Implementation experiences and insights from the scale-up of an HIV assisted partner notification intervention in Central Asia.

INTRODUCTION: WHO recommends assisted partner notification (APN) for people living with HIV (PLHIV). These services have not been widely scaled in Central Asia. We describe the results from an APN intervention implemented within a programme focused on PLHIV and people who inject drugs in Kazakhstan, the Kyrgyz Republic and Tajikistan. METHODS: Routine data from index cases and their partners were analysed from equal-length periods before and after APN launch. Prior to APN index cases could recruit partners using passive referral, and under APN, had their choice of passive referral or APN (provider, contract or dual-referral). We compared the demographic characteristics of index cases and their sexual/injecting partners from the pre-APN and APN periods, described the number/proportion of HIV cases found (positivity rate) and evaluated predictors of HIV infection among partners using logistic regression. RESULTS: Under APN 2676 PLHIV served as index cases and recruited 3735 partners for testing, compared to 4418 index cases and 2240 partners during the pre-APN period. A total of 322 (8.6%) partners were rapid test positive during APN versus 161 (7.2%, p = 0.048) before APN. Women represented 38% of APN index cases (vs. 42% pre-APN), 52% of partners tested (vs. 50% pre-APN) and 56% of all PLHIV identified (vs. 63% pre-APN). Compared to the pre-APN period, the number of partners tested per index case recruited increased (0.5 to 1.4, p < 0.001) and the number of index cases needed to find one HIV-positive partner decreased significantly (27.4 to 8.3, p < 0.001) under APN. CONCLUSIONS: APN was feasibly integrated within a people who inject drugs and PLHIV-focused HIV programme, and was acceptable to high-risk populations in Central Asia. Under APN, large numbers of sexual and injecting partners of PLHIV - including women and non-marital partners - were tested while maintaining high positivity rates. Relative to the pre-APN period, APN approximately tripled the number of partners recruited per index case and reduced the number of index cases needed to find a positive partner by >3 times.

Prevention of sexually transmitted HIV infections through the President's Emergency Plan for AIDS Relief: a history of achievements and lessons learned.

HIV prevention in the President's Emergency Plan for AIDS Relief (PEPFAR) began when both data on HIV prevalence and the toolbox of interventions for prevention of sexual transmission were relatively limited. PEPFAR's early focus was on scaling-up information, education, and communication programs that included messaging on abstinence for youth and faithfulness primarily through nongovernmental organizations, including faith-based organizations. Additional activities included condom promotion, distribution, and social marketing. In epidemics concentrated within key populations, PEPFAR's prevention efforts focused on a minimum package of services including outreach, information, education, and communication programs, STI treatment (where appropriate), and condom promotion and distribution. As more epidemiological data became available and with experience gleaned in these early efforts, the need for tailored and flexible approaches became evident. The next iteration of prevention efforts still emphasized behavioral interventions, but incorporated a sharper focus on key epidemic drivers, especially multiple partners; a data-driven emphasis on high transmission areas and populations, including prevention with people living with HIV; and a more strategic and coordinated approach at the national level. Recently, the paradigm for prevention efforts has shifted yet again. Evidence that biomedical interventions such as male circumcision, treatment for prevention of vertical and horizontal transmission, and treatment itself could lead to declines in incidence has refocused PEPFAR's prevention portfolio. New guidance on sexually transmitted HIV focuses on combination prevention, emphasizing biomedical, behavioral and structural approaches. Landmark speeches by the President and the Secretary of State and new ambitious targets for PEPFAR point toward a new goal: an AIDS-free generation.

Trpc2-deficient lactating mice exhibit altered brain and behavioral responses to bedding stimuli.

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.

Social isolation reduces mammary development, tumor incidence, and expression of epigenetic regulators in wild-type and p53-heterozygotic mice.

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 with group-housed (GH) controls, with IH mice having significantly fewer preterminal end buds. This morphologic 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. Furthermore, IH altered mammary transcripts of genes associated with DNA methylation; transcripts for methyl-binding protein 2 and DNA methyltransferase 3b (DNMT3b), but not DNMT1 and DNMT3a, were reduced in IH compared with GH females. Interestingly, the glands of p53(+/-) females showed reduced expression of all these mediators compared with wild-type 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 might confound studies of tumorigenesis by altering mammary development in mouse models.

Maternal aggression: new insights from Egr-1.

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.

Gene array profiling of large hypothalamic CNS regions in lactating and randomly cycling virgin mice.

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 multiarray (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.

Differential fos activation in virgin and lactating mice in response to an intruder.

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 mitral and granular layers of accessory olfactory bulb, regions of the amygdala, dorsal BNST, and caudal portions of the hypothalamic attack area. These increases in Fos-IR with testing suggest alterations in the circuitry governing response to pheromonal cues and imply some commonalities between the circuitries governing maternal aggression and intermale aggression. These results support the hypothesis that pregnancy and lactation induce substantial changes in brain circuitry and function; changes that enable maternal defense of offspring by altering the neural response to an intruder male.

Elevated stress sensitivity in corticotropin-releasing factor receptor 2 deficient mice decreases maternal, but not intermale aggression.

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.

Predatory aggression, but not maternal or intermale aggression, is associated with high voluntary wheel-running behavior in mice.

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 (>120 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.