Risk factors for horse falls in New Zealand Thoroughbred jumps racing.

This study aimed to determine the incidence of, and risk factors for race-day horse falls in Thoroughbred jumps (hurdle and steeplechase) racing in New Zealand. Incidence rates for race-day horse falls in jumps races from 2005/6 - 2018/19 racing seasons (n = 13,648 race day starts) were calculated per 1000 starts. Univariable and multivariable analyses of race-, horse- and jockey-level risk factors for horse falls were conducted using Poisson regression in a generalised linear mixed model. The incidence rate of horse falls in jumps races was 42 (95 % confidence intervals [CI], 39 - 45) per 1000 starts. Horse falls in steeplechase races were 1.6 (95 % CI, 1.4 - 1.9) times more likely than hurdle races. The incidence rate ratio (IRR) for horses falling at the last three jumps in comparison with the first three jumps was 3.1 (95 % CI, 2.8 - 3.5) for hurdle and 4.4 (95 % CI, 3.9 - 5.0) for steeplechase races. Greater jockey (age, P = 0.02) and horse experience (P = 0.001) were associated with a lower IRR of falls (P = 0.05). Longer races (P = 0.02) and those held in autumn compared to winter (IRR 1.4; 95 % CI, 1.0 - 1.8; P = 0.05) were associated with a higher rate of falling in steeplechase races. A regulatory change enhancing discretionary ability of jockeys to pull up 'in-race' was associated with reduced horse falls (IRR 0.65; 95 % CI, 0.51 - 0.82; P = 0.001). Pragmatic rule changes within the industry can have a positive effect on reducing risk and improving equine welfare.

Effects of Theileria orientalis Ikeda type infection on libido and semen quality of bulls.

There is an epidemic in New Zealand of infectious bovine anaemia associated with Theileria orientalis Ikeda type, an obligate intracellular protozoan parasite. To establish whether T. orientalis Ikeda type infection adversely affects fertility of bulls used for natural mating, a randomised controlled experimental study was conducted. Ten of 17 2-year-old Friesian bulls that had not been previously infected with T. orientalis were infected with T. orientalis Ikeda type and then evaluations occurred during a 20-week period. There were semen and libido evaluations every 2 weeks, starting 4 weeks before the date of infection. In addition, there were blood collections, for haematocrit and infection intensity evaluations, rectal temperatures recorded, and bulls weighed three times weekly for 13 weeks after infection and then once weekly until completion of the study. Physical activity meters were also attached from Days 9-60 and 65-124 post-infection. The ten bulls were successfully infected with T. orientalis Ikeda type and this resulted in a decrease in HCT to about 0.25 by 70 days post-infection. There were no effects of infection on semen quality; however, during the acute phase of infection, when the infection intensity was rapidly increasing, the infected bulls took a longer time period for repeated mounting of females, and were less dominant in the herd social heiracrchy. In conclusion, although the transitory effects on libido could reduce conception rates, the overall effects of T. orientalis Ikeda type infection on bull fertility will probably be little.

Assessing and visualising hazard impacts to enhance the resilience of Critical Infrastructures to urban flooding.

The design, construction and maintenance of Critical Infrastructures (CI) is commonly based on standards that are rigorous, so as to withstand any climate or weather-linked pressures. However, due to climate change, climate characteristics may shift, resulting in increased frequency/magnitude of potential failures, or exposure to new unknown risks. As vital components for the normal functioning of modern societies, the resilience of CIs under climate stressors encompasses their structural integrity, their operational elements, and their capacity to maximize business output. In this work, we propose an integrated and participatory methodological approach to enhance the resilience of interconnected CIs to urban flooding under climate change, by assessing the risk and introducing adaptation measures. The main objectives of the proposed methodology and approach are: (i) to provide scientific evidence for better understanding of how future climate regimes might affect normal operation of interconnected CI in urban areas during their lifespan; (ii) to assess the cost-effectiveness of different adaptation measures; (iii) to involve local stakeholders and operators in the co-design of the approach, as well as the assessment and the evaluation of adaptation measures; (iv) to combine computational modelling with advanced 3D visualisation techniques for effectively engaging stakeholders in decision making; (v) to include risk assessment and damage functions co-designed by end-users and local stakeholders; (vi) to integrate all of the aforementioned components in a specifically designed cloud platform as a Decision Support System for end-users, (vii) to validate the DSS by the end users and local stakeholders. The paper presents the computational background and tools. Additionally, it describes a Case Study in Torbay, UK, where the full methodology and the proposed participatory approach have been applied, with all the specifics, i.e., the scenarios of extreme flooding, the numerical and visualisation results, the response of the stakeholders and the evaluation of selected adaptation measures.

Magnetically controlled growing rods in the treatment of early-onset scoliosis: a note of caution.

The MAGnetic Expansion Control (MAGEC) system is used increasingly in the management of early-onset scoliosis. Good results have been published, but there have been recent reports identifying implant failures that may be associated with significant metallosis surrounding the implants. This article aims to present the current knowledge regarding the performance of this implant, and the potential implications and strategies that may be employed to identify and limit any problems. We urge surgeons to apply caution to patient and construct selection; engage in prospective patient registration using a spine registry; ensure close clinical monitoring until growth has ceased; and send all explanted MAGEC rods for independent analysis. The MAGEC system may be a good instrumentation system for the treatment of early-onset scoliosis. However, it is innovative and like all new technology, especially when deployed in a paediatric population, robust systems to assess long-term outcome are required to ensure that patient safety is maintained. Cite this article: Bone Joint J 2017;99-B:708-13.

The role of needle tip position on the accuracy of diagnostic selective nerve root blocks in spinal deformity.

PURPOSE: The specificity of a selective nerve root block (SNRB) is dependant on isolating only the required nerve root whilst avoiding injectate flow to traversing nerves. Needle tip position is therefore crucial. Nerve root blocks (SNRBs) in the presence of deformity can be particularly technically challenging to perform. The aims of this study were to document the relationship of needle tip position and SNRB accuracy in patients with and without spinal deformity. METHODS: Over an 8-month period, all SNRBs performed by one spinal surgeon were included. Patients with radiographic evidence of spinal deformity were analysed separately and their lumbar deformity graded using the Schwab grading system. Needle tip position in relation to the superior pedicle and flow of contrast was documented. RESULTS: 76 patients received 85 injections without deformity, 26 patients with deformity underwent 30 SNRBs. In the normal spinal alignment group, there was on overall accuracy of 70.1% regardless of needle tip position, which improved to 91.8% for a lateral needle tip position (P < 0.001). In patients with deformity, the overall accuracy was significantly lower irrespective of needle tip position 36 versus 70%, respectively (P < 0.0019). CONCLUSIONS: Selective nerve root blocks are accurate in patients without deformity where a needle tip placement lateral to the middle third of the pedicle is achieved. The presence of spinal deformity significantly reduces the accuracy of SNRBs with a higher chance of epidural infiltration.

The effect of posture on Quantec measurements.

The effect of moving the patient's centre of gravity from one extreme to the other, where the weight is entirely supported on the left or right foot at either extreme, was investigated in 33 patients attending for surface topography measurements with the Quantec Spinal Measurement System. Average changes of about 20 were seen in the measured curvature of the lower spine line and pelvic tilt, but there was considerable variation between individual patients. When such extremes of stance were included, the reproducibility of measurements of the curvature of the lower spine, pelvic tilt and vertical alignment was poorer, but not to the extent that a significant improvement in reproducibility would be expected if the patient's centre of gravity was closely controlled with, for example, a force platform.

Monitoring the thoracic sagittal curvature in kyphoscoliosis with surface topography: a trend analysis of 57 patients.

Records of Quantec measurements of tlie kypliotic curvature of the back were reviewed for all patients attending the children's orthopaedic clinic who were referred for back shape measurements. Of these, 57 children had five or more preoperative visits allowing trends to be calculated. Linear trends were found in 30 of the patients, with gradients ranging from 1.1 degree/yr to 7.2(0)1/yr. On average, the scatter of measurements about the trend line, or about the mean value in the other 27 cases, compared well with that expected from repeatability studies but the amount of scatter varied from one patient to another. This may well be due to sampling. Where such measurements are monitored for evidence of change in an individual patient, the possibility of larger than average scatter about any emerging trend should be considered.

Placental regulation of insulin-like growth factor axis in monochorionic twins with chronic twin-twin transfusion syndrome.

To test the hypothesis that severe growth restriction (intrauterine growth retardation) in donor twins with chronic twin-twin transfusion syndrome (TTTS), a common complication of monochorionic twin pregnancy, is due to an aberration in the insulin-like growth factor (IGF) axis, we studied 25 sets of monochorionic twins with (n = 13) and without (n = 12) TTTS. Maternal and cord blood samples were collected at birth and analyzed for IGF-I, IGF-II, IGF-binding protein-1 (IGFBP-1), and IGFBP-1 phosphorylation status. Fetal IGF-II levels in the recipient twins with TTTS were higher than those in the donor twins (829 +/- 45 vs. 543 +/- 60 ng/mL; P < 0.001), but were comparable with those in the non-TTTS twin pairs. IGF-I levels in recipient and donor twin pairs were similar. The total IGFBP-1 concentration was higher in the donor twins than in the recipients (1153 +/- 296 vs. 419 +/- 108 ng/mL; P < 0.001) and non-TTTS twin pairs (P < 0.01). The percent less phosphorylated IGFBP-1 was higher in the recipients than in the donor twins (P < 0.05). There were no differences in IGF-I, IGF-II, and IGFBP-1 levels between non-TTTS twin pairs. Maternal levels of IGFs were comparable in the two groups. In the TTTS group, fetal birth weight gave a positive correlation with serum IGF-II levels (y = 0.25x + 361.1; r = 0.47; P < 0.05), and a negative association with IGFBP-1 levels (y = -0.72x + 1593.6; r = 0.58; P < 0.01). Our data argue against intertwin transfusion as the cause of intrauterine growth retardation in the donor twin and provide evidence that the placenta is the key regulator of the fetal IGF axis, especially when fetal genotype and maternal environments are similar.

A confocal microscopic study of synaptic inputs to gonadotropin-releasing hormone cells in mouse brain: regional differences and enhancement by estrogen.

Even though the cells producing gonadotropin-releasing hormone (GnRH) are scattered in the basal forebrain, a large proportion of them is present in the organum vasculosum of the lamina terminalis (OVLT) and in the preoptic area. The present studies were undertaken to investigate whether there is any difference in the number of synaptic inputs between GnRH cells located in the OVLT and those located at more anterior levels of the brain. Immunohistochemical staining for the synaptic marker synaptophysin coupled with confocal microscopy was employed to analyze synaptic inputs to GnRH cells located at the two levels examined. The results indicate that GnRH cells in the OVLT region receive a greater number of synaptophysin-immunoreactive appositions as compared with those located in the anterior septum. This supports the existence of subsets among the GnRH cells located in the basal forebrain. The effect of estradiol on the number of synaptophysin-immunoreactive appositions onto GnRH cells was also studied. Treatment of ovariectomized mice with estradiol significantly enhanced the number of synaptophysin-immunoreactive appositions to GnRH cells located at both levels examined. Thus the effect of estrogen on GnRH cells may be mediated in part by changes in the number of synaptic contacts.

Increased synaptic input to gonadotropin releasing hormone cells in preoptic area grafts that support reproductive development in female hypogonadal mice.

Ultrastructural studies have established that gonadotropin releasing hormone (GnRH) neuronal cell bodies receive sparse synaptic input compared to other neuronal cell types. In the present studies, immunocytochemistry for the presynaptic marker synaptophysin, coupled with confocal microscopy, was employed to evaluate whether there was a difference in synaptic input to GnRH cells within preoptic area grafts (hypogonadal, HPG; preoptic area, POA) in hypogonadal female mice that did or did not show ovarian development. GnRH cells in HPG/POA mice with ovarian development exhibited significantly higher numbers of synaptophysin immunoreactive (syn-IR) appositions as compared with HPG/POA mice without ovarian development. This suggests that synaptic input to the grafted GnRH cells is important for the correction of reproductive functions in HPG/POA mice. Following mating, Fos immunoreactivity was present in several GnRH cells in HPG mice with successful POA grafts, indicating the establishment of neuronal projections conveying somatosensory information to the GnRH cells in these mice. The presence of a higher number of syn-IR appositions to GnRH cells in the successful grafts supports this hypothesis.

Soluble factors guide gonadotropin-releasing hormone axonal targeting to the median eminence.

Axons of GnRH neurons terminate at the median eminence in the medial basal hypothalamus (MBH) of the brain early in development. Similarly, GnRH neurons in grafts of preoptic area (POA) tissue within the third ventricle of hypogonadal mice preferentially innervate the median eminence. Organotypic cocultures of POA explants with other neural tissues suggest that a soluble substance(s) derived from the MBH may be directing this targeting. To begin to identify diffusable chemoattractants, we used preincubated heparin-coated acrylic beads to present specific solutes to POA explants on collagen- and laminin-coated membranes in insert chambers. GnRH axons grew on the membrane in greater number and with longer axons toward conditioned medium from MBH cultures than on the side away from the beads (P < 0.01). In contrast, GnRH axons showed no preferential outgrowth when incubated with beads soaked in control, defined medium. The attraction of MBH-conditioned medium was not generalizable to all neuroendocrine neurons, as it was not seen for galanin immunoreactive outgrowth from POA explants. There also were more GnRH axons toward conditioned medium from mouse brain microvascular endothelial cells, but no difference in axon length. Basic fibroblast growth factor (bFGF), a component of both endothelial cells and ventricular tanycytes, significantly attracted more and longer GnRH axons. Thus, bFGF may be one of the soluble factors directing GnRH outgrowth to the median eminence. However, as with so many other redundancies in the reproductive system, it is unlikely that it is the only targeting factor, as bFGF knockout mice are reported to be reproductively competent.

Effect of N-methyl-D,L-aspartate (NMA) on gonadotropin-releasing hormone (GnRH) gene expression in male mice.

The glutamate analog N-methyl-D,L-aspartate (NMA) affects the regulation of GnRH and LH release in mammals. Several laboratories have reported a rapid and transient increase in GnRH mRNA levels of male rats after NMA injection. Studies employing the simultaneous measurements of nuclear GnRH primary transcript RNA, a reflection of gene transcription, and GnRH mRNA suggest that NMA's effect on GnRH gene expression in the rat is likely due to post-transcriptional regulation. Despite the increasingly widespread use of transgenic mice, surprisingly little is known about the regulation of GnRH gene expression in the mouse. In this study, we assessed in detail the effects of NMA on GnRH gene expression in adult male mice. In the first experiment, GnRH mRNA levels in mice killed 60-min post-NMA injection (20 mg/kg bw, ip; n=9/treatment group) were lower (P<0.05) when compared to controls (saline vehicle). In the second experiment, mice (n=7/treatment group) were administered NMA or saline vehicle and were killed at 15-, 60- and 120-min post-injection. Consistent with the first experiment, treatment with NMA resulted in a significant decrease (P<0.05) in cytoplasmic GnRH mRNA compared to control levels at 15- and 60-min but not 120-min. NMA treatment decreased the nuclear GnRH primary transcript RNA at 120-min but not at earlier time points. In summary, we have shown that regulation by NMA of GnRH gene expression in mice differs substantially from rats. This differential regulation of GnRH gene expression between rats and mice warrants further investigation.

Galanin immunoreactivity in mouse basal forebrain: sex differences and discrete projections of galanin-containing cells beyond the blood-brain barrier.

The distribution of galanin-immunoreactive (GAL-IR) cell bodies in the basal forebrain of mice was investigated. The overall pattern of staining for GAL in the area of brain analyzed was similar to that reported in other species with noticeable variations. Distinctive groups of GAL-IR cells were present in the bed nucleus of stria terminalis (BNST), supraoptic nucleus, retrochiasmatic supraoptic nucleus (SOR), magnocellular paraventricular nucleus, arcuate nucleus (ARC) and the nucleus circularis which is one of the cell groups belonging to the accessory magnocellular system. Comparison of the number of GAL-IR cells between the sexes indicated sexual dimorphism in the BNST, SOR and the ARC. As compared with female mice, the mean number of GAL-IR cells/section in the BNST and the SOR was higher and that in the ARC was lower in the males. Unlike in rats, the preoptic area contained mostly scattered GAL-IR cell bodies. Intraperitoneal injection of the retrograde tracer fluoro-gold in male mice resulted in uptake of fluoro-gold by selective GAL-IR cell groups in the basal forebrain suggesting that only some of these cell groups may project outside the blood-brain barrier whereas others may be involved in intracerebral neural transmission.

Measurements of the effectiveness of dust control on cut-off saws used in the construction industry.

Materials used in the construction industry frequently contain large quantities of silica. When they are cut or shaped with power tools considerable respirable dust can be produced. Three dust control systems for use with cut-off saws have been evaluated on site: wet dust suppression using mains water, the same system using water from a portable water tank, and local exhaust ventilation. The efficiency of water suppression on cut-off saws has been precisely quantified in controlled laboratory conditions by means of measurements with and without dust control. When dust control was used on-site, the mean concentrations of airborne silica were reduced by a factor of between three and seven, the accuracy being limited by the relatively high limit of detection for silica. All controls systems generally reduced respirable dust levels by at least 90%. Although the effectiveness of dust suppression did not depend on blade type, a diamond blade was more effective than a resin-bonded blade with the pressurised water system; cutting a slab with this type of blade could be completed before the water tank required repressurization. In laboratory tests, the application of water reduced the dust concentration to < 4% of its value without control. The method for monitoring the dust concentration was sufficiently sensitive to measure a difference in concentration produced during cutting in different directions. It is important, however, that the pressure in supply reservoirs is properly maintained, that the water is correctly applied and that it is used at the correct rate. If this is done effective dust control can be achieved.

The appearance on MRI of vertebrae in acute compression of the spinal cord due to metastases.

We studied MR images of the spine in a consecutive series of 100 patients with acute compression of the spinal cord due to metastases. All patients had documented neurological deficit and histologically proven carcinoma. MRI was used to localise bony metastatic involvement and soft-tissue impingement of the cord. A systematic method of documenting metastatic involvement is described. A total of 43 patients had compression at multiple levels; 160 vertebral levels were studied. In 120 vertebrae (75%), anterior, lateral and posterior bony elements were involved. Soft-tissue impingement of the spinal cord often involved more than one quadrant of its circumference. In 69 vertebrae (43%) there was concomitant anterior and posterior compression. Isolated involvement of a vertebral body was observed in only six vertebrae (3.8%). We have shown that in most cases of acute compression of the spinal cord due to metastases there is coexisting involvement of both anterior and posterior structures.

Mechanisms for the regulation of gonadotropin-releasing hormone gene expression in the developing mouse.

The release of GnRH peptide from neuroterminals in the median eminence increases during postnatal development. We were interested in determining the biosynthetic component contributing to the regulation of GnRH decapeptide levels, and ascertaining the molecular mechanism for these changes. Male and female C57bl/6 mice, from embryonic day (E)16 through postnatal day (P)60, were killed, and the preoptic area-anterior hypothalamus was dissected out. Cytoplasmic and nuclear RNA were extracted separately. Levels of GnRH messenger RNA (mRNA) and primary transcript were quantitated in individual preoptic area-anterior hypothalamus cytoplasmic and nuclear fractions, respectively, by ribonuclease protection assays. Serum LH levels were assayed by RIA. GnRH mRNA levels in the cytoplasm increased gradually and significantly during postnatal development in both males and females, reaching a peak at P55 in females and P40 in males. GnRH primary transcript levels in the nucleus, an index of GnRH gene transcription, changed in a completely different manner developmentally, and they differed between male and female mice. GnRH primary transcript levels in males were quite low until P5, when they underwent an increase of approximately 4-fold, between P5 and P7. They continued to increase through P15, at which time they reached adult levels. In females, GnRH primary transcript levels were high at E16, decreased to a nadir at P5, and then underwent an increase of approximately 5-fold to P7, which were comparable with adult levels. The large and sexually dimorphic changes in GnRH primary transcript between E16 and P7, in the absence of similar changes in GnRH mRNA, suggest that differential mechanisms, such as gene transcription and mRNA stability, play a role in determining levels of GnRH mRNA at different stages of development.

Out-of-pocket health spending by poor and near-poor elderly Medicare beneficiaries.

OBJECTIVE: To estimate out-of-pocket health care spending by lower-income Medicare beneficiaries, and to examine spending variations between those who receive Medicaid assistance and those who do not receive such aid. DATA SOURCES AND COLLECTION: 1993 Medicare Current Beneficiary Survey (MCBS) Cost and Use files, supplemented with data from the Bureau of the Census (Current Population Survey); the Congressional Budget Office; the Health Care Financing Administration, Office of the Actuary (National Health Accounts); and the Social Security Administration. STUDY DESIGN: We analyzed out-of-pocket spending through a Medicare Benefits Simulation model, which projects out-of-pocket health care spending from the 1993 MCBS to 1997. Out-of-pocket health care spending is defined to include Medicare deductibles and coinsurance; premiums for private insurance, Medicare Part B, and Medicare HMOs; payments for non-covered goods and services; and balance billing by physicians. It excludes the costs of home care and nursing facility services, as well as indirect tax payments toward health care financing. PRINCIPAL FINDINGS: Almost 60 percent of beneficiaries with incomes below the poverty level did not receive Medicaid assistance in 1997. We estimate that these beneficiaries spent, on average, about half their income out-of-pocket for health care, whether they were enrolled in a Medicare HMO or in the traditional fee-for-service program. The 75 percent of beneficiaries with incomes between 100 and 125 percent of the poverty level who were not enrolled in Medicaid spent an estimated 30 percent of their income out-of-pocket on health care if they were in the traditional program and about 23 percent of their income if they were enrolled in a Medicare HMO. Average out-of-pocket spending among fee-for-service beneficiaries varied depending on whether beneficiaries had Medigap policies, employer-provided supplemental insurance, or no supplemental coverage. Those without supplemental coverage spent more on health care goods and services, but spent less than the other groups on prescription drugs and dental care-services not covered by Medicare. CONCLUSIONS: While Medicaid provides substantial protection for some lower-income Medicare beneficiaries, out-of-pocket health care spending continues to be a substantial burden for most of this population. Medicare reform discussions that focus on shifting more costs to beneficiaries should take into account the dramatic costs of health care already faced by this vulnerable population.

Expression of galanin immunoreactivity in gonadotropin-releasing hormone neurons in mice: a confocal microscopic study.

The expression of galanin immunoreactivity (galanin-IR) in gonadotropin-releasing hormone (GnRH) neurons was investigated in mice using double label immunohistochemistry combined with confocal laser scanning microscopy. A large proportion of GnRH cells in proestrous mice and very few GnRH cells in male mice exhibited galanin-IR. These results are consistent with earlier reports in rats. Unlike in rats, the proportion of GnRH cells coexpressing galanin in mice was high following ovariectomy (OVX) and the treatment of OVX mice with estrogen decreased the number of GnRH cells with galanin-IR. The GnRH system can be considered more active during proestrous and following OVX since the output of luteinizing hormone is elevated during these phases in females. Since the induction of galanin-IR in GnRH cells is more pronounced in OVX and proestrous mice, the expression of galanin-IR in GnRH cells in mice appears to be an activation-dependent phenomenon rather than a direct effect of estrogen. However, in OVX mice treated with steroids to induce an LH surge the number of GnRH cells with galanin-IR was not proportionately increased. The possible reasons for this discrepancy are also discussed.

Androgen receptor immunoreactivity in specific neural regions in normal and hypogonadal male mice: effect of androgens.

This study examined the distribution and regulation of androgen receptor immunoreactivity (IR) in the brain of the hypogonadal (hpg) male mouse, genetically deficient in GnRH. Five groups of animals were studied: intact, castrated, or castrated and testosterone propionate (TP)-treated normal adult male mice, and intact or TP-treated hpg adult male mice. All groups were studied 1 week after treatment. Five regions of the brain with high concentrations of androgen receptors in normal animals were examined, including the medial preoptic area, the lateral ventral septum, the ventromedial hypothalamus, the bed nucleus of the stria terminalis and the medial amygdala. The results showed that the congenital absence of GnRH results in minimal expression of androgen receptor-IR in mice in all regions examined. However, treatment with exogenous testosterone for 1 week was sufficient to induce the numbers of neurons containing androgen receptors, as detected by immunocytochemistry, into the range seen in normal male mice in all the areas studied except the VMH. Similar plasticity was also observed in normal males after 1 week of castration and TP replacement.

Preoptic area grafts implanted in mammillary bodies of hypogonadal mice: patterns of GnRH neuronal projections.

Gonadotropin-releasing hormone (GnRH) axons project to the median eminence, where the peptide is released to stimulate pituitary gonadotrophs. Hypogonadal mice (hpg) do not synthesize GnRH due to a deletion in the gene. When neonatal preoptic area (POA) tissue from normal mice containing GnRH neurons is transplanted into the third ventricle of hpg mice, GnRH axons exit the graft and specifically project to the median eminence, where the release of GnRH in the portal circulation induces the stimulation of the pituitary-gonadal axis. To test the hypothesis that the median eminence region is critical to targeting, we placed POA grafts in the region of the mammillary bodies, which never contains GnRH cell bodies, but is nevertheless close to the median eminence. Control mice received bilateral grafts into the anterior hypothalamus. GnRH axons innervated the median eminence in animals with grafts in the mammillary bodies and posterior hypothalamus. Mice with such grafts for 4-5 months had gonadal development, while those with grafts for shorter periods did not. Anterior hypothalamic grafts merged into the third ventricle and, consistent with previous studies, this resulted in GnRH innervation of the median eminence and gonadal development. However, when grafts were located within dorsal regions such as the thalamus, no median eminence innervation was seen. In these cases, GnRH axons borrowed other bundles of fibers to travel within the host brain. The pattern of innervation from grafts within ventro-caudal regions of the hypothalamus vs. that from dorsal regions supported the hypothesis that the median eminence releases diffusible substances directing GnRH outgrowth.