Trajectories of otitis media and association with health determinants among Indigenous children in Australia: the Longitudinal Study of Indigenous Children.

OBJECTIVES: Indigenous children in Australia experience high burden of persistent otitis media (OM) from very early age. The aim was to identify distinct trajectories of OM in children up to age 10-12 years and examine the association with socio-economic determinants. STUDY DESIGN: A multistage clustered national panel survey. METHODS: The study analysed the birth cohort of the Longitudinal Study of Indigenous Children from 2008 to 2018, comprising 11 study waves. Group-based trajectory modelling was used to identify different trajectories of OM outcome. Multinomial logistic regression was applied to examine the relationship between trajectories and individual, household and community-level socio-economic determinants. RESULTS: This analysis included 894 children with at least three responses on OM over the 11 waves, and the baseline mean age was 15.8 months. Three different trajectories of OM were identified: non-severe OM prone, early/persistent severe OM and late-onset severe OM. Overall, 11.4% of the children had early/persistent severe OM from birth to 7.5 to nine years, while late-onset severe OM consisted of 9.8% of the children who had first OM from age 3.5 to five years. Children in communities with middle and the highest socio-economic outcomes have lower relative risk of early/persistent severe OM (adjusted relative risk ratio = 0.39, 95% confidence interval = 0.22-0.70 and adjusted relative risk ratio = 0.22, 95% confidence interval = 0.09-0.52, respectively) compared to children in communities with lowest socio-economic outcomes. CONCLUSION: Efforts to close the gap in the quality of life of Indigenous children must prioritise strategies that prevent severe ear disease (runny ears and perforation), including improved healthcare access, reduced household crowding, and better education, and more employment opportunities.

Arterial Spin-Labeling Perfusion Metrics in Pediatric Posterior Fossa Tumor Surgery.

BACKGROUND AND PURPOSE: Pediatric posterior fossa tumors often present with hydrocephalus; postoperatively, up to 25% of patients develop cerebellar mutism syndrome. Arterial spin-labeling is a noninvasive means of quantifying CBF and bolus arrival time. The aim of this study was to investigate how changes in perfusion metrics in children with posterior fossa tumors are modulated by cerebellar mutism syndrome and hydrocephalus requiring pre-resection CSF diversion. MATERIALS AND METHODS: Forty-four patients were prospectively scanned at 3 time points (preoperatively, postoperatively, and at 3-month follow-up) with single- and multi-inflow time arterial spin-labeling sequences. Regional analyses of CBF and bolus arrival time were conducted using coregistered anatomic parcellations. ANOVA and multivariable, linear mixed-effects modeling analysis approaches were used. The study was registered at clinicaltrials.gov (NCT03471026). RESULTS: CBF increased after tumor resection and at follow-up scanning (P = .045). Bolus arrival time decreased after tumor resection and at follow-up scanning (P = .018). Bolus arrival time was prolonged (P = .058) following the midline approach, compared with cerebellar hemispheric surgical approaches to posterior fossa tumors. Multivariable linear mixed-effects modeling showed that regional perfusion changes were more pronounced in the 6 children who presented with symptomatic obstructive hydrocephalus requiring pre-resection CSF diversion, with hydrocephalus lowering the baseline mean CBF by 20.5 (standard error, 6.27) mL/100g/min. Children diagnosed with cerebellar mutism syndrome (8/44, 18.2%) had significantly higher CBF at follow-up imaging than those who were not (P = .040), but no differences in pre- or postoperative perfusion parameters were seen. CONCLUSIONS: Multi-inflow time arterial spin-labeling shows promise as a noninvasive tool to evaluate cerebral perfusion in the setting of pediatric obstructive hydrocephalus and demonstrates increased CBF following resolution of cerebellar mutism syndrome.

Serological responses to Anthrax Vaccine Precipitated (AVP) increase with time interval between booster doses.

We undertook a Phase 4 clinical trial to assess the effect of time interval between booster doses on serological responses to AVP. The primary objective was to evaluate responses to a single booster dose in two groups of healthy adults who had previously received a complete 4-dose primary course. Group A had received doses on schedule while Group B had not had one for ≥2 years. Secondary objectives were to evaluate the safety and tolerability of AVP booster doses, and to gain information on correlates of protection to aid future anthrax vaccine development. Blood samples were taken on Day 1 before dosing, and on Days 8, 15, 29 and 120, to measure Toxin Neutralisation Assay (TNA) NF50 values and concentrations of IgG antibodies against Protective Antigen (PA), Lethal Factor (LF) and Edema Factor (EF) by ELISA. For each serological parameter, fold changes from baseline following the trial AVP dose were greater in Group B than Group A at every time-point studied. Peak responses correlated positively with time since last AVP dose (highest values being observed after intervals of ≥10 years), and negatively with number of previous doses (highest values occurring in individuals who had received a primary course only). In 2017, having reviewed these results, the Joint Committee on Vaccination and Immunisation (JCVI) updated UK anthrax vaccination guidelines, extending the interval between routine AVP boosters from one to 10 years. Booster doses of AVP induce significant IgG responses against the three anthrax toxin components, particularly PA and LF. Similarly high responses were observed in TNA, a recognised surrogate for anthrax vaccine efficacy. Analysis of the 596 TNA results showed that anti-PA and anti-LF IgG make substantial independent contributions to neutralisation of anthrax lethal toxin. AVP may therefore have advantages over anthrax vaccines that depend on generating immunity to PA alone.

Yeast carboxypeptidase Y can be translocated and glycosylated without its amino-terminal signal sequence.

We have constructed a series of mutations in the signal sequence of the yeast vacuolar protein carboxypeptidase Y (CPY), and have used pulse-chase radiolabeling and immunoprecipitation to examine the in vivo effects of these mutations on the entry of the mutant CPY proteins into the secretory pathway. We find that introduction of a negatively charged residue, aspartate, into the hydrophobic core of the signal sequence has no apparent effect on signal sequence function. In contrast, internal in-frame deletions within the signal sequence cause CPY to be synthesized as unglycosylated precursors. These are slowly and inefficiently converted to glycosylated precursors that are indistinguishable from the glycosylated forms produced from the wild-type gene. These precursors are converted to active CPY in a PEP4-dependent manner, indicating that they are correctly localized to the vacuole. Surprisingly, a deletion mutation that removes the entire CPY signal sequence has a similar effect: unglycosylated precursor accumulates in cells carrying this mutant gene, and greater than 10% of it is posttranslationally glycosylated. Thus, the amino-terminal signal sequence of CPY, while important for translocation efficiency, is not absolutely required for the translocation of this protein.

Biogenesis of porin of the outer mitochondrial membrane involves an import pathway via receptors and the general import pore of the TOM complex.

Porin, also termed the voltage-dependent anion channel, is the most abundant protein of the mitochondrial outer membrane. The process of import and assembly of the protein is known to be dependent on the surface receptor Tom20, but the requirement for other mitochondrial proteins remains controversial. We have used mitochondria from Neurospora crassa and Saccharomyces cerevisiae to analyze the import pathway of porin. Import of porin into isolated mitochondria in which the outer membrane has been opened is inhibited despite similar levels of Tom20 as in intact mitochondria. A matrix-destined precursor and the porin precursor compete for the same translocation sites in both normal mitochondria and mitochondria whose surface receptors have been removed, suggesting that both precursors utilize the general import pore. Using an assay established to monitor the assembly of in vitro-imported porin into preexisting porin complexes we have shown that besides Tom20, the biogenesis of porin depends on the central receptor Tom22, as well as Tom5 and Tom7 of the general import pore complex (translocase of the outer mitochondrial membrane [TOM] core complex). The characterization of two new mutant alleles of the essential pore protein Tom40 demonstrates that the import of porin also requires a functional Tom40. Moreover, the porin precursor can be cross-linked to Tom20, Tom22, and Tom40 on its import pathway. We conclude that import of porin does not proceed through the action of Tom20 alone, but requires an intact outer membrane and involves at least four more subunits of the TOM machinery, including the general import pore.

Selectivity changes in site-directed mutants of the VDAC ion channel: structural implications.

The gene encoding the yeast mitochondrial outer membrane channel VDAC was subjected to site-directed mutagenesis to change amino acids at 29 positions to residues differing in charge from the wild-type sequence. The mutant genes were then expressed in yeast, and the physiological consequences of single and multiple amino acid changes were assessed after isolation and insertion of mutant channels into phospholipid bilayers. Selectivity changes were observed at 14 sites distributed throughout the length of the molecule. These sites are likely to define the position of the protein walls lining the aqueous pore and hence, the transmembrane segments. These results have been used to develop a model of the open state of the channel in which each polypeptide contributes 12 beta strands and one alpha helix to form the aqueous transmembrane pathway.

Multicopy suppressors of phenotypes resulting from the absence of yeast VDAC encode a VDAC-like protein.

The permeability of the outer mitochondrial membrane to most metabolites is believed to be based in an outer membrane, channel-forming protein known as VDAC (voltage-dependent anion channel). Although multiple isoforms of VDAC have been identified in multicellular organisms, the yeast Saccharomyces cerevisiae has been thought to contain a single VDAC gene, designated POR1. However, cells missing the POR1 gene (delta por1) were able to grow on yeast media containing a nonfermentable carbon source (glycerol) but not on such media at elevated temperature (37 degrees C). If VDAC normally provides the pathway for metabolites to pass through the outer membrane, some other protein(s) must be able to partially substitute for that function. To identify proteins that could functionally substitute for POR1, we have screened a yeast genomic library for genes which, when overexpressed, can correct the growth defect of delta por1 yeast grown on glycerol at 37 degrees C. This screen identified a second yeast VDAC gene, POR2, encoding a protein (YVDAC2) with 49% amino acid sequence identity to the previously identified yeast VDAC protein (YVDAC1). YVDAC2 can functionally complement defects present in delta por1 strains only when it is overexpressed. Deletion of the POR2 gene alone had no detectable phenotype, while yeasts with deletions of both the POR1 and POR2 genes were viable and able to grow on glycerol at 30 degrees C, albeit more slowly than delta por1 single mutants. Like delta por1 single mutants, they could not grow on glycerol at 37 degrees C. Subcellular fractionation studies with antibodies which distinguish YVDAC1 and YVDAC2 indicate that YVDAC2 is normally present in the outer mitochondrial membrane. However, no YVDAC2 channels were detected electrophysiologically in reconstituted systems. Therefore, mitochondrial membranes made from wild-type cells, delta por1 cells, delta por1 delta por2 cells, and delta por1 cells overexpressing YVDAC2 were incorporated into liposomes and the permeability of resulting liposomes to nonelectrolytes of different sizes was determined. The results indicate that YVDAC2 does not confer any additional permeability to these liposomes, suggesting that it may not normally form a channel. In contrast, when the VDAC gene from Drosophila melanogaster was expressed in delta por1 yeast cells, VDAC-like channels could be detected in the mitochondria by both bilayer and liposome techniques, yet the cells failed to grow on glycerol at 37 degrees C. Thus, channel-forming activity does not seem to be either necessary or sufficient to restore growth on nonfermentable carbon sources, indicating that VDAC mediates cellular functions that do not depend on the ability to form channels.

Biochemical and genetic analysis of the mitochondrial response of yeast to BAX and BCL-X(L).

The BCL-2 family includes both proapoptotic (e.g., BAX and BAK) and antiapoptotic (e.g., BCL-2 and BCL-X(L)) molecules. The cell death-regulating activity of BCL-2 members appears to depend on their ability to modulate mitochondrial function, which may include regulation of the mitochondrial permeability transition pore (PTP). We examined the function of BAX and BCL-X(L) using genetic and biochemical approaches in budding yeast because studies with yeast suggest that BCL-2 family members act upon highly conserved mitochondrial components. In this study we found that in wild-type yeast, BAX induced hyperpolarization of mitochondria, production of reactive oxygen species, growth arrest, and cell death; however, cytochrome c was not released detectably despite the induction of mitochondrial dysfunction. Coexpression of BCL-X(L) prevented all BAX-mediated responses. We also assessed the function of BCL-X(L) and BAX in the same strain of Saccharomyces cerevisiae with deletions of selected mitochondrial proteins that have been implicated in the function of BCL-2 family members. BAX-induced growth arrest was independent of the tested mitochondrial components, including voltage-dependent anion channel (VDAC), the catalytic beta subunit or the delta subunit of the F(0)F(1)-ATP synthase, mitochondrial cyclophilin, cytochrome c, and proteins encoded by the mitochondrial genome as revealed by [rho(0)] cells. In contrast, actual cell killing was dependent upon select mitochondrial components including the beta subunit of ATP synthase and mitochondrial genome-encoded proteins but not VDAC. The BCL-X(L) protection from either BAX-induced growth arrest or cell killing proved to be independent of mitochondrial components. Thus, BAX induces two cellular processes in yeast which can each be abrogated by BCL-X(L): cell arrest, which does not require aspects of mitochondrial biochemistry, and cell killing, which does.

Cloning and molecular characterization of a voltage-dependent anion-selective channel (VDAC) from Drosophila melanogaster.

A full length voltage-dependent anion-selective channel (VDAC) cDNA was cloned from Drosophila melanogaster by expression library screening using an antibody against an insect VDAC protein. The cDNA clone (denoted DmVDAC) is 1082 base pairs (bp) in length and contains an open reading frame (bp 62-907) encoding a 282 amino acid protein which has a predicted molecular mass of 30550 Da, a predicted pI of 6.98 and no cysteines. Hydrophobicity analysis suggests 15 or 16 membrane-spanning domains. The DmVDAC amino acid sequence has variable homology with VDACs from other species ranging from 62% identity with a human VDAC to 23% identity with a Dictyostelium discoideum VDAC. DmVDAC has 92% identity with the 38 conserved residues in a VDAC consensus sequence. DmVDAC was expressed in VDAC-null yeast but failed to rescue viability. DmVDAC has 88% identity at the amino acid level and 99% identity at the nucleic acid level with a recently reported D. melanogaster VDAC sequence (A. Messina et al., FEBS Lett. 384 (1996) 9-13). Homology analyses with the Messina and other VDAC sequences indicate that the amino acid differences are due to minor errors in the Messina sequence. Southern blots and chromosomal in situ hybridizations suggest a single VDAC gene occurs in the fly with a locus at 32B on the left arm of the second chromosome.

The molecular genetics of retinoic acid receptors: cardiovascular and limb development.

The vitamin A metabolite retinoic acid (RA) is utilized as a signalling molecule in wide variety of developmental processes, defined by defects which occur after nutritional vitamin A deficiency or after exposure to excess vitamin A. We have initiated a genetic analysis of RA function through the establishment of lines of mice which carry germline mutations in the genes which encode retinoid receptors. Defects which result from developmental RA deficiency or excess have been recovered in embryos which are deficient in various combinations of retinoid receptors. In this chapter, our current understanding of the role of RA and retinoid receptors in cardiovascular and limb development are described, as for these our level of understanding is most advanced.

Laboratory and clinical features of self-poisoning with salbutamol and terbutaline.

A method has been developed for the simultaneous determination of the sympathomimetic drugs salbutamol and terbutaline in the plasma of poisoned patients, using ion-pair high-performance liquid chromatography with amperometric detection. Plasma concentrations of the drugs, measured in 8 poisoned patients, were well above the therapeutic range. The clinical and metabolic effects of overdose with these drugs were considerably less severe than those seen in patients with plasma theophylline concentrations elevated to the same degree.

Plasma glutathione S-transferase measurements by radioimmunoassay: a sensitive index of hepatocellular damage in man.

Plasma glutathione S-transferase (GST) basic and N/A2b concentrations have been measured by specific radioimmunoassay in serial samples taken from patients admitted following a paracetamol overdose. The activity of alanine aminotransferase (ALT) and aspartate aminotransferase (AST) were also measured. The sensitivities of the various measurements for detecting hepatocellular damage were compared. The measurement of either basic or N/A2b GST proved equally sensitive for detecting liver damage and both were superior to aminotransferase measurements. The abnormalities in GST were, on average, approximately 5- to 10-fold greater than the conventional aminotransferase measurements provided that correct timing of sampling was employed. The data presented suggest GST measurement is a sensitive non-invasive method for investigating acute drug-induced hepatotoxicity. The short plasma half-life of GST also allows early recognition of when active cellular damage has ceased.

Competitive behavior in male rats: aggression and success enhanced by medial hypothalamic lesions as well as by testosterone implants.

Castrated male hooded rats were given electrolytic lesions of the medial hypothalamus or sham lesions. Another group of castrated rats was implanted subcutaneously with bilateral testosterone-filled Silastic capsules or empty capsules. Lesioned animals with a high defensiveness (reactivity) score toward the experimenter were each placed in a cage with a sham-lesioned animal of a similar weight. Animals with testosterone implants were likewise housed with an animal of similar weight without a testosterone implant. Following a period of adaptation to a 23-hr water deprivation schedule, each pair of rats was given daily competition tests on each of 6 days. During the tests, a single water spout was placed in the cage for a 4-min period. The spout was surrounded by a plastic ring which prevented more than one animal from drinking at any time. Access to an unencumbered water spout was present following the competition test for 1-hr each day. Rats with medial hypothalamic lesions displayed more aggression than sham-lesioned rats during the competition tests and were able to spend more time drinking. Rats with testosterone implants were more successful in maintaining access to the spout but did not consistently display more aggression than their cagemates without testosterone implants. The aggression of the lesioned rats was defensive while that of animals with testosterone implants corresponded to intermale social aggression. These results demonstrate that a competitive situation can elicit intermale social aggression mediated by testosterone and defensiveness induced by medial hypothalamic lesions.

Defensive aggression and testosterone-dependent intermale social aggression are each elicited by food competition.

Castrated rats with medial hypothalamic lesions or sham lesions and castrated rats with testosterone implants or sham implants were placed on a 23-hr food deprivation schedule, adapted to a highly palatable liquid food, and then housed in pairs. The pairs were observed in competition for the highly palatable food over a 4-min period on each of six days. On the first three days, the food was dispensed in a way that allowed only one animal at a time to drink while during the second three days both animals could drink simultaneously. The pairs of animals were then separated, individually adapted to a bland liquid food, and paired with a different animal for a second series of competition tests. With highly palatable food as the incentive, rats made hyperdefensive by medical hypothalamic lesions were more successful at maintaining access to the food and more aggressive than their sham-lesioned competitors on tests when food access was restricted to a single animal but not on tests when both animals could drink simultaneously. With bland food as the incentive, lesioned animals were not consistently more successful in maintaining access to the food but were significantly more aggressive than their cagemates. With the highly palatable food, castrated males with testosterone implants were neither more successful in maintaining access to the food nor more aggressive than their cagemates with sham implants. However, when paired with an unfamiliar cagemate in preparation for competition tests with the bland food, most rats with testosterone implants attacked the new cagemate using a lateral attack and displaying piloerection.(ABSTRACT TRUNCATED AT 250 WORDS)

Competitive behavior: intact male rats but not hyperdefensive males with medial hypothalamic lesions share water with females.

Male hooded rats with medial hypothalamic lesions or sham lesions were given tests of defensiveness toward an experimenter. The 8 lesioned males with the highest defensiveness scores and 7 sham-lesioned males were each placed in a double cage with a single intact female. For each pair of rats, food was continuously present but water was available for only 1 hr/day through a single water spout. Beginning on the fifth day of water deprivation, each pair of animals was given a 4-min water competition test on 3 consecutive days. Competition for water was created by placing a plastic ring over the hole in the cage where the water spout entered the cage. The ring restricted access to the spout to a single animal and was put in place 5 min before water was given. One hr following the competition test, each pair of animals was given access to a single unencumbered spout for a 1-hr period. Rats with medial hypothalamic lesions drank significantly more and initiated more aggression than their female cagemates during the 4-min competition tests. Sham-lesioned rats neither drank significantly more nor were more aggressive than their female cagemates. These results are consistent with previous observations indicating that the aggressiveness of rats with medial hypothalamic lesions can be elicited by a competition situation.

Defensive aggression toward an experimenter: no differences between males and females following septal, medial accumbens, or medial hypothalamic lesions in rats.

Septal, medial accumbens, medial hypothalamic, or sham lesions were each made in female and male hooded rats. Behavioral testing of defensiveness toward the experimenter was done blind at 6, 9, and 12 days postoperatively by a person who was unaware of the purpose of the experiment. There were no quantitative differences in the defensiveness displayed by male and female rats: both sexes displayed the increase in defensiveness characteristic of each lesion. It is argued that the neural systems modulating defensiveness may be similar in male and female rats and that this is related to evidence from human experiments indicating that comparable levels of defensive aggression are emitted by males and females under controlled experimental conditions.

Intermale social aggression: reinstatement in castrated rats by implants of testosterone propionate in the medial hypothalamus.

Male hooded rats were castrated, subcutaneously implanted with testosterone-filled silastic tubes, and individually housed with an intact adult female rat. An unfamiliar male intruder was introduced into each colony on a weekly basis and the aggressive behavior of the resident male was recorded. When the intermale social aggressive behavior of the resident male toward the intruder reached a high level in terms of a composite aggression score, the subcutaneous testosterone tubes were removed. Weekly tests of aggression toward unfamiliar intruders continued until the aggression of the resident male dropped to a low level for two successive weeks in terms of our composite aggression score. Bilateral implants of pellets of testosterone propionate were then made into the medial hypothalamus or adjacent tissue. A control group was implanted with cholesterol pellets into the medial hypothalamus. During four weekly tests following the implant, rats with testosterone propionate implants in the medial hypothalamus showed increases in lateral attacks, lateral attack duration, bites, and piloerection. The increase in aggression was not consistently displayed by animals with testosterone propionate implants dorsal or anterior to the medial hypothalamus or by animals with cholesterol implants in the medial hypothalamus. These results suggest that the medial hypothalamus or closely adjacent tissue contains testosterone-sensitive neural circuitry modulating intermale social aggression.

Intermale social aggression in rats: suppression by medial hypothalamic lesions independently of enhanced defensiveness or decreased testicular testosterone.

Medial hypothalamic lesions or sham lesions were made in castrated adult male rats with subcutaneous implants of testosterone-filled silastic capsules. Seven days following surgery all animals were given a test of defensiveness (reactivity) toward an experimenter. The following day, groups composed of one lesioned male rat, one sham-lesioned male rat, and one intact female rat were placed in large cages. Beginning two weeks later, unfamiliar intruders were introduced into each colony on a weekly basis and the aggressive behavior of the residents recorded. All 12 of the sham-lesioned animals but only 2 of 12 lesioned animals displayed substantial intermale social aggression toward intruders. Analysis of individual elements of intermale social aggression indicated that the lesioned animals were deficient in attack, bite, and piloerection but not in on-top behavior. The deficit in intermale social aggression was not correlated with defensiveness toward the experimenter or body weight of the lesioned animals. It is argued that the medial hypothalamus plays a role in the modulation of intermale social aggression which is independent of its role in modulating defensiveness or testosterone production. These results also demonstrate that intermale social aggression develops even when testosterone levels are held relatively constant by replacing testicular testosterone with an artificial testosterone source.

Cohabitation with a female activates testosterone-dependent social aggression in male rats independently of changes in serum testosterone concentration.

Male hooded rats (350 to 450 g) were sham-castrated, castrated and implanted with testosterone-filled, or castrated and implanted with empty Silastic tubes. Twenty-four hours postoperatively the animals in each group were housed with a female or a male similar in size to the female. Beginning one week following surgery and continuing for three weeks thereafter, the female or male cagemate was removed once each week while a 15-min test of aggression toward an unfamiliar male intruder was conducted. During the aggression tests, lateral attacks, lunge attacks, bites, on-top, and piloerection were recorded. At the first aggression test, males housed with females were significantly more aggressive than their counterparts housed with males. In contrast, different testosterone regimes did not consistently influence the initial activation of intermale social aggression. At the second and third tests, males with testicular testosterone or a replacement were significantly more aggressive than their castrated controls on most measures but males housed with females continued to be more aggressive than the comparable group housed with males. These results suggest that normal fluctuations in serum testosterone concentration associated with sexual interaction are not necessary for the initial activation of intermale social aggression. Both repeated exposure to unfamiliar males as well as cohabitation with a female are effective stimuli for activation of testosterone-dependent social aggression.

Activation of aggression in female rats by normal males and by castrated males with testosterone implants.

Female hooded rats were continuously housed with an intact male, a castrated male with subcutaneous testosterone implants, or two other females. At weekly intervals over a 10-week period, the cagemate(s) and pups were removed and aggression by the female toward an unfamiliar female intruder was observed over a 15-min period. On the 11th week each female was subjected to this intruder test in an unfamiliar cage. On the 12th week, a final test was conducted in each female's living cage with a male rather than a female as the intruder. The aggressive behaviors recorded were attacks, bites, on-top, and piloerection. Females housed with normal males displayed a significant increase in aggression prior to parturition. Their aggressiveness persisted through the 10th test with peaks at parturition and the start of lactation. Females housed with castrated males also displayed significant increases in aggression but without the peaks associated with parturition and lactation. Their aggressiveness also persisted throughout the test period. Females housed with other females showed a small increase in aggression over weeks. All groups showed virtually no aggression in the unfamiliar cage. All females displayed some aggression toward a male intruder but the level of aggression was highest in maternal females. The results demonstrate that aggression qualitatively similar to that displayed following parturition and during lactation can be elicited in nulliparous females.