Journal of acquired immune deficiency syndromes (1999), Jan 15, 2015
This review assesses the impact of prevention interventions for people living with HIV on HIV-rel... more This review assesses the impact of prevention interventions for people living with HIV on HIV-related mortality, morbidity, retention in care, quality of life, and prevention of ongoing HIV transmission in resource-limited settings (RLSs). We conducted a systematic review of studies reporting the results of prevention interventions for people living with HIV in RLS published between January 2000 and August 2014. Standardized methods of searching and data abstraction were used. Ninety-two studies met the eligibility criteria: 24 articles related to adherence counseling and support, 13 on risk reduction education and condom provision, 19 on partner HIV testing and counseling, 14 on provision of family planning services, and 22 on assessment and treatment of other sexually transmitted infections. Findings indicate good evidence that adherence counseling and sexually transmitted infection treatment can have a high impact on morbidity, whereas risk reduction education, partner HIV testin...
Lactating (L) mice display fierce aggression towards novel, male mice, while virgin (V) mice do n... more Lactating (L) mice display fierce aggression towards novel, male mice, while virgin (V) mice do not. This study compares patterns of brain activation in V and L mice in response to a novel intruder using immunohistochemical detection of Fos (Fos-IR). Animals were sampled 120 min after either a sham or real 10 min test with a male intruder. L mice were aggressive towards intruders, but V mice were not. In general, Fos-IR for both groups increased with exposure to an intruder, with L mice showing higher increases in Fos-IR than V mice. In only medial preoptic nucleus and ventral portion of bed nucleus of stria terminalis (BNST) was Fos-IR significantly increased in both groups with testing. In V mice, testing resulted in Fos-IR increases in an additional 10 regions examined that did not reach significance in L mice, including lateral septum, lateral and medial preoptic areas, and anterior hypothalamus. Fos-IR also increased with testing in nine regions unique to L mice, including the ...
We have entered a new era in HIV prevention whereby priorities have expanded from biomedical disc... more We have entered a new era in HIV prevention whereby priorities have expanded from biomedical discovery to include implementation, effectiveness, and the effect of combination prevention at the population level. However, gaps in knowledge and implementation challenges remain. In this Review we analyse trends in the rapidly changing landscape of HIV prevention, and chart a new path for HIV prevention research that focuses on the implementation of effective and efficient combination prevention strategies to turn the tide on the HIV pandemic.
Predatory (towards crickets), intermale, and maternal aggression were examined in four replicate ... more Predatory (towards crickets), intermale, and maternal aggression were examined in four replicate lines of mice that had been selectively bred for high wheel-running (S) and in four random-bred control lines (C). In generation 18, individual differences in both predatory and intermale aggression were significantly consistent across four trial days, but predatory and intermale aggression were uncorrelated both at the individual level and among the eight line means. Latencies to attack crickets were significantly lower in S lines as a group. Intermale aggression, however, did not differ between S and C lines. S lines were significantly smaller in body mass, but did not differ in either testes mass or plasma testosterone. In generations 28 and 30, respectively, S and C lines did not differ in either maternal or intermale aggression. However, significant differences among the individual lines were found for maternal aggression, and one S line exhibited an extremely high mean time of aggression (Ͼ120 sec for a 5-min test). Maternal and intermale aggression were not correlated among the eight line means or at the level of individual variation. Overall, our results suggest: (1) predatory aggression and voluntary wheel-running are positively related at the genetic level; (2) predatory and intermale aggression are unrelated at a genetic level; and (3) maternal and intermale aggression are not tightly related at the genetic level. Possible relationships between predatory aggression, dopamine, and wheel-running behavior are discussed.
Chronic stress is associated with more rapid tumor progression, and recent evidence suggests that... more Chronic stress is associated with more rapid tumor progression, and recent evidence suggests that stress may contribute to social and ethnic disparities in the incidence and mortality of breast cancer. We evaluated the p53 +/-FVB/N mouse as a model to investigate effects of chronic social stress on mammary gland development, gene expression and tumorigenesis. We individually housed (IH) wild type and p53 +/female FVB/N mice, starting at weaning. At 14 weeks of age, both wild type and p53 +/-IH mice showed strikingly reduced mammary development compared to group-housed (GH) controls, with IH mice having significantly fewer pre-terminal end buds. This morphological difference was not reflected in levels of mammary transcripts for estrogen receptor alpha or progestin receptor. However, IH increased levels of mRNA for the kisspeptin receptor in the medial preoptic area of the hypothalamus, associated with reduced duration of estrous cycles. Further, IH altered mammary transcripts of genes associated with DNA methylation; transcripts for methyl binding protein 2 and DNA methyltransferase (DNMT) 3b, but not DNMT 1 and DNMT3a, were reduced in IH, compared to GH females. Interestingly, glands of p53 +/females displayed reduced expression of all these mediators, compared to wildtype females. However, contrary to our initial hypothesis, IH did not increase mammary tumorigenesis. Rather, p53 +/-GH females developed significantly more mammary tumors than IH mice. Together, these data suggest that social isolation initiated at puberty may confound studies of tumorigenesis by altering mammary development in mouse models.
Lactating mice display fierce aggression towards novel, male mice. This study compares neuronal a... more Lactating mice display fierce aggression towards novel, male mice. This study compares neuronal activity in the brains of aggression-tested (T) and -untested (U) mice using early growth response factor 1 (Egr-1; also known as Krox 24, NGFI-A, Zif268, Tis8, and ZENK) as a measure of neuronal activity. Animals were sampled 90 min after either a sham or real 7-min test with a male intruder, after which their brains were examined for immunoreactivity to Egr-1 (Egr-IR). Significant increases in Egr-IR in T mice were identified in 11 of 40 brain regions, including paraventricular nucleus of the hypothalamus; anterior and lateral hypothalamus (both posterior portion); ventromedial hypothalamus; lateral periaqueductal gray; and medial, central, and basolateral amygdala. Posterodorsal (MePD) and posteroventral medial amygdala were examined for the first time in association with maternal aggression. MePD, a region associated with both sexual and aggressive behaviors in rats, hamsters, and mice, showed increased Egr-IR in association with testing. Taken together, the results from this study provide new insights into the neural circuits regulating maternal behaviors.
The trpc2 gene encodes an ion channel involved in pheromonal detection and is found in the vomero... more The trpc2 gene encodes an ion channel involved in pheromonal detection and is found in the vomeronasal organ. In tprc2 -/knockout (KO) mice, maternal aggression (offspring protection) is impaired and brain Fos expression in females in response to a male are reduced. Here we examine in lactating wild-type (WT) and KO mice behavioral and brain responses to different olfactory/ pheromonal cues. Consistent with previous studies, KO dams exhibited decreased maternal aggression and nest building, but we also identified deficits in nighttime nursing and increases in pup weight. When exposed to the bedding tests, WT dams typically ignored clean bedding, but buried male-soiled bedding from unfamiliar males. In contrast, KO dams buried both clean and soiled bedding. Differences in brain Fos expression were found between WT and KO mice in response to either no bedding, clean bedding, or soiled bedding. In the accessory olfactory bulb, a site of pheromonal signal processing, KO mice showed suppressed Fos activation in the anterior mitral layer relative to WT mice in response to clean and soiled bedding. However, in the medial and basolateral amygdala, KO mice showed a robust Fos response to bedding, suggesting that regions of the amygdala canonically associated with pheromonal sensing can be active in the brains of KO mice, despite compromised signaling from the vomeronasal organ. Together, these results provide further insights into the complex ways by which pheromonal signaling regulates the brain and behavior of the maternal female.
Maternal aggression is a form of aggression towards intruders by lactating females that is critic... more Maternal aggression is a form of aggression towards intruders by lactating females that is critical for defense of offspring. During lactation, fear and anxiety are reduced, the CNS is less responsive to the anxiogenic neuropeptide, corticotropin-releasing factor (CRF), and central injections of CRF inhibit maternal aggression. Together, these previous findings suggest that decreased CRF neurotransmission during lactation supports normal maternal aggression expression. Recent work indicates that mice deficient in CRF receptor 2 (CRFR2) display increased anxiety-like behaviors, have a hypersensitive stress response, and overproduce CRF. In this study, we examined both maternal and intermale aggression in wild-type (WT) and CRFR2-deficient mice. CRFR2-mutant mice exhibited significant deficits in maternal aggression on postpartum Day 4 relative to WT mice in terms of percentage displaying aggression, mean number of attacks, and mean time in aggressive encounters. However, time sniffing male intruder, pup retrieval, number of pups, and performance on the elevated plus maze were similar between genotypes. In contrast, intermale aggression did not differ between genotype in any measure on any of three consecutive test days. For neither form of aggression did sites of attacks on the intruder differ between genotype. Taken together, the results suggest that differences in stress sensitivity and the overproduction of CRF of the knockout (KO) mice specifically affects maternal, but not intermale aggression.
Genomic imprinting represents a mechanism through which parent-of-origin effects on offspring dev... more Genomic imprinting represents a mechanism through which parent-of-origin effects on offspring development may be mediated. However, investigation of the influence of imprinted genes on behavior has been limited. Here the authors investigate the role of the maternally imprinted/paternally expressed gene, Peg3, in several aspects of behavior using both 129Sv-and B6-Peg3 mutant female mice. Virgin Peg3 females on both genetic backgrounds were less exploratory and had higher rates of defecation with strain-dependent effects on activity levels and olfactory discrimination. Reproductive success, pup retrieval, and postnatal maternal care of pups were reduced in these females whereas indices of maternal aggression were higher among B6 Peg3-KO females. Differences in maternal care were apparent in females caring for biological or cross-fostered offspring and deficits in pup retrieval apparent beyond the immediate postpartum period. Oxytocin receptor binding in the MPOA and LS was reduced in Peg3-KO females. Thus, the authors demonstrate that disruptions to Peg3 influences aspects of female behavior that are critical for mediating maternal effects on offspring development, such as postpartum licking/ grooming, and that effects of Peg3 are dependent on the maternal genetic background.
Social learning theory-based models have recently provided the foundation for a series of twelve ... more Social learning theory-based models have recently provided the foundation for a series of twelve controlled human immunodeficiency virus (HIV) risk reduction intervention studies that have examined sexual behavior change. These interventions have been tested with adolescents, gay and bisexual men, inner-city women, college students, and seriously mentally ill adults. We report the first meta-analysis of these intervention studies. We found that, as expected, the mean weighted effect of HIV-risk reduction interventions on behavioral outcomes was positive and strongly significant (d+ = 0.25). Moreover, the studies" effect sizes were consistently positive, ranging from 0.I1 to 0.53, and were largest when the outcomes were measured close in time to the intervention. We discuss other methodological challenges that, if solved, should enhance the success of future HIV-risk reduction interventions.
A dramatic example of neuronal and physiological plasticity in adult mammals occurs during the tr... more A dramatic example of neuronal and physiological plasticity in adult mammals occurs during the transition from a non-maternal to a maternal, lactating state. In this study we compared gene expression within a large continuous region of the CNS involved in maternal behaviors (hypothalamus, preoptic regions, and nucleus accumbens) between lactating (L) (postpartum Day 7) and randomly cycling virgin (V) outbred mice. Using high density oligonucleotide arrays representing 11,904 genes, two statistical algorithms were used to identify significant differences in gene expression: robust multi array (p < 0.001) (n = 92 genes) and significance analysis of microarrays using a 10% false discover rate (n = 114 genes). 27 common genes were identified as significant using both techniques. A subset of genes (n = 5) were selected and examined by real-time PCR. Our findings were consistent with previous published work. For example, neuropeptide Y (NPY) and proenkephalin were elevated in L mice, whereas POMC was decreased. Increased levels of NPY Y2 receptor and polo-like kinase and decreased levels of endothelin receptor type b in L mice are examples of novel gene expression changes not previously identified. Expression differences occurred in broad classes. Together, our findings provide possible new material on gene expression changes that may support maternal behaviors. The advantages and drawbacks of sampling large CNS regions using arrays are discussed.
Journal of acquired immune deficiency syndromes (1999), Jan 15, 2015
This review assesses the impact of prevention interventions for people living with HIV on HIV-rel... more This review assesses the impact of prevention interventions for people living with HIV on HIV-related mortality, morbidity, retention in care, quality of life, and prevention of ongoing HIV transmission in resource-limited settings (RLSs). We conducted a systematic review of studies reporting the results of prevention interventions for people living with HIV in RLS published between January 2000 and August 2014. Standardized methods of searching and data abstraction were used. Ninety-two studies met the eligibility criteria: 24 articles related to adherence counseling and support, 13 on risk reduction education and condom provision, 19 on partner HIV testing and counseling, 14 on provision of family planning services, and 22 on assessment and treatment of other sexually transmitted infections. Findings indicate good evidence that adherence counseling and sexually transmitted infection treatment can have a high impact on morbidity, whereas risk reduction education, partner HIV testin...
Lactating (L) mice display fierce aggression towards novel, male mice, while virgin (V) mice do n... more Lactating (L) mice display fierce aggression towards novel, male mice, while virgin (V) mice do not. This study compares patterns of brain activation in V and L mice in response to a novel intruder using immunohistochemical detection of Fos (Fos-IR). Animals were sampled 120 min after either a sham or real 10 min test with a male intruder. L mice were aggressive towards intruders, but V mice were not. In general, Fos-IR for both groups increased with exposure to an intruder, with L mice showing higher increases in Fos-IR than V mice. In only medial preoptic nucleus and ventral portion of bed nucleus of stria terminalis (BNST) was Fos-IR significantly increased in both groups with testing. In V mice, testing resulted in Fos-IR increases in an additional 10 regions examined that did not reach significance in L mice, including lateral septum, lateral and medial preoptic areas, and anterior hypothalamus. Fos-IR also increased with testing in nine regions unique to L mice, including the ...
We have entered a new era in HIV prevention whereby priorities have expanded from biomedical disc... more We have entered a new era in HIV prevention whereby priorities have expanded from biomedical discovery to include implementation, effectiveness, and the effect of combination prevention at the population level. However, gaps in knowledge and implementation challenges remain. In this Review we analyse trends in the rapidly changing landscape of HIV prevention, and chart a new path for HIV prevention research that focuses on the implementation of effective and efficient combination prevention strategies to turn the tide on the HIV pandemic.
Predatory (towards crickets), intermale, and maternal aggression were examined in four replicate ... more Predatory (towards crickets), intermale, and maternal aggression were examined in four replicate lines of mice that had been selectively bred for high wheel-running (S) and in four random-bred control lines (C). In generation 18, individual differences in both predatory and intermale aggression were significantly consistent across four trial days, but predatory and intermale aggression were uncorrelated both at the individual level and among the eight line means. Latencies to attack crickets were significantly lower in S lines as a group. Intermale aggression, however, did not differ between S and C lines. S lines were significantly smaller in body mass, but did not differ in either testes mass or plasma testosterone. In generations 28 and 30, respectively, S and C lines did not differ in either maternal or intermale aggression. However, significant differences among the individual lines were found for maternal aggression, and one S line exhibited an extremely high mean time of aggression (Ͼ120 sec for a 5-min test). Maternal and intermale aggression were not correlated among the eight line means or at the level of individual variation. Overall, our results suggest: (1) predatory aggression and voluntary wheel-running are positively related at the genetic level; (2) predatory and intermale aggression are unrelated at a genetic level; and (3) maternal and intermale aggression are not tightly related at the genetic level. Possible relationships between predatory aggression, dopamine, and wheel-running behavior are discussed.
Chronic stress is associated with more rapid tumor progression, and recent evidence suggests that... more Chronic stress is associated with more rapid tumor progression, and recent evidence suggests that stress may contribute to social and ethnic disparities in the incidence and mortality of breast cancer. We evaluated the p53 +/-FVB/N mouse as a model to investigate effects of chronic social stress on mammary gland development, gene expression and tumorigenesis. We individually housed (IH) wild type and p53 +/female FVB/N mice, starting at weaning. At 14 weeks of age, both wild type and p53 +/-IH mice showed strikingly reduced mammary development compared to group-housed (GH) controls, with IH mice having significantly fewer pre-terminal end buds. This morphological difference was not reflected in levels of mammary transcripts for estrogen receptor alpha or progestin receptor. However, IH increased levels of mRNA for the kisspeptin receptor in the medial preoptic area of the hypothalamus, associated with reduced duration of estrous cycles. Further, IH altered mammary transcripts of genes associated with DNA methylation; transcripts for methyl binding protein 2 and DNA methyltransferase (DNMT) 3b, but not DNMT 1 and DNMT3a, were reduced in IH, compared to GH females. Interestingly, glands of p53 +/females displayed reduced expression of all these mediators, compared to wildtype females. However, contrary to our initial hypothesis, IH did not increase mammary tumorigenesis. Rather, p53 +/-GH females developed significantly more mammary tumors than IH mice. Together, these data suggest that social isolation initiated at puberty may confound studies of tumorigenesis by altering mammary development in mouse models.
Lactating mice display fierce aggression towards novel, male mice. This study compares neuronal a... more Lactating mice display fierce aggression towards novel, male mice. This study compares neuronal activity in the brains of aggression-tested (T) and -untested (U) mice using early growth response factor 1 (Egr-1; also known as Krox 24, NGFI-A, Zif268, Tis8, and ZENK) as a measure of neuronal activity. Animals were sampled 90 min after either a sham or real 7-min test with a male intruder, after which their brains were examined for immunoreactivity to Egr-1 (Egr-IR). Significant increases in Egr-IR in T mice were identified in 11 of 40 brain regions, including paraventricular nucleus of the hypothalamus; anterior and lateral hypothalamus (both posterior portion); ventromedial hypothalamus; lateral periaqueductal gray; and medial, central, and basolateral amygdala. Posterodorsal (MePD) and posteroventral medial amygdala were examined for the first time in association with maternal aggression. MePD, a region associated with both sexual and aggressive behaviors in rats, hamsters, and mice, showed increased Egr-IR in association with testing. Taken together, the results from this study provide new insights into the neural circuits regulating maternal behaviors.
The trpc2 gene encodes an ion channel involved in pheromonal detection and is found in the vomero... more The trpc2 gene encodes an ion channel involved in pheromonal detection and is found in the vomeronasal organ. In tprc2 -/knockout (KO) mice, maternal aggression (offspring protection) is impaired and brain Fos expression in females in response to a male are reduced. Here we examine in lactating wild-type (WT) and KO mice behavioral and brain responses to different olfactory/ pheromonal cues. Consistent with previous studies, KO dams exhibited decreased maternal aggression and nest building, but we also identified deficits in nighttime nursing and increases in pup weight. When exposed to the bedding tests, WT dams typically ignored clean bedding, but buried male-soiled bedding from unfamiliar males. In contrast, KO dams buried both clean and soiled bedding. Differences in brain Fos expression were found between WT and KO mice in response to either no bedding, clean bedding, or soiled bedding. In the accessory olfactory bulb, a site of pheromonal signal processing, KO mice showed suppressed Fos activation in the anterior mitral layer relative to WT mice in response to clean and soiled bedding. However, in the medial and basolateral amygdala, KO mice showed a robust Fos response to bedding, suggesting that regions of the amygdala canonically associated with pheromonal sensing can be active in the brains of KO mice, despite compromised signaling from the vomeronasal organ. Together, these results provide further insights into the complex ways by which pheromonal signaling regulates the brain and behavior of the maternal female.
Maternal aggression is a form of aggression towards intruders by lactating females that is critic... more Maternal aggression is a form of aggression towards intruders by lactating females that is critical for defense of offspring. During lactation, fear and anxiety are reduced, the CNS is less responsive to the anxiogenic neuropeptide, corticotropin-releasing factor (CRF), and central injections of CRF inhibit maternal aggression. Together, these previous findings suggest that decreased CRF neurotransmission during lactation supports normal maternal aggression expression. Recent work indicates that mice deficient in CRF receptor 2 (CRFR2) display increased anxiety-like behaviors, have a hypersensitive stress response, and overproduce CRF. In this study, we examined both maternal and intermale aggression in wild-type (WT) and CRFR2-deficient mice. CRFR2-mutant mice exhibited significant deficits in maternal aggression on postpartum Day 4 relative to WT mice in terms of percentage displaying aggression, mean number of attacks, and mean time in aggressive encounters. However, time sniffing male intruder, pup retrieval, number of pups, and performance on the elevated plus maze were similar between genotypes. In contrast, intermale aggression did not differ between genotype in any measure on any of three consecutive test days. For neither form of aggression did sites of attacks on the intruder differ between genotype. Taken together, the results suggest that differences in stress sensitivity and the overproduction of CRF of the knockout (KO) mice specifically affects maternal, but not intermale aggression.
Genomic imprinting represents a mechanism through which parent-of-origin effects on offspring dev... more Genomic imprinting represents a mechanism through which parent-of-origin effects on offspring development may be mediated. However, investigation of the influence of imprinted genes on behavior has been limited. Here the authors investigate the role of the maternally imprinted/paternally expressed gene, Peg3, in several aspects of behavior using both 129Sv-and B6-Peg3 mutant female mice. Virgin Peg3 females on both genetic backgrounds were less exploratory and had higher rates of defecation with strain-dependent effects on activity levels and olfactory discrimination. Reproductive success, pup retrieval, and postnatal maternal care of pups were reduced in these females whereas indices of maternal aggression were higher among B6 Peg3-KO females. Differences in maternal care were apparent in females caring for biological or cross-fostered offspring and deficits in pup retrieval apparent beyond the immediate postpartum period. Oxytocin receptor binding in the MPOA and LS was reduced in Peg3-KO females. Thus, the authors demonstrate that disruptions to Peg3 influences aspects of female behavior that are critical for mediating maternal effects on offspring development, such as postpartum licking/ grooming, and that effects of Peg3 are dependent on the maternal genetic background.
Social learning theory-based models have recently provided the foundation for a series of twelve ... more Social learning theory-based models have recently provided the foundation for a series of twelve controlled human immunodeficiency virus (HIV) risk reduction intervention studies that have examined sexual behavior change. These interventions have been tested with adolescents, gay and bisexual men, inner-city women, college students, and seriously mentally ill adults. We report the first meta-analysis of these intervention studies. We found that, as expected, the mean weighted effect of HIV-risk reduction interventions on behavioral outcomes was positive and strongly significant (d+ = 0.25). Moreover, the studies" effect sizes were consistently positive, ranging from 0.I1 to 0.53, and were largest when the outcomes were measured close in time to the intervention. We discuss other methodological challenges that, if solved, should enhance the success of future HIV-risk reduction interventions.
A dramatic example of neuronal and physiological plasticity in adult mammals occurs during the tr... more A dramatic example of neuronal and physiological plasticity in adult mammals occurs during the transition from a non-maternal to a maternal, lactating state. In this study we compared gene expression within a large continuous region of the CNS involved in maternal behaviors (hypothalamus, preoptic regions, and nucleus accumbens) between lactating (L) (postpartum Day 7) and randomly cycling virgin (V) outbred mice. Using high density oligonucleotide arrays representing 11,904 genes, two statistical algorithms were used to identify significant differences in gene expression: robust multi array (p < 0.001) (n = 92 genes) and significance analysis of microarrays using a 10% false discover rate (n = 114 genes). 27 common genes were identified as significant using both techniques. A subset of genes (n = 5) were selected and examined by real-time PCR. Our findings were consistent with previous published work. For example, neuropeptide Y (NPY) and proenkephalin were elevated in L mice, whereas POMC was decreased. Increased levels of NPY Y2 receptor and polo-like kinase and decreased levels of endothelin receptor type b in L mice are examples of novel gene expression changes not previously identified. Expression differences occurred in broad classes. Together, our findings provide possible new material on gene expression changes that may support maternal behaviors. The advantages and drawbacks of sampling large CNS regions using arrays are discussed.
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