Prevalence, risk factors and vaccination efficacy of contagious ovine ecthyma (orf) in England.

Orf is a viral disease found in English sheep flocks which can cause economic losses. It is a zoonosis with little epidemiological research available in the UK. In 2012, 3000 questionnaires were sent to English sheep farms in order to investigate the prevalence of orf, determine vaccination efficacy and to identify some of the potential risk factors. The usable response rate was 25.4 per cent. The usable farms (N=762 in the years 2011 and 2012) were used to model the percentage of animals affected on the farm, and the probability of a farm being found with the disease. The disease prevalence (DP) was standardised for the year and calculated as 1.88 per cent for ewes and 19.53 per cent for lambs. The disease risk ratio (RR) for the use of the vaccine was calculated as 2.04 for ewes and 0.75 for lambs, and therefore, the study found that lamb vaccination was beneficial (RR <1). Weed infestation and an increased number of orphan lambs were associated with increased cases of orf. We conclude that the DP in ewes and lambs affect each other, though the impact is higher for lambs in the presence of increasing prevalence in ewes. A short lambing season lowers the probability of a farm experiencing cases of orf. Vaccination was effective in lambs but not in ewes, though lambs benefitted when ewes were vaccinated (reduced orf prevalence in lambs born from vaccinated ewes), probably because any unvaccinated ewes may have been carriers that could spread the virus to the new-born lambs.

Historical and current perspectives on the treatment, control and pathogenesis of milk fever in dairy cattle.

Milk fever has been recognised in cattle for about 215 years and its clinical signs have not changed since they were described by Victorian veterinary surgeons in the mid-nineteenth century. It was only 80 years ago that abnormal parathyroid gland function was associated with the pathogenesis of the hypocalcaemia characteristic of the disease, and the current basis for its treatment with intravenous calcium salts was established. Although this treatment is effective, most recent research has focused on preventing the disease through an understanding of the endocrine control of extracellular calcium homeostasis. In the 1970s the synthetic vitamin D analogue 1alpha-hydroxycholecalciferol was developed for intramuscular injection before a cow calved, but variable results encouraged other preventive strategies to be considered, including restricting the dietary intake of calcium, and manipulating the dietary cation-anion balance of cows before they calved. Currently, the role of extracellular calcium receptors in the parathyroid gland is under investigation as a preliminary step to devising more effective treatments and/or preventive methods for milk fever.

Conservation of Pitx1 expression during amphibian limb morphogenesis.

In contrast to the pattern of limb emergence in mammals, chicks, and the newt N. viridescens, embryos such as Xenopus laevis and Eleutherodactylus coqui initiate pelvic limb buds before they develop pectoral ones. We studied the expression of Pitx1 in X. laevis and E. coqui to determine if this paired-like homeodomain transcription factor directs differentiation specifically of the hindlimb, or if it directs the second pair of limbs to form, namely the forelimbs. We also undertook to determine if embryonic expression patterns were recapitulated during the regeneration of an amputated limb bud. Pitx1 is expressed in hindlimbs in both X. laevis and E. coqui, and expression is similar in both developing and regenerating limb buds. Expression in hindlimbs is restricted to regions of proliferating mesenchyme.

Serum cholesterol and risk of Alzheimer disease: a community-based cohort study.

OBJECTIVES: To examine the association of serum total cholesterol (TC) and high density lipoprotein (HDL) levels and subsequent incidence of dementia and Alzheimer disease (AD) in a population-based cohort study. METHODS: A cohort of cognitively intact persons, aged 65 and older, was randomly selected from Group Health Cooperative (GHC), a large health maintenance organization, and was assessed biennially for dementia. Premorbid levels of TC and HDL were obtained from a computerized clinical laboratory database at GHC. Cox proportional hazards regression was used to calculate hazard ratios (HR, 95% CI) for dementia and AD associated with quartiles of TC and HDL levels. RESULTS: Of the 2,356 eligible participants, 2,141 had at least one serum TC measure prior to the initial enrollment. Using the lowest TC quartiles as the reference group, the HR in the highest TC quartiles was not significantly elevated for dementia (1.16, 0.81 to 1.67) or for AD (1.00, 0.61 to 1.62) after adjusting for age, sex, education, baseline cognition, vascular comorbidities, body mass index, and lipid-lowering agent use. Serum HDL showed a similar lack of significant association with risk of dementia or AD. Models that included the presence of one or more APOE-epsilon4 alleles showed a typical association of epsilon4 with AD risk. This association was not materially modified by inclusion of TC level. CONCLUSION: The data do not support an association between serum total cholesterol or high density lipoprotein in late life and subsequent risk of dementia or Alzheimer disease (AD). The increased risk of AD with APOE-epsilon4 is probably not mediated by serum total cholesterol levels.

Cognitive differences in dementia patients with autopsy-verified AD, Lewy body pathology, or both.

OBJECTIVE: To examine the neuropsychological profile of dementia patients from a community-based autopsy sample of dementia, comparing Alzheimer disease (AD), Lewy body pathology (LBP) alone, and LBP with coexistent AD (AD/LBP). METHODS: The authors reviewed 135 subjects from a community-based study of dementia for whom autopsy and brain tissue was available. Diagnostic groups were determined according to standard neuropathologic methods and criteria, and the presence of LBs was determined using alpha-synuclein immunostaining. Neuropathologically defined diagnostic groups of AD, AD/LBP, and LBP were examined for differences on neuropsychological test performance at the time of initial study enrollment. RESULTS: There were 48 patients with AD alone, 65 with LB and AD pathology (AD/LBP), and 22 with LBP alone (LBP alone). There were no significant differences between groups demographically or on performance of enrollment Mini-Mental State Examination (MMSE) or Dementia Rating Scale (DRS). AD patients performed worse than the LBP patients on memory measures (Fuld Object Memory Evaluation Delayed Recall, Wechsler Memory Scale Logical Memory Immediate and Delayed Recall; p < 0.05) and a naming task (Consortium to Establish a Registry for Alzheimer's Disease Naming; p < 0.05). LBP patients were more impaired than AD patients on executive function (Trail Making Test Part B; p < 0.05) and attention tasks (Wechsler Adult Intelligence Scale-Revised Digit Span; p < 0.05). Decline in MMSE and DRS scores over time were greatest in the patients with AD/LBP. CONCLUSIONS: In a community-based sample of older, medically complicated patients with dementia, there are neuropsychological differences between dementia subtypes at the time of diagnosis. In particular, patients with Alzheimer disease (AD) alone and AD/Lewy body pathology (LBP) had more severe memory impairment than patients with LBP. LBP alone was associated with more severe executive dysfunction. Patients with AD/LBP had the most rapid rate of cognitive decline.

Statin therapy and risk of dementia in the elderly: a community-based prospective cohort study.

OBJECTIVE: To assess the association between statin therapy and risk of Alzheimer disease (AD) in a prospective cohort study with documented statin exposure and incident dementia. METHODS: This is a prospective, cohort study of statin use and incident dementia and probable AD. A cohort of 2,356 cognitively intact persons, aged 65 and older, were randomly selected from a health maintenance organization (HMO), and were assessed biennially for dementia. Statin use was identified using the HMO pharmacy database. A proportional hazards model with statin use as a time-dependent covariate was used to assess the statin-dementia/AD association. RESULTS: Among 312 participants with incident dementia, 168 had probable AD. The unadjusted hazard ratios (HRs) with statin use were 1.33 (95% CI 0.95 to 1.85) for all-cause dementia and 0.90 (CI 0.54 to 1.51) for probable AD. Adjusted corresponding HRs were 1.19 (CI 0.82 to 1.75) and 0.82 (CI 0.46 to 1.46). A subgroup analysis of participants with at least one APOE-epsilon4 allele who entered the study before age 80 produced an adjusted HR of 0.33 (CI 0.10 to 1.04). CONCLUSION: Employing time-dependent proportional hazards modeling, the authors found no significant association between statin use and incident dementia or probable AD. In contrast, when the data were analyzed, inappropriately, as a case-control study, the authors found an OR of 0.55 for probable AD, falsely indicating a protective effect of statins. Study design and analytic methods may explain the discrepancy between the current null findings and earlier findings.

Aryl hydrocarbon receptor response to indigoids in vitro and in vivo.

Indigo and indirubin have been reported to be present at low levels in human urine. The possibility that indigoids are physiological ligands of the aryl hydrocarbon receptor (AhR) has been suggested by initial studies in yeast, where indirubin was found to be 50 times more potent than 2,3,7,8-tetrachlorodibenzo[p]dioxin (TCDD), and indigo was found to be equipotent. To demonstrate that these indigoids are bona fide agonists in mammalian systems, we employed a number of in vitro and in vivo measures of AhR agonist potency. In a hepatoma cell reporter system, indigo yielded an EC50 of approximately 5x10(-6)M (indirubin 3' -oxime EC50 approximately 5x10(-7)M, indirubin EC50 approximately 1x10(-7)M). A comparison of these EC50 values with that of 2,3,7,8-tetrachlorodibenzofuran (TCDBF) ( approximately 3x10(-9)M) indicated that these compounds are less potent than classic halogenated-dibenzofurans or -dibenzo-p-dioxins. Competitive binding assays for AhR occupancy showed similar IC50 values for indirubin and TCDBF ( approximately 2x10(-9) and 5x10(-9)M), with the IC50 values of indigo and indirubin 3' -oxime being approximately 10-fold higher. When rats were treated with these indigoids in the range of 1.5-50mg/kg, induction of hepatic cytochrome P450 1A1 was detected. Differences in the rank-order of potency observed in vivo and in vitro could, in part, be explained by metabolism. Although their biological potencies are not as high as has been previously suggested, collectively the results show that these indole-derived pigments are agonists of AhR in vivo. The in vivo results suggest that solubility, distribution, and metabolism influence the response to the compounds.

Formation and mass spectrometric analysis of DNA and nucleoside adducts by S-(1-acetoxymethyl)glutathione and by glutathione S-transferase-mediated activation of dihalomethanes.

The dihalomethane CH(2)Cl(2) is an industrial solvent of potential concern to humans because of its potential genotoxicity and carcinogenicity. To characterize DNA damage by dihalomethanes, a rapid DNA digestion under acidic conditions was developed to identify alkali labile DNA-dihalomethane nucleoside adducts using HPLC-electrospray mass spectrometry. DNA digestion worked best using pH 5.0 sodium acetate buffer, a 30 min incubation with DNase II and phosphodiesterase II, and a 2 h acid phosphatase digest. DNA was modified with S-(1-acetoxymethyl)glutathione (GSCH(2)OAc), a reagent modeling activated dihalomethanes. Adducts to G, A, and T were detected at high ratios of GSCH(2)OAc/DNA following digestion of the DNA with the procedure used here. The relative efficacy of adduct formation was G > T > A >> C. The four DNA nucleosides were also reacted with the dihalomethanes CH(2)Cl(2) and CH(2)Br(2) in the presence of glutathione (GSH) and GSH S-transferases from bacteria (DM11), rat (GST 5-5), and human (GST T1-1) under conditions that produce mutations in bacteria. All enzymes formed adducts to all four nucleosides, with dGuo being the most readily modified nucleoside. Thus, the pattern paralleled the results obtained with the model compounds GSCH(2)OAc and DNA. CH(2)Cl(2) and CH(2)Br(2) yielded similar amounts of adducts under these conditions. The relative efficiency of adduct formation by GSH transferases was rat 5-5 > human T1-1 > bacterial DM11, showing that human GSH transferase T1-1 can form dihalomethane adducts under the conditions used. Although the lability of DNA adducts has precluded more sophisticated experiments and in vivo studies have not yet been possible, the work collectively demonstrates the ability of several GSH transferases to generate DNA adducts from dihalomethanes, with G being the preferred site of adduction in both this and the GSCH(2)OAc model system.

Analysis of the kinetic mechanism of haloalkane conjugation by mammalian theta-class glutathione transferases.

Glutathione (GSH) transferases (GSTs) catalyze the conjugation of small haloalkanes with GSH. In the case of dihalomethanes and vic-1,2-dihaloalkanes, the reaction leads to the formation of genotoxic GSH conjugates. A generally established feature of the reaction of the mammalian theta-class GSTs, which preferentially catalyze these reactions, is the lack of saturability of the rate with regard to the substrate concentration. However, the bacterial GST DM11 catalyzes the same reactions with a relatively low K(m). Recently, DM11 has been shown to exhibit burst kinetics, with a rate-determining k(off) rate for product (Stourman et al. (2003) Biochemistry 42, 11048-11056). We examined rat GST 5-5 and human GST T1-1 and did not detect any burst kinetics in the conjugation of C(2)H(5)Cl, CH(2)Br(2), or CH(2)Cl(2), distinguishing these enzymes from GST DM11. The kinetic results were fit to a minimal mechanism in which the rate-limiting step is halide displacement. The differences in the steady state kinetics of conjugations catalyzed by bacterial GST DM11 and the mammalian GSTs 5-5 and T1-1 are concluded to be the result of differences in the rate-limiting steps and not to inherent enzyme affinity for the haloalkanes. The results may be interpreted in the context of a model in which the halide order affects the rate of carbon-halogen bond cleavage of all such reactions catalyzed by the GSTs. With GST DM11, the halide order is manifested in the K(m) parameter but not k(cat). With mammalian GSTs, the high K(m) is difficult to estimate. With all of the GSTs, the halide order is seen in the enzyme efficiency, k(cat)/K(m), with C-Br cleavage approximately 10-fold faster than C-Cl cleavage. The ratio k(cat)/K(m) is the most relevant parameter for issues of risk assessment.

Fluctuations in viscous fingering.

Our experiments on viscous (Saffman-Taylor) fingering in Hele-Shaw channels reveal finger width fluctuations that were not observed in previous experiments, which had lower aspect ratios and higher capillary numbers Ca. These fluctuations intermittently narrow the finger from its expected width. The magnitude of these fluctuations is described by a power law, Ca(-0.64), which holds for all aspect ratios studied up to the onset of tip instabilities. Further, for large aspect ratios, the mean finger width exhibits a maximum as Ca is decreased instead of the predicted monotonic increase.

Head circumference and incident Alzheimer's disease: modification by apolipoprotein E.

BACKGROUND: The clinical expression of AD likely occurs when the accumulation of degeneration in specific brain regions leads to the descent below a critical threshold of "brain reserve" beyond which normal cognitive function cannot be maintained. The association between head circumference (HC), a measure of brain reserve, and the incidence of probable AD was examined in a large nondemented cohort that has been followed since 1992 and its modification by APOE epsilon 4 genotype. METHODS: Fifty-nine incident cases of probable AD were identified from 1,869 initially nondemented individuals seen at the baseline examination (1992 to 1994) and followed for a mean of 3.8 years. Variables measured at baseline included age, education, gender, HC, height, weight, and score on the National Adult Reading Test-Revised. APOE was genotyped at the time of the first biennial examination (1994 to 1996) and was available for 1,111 individuals in the cohort. Cox proportional hazard regression was performed to estimate hazard ratios (HR) for probable AD for HC and other covariates. RESULTS: Incident cases were significantly older, less educated, shorter, and lighter, had lower estimated verbal IQ scores, and were more likely to have at least one APOE epsilon 4 allele than unaffected individuals. The HR associated with the lowest tertile of HC (<21.4 inches) adjusted for education, gender, and APOE epsilon 4 was 2.3 (95% CI 0.7 to 6.9, p = 0.16). The HR for one or two APOE epsilon 4 alleles was significant (HR = 4.8, 95% CI 1.8 to 12.9, p = 0.002). The combination of low HC and APOE epsilon 4 strongly predicted earlier onset of AD with HR = 14.1 (95% CI 3.0 to 65, p = 0.0007). CONCLUSIONS: Smaller HC, in the presence of the APOE epsilon 4 allele, hastens the age at onset of AD. These results support the brain reserve hypothesis and its importance in precipitating the clinical expression of AD among genetically predisposed individuals.

Applying scientific criteria to therapeutic interchange: a balanced analysis of low-molecular-weight heparins.

Under pressure to provide cost-effective healthcare, many healthcare systems have adopted Therapeutic Interchange (TI) programs-the interchange of therapeutically equivalent but chemically unique drugs-to reduce the total cost of therapy without compromising patient care. To be appropriate and feasible, a TI program for any class of drugs must meet certain rigorous criteria and undergo medical, financial, tactical, and legal reviews. Moreover, once a TI program is implemented, a process to monitor its success should be established. Application of the TI criteria to low-molecular-weight heparins (LMWHs) reveals that a blanket TI program for LMWHs does not appear advisable at this time.

Healthcare utilization and costs in managed care patients with Alzheimer's disease during the last few years of life.

OBJECTIVES: To learn whether managed care patients with Alzheimer's disease (AD) are more or less costly to care for than patients with other forms of dementia or patients without dementia during the last few years of life. DESIGN: Case control study. SETTING: A health maintenance organization base population. PARTICIPANTS: Three groups of subjects (mean age 85) who were deceased members of a dementia registry obtained from a health maintenance organization base population: 263 subjects with clinically diagnosed probable AD, 133 subjects with other forms of dementia, and 100 cognitively intact controls. MEASUREMENTS: Utilization records were examined for the 3 years preceding death. RESULTS: In all subcategories and in aggregate, utilization and costs of care were either similar or lower for patients with AD than for the other groups, even after controlling for age, gender, and comorbidity. CONCLUSIONS: Persons with AD do not incur higher costs than persons with other types of dementia or age-matched persons without dementia in a mature health maintenance organization during the last few years of life, when utilization is likely to be highest.

Delayed appearance of carbon granulomas of the scalp after use of carbon fiber pins for refixation of a stereotactic head frame. Case report.

The authors present a case involving the formation of several carbon granulomas in the scalp of a woman 7 years after she underwent craniotomy. Her operation had included the use of carbon fiber pins for refixation of a stereotactic head frame. Carbon granulomas have been noted in multiple organs following surgical or traumatic carbon deposition, but have not been reported in association with neurosurgical carbon fiber pins used for head fixation. The lesions in this case arose a few months after initiation of chemotherapy for the patient's brain tumor. The relationship of carbon and cutaneous granuloma formation to adjuvant therapies and treatment strategies is discussed.

Using census data and birth certificates to reconstruct the early-life socioeconomic environment and the relation to the development of Alzheimer's disease.

The early-life environment and its effect on growth and maturation of children and adolescents are associated with several adult chronic diseases, including Alzheimer's disease. Because it is not feasible to collect information prospectively over the average life span, methods to reconstruct the early-life environment of the aged are necessary to evaluate these associations. In a community-based case-control study conducted in the United States, we collected U.S. census records and birth certificates to reconstruct the early-life socioeconomic environment of each elderly subject. Information was found on 82% of the available Alzheimer's disease cases (239 of 292) and 87% of the available controls (245 of 282). We investigated risk of Alzheimer's disease associated with father's occupation, parental age, household size, sibship size, and birth order. Subjects whose fathers were unskilled manual workers or laborers were at higher risk for Alzheimer's disease (odds ratio = 1.80, 95% confidence interval = 1.19--2.73). The risk of Alzheimer's disease was increased with increasing number of people in the household. We also evaluated whether subjects with the apolipoprotein epsilon 4 allele (APOE epsilon 4), a strong genetic risk factor that is not a necessary cause or a sufficient cause by itself for the development of Alzheimer's disease, were at higher risk than subjects who did not carry this allele. Among subjects with the APOE epsilon 4 allele whose fathers held lower-socioeconomic level occupations, the odds of developing Alzheimer's disease were higher (odds ratio = 2.35, 95% confidence interval = 1.07--5.16) compared with subjects without the allele (odds ratio = 1.40, 95% confidence interval = 0.78--2.52). Subjects carrying the APOE epsilon 4 allele alone have a threefold increased risk of Alzheimer's disease (odds ratio = 3.17, 95% confidence interval = 1.99--5.04). Compared with subjects with neither risk factor, subjects with both the genetic and the environmental risk factors (household size of seven or more and father's occupation being manual) had a relatively high risk of Alzheimer's disease (odds ratio = 14.8, 95% confidence interval = 4.9--46). The data suggest that APOE epsilon 4 may modify the associations between father's occupation, other early-life environmental factors, and development of Alzheimer's disease in late life.

Suppression of dripping from a ceiling.

An isothermal layer suspended from a surface is gravitationally (Rayleigh-Taylor) unstable. We find that, when a vertical temperature difference DeltaT above a critical value (DeltaT)(c) is imposed across the liquid-gas layer system (heated from below), the restoring force provided by the temperature-dependent surface tension (thermocapillarity) can stabilize the layer. Our measurements of the most unstable wave number for DeltaT<(DeltaT)(c) agree well with our linear stability analysis. The instability occurs at long wavelengths: the most unstable wavelength at (DeltaT)(c) is infinite.

A silica-based mitochondrial DNA extraction method applied to forensic hair shafts and teeth.

The purpose of this study is to evaluate the applicability of a nonorganic DNA extraction method for use in the analysis of environmentally compromised forensic hair shaft and tooth samples. The condition of the samples included cases of water decomposition, severe incineration, and varying stages of putrefaction. Enzymatic amplification and manual sequencing of the first segment of the mitochondrial hypervariable region were performed successfully on each of the 20 autopsied individuals. The results indicate that the silica-based extraction method produces mtDNA suitable for genetic identification from forensic samples including hair shafts and teeth.

Ethnicity and cognitive performance among older African Americans, Japanese Americans, and Caucasians: the role of education.

This cross-sectional analysis evaluated the association between ethnicity and cognitive performance and determined whether education modifies this association for nondemented older people (103 African Americans, 1,388 Japanese Americans, 2,306 Caucasians) in a study of dementia incidence. African Americans scored lower (median 89 out of 100) than Japanese Americans (93) and Caucasians (94) on the Cognitive Abilities Screening Instrument (CASI). Education affected CA