Primary infection with Zika virus provides one-way heterologous protection against Spondweni virus infection in rhesus macaques.

Spondweni virus (SPONV) is the closest known relative of Zika virus (ZIKV). SPONV pathogenesis resembles that of ZIKV in pregnant mice, and both viruses are transmitted by Aedes aegypti mosquitoes. We aimed to develop a translational model to further understand SPONV transmission and pathogenesis. We found that cynomolgus macaques (Macaca fascicularis) inoculated with ZIKV or SPONV were susceptible to ZIKV but resistant to SPONV infection. In contrast, rhesus macaques (Macaca mulatta) supported productive infection with both ZIKV and SPONV and developed robust neutralizing antibody responses. Crossover serial challenge in rhesus macaques revealed that SPONV immunity did not protect against ZIKV infection, whereas ZIKV immunity was fully protective against SPONV infection. These findings establish a viable model for future investigation into SPONV pathogenesis and suggest that the risk of SPONV emergence is low in areas with high ZIKV seroprevalence due to one-way cross-protection between ZIKV and SPONV.

Frequent first-trimester pregnancy loss in rhesus macaques infected with African-lineage Zika virus.

In the 2016 Zika virus (ZIKV) pandemic, a previously unrecognized risk of birth defects surfaced in babies whose mothers were infected with Asian-lineage ZIKV during pregnancy. Less is known about the impacts of gestational African-lineage ZIKV infections. Given high human immunodeficiency virus (HIV) burdens in regions where African-lineage ZIKV circulates, we evaluated whether pregnant rhesus macaques infected with simian immunodeficiency virus (SIV) have a higher risk of African-lineage ZIKV-associated birth defects. Remarkably, in both SIV+ and SIV- animals, ZIKV infection early in the first trimester caused a high incidence (78%) of spontaneous pregnancy loss within 20 days. These findings suggest a significant risk for early pregnancy loss associated with African-lineage ZIKV infection and provide the first consistent ZIKV-associated phenotype in macaques for testing medical countermeasures.

Fetal loss in pregnant rhesus macaques infected with high-dose African-lineage Zika virus.

Countermeasures against Zika virus (ZIKV), including vaccines, are frequently tested in nonhuman primates (NHP). Macaque models are important for understanding how ZIKV infections impact human pregnancy due to similarities in placental development. The lack of consistent adverse pregnancy outcomes in ZIKV-affected pregnancies poses a challenge in macaque studies where group sizes are often small (4-8 animals). Studies in small animal models suggest that African-lineage Zika viruses can cause more frequent and severe fetal outcomes. No adverse outcomes were observed in macaques exposed to 1x104 PFU (low dose) of African-lineage ZIKV at gestational day (GD) 45. Here, we exposed eight pregnant rhesus macaques to 1x108 PFU (high dose) of African-lineage ZIKV at GD 45 to test the hypothesis that adverse pregnancy outcomes are dose-dependent. Three of eight pregnancies ended prematurely with fetal death. ZIKV was detected in both fetal and placental tissues from all cases of early fetal loss. Further refinements of this exposure system (e.g., varying the dose and timing of infection) could lead to an even more consistent, unambiguous fetal loss phenotype for assessing ZIKV countermeasures in pregnancy. These data demonstrate that high-dose exposure to African-lineage ZIKV causes pregnancy loss in macaques and also suggest that ZIKV-induced first trimester pregnancy loss could be strain-specific.

How are Consumer Sleep Technology Data Being Used to Deliver Behavioral Sleep Medicine Interventions? A Systematic Review.

BACKGROUND: The rapid growth of consumer sleep technology demonstrates the population's interest in measuring sleep. However, the extent to which these devices can be used in the delivery of behavioral sleep interventions is currently unknown. The objectives of this systematic review were to evaluate the use of consumer sleep technology (wearable and mobile) in behavioral sleep medicine interventions, identify gaps in the literature and potential future directions. METHODS: We completed a scoping review of studies conducted in adult populations that used consumer sleep tracking technology to deliver sleep-related interventions. RESULTS: Our initial search returned 4,538 articles and 14 articles met our inclusion/exclusion criteria. Results demonstrated that wearable devices are being used for two main purposes: 1. To deliver treatment for insomnia and 2. Sleep monitoring as part of overall wellness programs. Half of the articles reviewed (n = 7) used consumer sleep technology in a cognitive behavioral therapy for insomnia. The majority of the studies reviewed (n = 10) were fully digital, without human intervention, and only two small studies evaluated interventions delivered with and without a sleep tracking device. CONCLUSIONS: These studies demonstrate opportunities to utilize consumer sleep trackers in insomnia treatment and wellness programs, but most new and innovative interventions are in the early, feasibility stages. Future research is needed to determine how to leverage wearables to improve existing behavioral sleep treatments and determine how this technology can engage patients and reduce barriers to behavioral sleep medicine interventions.

Previous exposure to dengue virus is associated with increased Zika virus burden at the maternal-fetal interface in rhesus macaques.

Concerns have arisen that pre-existing immunity to dengue virus (DENV) could enhance Zika virus (ZIKV) disease, due to the homology between ZIKV and DENV and the observation of antibody-dependent enhancement (ADE) among DENV serotypes. To date, no study has examined the impact of pre-existing DENV immunity on ZIKV pathogenesis during pregnancy in a translational non-human primate model. Here we show that macaques with a prior DENV-2 exposure had a higher burden of ZIKV vRNA in maternal-fetal interface tissues as compared to DENV-naive macaques. However, pre-existing DENV immunity had no detectable impact on ZIKV replication kinetics in maternal plasma, and all pregnancies progressed to term without adverse outcomes or gross fetal abnormalities detectable at delivery. Understanding the risks of ADE to pregnant women worldwide is critical as vaccines against DENV and ZIKV are developed and licensed and as DENV and ZIKV continue to circulate.

Early Embryonic Loss Following Intravaginal Zika Virus Challenge in Rhesus Macaques.

Zika virus (ZIKV) is an arthropod-borne virus (arbovirus) and is primarily transmitted by Aedes species mosquitoes; however, ZIKV can also be sexually transmitted. During the initial epidemic and in places where ZIKV is now considered endemic, it is difficult to disentangle the risks and contributions of sexual versus vector-borne transmission to adverse pregnancy outcomes. To examine the potential impact of sexual transmission of ZIKV on pregnancy outcome, we challenged three rhesus macaques (Macaca mulatta) three times intravaginally with 1 x 107 PFU of a low passage, African lineage ZIKV isolate (ZIKV-DAK) in the first trimester (~30 days gestational age). Samples were collected from all animals initially on days 3 through 10 post challenge, followed by twice, and then once weekly sample collection; ultrasound examinations were performed every 3-4 days then weekly as pregnancies progressed. All three dams had ZIKV RNA detectable in plasma on day 3 post-ZIKV challenge. At approximately 45 days gestation (17-18 days post-challenge), two of the three dams were found with nonviable embryos by ultrasound. Viral RNA was detected in recovered tissues and at the maternal-fetal interface (MFI) in both cases. The remaining viable pregnancy proceeded to near term (~155 days gestational age) and ZIKV RNA was detected at the MFI but not in fetal tissues. These results suggest that sexual transmission of ZIKV may represent an underappreciated risk of pregnancy loss during early gestation.

Initial evaluation of a mobile SARS-CoV-2 RT-LAMP testing strategy.

Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) control in the United States remains hampered, in part, by testing limitations. We evaluated a simple, outdoor, mobile, colorimetric reverse transcription loop-mediated isothermal amplification (RT-LAMP) assay workflow where self-collected saliva is tested for SARS-CoV-2 RNA. From July 16 to November 19, 2020, 4,704 surveillance samples were collected from volunteers and tested for SARS-CoV-2 at 5 sites. A total of 21 samples tested positive for SARS-CoV-2 by RT-LAMP; 12 were confirmed positive by subsequent quantitative reverse-transcription polymerase chain reaction (qRT-PCR) testing, while 8 were negative for SARS-CoV-2 RNA, and 1 could not be confirmed because the donor did not consent to further molecular testing. We estimated the RT-LAMP assay's false-negative rate from July 16 to September 17, 2020 by pooling residual heat-inactivated saliva that was unambiguously negative by RT-LAMP into groups of 6 or less and testing for SARS-CoV-2 RNA by qRT-PCR. We observed a 98.8% concordance between the RT-LAMP and qRT-PCR assays, with only 5 of 421 RT-LAMP negative pools (2,493 samples) testing positive in the more sensitive qRT-PCR assay. Overall, we demonstrate a rapid testing method that can be implemented outside the traditional laboratory setting by individuals with basic molecular biology skills and can effectively identify asymptomatic individuals who would not typically meet the criteria for symptom-based testing modalities.

Initial Evaluation of a Mobile SARS-CoV-2 RT-LAMP Testing Strategy.

Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) control in the United States remains hampered, in part, by testing limitations. We evaluated a simple, outdoor, mobile, colorimetric reverse-transcription loop-mediated isothermal amplification (RT-LAMP) assay workflow where self-collected saliva is tested for SARS-CoV-2 RNA. From July 16, 2020, to November 19, 2020, surveillance samples (n = 4704) were collected from volunteers and tested for SARS-CoV-2 at 5 sites. Twenty-one samples tested positive for SARS-CoV-2 by RT-LAMP; 12 were confirmed positive by subsequent quantitative reverse-transcription polymerase chain reaction (qRT-PCR) testing, whereas 8 tested negative for SARS-CoV-2 RNA, and 1 could not be confirmed because the donor did not consent to further molecular testing. We estimated the false-negative rate of the RT-LAMP assay only from July 16, 2020, to September 17, 2020 by pooling residual heat-inactivated saliva that was unambiguously negative by RT-LAMP into groups of 6 or fewer and testing for SARS-CoV-2 RNA by qRT-PCR. We observed a 98.8% concordance between the RT-LAMP and qRT-PCR assays, with only 5 of 421 RT-LAMP-negative pools (2493 total samples) testing positive in the more-sensitive qRT-PCR assay. Overall, we demonstrate a rapid testing method that can be implemented outside the traditional laboratory setting by individuals with basic molecular biology skills and that can effectively identify asymptomatic individuals who would not typically meet the criteria for symptom-based testing modalities.

Facilitating the quality of care in a specialist Pacific ophthalmic nursing workforce.

BACKGROUND: Sufficient, appropriately trained health personnel need to be retained in the workforce, and their performance maintained, to achieve quality care. Mid-level ophthalmic personnel in Western Pacific Island Countries and Territories (WPICT) are no exception. AIM: The study aims to assess influences on the quality of care provided by specialist mid-level ophthalmic personnel in WPICT and devise strategies to train, retain and maintain performance of these personnel. METHODS: A situational assessment employed a checklist and semi-structured interviews with specialist mid-level ophthalmic personnel, nursing bodies and Ministry of Health representatives from seven WPICT. A selective literature review guided strategies to address the issues identified. RESULTS: Appropriate training allows nurses to fulfill a mid-level role in WPICT as specialist ophthalmic nurses. Resources generally do not restrict practice. Nursing structures have generally failed to support professionalism: scope and conditions of service, clinical supervision, career structures, professional recognition and opportunities for continuing professional development are rudimentary. Ophthalmic nurses were dissatisfied with the lack of specialty recognition, career progression and salary increase. Regional and local strategies tailored to each country have been devised to establish sustainable processes for support. CONCLUSION: Salary was a major cause of dissatisfaction. It should be addressed along with professional recognition and related processes. Without professional support, specialist and advanced cadres within nursing may cease to exist, nurses' performance may be affected or they may leave. Specialist ophthalmic nursing, recognized, situated within and properly supported by nursing structures can provide a model for specialist clinical care for other specialties and in other countries.

Predicting biodegradable volatile solids degradation profiles in the composting process.

This paper presents a new method for the prediction of the pattern of biodegradable volatile solids (BVS) degradation in the composting process. The procedure is based on a re-arrangement of the heat balance around a composting system to numerically solve for the rate of BVS carbon (BVS-C) disappearance. Input data for the model was obtained from composting experiments conducted in a laboratory-scale, constant temperature difference (CTD) reactor simulating a section of an aerated static pile, and using a simulated feedstock comprising ostrich feed, shredded paper, finished compost and woodchips. These experiments also provided validation data in the form of exit gas CO(2) carbon (CO(2)-C) profiles. The model successfully predicted the generic shape of experimental substrate degradation profiles obtained from CO(2) measurements, but under the conditions and assumptions of the experiment, the profiles were quantitatively different, giving an over-estimate of BVS-C. Both measured CO(2)-C and predicted BVS-C profiles were moderately to well fitted by a single exponential function, with replicated rate coefficient values of 0.08 and 0.09 d(-1), and 0.06 and 0.07 d(-1), respectively. In order to explore the underlying shape of the profiles, measured and predicted data at varying temperature were corrected to a constant temperature of 40 degrees C, using the temperature correction function of Rosso et al. [Rosso, L., Lobry, J.R., and Flandrois, J.P., 1993. An unexpected correlation between cardinal temperatures of microbial growth highlighted by a new model. Journal of Theoretical Biology, 162, 447-463], with cardinal temperatures of 5, 59 and 85 degrees C. Multi-phase profiles were generated for both the measured CO(2)-C and the predicted BVS-C data in this case. However, when alternative cardinal temperatures of 5, 55 and 80 degrees C, or 5, 50 and 80 degrees C, were used, the predicted profiles assumed an exponential shape, and excellent fits were obtained using a double exponential function. These findings support the argument that a substrate degradation curve generated under laboratory conditions at 40 degrees C, would, given correct cardinal temperatures, generate a correct substrate degradation profile under varying temperature conditions and that this in turn would enable an accurate and precise prediction of the temperature profile, using a heat and mass balance approach. In order to realise this prospect, it is proposed that further work to obtain experimental data under completely mixed conditions, more accurately estimate the overall heat transfer coefficient and obtain correct values for the cardinal temperatures used in the temperature correction function, is required.

An evaluation of substrate degradation patterns in the composting process. Part 1: profiles at constant temperature.

This paper examines the patterns of 32 constant temperature substrate degradation profiles obtained from the composting literature, and evaluates the use of a single exponential model, a double exponential model and a non-logarithmic Gompertz model in describing their behaviour. Profiles were found to be predominantly either sigmoidal in shape, or to exhibit multi-phase behaviour, with a relatively small proportion of convex curves. Of the constant temperature profiles, 26 were either not well modelled by any of the above functions, or of such differing profiles that none of the above functions was applicable. Goodness of fit was measured using a normalised error function, and rated using a five-category descriptive scale, ranging from excellent to poor. No fits rated as excellent were observed. Fits rated as good were obtained for three data sets when using a single exponential function, for two data sets when using a double exponential function, and for one data set when using the non-logarithmic Gompertz function. The remainder of the fits were rated as moderate to poor. It is concluded that the evidence supporting the use of the single exponential model, the double exponential model or the non-logarithmic Gompertz model to describe substrate degradation profiles generated at constant temperature is limited. Further work is suggested in order to establish standard procedures and a standard simulated composting mixture for substrate degradation studies and to build a more comprehensive set of long-term substrate degradation profile data at constant temperature, and under non-limiting moisture and oxygen concentration conditions.

An evaluation of substrate degradation patterns in the composting process. Part 2: temperature-corrected profiles.

In this paper, the patterns of 44 substrate degradation profiles obtained from the composting literature are examined following their correction to a constant temperature of 40 degrees C, using a new procedure presented in this work. The applicability of a single exponential model, a double exponential model and a non-logarithmic Gompertz model in describing their behaviour is then evaluated. Multi-phase profiles were most commonly seen, with convex shapes observed in only a relatively small proportion of the profiles. Convex shapes were also embedded within other profiles, either preceeded by a lag phase, or followed by non-convex behaviour. Sigmoidal patterns were relatively rare. Of the temperature-corrected data sets examined, 33 were found to be either not well modelled by, or inappropriate for, any of the above models. Two fits rated as good were obtained when using the single exponential model, and one fit rated as excellent, plus one fit rated as good, were obtained when using the double exponential model. A single fit rated as excellent was found when using the non-logarithmic Gompertz model. The lag phase, which was observed in many data sets, was successfully modelled using the non-logarithmic Gompertz function where excellent and good fits were obtained, but as expected this phase of the profile could not be modelled by either the single or double exponential functions. When the lag phase or post-convex curve data was removed from 20 data sets, use of the single exponential function resulted in three fits rated as excellent and two rated as good. When a double exponential model was applied to these data sets, three fits rated as good were obtained, whilst application of the modified Gompertz model gave one fit rated as good. The remainder of the fits were rated as moderate to fair. It is concluded that the evidence supporting the use of the single exponential model, the double exponential model or the non-logarithmic Gompertz model to describe full substrate degradation profiles in composting following their adjustment for temperature effects is limited. Further work is suggested in order to investigate the nature of those profiles which were not well modelled, to more precisely ascertain the cardinal temperatures for composting used in the function of Rosso et al. (1993) [Rosso, L., Lobry, J.R., Flandrois, J.P., 1993. An unexpected correlation between cardinal temperatures of microbial growth highlighted by a new model. J. Theor. Biol 162, 447-463.], which was employed in the present temperature correction procedure, and to incorporate correction for varying moisture and oxygen concentrations.

Mathematical modelling of the composting process: a review.

In this paper mathematical models of the composting process are examined and their performance evaluated. Mathematical models of the composting process have been derived from both energy and mass balance considerations, with solutions typically derived in time, and in some cases, spatially. Both lumped and distributed parameter models have been reported, with lumped parameter models presently predominating in the literature. Biological energy production functions within the models included first-order, Monod-type or empirical expressions, and these have predicted volatile solids degradation, oxygen consumption or carbon dioxide production, with heat generation derived using heat quotient factors. Rate coefficient correction functions for temperature, moisture, oxygen and/or free air space have been incorporated in a number of the first-order and Monod-type expressions. The most successful models in predicting temperature profiles were those which incorporated either empirical kinetic expressions for volatile solids degradation or CO2 production, or which utilised a first-order model for volatile solids degradation, with empirical corrections for temperature and moisture variations. Models incorporating Monod-type kinetic expressions were less successful. No models were able to predict maximum, average and peak temperatures to within criteria of 5, 2 and 2 degrees C, respectively, or to predict the times to reach peak temperatures to within 8 h. Limitations included the modelling of forced aeration systems only and the generation of temperature validation data for relatively short time periods in relation to those used in full-scale composting practice. Moisture and solids profiles were well predicted by two models, but oxygen and carbon dioxide profiles were generally poorly modelled. Further research to obtain more extensive substrate degradation data, develop improved first-order biological heat production models, investigate mechanistically-based moisture correction factors, explore the role of moisture tension, investigate model performance over thermophilic composting time periods, provide more information on model sensitivity and incorporate natural ventilation aeration expressions into composting process models, is suggested.

Physical modelling of the composting environment: a review. Part 1: Reactor systems.

In this paper, laboratory- and pilot-scale reactors used for investigation of the composting process are described and their characteristics and application reviewed. Reactor types were categorised by the present authors as fixed-temperature, self-heating, controlled temperature difference and controlled heat flux, depending upon the means of management of heat flux through vessel walls. The review indicated that fixed-temperature reactors have significant applications in studying reaction rates and other phenomena, but may self-heat to higher temperatures during the process. Self-heating laboratory-scale reactors, although inexpensive and uncomplicated, were shown to typically suffer from disproportionately large losses through the walls, even with substantial insulation present. At pilot scale, however, even moderately insulated self-heating reactors are able to reproduce wall losses similar to those reported for full-scale systems, and a simple technique for estimation of insulation requirements for self-heating reactors is presented. In contrast, controlled temperature difference and controlled heat flux laboratory reactors can provide spatial temperature differentials similar to those in full-scale systems, and can simulate full-scale wall losses. Surface area to volume ratios, a significant factor in terms of heat loss through vessel walls, were estimated by the present authors at 5.0-88.0m(2)/m(3) for experimental composting reactors and 0.4-3.8m(2)/m(3) for full-scale systems. Non-thermodynamic factors such as compression, sidewall airflow effects, channelling and mixing may affect simulation performance and are discussed. Further work to investigate wall effects in composting reactors, to obtain more data on horizontal temperature profiles and rates of biological heat production, to incorporate compressive effects into experimental reactors and to investigate experimental systems employing natural ventilation is suggested.

Physical modelling of the composting environment: a review. Part 2: Simulation performance.

This paper reviews previously published heat balance data for experimental and full-scale composting reactors, and then presents an evaluation of the simulation performance of laboratory and pilot-scale reactors, using both quantitative and qualitative temperature profile characteristics. The review indicates that laboratory-scale reactors have typically demonstrated markedly different heat balance behaviour in comparison to full-scale systems, with ventilative heat losses of 36-67%, and 70-95% of the total flux, respectively. Similarly, conductive/convective/radiative (CCR) heat losses from laboratory reactors have been reported at 33-62% of the total flux, whereas CCR losses from full-scale composting systems have ranged from 3% to 15% of the total. Full-scale windrow temperature-time profiles from the literature were characterised by the present authors. Areas bounded by the curve and a 40 degrees C baseline (A(40)) exceeded 624 degrees C. days, areas bounded by the curve and a 55 degrees C baseline (A(55)) exceeded 60 degrees C days, and times at 40 and 55 degrees C were >46 days and >24 days, respectively, over periods of 50-74 days. For forced aeration systems at full scale, values of A(40) exceeded 224 degrees C days, values of A(55) exceeded 26 degrees C days, and times at 40 and 55 degrees C were >14 days and >10 days, respectively, over periods of 15-35 days. Values of these four parameters for laboratory-scale reactors were typically considerably lower than for the full-scale systems, although temperature shape characteristics were often similar to those in full-scale profiles. Evaluation of laboratory-, pilot- and full-scale profiles from systems treating the same substrate showed that a laboratory-scale reactor and two pilot-scale reactors operated at comparatively high aeration rates poorly simulated full-scale temperature profiles. However, the curves from two moderately insulated, self-heating, pilot-scale reactors operated at relatively low aeration rates appeared to closely replicate full-scale temperature profiles. The importance of controlling aeration rates and CCR losses is discussed and further work suggested in order to investigate the links between simulation of the composting environment and process performance.

Effects of ethane dimethane sulfonate on the functional structure of the adult rat testis.

In ethane dimethane sulfonate (EDS)-treated adult Sprague Dawley rats, Leydig cells (LC) were not present up to 14 days but seen at 21 days. They increased in number thereafter and reached the values of age-matching controls (i.e., 150-day-old untreated) at day 60. Mesenchymal cell number per testis also increased and reached a peak at day 21, and remained at a higher (p<.05) value than the controls at days 28-60. LC were smaller at day 21, but were larger at days 28-60 (compared to untreated 90- and 150-day-old rats) and secreted more testosterone at day 60 compared to both control groups. Testes of treated rats had greater numbers of macrophages (except at day 28) and they were smaller than those in untreated rats and 60-day EDS rats. Immunolabeling studies on 3beta-HSD, 11beta-HSD1, and LH receptor activity and androgen data agreed with morphological findings. The relationship between mesenchymal and LC numbers during LC differentiation following EDS treatment is reminiscent of this process in prepubertal testis. The presence of increased numbers of macrophages in treated testes agreed with the role of macrophages on LC differentiation. The absence of aging signs in LC of 60-day treated rats who were 150 days of age can be attributed at least in part to their newly differentiated status in older rats (i.e., equivalent to pubertal LC and not to aged LC). Larger LC observed in EDS rats at days 28-60 and their increased testosterone secretory capacity at day 60 (compared to controls) are attributed to elevated plasma LH levels and locally produced factors in EDS rats.

Investigation of the possible spread of foot-and-mouth disease virus by the burning of animal carcases on open pyres.

An atmospheric dispersion model was used to predict the airborne spread and concentrations of foot-and-mouth disease virus within the plumes generated by 11 pyres built to burn infected carcases during the epidemic of 2001 in the UK. On the basis of assumptions about the quantity of virus emitted during the three hours after the pyres were built and the threshold concentration of virus required to cause an infection in cattle, it was concluded that none of the disease breakdowns which occurred under the plumes was due to the spread of virus from the pyres.

Early development of the mesencephalic trigeminal nucleus.

The cells of the mesencephalic trigeminal nucleus (MTN) are the proprioceptive sensory neurons that innervate the jaw muscles. Interestingly, their evolution is generally thought to have been concomitant with that of the jaws. They are also the first born neurons of the mesencephalon, and their axons pioneer some of the major tracts within the brain. The cells of the MTN are also paradoxical in being the only group of intramedullary primary sensory neurons in amniotes. However, we know little about the early development of these important neurons, and we have analysed this here. To study the earliest stages of MTN development, we have used a battery of neural crest markers to try and pinpoint the progenitors of the MTN. We find that, contrary to current perceptions, the progenitors of the MTN are not highlighted by these markers, suggesting that they are not neural crest derived. However, the cells of the MTN are marked by means of their expression of Brn-3a. This gene labels cells that arise either side of the dorsal midline, extending rostrally from the isthmus across the roof of the mesencephalon. We have further demonstrated that the MTN develops under the influence of the Fgf-8 secreted by the isthmus. Ectopic Fgf-8 application promotes MTN development, whereas inhibiting Fgf-8 function in vivo drastically affects MTN development.

Developmental expression of fibroblast growth factor (FGF) receptors in neural stem cell progeny. Modulation of neuronal and glial lineages by basic FGF treatment.

Neural stem cells (NSCs) are self-renewable, multipotential cells capable of differentiating into the three major neural cell types, but the mechanisms which regulate their development are not fully understood. Both basic fibroblast growth factor (bFGF) and epidermal growth factor (EGF) promote the proliferation of NSCs. However, studies on the role of FGFs in the differentiation of EGF-expanded NSCs are still incomplete. We have studied the expression of distinct FGF receptors (FGFRs) in the progeny of EGF-expanded NSCs isolated from E15 rat striatum. In situ hybridization analysis and immunocytochemistry showed a developmentally related expression pattern and a cell lineage-specific distribution of these receptors. FGFR1 and FGFR2 were identified in many early precursors and in the oligodendrocyte lineage. The latter receptor was also present in a subpopulation of astrocytes. FGFR3 was detected in a restricted population of early precursors, in oligodendroglial progenitors, and in neurons and protoplasmic astrocytes of late-term cultures. Basic FGF treatment of the progeny of NSCs increased the proliferative rate of precursors and the number of oligodendrocytes generated, whereas the number of differentiating neurons was significantly reduced. Together these data provide evidence that FGFs modulate the development of EGF-expanded NSCs, and that this is at least partly determined by a cell lineage-specific expression of multiple FGFRs.

Relationship of the degree of goniodysgenesis and other ocular measurements to glaucoma in Great Danes.

OBJECTIVES: To assess the association between goniodysgenesis, ocular measurements, and glaucoma in Great Danes. ANIMALS: 180 Great Danes. PROCEDURE: Eye examination and measurements were obtained from 180 Great Danes; for 30 of these dogs, depth of the anterior chamber, vitreal body length, and total depth of the globe were also measured. These data were merged with electronic pedigree information on 43,371 kennel club registered Great Danes. Relationships among goniodysgenesis, ocular measurements, and glaucoma and the heritability of goniodysgenesis were estimated. RESULTS: The degree of goniodysgenesis was significantly and positively associated with the likelihood of glaucoma. There was a significant association between the degree of goniodysgenesis in offspring and parents. The estimated heritability of the degree of goniodysgenesis was 0.52. The depth of the anterior chamber of the eye was also a good predictor of goniodysgenesis (ie, the dog was almost certain to have glaucoma if the depth was < 3.7 mm). If both parents had goniodysgenesis < 70%, then with 95% confidence, the occurrence of glaucoma in the ensuing offspring would be < 4/1000. This strategy translates to ensuring that the depth of the anterior chamber of the eye is > 3.7 mm for both parents. CONCLUSIONS AND CLINICAL RELEVANCE: The strong and significant correlation among goniodysgenesis, other eye measurements, and glaucoma and the significant heritability of goniodysgenesis suggests that glaucoma may be heritable in Great Danes. If so, glaucoma can be controlled by breeding only from sires and dams with a minimum degree of goniodysgenesis.