Associations between Johne's disease and fertility in UK dairy herds.

The objective of this observational study was to quantify associations between Mycobacterium avium subspecies paratuberculosis (MAP) antibody status and a variety of fertility outcomes, in UK dairy cattle. Longitudinal milk recording, fertility and MAP antibody enzyme-linked immunosorbent assay (ELISA) milk test data were collated retrospectively from 121,762 lactations in 78 herds. Datasets were structured into appropriate units to suit outcomes and enable temporal association between current and future MAP status, and fertility measures. Current MAP status was categorised according to most recent status within 180 days, with time-related future MAP status assigned based on MAP antibody ELISA milk test data for each cow. Multilevel multivariable logistic regression models were used to evaluate associations between MAP status and 21-day pregnancy and submission rate and conception risk. Posterior predictions and cross-validation techniques were used to assess model fit and check model building assumptions. A negative association was found between risk of insemination (Odds Ratio [OR], 0.78; 95% Credible Interval [CI], 0.66-0.92) and conception occurring (OR, 0.65; CI, 0.5-0.84) and transition from negative to non-negative MAP test status in the next 30-90 days. A positive association was observed between risk of insemination (OR, 1.34; CI, 1.16-1.52) and conception occurring (OR, 1.26; CI, 1.11-1.43) and transition from negative to non-negative MAP test status in the next 90-180 days. Current positive MAP test status was negatively and positively associated with insemination (OR, 0.59; CI, 0.49-0.70) and conception risk (OR, 1.12; CI, 0.96-1.30), respectively. Herd managers will have had access to test results, declaring cows with past recent or multiple positive MAP antibody ELISA results not to be bred, negatively influencing insemination risk. Overall, these results demonstrate the temporal association between a positive MAP antibody ELISA result and dairy cow fertility outcomes, with particular variability prior to a positive MAP antibody ELISA result.

Hoof lesions in partly housed pasture-based dairy cows.

Lameness is a symptom of a painful disorder affecting the limbs, which impacts dairy cow welfare and productivity. Lameness is primarily caused by hoof lesions. The prevalence of different lesion types can differ depending on environmental conditions and farm management practices. The aims of this observational study were to establish the cow-level and herd-level lesion prevalence during both housing and grazing periods in a partly housed, pasture-based system, establish the prevalence of lesions always associated with pain ("alarm" lesion), identify the lesions associated with a higher lameness score, determine relationships between lesions, and identify risk factors for digital dermatitis. On 98 farms during the grazing period and on 74 of the same farms during the housing period, every cow was lameness scored (0-3 lameness scoring scale), and the hind hooves of lame cows (score 2 and 3) were examined (maximum 20 cows per visit) and the prevalence of each lesion type recorded. To gather data on potential predictors for the risk factor analysis, a questionnaire with the farmer was conducted on lameness management practices and infrastructure measurements were taken at each visit. Cow-level data were also collected (e.g., parity, breed, milk yield, and so on). Noninfectious lesions were found to be more prevalent than infectious lesions in this system type. The most prevalent lesion types during both grazing and housing periods were white line separation, sole hemorrhages and overgrown claws; all remaining lesions had a cow-level prevalence of less than 15%. The cow-level prevalence of alarm lesions was 19% during the grazing period and 25% during the housing period; the most prevalent alarm lesion was sole ulcers during both periods. We found significantly more foreign bodies within the hoof sole (grazing = 14%, housing = 7%) and overgrown claws (grazing = 71%, housing = 55%) during the grazing period compared with the housing period. Cows with foul of the foot, sole ulcer, white line abscess, toe necrosis or an amputated claw had higher odds of being more severely lame, compared with mildly lame. The strongest correlation between lesions were between toe necrosis and digital dermatitis (r = 0.40), overgrown claws and corkscrew claws (r = 0.33), and interdigital hyperplasia and digital dermatitis (r = 0.31) at herd level. At the cow level, the strongest correlation was between overgrown claws and corkscrew claws (r = 0.27), and digital dermatitis and heel erosion (r = 0.22). The farmers' perception of the presence of digital dermatitis (and lameness) was significantly correlated with the actual presence of digital dermatitis recorded. Additional risk factors for the presence of digital dermatitis were cow track and verge width near the collecting yard, and stone presence on the cow tracks. Results from this study help further our understanding of the causes of lameness in partly housed, pasture-based dairy cows, and can be used to guide prevention and treatment protocols.

Lameness prevalence and management practices on Irish pasture-based dairy farms.

BACKGROUND: Lameness is a painful disease, which negatively impacts dairy cow production and welfare. The aim of this observational study was to determine herd lameness prevalence, describe current lameness management practices and identify the presence of established risk factors for lameness on Irish pasture-based dairy farms. Farms were visited once during grazing (99 farms) and again during housing (85 farms). Lameness scoring was carried out at each visit (AHDB 0-3 scale); cows were classified as lame if they scored two or three. Farm management practices and infrastructure characteristics were evaluated via farmer questionnaires and direct measurements of farm infrastructure. RESULTS: Median herd-level lameness prevalence was 7.9% (interquartile range = 5.6 - 13.0) during grazing and 9.1% (interquartile range = 4.9 - 12.0) during housing; 10.9% of cows were lame at a single visit and 3.5% were lame at both visits (chronically lame or had a repeat episode of lameness). Fifty-seven percent of farmers were not familiar with lameness scoring and only one farm carried out lameness scoring. Only 22% of farmers kept records of lame cows detected, and 15% had a lameness herd health plan. Twenty-eight percent of farmers waited more than 48 h to treat a lame cow, and 21% waited for more than one cow to be identified as lame before treating. Six percent of farmers carried out routine trimming and 31% regularly footbathed (> 12 times per year). Twelve percent put severely lame cows in a closer paddock and 8% stated that they used pain relief to treat severely lame cows. Over 50% of farms had at least one cow track measurement that was classified as rough or very rough, and cow tracks were commonly narrow for the herd size. On 6% of farms, all cubicle beds were bare concrete (no matting or bedding) and on a further 6% of farms, there was a combination of cubicles with and without matting or bedding. On 56% of farms, all pens contained less than 1.1 cubicles per cow and on 28% of farms, a proportion of pens contained less than 1.1 cubicles per cow. CONCLUSIONS: Overall, this study identified infrastructure and management practices which could be improved upon. The comparatively low lameness prevalence demonstrated, compared to fully housed systems, also highlights the benefits of a pasture-based system for animal welfare; however, there remains scope for improvement.

Cow- and herd-level risk factors for lameness in partly housed pasture-based dairy cows.

Lameness in dairy cows is a major animal welfare concern and has substantial economic impact through reduced production and fertility. Previous risk factor analyses have focused on housed systems, rather than those where cows were grazed for the majority of the year and housed only for the winter period. Therefore, the aim of this observational study was to identify a robust set of cow-level and herd-level risk factors for lameness in a pasture-based system, based on predictors from the housing and grazing periods. Ninety-nine farms were visited during the grazing period (April 2019-September 2019), and 85 farms were revisited during the housing period (October 2019-February 2020). At each visit, all lactating cows were scored for lameness (0 = good mobility, 1 = imperfect mobility, 2 = impaired mobility, 3 = severely impaired mobility), and potential herd-level risk factors were recorded through questionnaires and infrastructure measurements. Routine cow-level management data were also collected. Important risk factors for lameness were derived though triangulation of results from elastic net regression, and from logistic regression model selection using modified Bayesian information criterion. Both selection methods were implemented using bootstrapping. This novel approach has not previously been used in a cow-level or herd-level risk factor analysis in dairy cows, to the authors' knowledge. The binary outcome variable was lameness status, whereby cows with a lameness score of 0 or 1 were classed as non-lame and cows with a score of 2 or 3 were classed as lame. Cow-level risk factors for increased lameness prevalence were age and genetic predicted transmitting ability for lameness. Herd-level risk factors included farm and herd size, stones in paddock gateways, slats on cow tracks near the collecting yard, a sharper turn at the parlor exit, presence of digital dermatitis on the farm, and the farmers' perception of whether lameness was a problem on the farm. This large-scale study identified the most important associations between risk factors and lameness, based on the entire year (grazing and housing periods), providing a focus for future randomized clinical trials.

Field survey to evaluate space allowances for dairy cows in Great Britain.

Housing conditions can affect health of cows by increasing exposure to biological, chemical, and physical hazards, resulting in increased disease. A report in 2014 indicated that 99% of UK dairy cows are housed during winter months and that an increasing number of farms are committing to year-round indoor-housing management systems. Current literature does not provide a clear understanding of the relationship between cow health, welfare, and production, and the housing environment. Loafing space, in this case defined as non-feed, non-lying, and non-high traffic areas of the housed environment, is considered an important component of housing for dairy cows; however, the scientific literature associated with this subject is sparse internationally. The aim of this research was to explore current housing of dairy cows across Great Britain, with specific focus on understanding the practices and variability associated with space allowance. A secondary aim was to explore farmer opinions and knowledge on the value of living space. A single researcher visited 53 randomly selected farms, from a representative sample group, once during the winter housing period 2017-18. Data collection consisted of 3 elements: collation of basic farm details, precise measurement of adult dairy cow accommodation, and a questionnaire to capture farmer opinions on space allowances. Statistical analysis was undertaken to assess variation among farms in total space, loafing space, and living space per cow. A new metric, termed "living space," was defined to describe the additional space availability for dairy cows above that deemed to be a baseline requirement. Large variability was identified between farms in total space available per cow, with a range from 5.4 to 12.7 m2 [mean = 8.3 m2, median = 8.2 m2, interquartile range (IQR) = 1.9 m2]. The mean living space was 2.5 m2, with a range of 0.5 m2 to 6.4 m2 (median = 2.4 m2, IQR = 1.6 to 3.2 m2). Responses from a farmer questionnaire on importance of loafing space revealed that farmers felt it was essential for cow welfare, over half of farmers scoring this ≥8 on a 0 to 10 scale. Farmers were categorized into 4 latent classes based on their attitudes toward the importance of loafing space. In a linear model to predict the "living space" provided on each farm, geographical location and latent class of farmer attitude were covariates significantly associated with the amount of space provided. This study is the first worldwide to quantify variability in loafing and living spaces for dairy herds; further research is required to evaluate the extent to which variation in quantity and quality of space influences cow health, welfare, and productivity, as well as farm economics and emissions.

Associations between routinely collected Dairy Herd Improvement data and insemination outcome in UK dairy herds.

Milk constituent concentrations in samples taken during early lactation are often used to generate proxy measures for energy balance in dairy herds. This study aimed to explore associations between these and other measures routinely recorded by Dairy Herd Improvement schemes and insemination outcome, with an emphasis on the likely predictiveness of such measures for conception risk (the proportion of inseminations that are successful) at herd level. Data from 312 UK dairy herds were restructured so that each unit of data represented an insemination at less than 100 d in milk (DIM). Milk constituent concentrations from the first and second test days (corrected for the effects of season and DIM at sampling) were used as potential predictors of insemination outcome in a logistic regression model. Other predictors included representations of milk yield and other information routinely collected by Dairy Herd Improvement Associations; random effects were used to account for clustering at cow and herd levels. The final model included a large number of predictors, with several interaction and nonlinear terms. The relative effect sizes of the measures of early lactation milk constituent concentrations were small. The full model predicted just under 64% of observed variation in herd-year conception risk (i.e., the proportion of inseminations that were successful in each herd in each calendar year); however, around 40% was accounted for by the herd-level random effect. The predictors based on early lactation milk constituent concentrations accounted for less than 0.5% of observed variation, and representations of milk yield (both overall level of yield and early lactation curve shape) accounted for around 7%; DIM at insemination, parity, interservice interval, year, and month accounted for the remaining 15%. These results suggest that early lactation milk constituent information is unlikely to predict herd conception risk to a useful extent. The large proportion of observed variation explained by the herd-level random effect suggests that there are unmeasured (in this study) or unmeasurable factors that are consistent within a herd and are highly influential in determining herd conception risk.

Associations between dairy cow inter-service interval and probability of conception.

Recent research has indicated that the interval between inseminations in modern dairy cattle is often longer than the commonly accepted cycle length of 18-24 days. This study analysed 257,396 inseminations in 75,745 cows from 312 herds in England and Wales. The interval between subsequent inseminations in the same cow in the same lactation (inter-service interval, ISI) were calculated and inseminations categorised as successful or unsuccessful depending on whether there was a corresponding calving event. Conception risk was calculated for each individual ISI between 16 and 28 days. A random effects logistic regression model was fitted to the data with pregnancy as the outcome variable and ISI (in days) included in the model as a categorical variable. The modal ISI was 22 days and the peak conception risk was 44% for ISIs of 21 days rising from 27% at 16 days. The logistic regression model revealed significant associations of conception risk with ISI as well as 305 day milk yield, insemination number, parity and days in milk. Predicted conception risk was lower for ISIs of 16, 17 and 18 days and higher for ISIs of 20, 21 and 22 days compared to 25 day ISIs. A mixture model was specified to identify clusters in insemination frequency and conception risk for ISIs between 3 and 50 days. A "high conception risk, high insemination frequency" cluster was identified between 19 and 26 days which indicated that this time period was the true latent distribution for ISI with optimal reproductive outcome. These findings suggest that the period of increased numbers of inseminations around 22 days identified in existing work coincides with the period of increased probability of conception and therefore likely represents true return estrus events.

The association between age at first calving and survival of first lactation heifers within dairy herds.

The objective of this research was to evaluate the survival rate of primiparous heifers within a large sample of herds across the United Kingdom and specifically to assess the association between age at first calving (AFC) on their survival. Data from 437 herds were re-structured for analysis. Descriptive statistics were calculated, and a multilevel logistic regression model was used to explore factors associated with the risk of first lactation culling. Potential explanatory variables included AFC, herd size, culling rate within the whole herd, calving season, herd mean 305-day yield and herd mean calving interval. The mean within-herd culling rate for the primiparous heifers was 15.9%. The mean within-herd AFC was 29.6 months, with 35.9% of heifers having an AFC >30 months of age. Multivariable analysis revealed a negative association between survival rate of primiparous heifers and increasing AFC, and also associations with herd culling rate in older cows and calving season. This study highlights the importance of AFC for survival of primiparous heifers, as well as the need to address heifer wastage in herds with high culling rates.

Prediction of intramammary infection status across the dry period from lifetime cow records.

The dry period is very important for mammary gland health, with the aim not only to cure existing intramammary infections (IMI) but also to prevent new IMI. Although it is known that the dry period is an important time for optimizing udder health, the probability that individual cows will succumb to a new IMI or, if infected, will fail to cure an IMI is not well established. The aim of this study was to investigate whether lifetime cow data, available through routine on-farm milk recording, could be used to predict changes in IMI status across the dry period for individual cows that were (1) deemed high somatic cell count (SCC; >199,000 cells/mL) or (2) low SCC (<200,000 cells/mL) at the last test day before drying off. Milk recording data collected between September 1994 and July 2014 from 114 herds in the United Kingdom were used. Two 2-level random effects models were built and both cure and new IMI were used as outcome variables in separate models. Cows with a smaller proportion of test days with a high SCC in the lactation before drying off, a smaller proportion of test days recording a high SCC in the lactation before the current lactation, of lower parity, producing less milk before drying off, of lower days in milk at drying off, and of lower SCC just before drying off were more likely to cure across the dry period. Dry period length had no effect on the likelihood of cure. Individual cows with a smaller proportion of test days recording a high SCC in the lactation before the current, of lower parity, of lower milk production at drying off, and fewer days in milk at drying off were less likely to develop a new IMI. Dry period length was found to have no effect on the probability of new IMI. Model predictions showed that a high level of discrimination was possible between cows with a high and low risk of both cures and new infections across the dry period.

Current management practices and interventions prioritised as part of a nationwide mastitis control plan.

The objectives of this study were to report performance and management data taken from a sample of UK dairy farms that have participated in the Agriculture and Horticulture Development Board Dairy Mastitis Control Plan (DMCP) and to identify important mastitis prevention practices that are not currently widely implemented. A total of 234 UK dairy herds were included in the study from which farm management and udder health data were collected. Herds were grouped according to their mastitis epidemiology and could be classed as (i) environmental dry period (EDP) (i.e. environmental pathogen with majority of infections being acquired during the dry period), (ii) environmental lactation (EL), (iii) contagious dry period (CDP) or (iv) contagious lactation (CL). The results of this study showed that many mastitis-related management practices that are generally considered to be important were not widely performed. A better understanding of those practices not widely adopted by UK dairy farmers at present may aid practitioners in identifying and overcoming potential barriers to improved mastitis control.

Effect of early lactation foot trimming in lame and non-lame dairy heifers: a randomised controlled trial.

Foot trimming is a common management intervention in prevention of lameness in dairy cattle. Despite this, there is surprisingly limited experimental evidence on its efficacy, especially in regard to primiparous heifers. A randomised, negatively controlled trial was conducted to investigate the association between an early lactation foot trim on primiparous animals and production outcomes. 282 heifers were enrolled from eight farms in the UK, and randomly assigned to treatment or control groups. Milk yield (305-day-adjusted whole-milk yield) was not significantly different between groups (trimmed 7727 litres, untrimmed 7646 litres). However, multivariate regression analysis demonstrated that this relationship was confounded by lameness state. Animals that were lame at the time of trimming gave significantly more milk (734 litres, P=0.02) than those that were non-lame and untrimmed. The present results suggest that, based on milk production alone, it would not have been cost beneficial to trim all heifers; however, a targeted intervention aimed at lame animals would have delivered a substantial return on investment. As a very minimum, the authors recommend heifers should be regularly assessed in early lactation, and treated as soon as they are identifiably lame. The high prevalence of lesions identified suggests routine trimming for all heifers may be justifiable on welfare grounds even if the milk-yield benefits are marginal.

Variation in the interservice intervals of dairy cows in the United Kingdom.

An understanding of the normal estrous-cycle length of the cow is important when managing and monitoring dairy-herd fertility. Although the normal interovulatory interval is widely considered to be 21 d, some studies have found alternative intervals to be more prevalent; previously, most of the variation in interval length was expected to be between cows. The aim of this study was to assess the time between inseminations (interservice interval, ISI) in a large number of dairy cows and to explore possible associations between cow factors and estrous-cycle length. The study used ISI data from 42,252 cows in 159 herds across England and Wales. Univariate analysis of the subset of 114,572 intervals between 15 and 30 d (a range covering the increased frequency of ISI occurring at the expected time of the first return to estrus) following an insemination revealed a modal ISI of 22d. Primiparous heifers had a modal ISI of 21 d. Significant differences existed between the distribution of ISI for different yield groups, parity numbers, and the number of inseminations. Multilevel regression modeling was used to evaluate the associations between cow factors and ISI, while accounting for clustering at the herd and cow level. This revealed significant associations between predicted ISI and insemination number, days in milk, lactation 305-d milk yield, and month and year of insemination. Variance partition coefficients indicated that only 1% of variation in ISI was at the herd level, 12% at the animal level, and 87% at the insemination level, indicating that cycle length varies substantially more between cycles within a cow than between cows or herds. These findings suggest the normal range of ISI for modern UK dairy cows is longer than expected and cycle length has a large amount of unexplained variation within individual animals over time.

Resistance to the tyrosine kinase inhibitor axitinib is associated with increased glucose metabolism in pancreatic adenocarcinoma.

Alterations in energy (glucose) metabolism are key events in the development and progression of cancer. In pancreatic adenocarcinoma (PDAC) cells, we investigated changes in glucose metabolism induced by resistance to the receptor tyrosine kinase inhibitor (RTKI) axitinib. Here, we show that human cell lines and mouse PDAC cell lines obtained from the spontaneous pancreatic cancer mouse model (Kras(G12D)Pdx1-cre) were sensitive to axitinib. The anti-proliferative effect was due to a G2/M block resulting in loss of 70-75% cell viability in the most sensitive PDAC cell line. However, a surviving sub-population showed a 2- to 3-fold increase in [C-14]deoxyglucose ([C-14]DG) uptake. This was sustained in axitinib-resistant cell lines, which were derived from parental PDAC. In addition to the axitinib-induced increase in [C-14]DG uptake, we observed a translocation of glucose transporter-1 (Glut-1) transporters from cytosolic pools to the cell surface membrane and a 2-fold increase in glycolysis rates measured by the extracellular acidification rate (ECAR). We demonstrated an axitinib-induced increase in phosphorylated Protein Kinase B (pAkt) and by blocking pAkt with a phosphatidylinositol-3 kinase (PI3K) inhibitor we reversed the Glut-1 translocation and restored sensitivity to axitinib treatment. Combination treatment with both axitinib and Akt inhibitor in parental pancreatic cell line resulted in a decrease in cell viability beyond that conferred by single therapy alone. Our study shows that PDAC resistance to axitinib results in increased glucose metabolism mediated by activated Akt. Combining axitinib and an Akt inhibitor may improve treatment in PDAC.

Rate of transmission: a major determinant of the cost of clinical mastitis.

The aim of this research was to use probabilistic sensitivity analysis to evaluate the relative importance of different components of a model designed to estimate the cost of clinical mastitis (CM). A particular focus was placed on the importance of pathogen transmission relative to other factors, such as milk price or treatment costs. A stochastic Monte Carlo model was developed to simulate a case of CM at the cow level and to calculate the associated costs for 5 defined treatment protocols. The 5 treatment protocols modeled were 3 d of antibiotic intramammary treatment, 5 d of antibiotic intramammary treatment, 3 d of intramammary and systemic antibiotic treatment, 3d of intramammary and systemic antibiotic treatment plus 1 d of nonsteroidal antiinflammatory drug treatment, and 5 d of intramammary and systemic antibiotic treatment. Uniform distributions were used throughout the model to enable investigation of the cost of CM over a spectrum of clinically realistic scenarios without specifying which scenario was more or less likely. A risk of transmission parameter distribution, based on literature values, was included to model the effect of pathogen transmission to uninfected cows, from cows that remained subclinically infected after treatment for CM. Spearman rank correlation coefficients were used to evaluate the relationships between model input values and the estimated cost of CM. Linear regression models were used to explore the effect that changes to specific independent variables had on the cost of CM. Risk of transmission was found to have the strongest association with the cost of CM, followed by bacteriological cure rate, cost of culling, and yield loss. Other factors such as milk price, cost of labor, and cost of medicines were of minimal influence in comparison. The cost of CM was similar for all 5 treatment protocols. The results from this study suggest that, when seeking to minimize the economic impact of CM in dairy herds, great emphasis should be placed on the reduction of pathogen transmission from cows with CM to uninfected cows.

Associations between udder health and reproductive performance in United Kingdom dairy cows.

The objective of this research was to evaluate the relationship between udder health and reproductive performance in UK dairy cows. Data from 80 herds were restructured such that each unit of data represented a 2-d period during lactation where a cow was at risk of becoming pregnant. Multilevel discrete-time survival models were then used within a Bayesian framework to explore associations between reproductive outcomes and a variety of potential explanatory variables. Separate models were constructed using 2 different univariate binary outcomes: a cow becoming pregnant during a risk period and a cow becoming pregnant as a result of a given service. Potential explanatory variables included occurrence of clinical mastitis and a categorical representation of individual cow somatic cell count (SCC), both at a variety of timings relative to the risk period. Posterior predictions were used to assess model fit and to check model building assumptions. These demonstrated that the model represented the data well. Within-sample Monte Carlo simulation (i.e., use of the model to predict outcomes for cases within the data set, repeated over a large number of iterations) was used to illustrate results as posterior predicted relative risks. A negative association was found between reproductive performance and cases of clinical mastitis over a wide time frame relative to the risk period (from 28 d before to 70 d after the risk period). A similar negative association with the probability of a service leading to a pregnancy (pregnancy rate) was observed over the same time frame. Higher SCC recordings (i.e., those more likely to be associated with an intramammary infection) were also associated with decreased reproductive performance, especially where an individual cow SCC of greater than 399,000/mL was recorded in the 30 d following a risk period or service. This research demonstrates that both clinical and subclinical mastitis are associated with a reduction in reproductive performance, and that this influence varies in magnitude but can be exerted over a prolonged period.

Brn-3a/POU4F1 interacts with and differentially affects p73-mediated transcription.

The Brn-3a/POU4F1 POU transcription factor is critical for the survival and differentiation of specific sensory neurons during development or upon injury; by regulating expression of target genes, either directly or indirectly upon interaction with other proteins. In this study, we demonstrated the physical interaction of Brn-3a with different p73 isoforms and showed co-localization in sensory neurons arising from the neural crest. The biological effects of p73/ Brn-3a interaction depend on the particular p73 isoform, because co-expression of Brn-3a with TAp73 enhanced cell cycle arrest, whereas Brn-3a and DeltaNp73 cooperated to increase protection from apoptosis. Brn-3a antagonized TAp73 transactivation of pro-apoptotic Bax, but co-operated to increase transcription of the cell cycle regulator p21 CIP1/Waf1. The region 425-494 amino acids within the TAp73 C terminus were critical for Brn-3a to repress Bax transactivation, but not for cooperation on the p21 CIP1/Waf1 promoter. Our results suggest that co-factors binding to the p73 C terminus facilitate maximal activation on the Bax but not p21 CIP1/Waf1 promoter and that Brn-3a modulates this interaction. Thus, the physical interaction of Brn-3a with specific p73 isoforms will be critical for determining cell fate during neuronal development or in injured neurons expressing both factors.

The disturbances in odontogenesis in epidermolysis bullosa hereditaria letalis.

The disturbances in odontogenesis in a case of epidermolysis bullosa hereditaria letalis are described, with particular emphasis on the morphologic alterations in the ameloblasts and on the nature of vesicles in the enamel organ. These latter structures are compared to those found in the skin.

Autosomal dominant hypodontia with nail dysgenesis. Report of twenty-nine cases in six families.

Clinical details of twenty-three of twenty-nine cases of hypodontia and nail dysgenesis are presented. The classic features of severe hypodontia and a distinctive congenital nail defect were found in all families. The use of a simple method of sweat testing disclosed a minor deficiency of sweating in one family.