Age-dependent penetrance of different germline mutations in the BRCA1 gene.

AIMS: BRCA1 gene mutations have been extensively studied in relation to breast and ovarian cancer susceptibility. Various genotype-phenotype correlation attempts have yielded important data pertaining to the consequences of BRCA1 mutations. However, little is known about the effects of recurrent BRCA mutations on expressivity and the age of onset of cancer in a population. This study addresses whether different exon mutations have variable expressivity especially in relation to the age of onset of breast cancer. METHODS: Using a step-wise systematic approach, culminating in the sequencing of all BRCA1 and BRCA2 exons with the addition of multiplex ligation-dependent probe amplification, the relationship between disease phenotypes and gene mutations in 219 individuals and their family members was examined. RESULTS: It is shown that different BRCA1 gene mutations have distinct effects that influence the age of onset of breast or ovarian cancer. Mutations in exon 2 of the BRCA1 gene had significantly lower penetrance compared with mutations of exons 11, 13 and 20. The median age of affliction with breast cancer was 55 years for 185delAG in exon 2 (95% confidence interval (CI) 46.7 to 59.5), 47 years for the 4184delTCAA mutation in exon 11 (95% CI 39 to 55.4), and 41 years for exon 13 duplication (95% CI 32.9 to 49.7) of the BRCA1 gene. Moreover, 14 novel mutations in BRCA1 and BRCA2 genes in the Yorkshire/Humberside population were identified. CONCLUSIONS: The 185delAG mutation of the BRCA1 gene is a low penetrance mutation that is age dependent especially when compared with the exon 13 duplication mutation. The data have important ramifications on screening, genetic counselling and prophylactic treatment of BRCA1 gene mutation carriers.

Phylogenetic diversity of bacterial and archaeal communities in the anoxic zone of the Cariaco Basin.

Microbial community samples were collected from the anoxic zone of the Cariaco Basin at depths of 320, 500, and 1,310 m on a November 1996 cruise and were used to construct 16S ribosomal DNA libraries. Of 60 nonchimeric sequences in the 320-m library, 56 belonged to the epsilon subdivision of the Proteobacteria (epsilon-Proteobacteria) and 53 were closely related to ectosymbionts of Rimicaris exoculata and Alvinella pompejana, which are referred to here as epsilon symbiont relatives (ESR). The 500-m library contained sequences affiliated with the fibrobacteria, the Flexibacter-Cytophaga-Bacteroides division, the division Verrucomicrobia, the division Proteobacteria, and the OP3 candidate division. The Proteobacteria included members of the gamma, delta, epsilon and new candidate subdivisions, and gamma-proteobacterial sequences were dominant (25.6%) among the proteobacterial sequences. As in the 320-m library, the majority of the epsilon-proteobacteria belonged to the ESR group. The genus Fibrobacter and its relatives were the second largest group in the library (23.6%), followed by the delta-proteobacteria and the epsilon-proteobacteria. The 1,310-m library had the greatest diversity; 59 nonchimeric clones in the library contained 30 unique sequences belonging to the planctomycetes, the fibrobacteria, the Flexibacter-Cytophaga-Bacteroides division, the Proteobacteria, and the OP3 and OP8 candidate divisions. The proteobacteria included members of new candidate subdivisions and the beta, gamma, delta, and epsilon-subdivisions. ESR sequences were still present in the 1,310-m library but in a much lower proportion (8.5%). One archaeal sequence was present in the 500-m library (2% of all microorganisms in the library), and eight archaeal sequences were present in the 1,310-m library (13.6%). All archaeal sequences fell into two groups; two clones in the 1,310-m library belonged to the kingdom Crenarchaeota and the remaining sequences in both libraries belonged to the kingdom Euryarchaeota. The latter group appears to be related to the Eel-TA1f2 sequence, which belongs to an archaeon suggested to be able to oxidize methane anaerobically. Based on phylogenetic inferences and measurements of dark CO(2) fixation, we hypothesized that (i) the ESR are autotrophic anaerobic sulfide oxidizers, (ii) sulfate reduction and fermentative metabolism may be carried out by a large number of bacteria in the 500- and 1,310-m libraries, and (iii) members of the Euryarchaeota found in relatively large numbers in the 1,310-m library may be involved in anaerobic methane oxidation. Overall, the composition of microbial communities from the Cariaco Basin resembles the compositions of communities from several anaerobic sediments, supporting the hypothesis that the Cariaco Basin water column is similar to anaerobic sediments.

Methods for inducing neuronal loss in preweanling rats using intracerebroventricular infusion of kainic acid.

Excitotoxins, such as kainic acid (KA), have been shown to produce neuronal degeneration in the adult rat brain. While preweanling rats have been shown to be relatively resistant to the neurotoxicity of lower doses of KA, the presence of neuronal loss at higher doses (of KA) has only begun to be investigated in such animals. A reliable method of producing neuronal loss in preweanling rats is to administer nmol concentrations of KA via intracerebroventricular (i.c.v.) injections on postnatal day 7 (P7). Using a three-dimensional, non-biased cell counting technique, we have shown that neuronal loss is observed in the CA3 subfield of the hippocampal formation at P45 and P75. Further, immunohistochemical studies of markers for cell death may be useful to examine the types of cellular processes associated with such neuronal loss. Data from our own experiments suggest the activation of immediate-early genes in the neuronal loss produced by KA administration at P7. This developmental animal model of neuronal loss may be useful in studying neurodevelopmental disorders where the onset of symptoms or cognitive deficits is thought to follow an early developmental insult.

Sociosexual behaviour and paternity in procarbazine-exposed rats with or without regional testicular circulatory isolation.

Male Sprague-Dawley rats were used in two experiments in which a procarbazine bolus (400 mg kg-1 body mass) was administered with or without testicular circulatory isolation in the form of brief clamping of the spermatic cord and gubernaculum during drug administration. Separate tests of aggressiveness, sexual motivation, copulatory performance and paternity over the subsequent 6 weeks were used to assess functional changes resulting from testicular circulatory isolation. Experiment 1 compared intermale aggression and sexual motivation of animals in groups receiving procarbazine plus testicular circulatory isolation lasting 0, 15 or 45 min with that of animals in control groups with no clamp and no drug. Experiment 2 used a 2 x 2 factorial design to evaluate sexual performance and resulting paternity in animals 2 months after testicular circulatory isolation and drug exposure compared with that in control animals. Procarbazine treatment induced minimal disruption of normal interest in a receptive female, copulatory measures (intromissions or ejaculations) and structural integrity of seminal vesicles, bulbospongiosus muscles and ventral prostate glands. Animals exposed to the drug without testicular circulatory isolation were significantly less aggressive than animals in other groups. The most profound influence of procarbazine was on paternity. Males exposed to procarbazine with or without testicular circulatory isolation impregnated notably fewer females than did control males that were not exposed to the drug. There was no evidence of recovery of normal fertility up to 10 weeks after exposure to the drug. In conclusion, the deleterious influence of procarbazine on androgen-sensitive processes appears to be specific to intermale aggression and to fertility. The testicular circulatory isolation technique, for 45 min in particular, softened the impact of the drug on social behaviour, although procarbazine suppressed fecundity even with testicular circulatory isolation.

Adrenal axis activation by chronic social stress fails to inhibit gonadal function in male rats.

Stress in males via the hypothalamic-pituitary-adrenal (HPA) axis may set into motion varied physiological alterations, including dysfunction of the hypothalamic-pituitary-gonadal (HPG) axis. However, the influence of the HPA on the HPG axis may not always be inhibitory. Presence or absence of stimuli of sexual significance that typically activates the HPG axis may alter the influence of the adrenal axis on gonadal axes. In this project, we used male rats and chronic social stimulation that included brief or extended periods with female rats to examine HPA-HPG axes interactions. In experiment 1, we used intact males and a 'chronic social stress' paradigm developed in our previous research that induces social instability by daily changing the membership of group-housed males with females. Thymus weight was reduced and corticosterone levels were marginally increased by chronic social stress, indicating a HPA axis hyperactivity. The HPG axis was also activated as shown by the increased weight of the androgen-sensitive sex structures. These results indicate that when these two axes are stimulated together, neither interferes with nor suppresses activities of the other. Implants of corticosterone pellets to adrenalectomized animals that maintained constant, high corticosterone levels failed to reverse the gonadal hyperactivity induced by sexual stimulation. In a second experiment, we studied the influence of different intensity of sexual stimulations on HPA-HPG axes interactions. Increased corticosterone levels and adrenal weight, indicating a HPA hyperactivity, failed to inhibit HPG hyperactivity as measured by the increased sexual organs weight, whatever the sexual intensity of the stimulation. This work demonstrates that the gonadal axis is freed from suppression when sexual stimulation occurs together with stress. The general conclusion is that the nature of complex social settings is important in determining interactions between the two neuroendocrine axes.

Coelenterate Cnidae Capsules: Disulfide Linkages Revealed by Silver Cytochemistry and Their Differential Responses to Thiol Reagents.

The sulfur cytochemistry of cnidae from the Portuguese man-of-war Physalia physalis, the scyphozoan Cassiopeia xamachana, and the black coral Cirrhipathes luetkeni was evaluated on the basis of electron microscopy, X-ray microanalysis, amino acid analysis, and response to disulfide reducing agents. The cnidae examined included large and small holotrichous isorhizas in P. physalis, another small isorhiza in C. xamachana, and both spirocysts and microbasic mastigophore nematocysts in C. leutkeni. A strong reaction with methenamine-silver reagent was characteristic of all cnidae capsules, but the pattern and extent of that argentophilia was dependent upon the type of cnida and its state of maturity. The large isorhizas of P. physalis reacted primarily in the outermost capsule layers, but in C. xamachana isorhizas, silver stained the entire capsule with the exception of the outermost region. The small isorhizas of P. physalis and the mastigophore capsules of C. leutkeni stained throughout, whereas the spirocyst capsules were outlined by silver, clearly delineating the inner and outer layers. All of these reactions were abolished with alkylation, but only after treatment with disulfide reducing agents; alkylation alone diminished silver staining only slightly, indicating that the argentophilic response was due primarily to disulfide linkages. The cystine content of these cnidae varied from 4.1 to 4.7 mole percent for a given species, but amino acid analyses did not separate components of the cnidom. Cnidae, both within and among species, exhibited differential responses to the disulfide reducing agent dithiothreitol (DTT). Isolated, unfixed, large isorhizas of P. physalis discharged and appeared to dissolve rapidly in the presence of this reagent, whereas small isorhizas from both P. physalis and C. xamachana discharged, but dissolved slowly if at all. The discharge and solution responses of the capsule coincided with the complete development of the tubule. Cnidae containing an undeveloped or partially developed tubule were resistant to DTT, displayed a weak capsular argentophilia, and contained background levels of sulfur; these results suggest that formation of disulfide linkages is one of the final steps in capsular maturation. In contrast, mature nematocyst and spirocyst capsules in C. leutkeni tentacles were resistant to DTT among other reagents, despite the presence of disulfides. This suggests that other types of covalent, intermolecular linkages could play a prominent role in the development of capsular stability in this species.

The effects of chronic corticosterone on memory performance in the platform maze task.

Acquisition and reversal of a memory task dependent on hippocampal integrity were assessed in rats following chronic corticosterone treatment. Young adult male rats were injected daily with corticosterone (10 mg/kg, SC) for 8 weeks. Memory was assessed during the last week of treatment with an elevated platform maze. During acquisition trials, corticosterone-treated rats did not differ from vehicle-treated controls in either the location of first hole chosen nor in the latency to locate the escape hole. In the reversal trials, when the position of the escape hole was rotated 135 degrees, both groups successfully reversed their responses without persevering towards the previously rewarded escape hole location. These findings suggest that, despite the probability of corticosterone-induced changes in hippocampal physiology, chronic corticosterone treatment does not adversely affect performance in a memory task dependent on hippocampal integrity.

Effect of ovarian steroids on footshock avoidance learning and retention in female mice.

Mice were trained to avoid footshock in a T-maze, with retention tested one week later. Adult male CD-1 mice made their first avoidance during acquisition after fewer trials than random cycling females and with less variability. Female mice in diestrus, when plasma levels of progesterone are low, learned to avoid footshock faster than females in estrus. Ovariectomized (OVX) mice learned in fewer trials than intact random cycling mice. Similar differences, though of a smaller magnitude, were found on the retention tests (i.e. males had better retention than females, mice in diestrus showed better retention 8 days later when in the same part of the estrous cycle than those in estrus, and OVX mice had better retention than cycling females). OVX mice with estrogen implants learned faster than those with progesterone implants or progesterone plus estrogen implants. Hormonal status did not affect sensitivity to acoustic or footshock stimuli as measured by a startle reflex, nor did it affect activity. Pretraining administration of amphetamine, picrotoxin and strychnine attenuated the impairing effect of progesterone on acquisition. The possibility that progesterone may impair learning and to some extent, retention by facilitating the GABAergic activity and thereby reducing arousal level is discussed.

Kainic acid decreases hippocampal neuronal number and increases dopamine receptor binding in the nucleus accumbens: an animal model of schizophrenia.

Intracerebroventricular (i.c.v.) administration of kainic acid (KA) produces graded neuronal loss in the hippocampus and other regions of the medial temporal lobe. Many of these brain regions send excitatory projections to the nucleus accumbens, a dopaminergic brain area implicated in psychotomimetic and antipsychotic drug action. In the present study, neurochemical function in the nucleus accumbens and anterior caudate-putamen was examined one week after i.c.v. administration of 1.5, 4.5, or 6.6 nmol of KA. As expected, i.c.v. KA produced dose-dependent neuronal loss in the dorsal and ventral hippocampus. Extrahippocampal neuronal loss was also observed in the thalamus and piriform cortex in some of the KA-treated rats. While ambient levels of dopamine turnover and excitatory amino acids in the nucleus accumbens were unaltered by KA, administration of the highest KA dose elevated [3H]spiperone binding exclusively in the accumbens. Finally, behavioral hyperactivity was observed in KA-treated rats over a five-week period following i.c.v. administration. The pattern of neuronal loss, receptor upregulation, and behavioral hyperactivity found after i.c.v. KA administration may provide a useful animal model of the limbic neuropathology and neurochemical dysfunction associated with schizophrenia.

Norepinephrine modulation of social memory: evidence for a time-dependent functional recovery of behavior.

We tested the hypothesis that central nervous system (CNS) norepinephrine (NE) modulates the ability of an adult male rat to remember significant novel stimuli. Behavioral tests evaluated NE effects on general exploration and social memory. Results were that neither depletion nor elevation of NE impaired general exploration. Findings from the social memory setting suggested that animals tested 2 weeks after NE depletion were unable to discriminate novel from familiar juveniles in situations where untreated controls had no difficulty. Elevation of CNS NE, conversely, produced improved discrimination performance compared with control animals. Results suggest that activation of the CNS NE system is involved in the memory for novel stimuli. Performance of the NE-depleted group tested 3 months after treatment indicates a time-dependent functional recovery can occur in the presence of virtually total CNS NE depletion.

Endocrine interactions: adrenal steroids and precursors.

Adult male rats (n = 48) were castrated and treated daily for 4 wk with adrenal steroids in the presence or absence of adjuvant testosterone. Dehydroepiandrosterone (DHEA), DHEA sulfate, and androstenedione (2 mg/kg body wt) were administered as cyclodextrin complexes to mimic the pharmacodynamics of the endogenous products. Although they are the substrates for testosterone synthesis in target tissues, supplements of adrenal steroids alone were unable to maintain integrity of sociosexual responses and androgen target tissues after castration. More surprising, groups administered adrenal precursor plus testosterone showed substantial suppression of the typical restoration of reproductive systems in castrates receiving androgen therapy. The adrenal steroids, however, were not functionally identical. Each steroid interacted with testosterone to leave its own distinctive "footprint" on androgen-sensitive systems. The conclusion is that the endogenous adrenal products are not simply passive precursors of testosterone. Adrenal steroids may serve as endocrine regulators of androgen bioavailability and bioactivity.

Chronic corticosterone treatment impairs spontaneous alternation behavior in rats.

The present study used behavioral and morphological measures to assess hippocampal integrity in adult male rats after 8 weeks of daily corticosterone (10 mg/kg) injections. Behavioral testing during the final week of treatment revealed that spontaneous alternation behavior, a behavioral marker of hippocampal damage, was reduced in experimental animals without influencing exploration. Physiological assessment indicated that steroid exposure produced functional changes characteristic of prolonged exposure to stress or elevated plasma corticosterone, i.e., lower body weight and thymic involution. However, hippocampal cell loss was not observed in experimental rats. The data suggest that prolonged elevation of plasma corticosterone may significantly disrupt a hippocampal-sensitive behavior without producing gross morphological changes.

Steroidal interactions in the ageing endocrine system: absence of suppression and pathology in reproductive systems of old males from a mixed-sex socially stressful rat colony.

A paradigm using chronic social stress and multiple measures of the reproductive system were used to assess changes with ageing in the dynamics of endogenous steroid interactions. The 22- to 24-month-old male rats lived for 8 weeks in one of four types of colony, in groups of the same sex or groups of mixed sex including familiar or unfamiliar old males. Measures of endocrinology (circulating steroid levels), behaviour (exploration and sociosexual responses), physiology (body and organ weights and epididymal sperm count) and histology (adrenal and ventral prostate glands) served as markers of activation of the hypothalamic-pituitary-adrenal (HPA) or hypothalamic-pituitary-testicular (HPT) axes. Old males living under stable conditions as familiar same-sex colonies served as the comparison group. Results indicated clear chronic activation of the HPA axis in the unfamiliar all-male colonies and of the HPT axis in the familiar males from mixed-sex colonies, whereas both steroidal axes were stimulated in colonies of unfamiliar males and females. Findings from aged males under chronic stress suggested that reproductive dysfunction may be limited to situations in which activation of the HPA axis occurs without concurrent stimulation of the HPT axis. Data on steroidal interactions from mixed-sex groups suggested that (1) chronic excitation of the HPA failed to suppress function in the reproductive system of the old males, (2) their stress responses were little affected by chronic HPT activation and (3) there was no evidence for stress-induced pathology, even in the vulnerable prostate gland.(ABSTRACT TRUNCATED AT 250 WORDS)

Systemic NMDA treatment increases plasma ACTH in the neonatal female and male rat.

The present study was designed to examine the adrenocorticotropic hormone (ACTH) response to N-methyl-D-aspartate (NMDA) in neonatal rats. Subcutaneous injection of NMDA (30 mg/kg) was found to increase plasma ACTH concentrations two-fold after 15 min in 9-10 and 20-21 day-old female and male rats. Pretreatment with the competitive NMDA receptor antagonist CPP (10 mg/kg) failed to attenuate the ACTH response to NMDA in the younger rats, yet reduced the response in older ones. These findings indicate that NMDA can elevate plasma ACTH in both female and male neonatal rats, however this response is not sensitive to CPP antagonism until the end of the neonatal period.

Architectural and Mechanical Properties of the Black Coral Skeleton (Coelenterata: Antipatharia): A Comparison of Two Species.

Black coral skeletons are laminated composites, composed primarily of chitin fibrils and non-fibrillar protein. This paper examines mechanical properties of the composite and the architecture of the chitin component. Two species are shown to differ significantly in their tensile strength and fibril structure. The skeleton of Antipathes salix, a Caribbean species of commercial value, is stiffer, harder, darker, more dense, and more hydrophobic than Antipathes fiordensis from New Zealand. The chitin fibrils constitute a greater proportion of the skeleton in A. salix, where they are helically wound in an anticlockwise pattern within layer. Adjacent layers of skeleton are arranged with relatively small layer-to-layer fibril biases. There is no evidence of "helicoidal" structure in this skeleton. The fibrils in A. fiordensis are also wound anticlockwise within layer, but with rather large fibril biases between layers, giving the appearance of a meshwork. Large-scale helicoidal patterns with apparent rotations of 180{deg} characterize this material. Skeletal architecture is compared with the cuticle of insects and other arthropods. The skeletons of both species exhibit spines characteristic of the Antipatharia. We suggest that these have a significant reinforcing effect on the strength of the skeleton, contributing to an overdesign for the habitat in which these organisms presently occur.

Search for a male contraceptive: the effect of gossypol on sexual motivation and epididymal sperm.

Studies of men and animal models have reported informally that gossypol reduces fertility without behavioral disruptions. In the present research, we used an animal model and quantitative psychobiologic methods to examine the capacity of gossypol to suppress sperm reserves and to maintain both libido and performance. Sexually experienced male rats were exposed for 11 weeks to either 5, 10 or 20 mg gossypol/kg body weight, values representing the moderate to threshold dosages for induction of sterility. Behavioral changes over weeks of administration and reproductive physiology at necropsy were measured. Results showed that the expected dose-response reduction in gamete quantity and quality was accompanied by reductions in reproductive organ weights and copulatory performance, but the reductions were modest and principally with the higher dosages. On the other hand, there was the suggestion of a dose-response suppression of motivation, or interest in seeking and maintaining contact with a receptive female. Indeed, the characteristic pattern of a progressive loss of sperm motility and numbers with dose and time of exposure to gossypol closely paralleled the pattern of behavioral decrements. Implications of the data are that: 1.) gossypol may induce sterility in males at the expense of loss of motivation, and 2.) sexual performance and libido can vary in dependently. Future assessments of a substance under consideration as a contraceptive agent should consider quantitative measurement of both components of sexual behavior.

PIP: Researchers from the University of Missouri and the German Cancer Research Center compared sperm characteristics and sexual behavior of 32 150-day old Long Evans male rats who received doses of either 0, 5, 10, or 20 mg gossypol/kg body weight to learn motivation in seeking sexual contact with a receptive female and copulatory effectiveness in relation to epididymal sperm reserves and endocrine target tissues. Females included gonadally intact and ovariectomized rats. Even though none of the male rates experienced azoospermia after 11 weeks of receiving gossypol, significant reductions in sperm concentrations and motility occurred for those receiving 10-20 mg/kg body weight (p.01) indicating possible infertility. No changes in reproductive physiology (weight of sex organs) and sexual performance occurred between the control rats and those receiving 5 mg gossypol, but changes did occur between the control rats and both those receiving 10 and 20 mg gossypol. Sexual motivation fell as the dosage of gossypol increased. In fact, the interaction of amount and duration affected suppression. The gradual suppression of serum testosterone may have been responsible for the decline in libido. These results suggest that gossypol may indeed cause sterility, but also may reduce the libido. In addition, they show that sexual performance and motivation can differ independently.

IV fluids during surgery.

During an attempt to measure renal function during operation in six patients undergoing major abdominal surgery involving intestinal resection and blood loss in excess of 300 ml, it became apparent that the conventional recommendation for i.v. crystalloid fluid of 5-10 ml kg-1 h-1 was not sufficient to maintain cardiovascular stability and urine output, but a volume of 15 ml kg-1 h-1, given to a subsequent six patients, was adequate. Administration of low sodium (glucose) solutions also produced biochemical abnormalities of a severity not documented previously. A survey of the published literature on volumes of crystalloid fluids used supports the contention that, during major surgery, crystalloid requirements may be of the order of 10-15 ml kg-1 h-1 rather than 5-10 ml kg-1 h-1.

Interferons and bone. A comparison of the effects of interferon-alpha and interferon-gamma in cultures of human bone-derived cells and an osteosarcoma cell line.

Recombinant human interferon-alpha 2C and recombinant human interferon-gamma (5-1000 U/ml) inhibit the proliferation of normal human bone-derived cells and a human osteosarcoma cell line. In the bone-derived cells the inhibitory effect of interferon-gamma was significantly greater than that of interferon-alpha, whereas in the osteosarcoma cell line the inhibitory effects of both interferons were quantitatively similar. Interferon-alpha did not affect the alkaline phosphatase activity of either type of cells. In contrast, interferon-gamma affected the activity of the enzyme in both cell types: in the bone-derived cells the effect of interferon-gamma was stimulatory whereas in the osteosarcoma cells the effect was inhibitory. In both cell types interferon-gamma selectively inhibited the incorporation of radiolabelled proline into type I collagen. In the osteosarcoma cells, the effects of both interferons on collagen synthesis were quantitatively similar. In the bone-derived cells, however, interferon-alpha decreased proline incorporation into collagen and non-collagen proteins to a similar extent and thus did not affect collagen synthesis when expressed as a percentage of total protein synthesis. Two-dimensional polyacrylamide gel electrophoresis of the radiolabelled proteins of the cell layer synthesised by both cell types in the presence of either interferon demonstrated that this treatment enhanced or induced the synthesis of a total of 21 individual proteins (19 in bone cells, 14 in osteosarcoma), ranging in apparent molecular mass over 14-87 kDa. The set of proteins induced was different in all four combinations of cells and interferon. A tentative identification of several of the proteins was possible based upon estimation of molecular mass, preferential induction by interferon-alpha or interferon-gamma and differential induction in normal and transformed bone-derived cells. The results of this study demonstrate that interferons have complex effects upon the proliferative and biosynthetic activities of human bone-derived cells and demonstrate significant differences between the responses of normal cells and transformed bone-derived cell line. Further investigations will be required in order to determine whether or not these differences are unique to the osteosarcoma cell line or are a characteristic of the effects of interferons on bone-derived cells in general.