Seasonality and zoonotic foodborne pathogens in Canada: relationships between climate and Campylobacter, E. coli and Salmonella in meat products.

Infections due to Campylobacter, Escherichia coli and Salmonella pose a significant health burden in Canada, resulting in major costs to the health care system and economic impacts due to lost productivity resulting from illness. Recent literature suggests that climate may play a role in the prevalence of these pathogens along the food chain. This study used integrated surveillance data to examine associations between weather variables, serving as a proxy for climate, in agricultural areas and Campylobacter, generic E. coli and Salmonella contamination on samples of beef, poultry and swine meat products in Canada. Various temperature metrics (average, maximum and variability) were correlated with Campylobacter prevalence along the food chain. The prevalence of E. coli and Salmonella was correlated with both precipitation and temperatures metrics; however, analysis for E. coli was limited to beef and swine meats at retail settings, because prevalence in other combinations approached 100%, which obviated further analysis. Campylobacter contamination in poultry and swine at abattoir and retail settings demonstrated a seasonal trend, with increased prevalence generally from June or July through November, compared to the baseline month of December. Based on these analyses, Campylobacter is the most likely foodborne bacteria studied whose occurrence in meat products is affected by climatic changes in Canada. An exploratory analysis of data at the provincial scale, using Ontario as an example, revealed similar directional relationships between climate and bacterial prevalence.

Comparative efficacy of blanket versus selective dry-cow therapy: a systematic review and pairwise meta-analysis.

A systematic review and meta-analysis were conducted to determine the efficacy of selective dry-cow antimicrobial therapy compared to blanket therapy (all quarters/all cows). Controlled trials were eligible if any of the following were assessed: incidence of clinical mastitis during the first 30 DIM, frequency of intramammary infection (IMI) at calving, or frequency of IMI during the first 30 DIM. From 3480 identified records, nine trials were data extracted for IMI at calving. There was an insufficient number of trials to conduct meta-analysis for the other outcomes. Risk of IMI at calving in selectively treated cows was higher than blanket therapy (RR = 1.34, 95% CI = 1.13, 1.16), but substantial heterogeneity was present (I2 = 58%). Subgroup analysis showed that, for trials using internal teat sealants, there was no difference in IMI risk at calving between groups, and no heterogeneity was present. For trials not using internal teat sealants, there was an increased risk in cows assigned to a selective dry-cow therapy protocol, compared to blanket treatment, with substantial heterogeneity in this subgroup. However, the small number of trials and heterogeneity in the subgroup without internal teat sealants suggests that the relative risk between treatments may differ from the determined point estimates based on other unmeasured factors.

Comparative efficacy of antimicrobial treatments in dairy cows at dry-off to prevent new intramammary infections during the dry period or clinical mastitis during early lactation: a systematic review and network meta-analysis.

A systematic review and network meta-analysis were conducted to assess the relative efficacy of antimicrobial therapy given to dairy cows at dry-off. Eligible studies were controlled trials assessing the use of antimicrobials compared to no treatment or an alternative treatment, and assessed one or more of the following outcomes: incidence of intramammary infection (IMI) at calving, incidence of IMI during the first 30 days in milk (DIM), or incidence of clinical mastitis during the first 30 DIM. Databases and conference proceedings were searched for relevant articles. The potential for bias was assessed using the Cochrane Risk of Bias 2.0 algorithm. From 3480 initially identified records, 45 trials had data extracted for one or more outcomes. Network meta-analysis was conducted for IMI at calving. The use of cephalosporins, cloxacillin, or penicillin with aminoglycoside significantly reduced the risk of new IMI at calving compared to non-treated controls (cephalosporins, RR = 0.37, 95% CI 0.23-0.65; cloxacillin, RR = 0.55, 95% CI 0.38-0.79; penicillin with aminoglycoside, RR = 0.42, 95% CI 0.26-0.72). Synthesis revealed challenges with a comparability of outcomes, replication of interventions, definitions of outcomes, and quality of reporting. The use of reporting guidelines, replication among interventions, and standardization of outcome definitions would increase the utility of primary research in this area.

Comparative efficacy of teat sealants given prepartum for prevention of intramammary infections and clinical mastitis: a systematic review and network meta-analysis.

A systematic review and network meta-analysis were conducted to assess the relative efficacy of internal or external teat sealants given at dry-off in dairy cattle. Controlled trials were eligible if they assessed the use of internal or external teat sealants, with or without concurrent antimicrobial therapy, compared to no treatment or an alternative treatment, and measured one or more of the following outcomes: incidence of intramammary infection (IMI) at calving, IMI during the first 30 days in milk (DIM), or clinical mastitis during the first 30 DIM. Risk of bias was based on the Cochrane Risk of Bias 2.0 tool with modified signaling questions. From 2280 initially identified records, 32 trials had data extracted for one or more outcomes. Network meta-analysis was conducted for IMI at calving. Use of an internal teat sealant (bismuth subnitrate) significantly reduced the risk of new IMI at calving compared to non-treated controls (RR = 0.36, 95% CI 0.25-0.72). For comparisons between antimicrobial and teat sealant groups, concerns regarding precision were seen. Synthesis of the primary research identified important challenges related to the comparability of outcomes, replication and connection of interventions, and quality of reporting of study conduct.

Metabolic equivalents fail to indicate metabolic load in post-myocardial infarction patients during the modified Bruce treadmill walking test.

AIM: To investigate the suitability of metabolic equivalents (METs) for determining exercise intensity in phase-IV post-myocardial infarction (MI) men during the modified Bruce treadmill walking test (MBWT). METHODS: Twenty phase-IV post-MI men (mean±SD, aged 64.4±5.8 years) and 20 healthy non-cardiac male controls (59.8±7.6 years) participated. Participants performed a MBWT. Throughout the participants' heart rate (HR), heart rhythm, expired air parameters and ratings of perceived exertion (RPEs) were measured. MET values were compared between groups and those currently ascribed to each stage of the MBWT. RESULTS: General linear model analysis found no significant differences between groups during the MBWT for VO2, VCO2, HR, METs or RPEs (Borg 6-20 scale). Ascribed METs did not differ from mean METs of post-MIs or controls other than at stage 5 where post-MI METs were significantly lower. Irrespective, the post-MI group worked at a higher percentage of their anaerobic threshold (AT) (respiratory exchange ratio, RER=1.0) (F(2,5)=7.22, p<0.008), higher RER (F(2,5)=11.25, p<0.001) with increased breathing frequency (F(2,5)=7.22, p<0.001). Regression analysis revealed AT to be VO2 25.6 (mL/kg/min) for post-MI versus VO2 31.1 (mL/kg/min) for controls. Gross energy expenditure (kcal/min) was greater for the post-MI group compared with controls (F(2,5)=11.22, p<0.001). Throughout the MBWT, post-MI group worked at a higher %AT/MET than controls (F(2,196)=211.76, p<0.01). Body composition did not strongly influence %AT/MET, parameters of VO2, METs or RPE. CONCLUSION: During the MBWT, post-MI men worked more anaerobically per MET (%AT/MET) than controls. Therefore, current METs based on non-cardiac individuals appear unsuitable in determining the full metabolic load of the exercise intensity for cardiac patients during the MBWT.

Technical note: Digital quantification of eye pigmentation of cattle with white faces.

Cancer of the eye in cattle with white faces occurs less frequently in cattle with pigmented eyelids. Corneoscleral pigmentation is related to eyelid pigmentation and occurrence of lesions that may precede cancer. Objectives of this study were to assess 1) variation in the proportion of eyelid and corneoscleral pigmentation in Hereford, Bos taurus, and Bos indicus crossbreds and 2) the occurrence of lesions with the presence of pigmentation in those areas. Hereford and Bos indicus crosses (Brahman or Nellore with Angus and Hereford and straightbred Brafords) and Bos taurus crosses (Angus-Hereford) were included in the study (n = 1,083). Eyelid pigmentation proportions were estimated by pixel quantification and were evaluated as total proportions and for upper and lower eyelids distinctly for each eye. Fixed effects included breed type, age categories, and sex of the animal. Lesion presence (1) or absence (0) was obtained by visual appraisal of image and was assumed to be binomially distributed. Eyelid pigmentation proportions (overall, upper, and lower eyelids) for Hereford ranged from 0.65 ± 0.03 to 0.68 ± 0.03 and were significantly lower than Bos indicus (range from 0.93 ± 0.02 to 0.95 ± 0.02) or Bos taurus (ranged from 0.88 ± 0.02 to 0.92 ± 0.02) crosses. Corneoscleral pigmentation in Hereford cows (0.17 ± 0.06) did not differ (P = 0.91) from Hereford calves and yearlings (0.16 ± 0.07). Bos indicus and Bos taurus crossbred cows had larger corneoscleral pigmentation (0.38 ± 0.05 and 0.48 ± 0.04 for left eyes and 0.37 ± 0.05 and 0.53 ± 0.04 for right eyes, respectively) than all calves (P < 0.001), and their corneoscleral pigmentations were greater than that of Hereford cows (P < 0.003). Bos indicus and Bos taurus cows had greater proportions of left eye corneoscleral pigmentation (0.38 ± 0.05 and 0.48 ± 0.04, respectively) than Hereford cows (0.17 ± 0.06) and all young animal breed types (P < 0.05). Right eye proportions differed for all cow groups (P < 0.05; 0.53 ± 0.04, 0.37 ± 0.05, and 0.17 ± 0.06). Among calves and yearlings, Hereford had a lower right eye corneoscleral pigmentation proportion (0.16 ± 0.07) than Bos taurus (P = 0.02). The lesion proportion for Hereford (0.08 ± 0.03) was significantly greater than that of either Bos indicus (0.01 ± 0.005) or Bos taurus (0.01 ± 0.003). Crossbreeding with Bos taurus or Bos indicus animals appears to increase eye pigmentation, which may help reduce the occurrence of cancer in eyes of cattle with white faces.

Coxiella burnetii seropositivity and associated risk factors in sheep in Ontario, Canada.

Coxiella burnetii is a zoonotic bacterium that can cause abortion in sheep in late gestation, as well as the delivery of stillborn, and non-viable lambs (Rodolakis, 2006). A cross-sectional study was conducted in Ontario, Canada, to investigate C. burnetii exposure in sheep. Between August 2010 and January 2012, sera from 2363 reproductively active ewes from 72 farms were tested for C. burnetii specific antibodies using the CHEKIT Q fever ELISA Test kit (IDEXX Laboratories). Overall, exposure was common; sheep-level seroprevalence was 14.7% (347/2363, 95% CI: 13.3-16.2), and was higher in dairy sheep (24.3%, 181/744) than meat sheep (10.2%, 166/1619) (p<0.0001). At the farm-level, 48.6% (35/72, 95% CI: 37.2-60.1) of farms had at least one seropositive sheep. A mixed multivariable logistic model that controlled for farm-level clustering, identified risk factors associated (p<0.05) with sheep seropositivity. Increasing female flock size (logarithmic scale) was associated with increased odds of seropositivity. By way of illustration, increasing the female flock size from 100 to 200 increased the odds of seropositivity by 2.26 times (95% CI: 1.5-3.5). Sheep that lambed in an airspace separate from the flock had 11.3 times (95% CI: 2.9-43.6) the odds of seropositivity relative to other sheep. The practice of loaning sheep that returned to the farm increased odds of seropositivity by 8.1 times (95% CI: 1.8-33.6). Lambing pen hygiene practices also influenced odds of seropositivity. Relative to sheep from farms where all lambing pen hygiene measures were practiced after lambing (i.e., adding bedding, removing birth materials and disinfection), sheep from farms that only added bedding, or those that just added bedding and removed birthing materials had 5.9 times (95% CI: 1.1-32.1) and 9.0 times (95% CI: 2.2-36.9) the odds of seropositivity, respectively. These results can be used to inform prevention and control strategies with the aim of reducing C. burnetii exposure in sheep.

Coxiella burnetii seropositivity and associated risk factors in goats in Ontario, Canada.

Coxiella burnetii is a zoonotic bacterium, and infection in goats with this bacterium can result in abortion, stillbirth or birth of non-viable kids. A cross-sectional study was conducted to identify the seroprevalence and risk factors for C. burnetii exposure in Ontario goats. Sera were collected between August 2010 and February 2012, and tested for C. burnetii specific antibodies using an enzyme-linked immunosorbent assay (IDEXX). Overall, 63.2% (48/76, 95% CI=51.9-73.4) of farms had one or more seropositive goats. A higher farm-level seroprevalence of 78.6% (33/42) was found on dairy goat farms, compared to 44.1% (15/34) on meat goat farms (p<0.01). At the overall individual-animal level, 32.5% (714/2195, 95% CI=30.6-34.5) of goats were seropositive. Similarly, a higher individual-level seroprevalence was identified for dairy goats (43.7%, 633/1447) compared to meat goats (10.8%, 81/748) (p<0.001). A mixed multivariable logistic model that controlled for farm-level clustering identified risk factors associated with seropositivity (p<0.05). Increases in the female herd size (logarithmic scale) were associated with increased odds of seropositivity, while increases in male herd size had a negative association with seropositivity. If other sheep or goat farms were located in a 5-km radius, goats had 5.6 times (95% CI=1.01-30.8) times the odds of seropositivity compared to those that were not. Relative to goats from farms where all kidding pen hygiene was practiced (adding bedding, removing birth materials and disinfection after kidding), goats from farms which only added bedding and removed birth materials had a higher odds of seropositivity (OR=19.3, 95% CI=1.1-330.4), as did goats from farms which practiced none of these measures (OR=161.0, 95% CI=2.4-10822.2). An interaction term revealed kidding outdoors when there were no swine on farm had a protective effect on seropositivity compared to kidding indoors, or kidding outdoors with swine on the farm. These results can inform strategies to mitigate exposure to C. burnetii in Ontario.

Capecitabine and oxaliplatin in combination as first- or second-line therapy for metastatic breast cancer: a Wisconsin Oncology Network trial.

PURPOSE: Several cytotoxic chemotherapy regimens are active against metastatic breast cancer; however, benefits are modest and overall prognosis remains limited. For anthracycline and taxane-pretreated metastatic breast cancer, there remains a relative paucity of therapies with significant activity. This Phase II study evaluated the combination of capecitabine and oxaliplatin (XELOX) among patients with metastatic breast cancer being treated in the first- or second-line setting. METHODS: Patients received oxaliplatin 85 mg/m(2) on days 1 and 15, and capecitabine 1,500 mg/m(2) twice daily on days 1-7 and 15-21 of a 28-day cycle. Patients were treated until progression or intolerable toxicity. The primary objective was to estimate the objective response rate by the Response Evaluation Criteria in Solid Tumors (RECIST) criteria with tumor assessments every 8 weeks. RESULTS: Ten patients were treated of which 3 had received prior neurotoxic therapy in the metastatic setting. There were no confirmed complete responses, 5 patients had partial response, 4 patients had stable disease for at least 24 weeks, and one patient was unevaluable. Median time to progression (TTP) was 10.4 months (95% lower confidence bound [LCB]: 5.75 months), median progression-free survival (PFS) was 14.2 months (95% LCB: 6.14 months), and median overall survival (OS) was 19 months (95% LCB: 12.8 months). Multiple patients experienced pain syndromes and unusual neuropathies. Other common toxicities included fatigue, diarrhea, and nausea. CONCLUSIONS: XELOX is a promising regimen for anthracycline-pretreated metastatic breast cancer although careful patient selection is indicated and alternate dosing schedules should be explored to minimize neurologic morbidity.

The timing of educational investment: a neuroscientific perspective.

Economic models of investment in human capital sometimes refer to neuroscience as a means to support their underlying assumptions regarding human development. These assumptions have a crucial influence on the policy implications the models generate. We review the extent to which the neuroscience of development can be used to support a "learning begets learning" principle of human capital accumulation. We conclude that, although early neural development can be considered as foundational, it cannot be considered as a unitary phenomenon that proceeds in continuous fashion. Furthermore, the concept of the sensitive period, which is often used associated with the principle, suggests benefits of investment depend upon an individual's circumstances and developmental history, and particularly whether this can be classified as normal. A more recent model of investment has involved two different types of abilities, with outcomes demonstrating the value of including more sophisticated assumptions about human development. We conclude that, while current discussions of policy would benefit from a more careful interpretation of existing models, the potential for future work combining modern neuroscientific understanding with economic theory is considerable.

Investigation of the potential utility of a linomide analogue for treatment of choroidal neovascularization.

The aim of this study was to test the selectivity, in-vivo effectiveness, and potential mechanism of action of a linomide analogue (N-phenyl-1,2-dihydro-4-hydroxyl-2-oxo-quinoline-3-carboxamide, Lin05) for inhibition of choroidal neovascularization. The selectivity of Lin05 was tested in cell proliferation assays with human umbilical vein endothelial cells (HUVEC) and a retinal pigmented epithelial cell line(ARPE-19). In-vivo anti-angiogenic effect of Lin05 was investigated utilizing an experimental laser-induced choroidal neovascularization (ECNV) model in adult Brown Norway rats. Western blot and/or reverse transcriptase-PCR was used to test the effect of Lin05 on potential targets. Our results indicate that Lin05 is at least an 8-fold more selective inhibitor of endothelial cell proliferation compared to RPE cells. Systemic administration of Lin05 in an ECNV model was associated with a significant decrease in both vascular leakage on fluorescein angiography and lesion size by histopathology (p = 0.02). No systemic toxicity was detected for Lin05 in major organs such as the liver, lung and kidneys. Lin05 did not inhibit VEGF-induced VEGFR2 (KDR) phosphorylation in HUVEC nor was associated with decreased VEGF gene expression. Also it did not inhibit insulin-like growth factor (IGF-1) and Epidermal Growth Factor (EGF) induced activation of p42/p44 MAPK activation. It inhibited both PDGF- and bFGF-induced p42/p44 MAPK phosphorylation. However, the effect on PDGF was variable in different HUVEC cells. In conclusion, Lin05 is a potential anti-angiogenic agent for the treatment of eye diseases associated with pathological neovascularization. The anti-angiogenic effect of Lin05 is likely through inhibition of bFGF but not through inhibition of the VEGF/KDR pathway.

Procedures provided to Medicaid recipients by pediatric, general and public health dentists in the commonwealth of Virginia: fiscal years 1994 and 1995.

PURPOSE: The purpose of this study was to report any differences found among the mean percentages of procedures performed by three types of dental providers for each type of service performed. The study focused on the types of services provided by dentists to Medicaid children in Virginia. METHODS: Medicaid claims field for dental patients younger than age 21 were obtained and analyzed for fiscal years 1994 and 1995. Dental providers were categorized according to their practice: general practice (GP), pediatric dentist (PD) and public health dentist (PH). Each type of practitioner (GP, PD, and PH) was evaluated for percentages of diagnostic, preventive, and corrective services provided to their Medicaid patients. The preventive category was subdivided into preventive services (scaling, prophy, fluoride and oral hygiene instruction) and sealant services. RESULTS: For each type of service, the mean percentages of procedures performed were compared among the three types of dental providers. The evaluation of the diagnostic procedure variable resulted in the finding that GP practitioners performed a significantly greater percentage of diagnostic procedures to their Medicaid patients than do PD and PH dentists (p < 0.0001). The percentage of preventive procedures performed by PD and GP dentists was not significantly different but was significantly lower than those performed by PH dentists (p < 0.0001). Finally, PD dentists performed a significantly greater percentage of corrective procedures than both GP and PH dentists (p > 0.0037). CONCLUSION: Differences were found among the mean percentages of procedures performed by the three types of dental providers for each type of service performed.

Characterization of muscle actin genes in Drosophila virilis reveals significant molecular complexity in skeletal muscle types.

Actin is a ubiquitous and highly conserved eukaryotic protein required for cell motility and locomotion. In this manuscript, we characterize the four muscle actin genes of the insect Drosophila virilis and demonstrate strong similarities between the D. virilis genes and their homologues in Drosophila melanogaster; intron locations are conserved, and there are few amino acid differences between homologues. We also found strong conservation in temporal expression patterns of the muscle actin genes--the homologues of the D. melanogaster genes Act57B and Act87E are expressed throughout the life cycle, whereas the other two D. virilis genes, homologous to Act79B and Act88F are specific to pupal and adult stages. In situ hybridization revealed that each D. virilis gene is expressed in a unique pattern in the muscles of the thorax and abdomen. These muscle-specific patterns of actin isoforms suggest a greater physiological diversity for the adult muscles of insects than has been appreciated to date from their categorization into fibrillar, tubular (non-fibrillar) and supercontractile muscle types.

Results of a community pharmacy-based breast cancer risk-assessment and education program.

We tested the hypothesis that an education program addressing breast cancer screening schedules and modalities coupled with a breast cancer risk assessment provided by community pharmacists can increase women's confidence in performing screening practices endorsed by the American Cancer Society (ACS). This randomized, paired, pre-post study was conducted in six community pharmacies and two health-screening fairs; subjects were 140 women over 18 years of age. The pharmacist-administered program used the Breast Cancer Risk-Assessment Tool (Gail model) software provided by the National Cancer Institute of the National Institutes of Health. In addition, pharmacists provided education and training on breast self-examination (BSE), clinical breast examination (CBE), and mammography. Adherence to ACS guidelines for monthly BSE increased from 31% to 56% (p<0.001) for all women 6 months after the program. Performance of monthly BSE by women considered at high risk for developing breast cancer increased from 20% to 60% (p<0.005). The mean number of BSEs performed over 6 months increased from 2.69 to 4.09 (p<0.001). Women's confidence performing correct BSE improved from 6.41 to 7.04 (p<0.001) on a scale of 0-10. Adherence to ACS guidelines for CBE and mammography did not reveal statistically significant improvements except for better adherence to CBE in women aged 40-49 years (81% to 97%, p<0.025). The strength of the pharmacists' intervention may not appear as manipulation of high-risk patients' behavior but as improvement of self-directed behaviors, such as BSE, across all age groups.

Genome-wide study of aging and oxidative stress response in Drosophila melanogaster.

Aging is a universal but poorly understood biological process. Free radicals accumulate with age and have been proposed to be a major cause of aging. We measured genome-wide changes in transcript levels as a function of age in Drosophila melanogaster and compared these changes with those caused by paraquat, a free-radical generator. A number of genes exhibited changes in transcript levels with both age and paraquat treatment. We also found genes whose transcript levels changed with age but not with paraquat treatment. This study suggests that free radicals play an important role in regulating transcript levels in aging but that they are not the only factors. This genome-wide survey also identifies candidates for molecular markers of aging.

The modulation of B16BL6 melanoma metastasis is not directly mediated by cytolytic activity of natural killer cells in alcohol-consuming mice.

BACKGROUND: Previous studies in our laboratory indicate that alcohol consumption suppresses the metastasis of B16BL6 melanoma, whereas the cytolytic activity of natural killer (NK) cells is decreased in female C57BL/6 mice given 20% w/v alcohol in their drinking water. In the present study, we further evaluated the involvement of NK cells and alcohol consumption in the cytolytic activity of NK cells, the surface expression of NK phenotypic markers, and metastasis of B16BL6 melanoma in C57BL/6 beige (bgJ/bgJ) mutant mice, which possess inherently low NK-cell cytolytic activity. METHODS: Beige and control (bgJ/+) mice were given either water or 20% w/v of alcohol in drinking water for 6 1/2 to 7 weeks before assay for cytolytic activity, surface marker expression, and inoculation with B16BL6 melanoma intravenously or into the pinna of the ear. RESULTS: NK cytolytic activity was suppressed in beige mice, and alcohol consumption did not modulate further the cytolytic activity. Beige mice had a lower percentage of NK cells in the peripheral blood and spleen than control mice. Peripheral blood lymphocytes from beige mice also exhibited a reduced percentage of CD4+ T lymphocytes. Alcohol consumption similarly reduced the percentages of NK1.1- and LGL-1-expressing lymphocytes in the peripheral blood and spleen and reduced the percentage of CD8+ T lymphocytes in the peripheral blood in both control and beige mice. Tumor lung colonization was increased in beige mice relative to control mice after intravenous inoculation of B16BL6 melanoma. The increase was more pronounced in water-drinking beige mice than in control mice irrespective of alcohol consumption. Tumor lung colonization was significantly decreased (p < 0.05) by alcohol consumption in one experiment and partially decreased (p = 0.07) in the other. Mice that were inoculated into the pinna of the ear also exhibited a blunted antimetastatic response to alcohol consumption. CONCLUSIONS: These data suggest that the presence of the beige mutation diminishes the antimetastatic effect of alcohol consumption and that there is no interaction between alcohol consumption and NK-cell activity in the modulation of lung metastasis of B16BL6 melanoma cells.

A gain-of-function screen for genes that affect the development of the Drosophila adult external sensory organ.

The Drosophila adult external sensory organ, comprising a neuron and its support cells, is derived from a single precursor cell via several asymmetric cell divisions. To identify molecules involved in sensory organ development, we conducted a tissue-specific gain-of-function screen. We screened 2293 independent P-element lines established by P. Rorth and identified 105 lines, carrying insertions at 78 distinct loci, that produced misexpression phenotypes with changes in number, fate, or morphology of cells of the adult external sensory organ. On the basis of the gain-of-function phenotypes of both internal and external support cells, we subdivided the candidate lines into three classes. The first class (52 lines, 40 loci) exhibits partial or complete loss of adult external sensory organs. The second class (38 lines, 28 loci) is associated with increased numbers of entire adult external sensory organs or subsets of sensory organ cells. The third class (15 lines, 10 loci) results in potential cell fate transformations. Genetic and molecular characterization of these candidate lines reveals that some loci identified in this screen correspond to genes known to function in the formation of the peripheral nervous system, such as big brain, extra macrochaetae, and numb. Also emerging from the screen are a large group of previously uncharacterized genes and several known genes that have not yet been implicated in the development of the peripheral nervous system.

Androgen receptor YAC transgenic mice carrying CAG 45 alleles show trinucleotide repeat instability.

X-linked spinal and bulbar muscular atrophy (SBMA) is caused by a CAG repeat expansion in the first exon of the androgen receptor (AR) gene. Disease-associated alleles (37-66 CAGs) change in length when transmitted from parents to offspring, with a significantly greater tendency to shift size when inherited paternally. As transgenic mice carrying human AR cDNAs with 45 and 66 CAG repeats do not display repeat instability, we attempted to model trinucleotide repeat instability by generating transgenic mice with yeast artificial chromosomes (YACs) carrying AR CAG repeat expansions in their genomic context. Studies of independent lines of AR YAC transgenic mice with CAG 45 alleles reveal intergenerational instability at an overall rate of approximately 10%. We also find that the 45 CAG repeat tracts are significantly more unstable with maternal transmission and as the transmitting mother ages. Of all the CAG/CTG repeat transgenic mice produced to date the AR YAC CAG 45 mice are unstable with the smallest trinucleotide repeat mutations, suggesting that the length threshold for repeat instability in the mouse may be lowered by including the appropriate flanking human DNA sequences. By sequence-tagged site content analysis and long range mapping we determined that one unstable transgenic line has integrated an approximately 70 kb segment of the AR locus due to fragmentation of the AR YAC. Identification of the cis -acting elements that permit CAG tract instability and the trans -acting factors that modulate repeat instability in the AR YAC CAG 45 mice may provide insights into the molecular basis of trinucleotide repeat instability in humans.

Failure of endometrial cup development in the donkey-in-horse model of equine abortion.

The mature preinvasive chorionic girdles of horse, mule, donkey and extraspecies donkey-in-horse conceptuses, and the very young endometrial cups on d 37 of gestation in mares carrying horse, mule and transferred donkey-in-horse conceptuses, were compared histologically and ultrastructurally to determine possible mechanisms underlying failure of endometrial cup development in the donkey-in-horse model of equine abortion. The progenitor chorionic girdle from the failing donkey-in-house pregnancy was similar in size to the normal donkey chorionic girdle but the trophoblast cells within the former were smaller, less organised and showed definite signs of degeneration and pyknosis. In the 37 d endometrial cups both in the horse and mule pregnancies, the recently invaded, differentiated and enlarging endometrial cup cells had penetrated deeply into the endometrial stroma and were becoming tightly packed between the persisting endometrial glands. In the donkey-in-horse pregnancy, on the other hand, relatively few donkey chorionic girdle cells had begun the invasion process and the majority of these, having penetrated and dislodged the horse luminal epithelium, did not penetrate the basement membrane beneath. Very few cells had reached the endometrial stroma and these had already attracted considerable numbers of lymphocytes to the area. It is concluded that unknown factors in the horse uterus affect adversely all phases of the development, attachment and invasion of donkey chorionic girdle cells, thereby leading to very little or no endometrial cup development and equine chorionic gonadotropin secretion in the extraspecific donkey-in-horse pregnancy created by embryo transfer.

Religious issues in the capacity evaluation.

The authors explore the difficulties present in the capacity evaluation of patients with strong religious beliefs. The article reviews the legal protection for treatment refusal on religious grounds as well as psychiatry's approach to religion. Clinical cases encountered in an urban hospital are presented to highlight how the conflicts among psychiatric, religious, and legal issues can be resolved. Suggestions are made for incorporating an exploration of religious values into the capacity assessment.