‘five important questions’, enabling us to advance SRS enough to be considered as a fourth period of this scientific field. We found that SRS was less represented at the last sponge conference, despite an increase in the number of publications during the last decade. Moreover, the number of abstracts presented at sponge conferences contributed to a small portion (25%) of the published works in this area during the last decade. In addition, we found that two of the five Ereskovsky’s questions are still mostly not answered. Thus, we conclude that SRS is healthy and advancing steadily, especially in some subareas (e.g. developmental biology and life history). There are still much to advance, but this is still a strong field of biological science research.     

Knowledge and attitudes toward Tay-Sachs disease among a college student population.

To assess the feasibility of screening the single Jewish population for Tay-Sachs disease (TSD), a questionnaire examining the knowledge of and attitudes toward TSD and genetic screening was sent to 348 Yale University Jewish undergraduates. Of those students responding (63 percent), 78 percent were able to answer general genetic questions correctly while only 1.9 percent could answer specific Tay-Sachs questions correctly. A majority of the students (93.9 percent) indicated some concern about being a carrier for TSD, believed that carrier status would affect future social and reproductive behavior, and expressed an interest in having TS carrier status determined while still single (77.4 percent). Strong correlations were found between knowledge and attitudes, but no significant differences appeared between male and female respondents. In addition to leading to improvements in Tay-Sachs screening programs, the observations have led to suggestions that may be generalized to other genetic screening programs.     

Peroxiredoxin 6 phosphorylation and subsequent phospholipase A2 activity are required for agonist-mediated activation of NADPH oxidase in mouse pulmonary microvascular endothelium and alveolar macrophages

Peroxiredoxin 6 (Prdx6), a bifunctional enzyme with glutathione peroxidase and phospholipase A2 (PLA(2)) activities, participates in the activation of NADPH oxidase 2 (NOX2) in neutrophils, but the mechanism for this effect is not known. We now demonstrate that Prdx6 is required for agonist-induced NOX2 activation in pulmonary microvascular endothelial cells (PMVEC) and that the effect requires the PLA(2) activity of Prdx6. Generation of reactive oxygen species (ROS) in response to angiotensin II (Ang II) or phorbol 12-myristate 13-acetate was markedly reduced in perfused lungs and isolated PMVEC from Prdx6 null mice. Rac1 and p47(phox), cytosolic components of NOX2, translocated to the endothelial cell membrane after Ang II treatment in wild-type but not Prdx6 null PMVEC. MJ33, an inhibitor of Prdx6 PLA(2) activity, blocked agonist-induced PLA(2) activity and ROS generation in PMVEC by >80%, whereas inhibitors of other PLA(2)s were ineffective. Transfection of Prx6 null cells with wild-type and C47S mutant Prdx6, but not with mutants of the PLA(2) active site (S32A, H26A, and D140A), "rescued" Ang II-induced PLA(2) activity and ROS generation. Ang II treatment of wild-type cells resulted in phosphorylation of Prdx6 and its subsequent translocation from the cytosol to the cell membrane. Phosphorylation as well as PLA(2) activity and ROS generation were markedly reduced by the MAPK inhibitor, U0126. Thus, agonist-induced MAPK activation leads to Prdx6 phosphorylation and translocation to the cell membrane, where its PLA(2) activity facilitates assembly of the NOX2 complex and activation of the oxidase.     

Playing God,Playing Adam: The Politics and Ethics of Enhancement

The question of enhancement occupies a prominent place not only in current bioethical debates but also in wider public discussions about our human future. In all of these, the problem of enhancement is usually articulated via two sets of questions: moral questions over its permissibility, extent and direction; and technical questions over the feasibility of different forms of regenerative and synthetic alterations to human bodies and minds. This article argues that none of the dominant positions on enhancement within the field of bioethics is entirely satisfactory due to the limited, monadic, pre-technological and non-cultural conception of the human that is adopted in these models. Critically engaging with both opponents of enhancement (Habermas) and its advocates (Harris, Agar, Bostrom, Dworkin), Zylinska also takes some steps towards outlining a nonnormative ethics of enhancement. The latter sees its human and non-human subjects as always already enhanced, and hence dependent, relational and coevolving with technology.     

Effects of cod liver oil on tissue antioxidant pathways in normal and streptozotocin-diabetic rats

Lipid disorders and increased oxidative stress may exacerbate some complications of diabetes mellitus. Previous studies have implicated the beneficial effects of some antioxidants, omega-3 polyunsaturated fatty acids (PUFAs), eicosapentaenoic acid (EPA) and docosahexaenoic acid (DHA) in the protection of cells from the destructive effect of increased lipids and lipid peroxidation products. This study, therefore, was designed to investigate the effects of cod liver oil (CLO, Lysi Ltd. Island), which comprises mainly vitamin A, PUFAs, EPA and DHA. Effects were monitored on plasma lipids, lipid peroxidation products (MDA) and the activities of antioxidant enzymes, glutathione peroxidase (GSHPx) and catalase in heart, liver, kidney and lung of non-diabetic control and streptozotocin (STZ)-induced-diabetic rats. Two days after STZ-injection (55 mg kg(-1) i.p.), non-diabetic control and diabetic rats were divided randomly into two groups as untreated or treated with CLO (0.5 ml kg(-1) rat per day) for 12 weeks. Plasma glucose, triacylglycerol and cholesterol concentrations were significantly elevated in 12-week untreated-diabetic animals; CLO treatment almost completely prevented these abnormalities in triacylglycerol and cholesterol, but hyperglycaemia was partially controlled. CLO also provided better weight gain in diabetic animals. In untreated diabetic rats, MDA markedly increased in aorta, heart and liver but was not significantly changed in kidney and lung. This was accompanied by a significant increase in both GSHPx and catalase enzyme activities in aorta, heart, and liver of diabetic rats. In kidney and lung, diabetes resulted in reduced catalase while GSHPx was significantly activated. In aorta, heart, and liver, diabetes-induced changes in MDA were entirely prevented by CLO treatment. In the tissues of CLO-treated diabetic animals, GSHPx activity paralleled those of control animals. CLO treatment also caused significant improvements in catalase activities in every tissue of diabetic rats, but failed to affect MDA and antioxidant activity in control animals. The current study suggests that the treatment of diabetic rats with CLO provides better control of glucose and lipid metabolism, allows recovery of normal growth rate, prevents oxidative/peroxidative stress and ameliorates endogenous antioxidant enzyme activities in various tissues. Because CLO contains a plethora of beneficial compounds together, its use for the management of diabetes-induced complications may provide important advantages.     

Aerobic Biodegradation of High Explosives, Phase I - HMX

The Pantex facility near Amarillo, Texas, has soil and groundwater contaminated with differing combinations of high explosives (HEs), including hexahydro-1,3,5-trinitro-1,3,5-triazine (RDX), octahydro-1,3,5,7-tetranitro-1,3,5,7-tetrazocine (HMX), and 2,4,6-trinitrotoluene (TNT). This project was concerned with direct treatment of HMX in groundwater withdrawn at this plant. Several physical and chemical treatment schemes for the treatment of HMX have been successful. However, the successful biological treatment of HMX has been limited to anaerobic environments. The objective of this work was to identify microbial consortia and amendments capable of aerobically biodegrading HMX in water. Microbial consortia and amendments employed were provided as livestock manure and soil with its indigenous flora from nearby historically contaminated sites. Possible losses of HMX by nonbiological means such as adsorption and photolysis were accounted for by appropriate abiotic experiments. Loss of the parent compound was measured by high-performance liquid chromatography, using a modification of U.S. Environmental Protection Agency (EPA) Method 8330. Results varied from no degradation to a reduction of parent HMX from 6 to 1 mg/L in 5.2 days. Evidence for biodegradation was supported by the appearance of metabolites. Metabolite identification was performed at Oak Ridge National Laboratory. Five metabolites (four intermediate and one final) were identified.     

Menstrual Phase Response to Nocturnal Light

The aims of the study were to test whether nocturnal white light can normalize menstrual cycles in oligomenorrheic women, and whether the phase of the menstrual cycle in which light is given is important for the shortening effect. Twenty-five women with long menstrual cycles (35.9–53.4 days on average) were treated for 1–3 cycles, each of which was preceded and followed by at least two untreated cycles. Treatments were 100 watt bedside lights administered for 5 consecutive nights. They centered at three different phases of the menstrual cycle: 6–7th, 14–17th or 23–25th days of the treated cycle (early, middle or late treatment, respectively). On average, the treatment cycle lengths were modestly, but significantly reduced compared to the duration of baseline cycles (more than 11 %). The difference in the effects of the early, middle and late treatment was not significant. However, if middle or late treatments were administered in the latter half of the interval between the menstrual cycle onset and probable time of ovulation, reductions of the treated cycle length were substantial (more than 20 %, resulting in cycles less than 33 days on average; p &lt; 0.001). Other treatments produced only weak (up to 7 %), if any, cycle reductions. Moreover, we found a strong correlation (p &lt; 0.001) between the duration of baseline cycle and differential effect of middle treatment (compared to early or late treatment). Middle treatments reduced treated cycle duration to the normal range in the subjects with shorter mean baseline cycles (&lt;42 days), while in the subjects with longer duration of baseline cycle the shortening effect was produced by late treatments (p = 0.005 and p = 0.001, respectively). The results support the suggestion that a bedside lamp used on nights prior to ovulation can cause reduction of long menstrual cycles.     

Therapeutic effects of glycyrrhizin in mice infected with LP-BM5 murine retrovirus and mechanisms involved in the prevention of disease progression

Glycyrrhizin (GL), a plant extract, has been evaluated for its inhibitory effect on HIV replicationin vitro and for its improvement of clinical symptoms in HIV-infected patients. In this study, we used GL in a murine AIDS model (MAIDS) to evaluate these effects. C57BL/6 mice were inoculated with LP-BM5 murine leukemia virus to cause MAIDS. Treatment with GL supplemented with glycine and cysteine (Stronger Neo-Minophagen C, SNMC) was then begun on day 0 or 4 wks after virus inoculation. SNMC was administered three times a week for up to 19 wks. Immunological abnormalities were monitored with respect to the surface phenotype identified by two-color staining for CD3 and IL-2 receptorβ-chain. All mice infected with the virus alone developed MAIDS and died by 14 wks after infection. The immunopathogenesis was estimated to be an abnormal expansion of intermediate CD3 cells (i.e., extrathymic T cells) as well as other types of lymphocytes. SNMC did not change the total mortality rate. However, some mice that began the treatment on day 0 or 4 wks after infection survived 3 wks longer. Splenomegaly and lymphadenopathy in such mice were suppressed. These mice showed normal phenotypic features and normal responses to Con A. These results suggest that SNMC is effective in some MAIDS mice in preventing the progression of disease. When lymphocytes isolated from the liver, spleen and lymph nodes of diseased mice were culturedin vitro, they showed a spontaneous proliferation. Interestingly, such proliferation was inhibited by addition of liver lymphocytes, but not splenic lymphocytes, obtained from normal or SNMC-treated mice. Since liver lymphocytes contains intermediate CD3 cells with autoreactivity, they may possibly suppress the progression of disease.     

Testing the nest-homing abilities of a phytotelm-breeding frog, Chirixalus eiffingeri (Rhacophoridae)

We conducted a manipulative experiment to assess the homing of female Chirixalus eiffingeri to the nest. There were three experimental treatments and a control. For the control treatment, bamboo stumps were cut off at the base and reattached. In the first experimental treatment, when stumps were displaced 1 m, the proportion of stumps attended by females and the growth of tadpoles did not differ from the results of the control treatment, suggesting the 1-m stump displacement did not affect the nest homing of female frogs. In the second experimental treatment, when a bamboo stump was displaced 1 m and a new bamboo stump with tadpoles was put in its place, some females fed tadpoles in the displaced stump (3/12), but some fed tadpoles in the stump (3/12) at the original site. This finding suggests that the addition of a new stump confused the female frogs spatially, which resulted in females feeding the tadpoles in either stump. In the third experimental treatment, when a bamboo stump was displaced 1 m and a new stump without tadpoles was added at the original site, some female frogs fed tadpoles in the displaced stump (5/12) but some laid trophic eggs in the stump (4/12) at the original site, also indicating the female frogs were confused spatially. The overall results support the hypothesis that females rely on the spatial distribution of a nest stump, relative to other bamboo stumps, for nest homing to feed their offspring, and that stump location is an important cue to the nest homing of females.     

生物多样性研究及其问题

围绕生物多样性主要有3个理论问题需要进一步深入研究,（1）生物多样性与生态系统稳定性的关系：本世纪70年代以前,生态学家普遍认为,稳定性随生物多样性增加而提高;自70年代初一些理论生态学家向这一普遍看法提出挑战以来,在物种多样性层次出现了观点截然不同的两大阵营;（2）生物多样性和土地生产力的关系：达尔文（1872）的研究表明,生物多样性有利于土地生产力的提高,这一结论已被许多国家运用于指导农业实践;然而,本世纪70年代以来,一些生态学家向达尔文的这一观点提出了异议;（3）生物多样性与景观连通性：本世纪90年代以来,一些景观生态学家认为,景观连通性与生物多样性有正相关关系,但目前为数不多的研究还不能肯定这一结论的正确性。通过总结生物多样性的研究历史,发现,以上的急诊和结论基于27种不同的分析模型;并且这些模型中的大多数在理论上是不完善的,认为,运用理论上合理的模型、有关概念的统一正确定义和全面系统的实验对以上急诊和结论进行更进一步的论证与实证是必要的。     

Facilitating the Communicative Competence of the Child Witness

Efforts to elicit reliable testimony from children are frustrated by developmental limitations on children's communicative competence. This study examines (a) how children cope when adults ask incomprehensible questions, and (b) whether interview perfonnance can be enhanced by facilitating children's comprehension monitoring and response strategies. One hundred and eighty children, half 6 and half 8-years-olds, were assigned randomly within age group to 1 of 3 treatment conditions (training, instructions, control) and I of 2 interviewer conditions (familiar, unfamiliar). Children's memories of a previously staged event were tested with interview questions varying in comprehensibility. Results suggest that when confronted with difficult-to-comprehend questions regarding easily recalled information, children in the control group tried to answer anyway but were as likely to respond incorrectly as correctly. In contrast, when children were instructed to verbalize their lack of comprehension, and given a rationale for doing so, they performed significantly better than the control group. Moreover, when children received instructions and prepared for the interview with practice detecting and coping with noncomprehension, the training group demonstrated marked improvements in interview performance compared with the other 2 groups. Results demonstrate that although children's limited communication skills present a barrier to reliable testimony, it is one that might be minimized by instructions or preparation of child witnesses.     

Antitumor effects of human recombinant macrophage colony-stimulating factor against rat brain tumors

The tumoricidal effects of M-CSF were examined using two subcutaneously-transplanted rat brain tumor cell lines, 9L and T9 gliomas. In rats treated with high-dose M-CSF (16 million U/kg administered for 4 days a week for 3 weeks), 9L glioma growth was inhibited by 81.9% following subcutaneous (s.c.) injection and by 70.5% after intraperitoneal (i.p.) injection and T9 glioma growth was inhibited by 69.2% after i.p. injection. After short-term treatment with high-dose M-CSF (32 million U/kg administered s.c. for 6 consecutive days, 9L glioma growth was inhibited by 82.1%. All these inhibitory effects differed significantly compared with the respective untreated control groups. However, treatment with low-dose M-CSF (1.6 million U/kg administered s.c. for 4 days a week for 3 weeks) showed no significant effects against 9L and T9 glioma growth compared with the untreated controls. No significant effects of M-CSF against cell proliferation, measured as PCNA expression, were observed in any group. Significant hematopoietic effects on the leukocyte counts were observed only in the groups treated with high dose M-CSF. These results suggest that M-CSF at a high dose which produces hematopoietic effects on peripheral leukocytes inhibits the growth of gliomas. This inhibitory effect may have been due to a tumoricidal mechanism of M-CSF that depended on the production or release of some hematopoietic soluble factors, but was independent of PCNA expression by the tumors.Abbreviations BBB blood-brain barrier - G-CSF granulocyte colony-stimulating factor - GM-CSF granulocyte-macrophage colony-stimulating factor - hM-CSF human macrophage colony-stimulating factor - IFN interferon - IL-1 interleukin-1 - IL-6 interleukin-6 - M-CSF macrophage colony-stimulating factor - PCNA proliferating cell nuclear antigen - rhM-CSF recombinant human macrophage colony-stimulating factor - TNF tumor necrosis factor