Placental pathology, immune responses, bacteriologic findings and clinical signs in pregnant cattle vaccinated with Brucella abortus strain RB51

To determine the placental tropism, abortigenicity, immunogenicity and effect on TNF-[alpha] levels, pregnant cattle were vaccinated IV (n = 10) or SC (n = 5) with the vaccine Brucella abortus strain RB51 (SRB51), SC with strain 19 (S19) (n = 5), or saline (n = 5) at 6 months gestation. Eight of ten IV vaccinated heifers developed placentitis and fetal infection. Strain RB51 was cultured from all tissues in which lesions were seen. No lesions were seen in SC vaccinated cattle and SRB51 was isolated from 2/5 superficial cervical lymph nodes in the area draining the site of SC vaccination. One premature calf born to an IV vaccinated heifer had mild interstitial pneumonia and disseminated SRB51 infection. No lesions were seen in other calves from IV vaccinated heifers, heifers vaccinated SC with SRB51 or S19, and neither SRB51 nor S19 could be recovered from calves of SC vaccinated cattle. Maternal PBMC from SRB51 vaccinates and S19 vaccinates showed proliferative responses to both [gamma]-irradiated SRB51 and S19 which were greater than controls. Strain RB51 vaccinates did not develop antibodies detected by the standard tube agglutination test, but did develop antibodies to SRB51 that reacted in a dot ELISA test with irradiated SRB51. Radioimmunoassay for bovine TNF-[alpha] showed no elevations in plasma from vaccinated cattle that differed from controls (P \u3e 0.05). Similarly, TNF-[alpha] levels in amniotic or allantoic fluids from vaccinated cattle were not different from controls (P \u3e 0.05). Immunohistochemistry for TNF-[alpha] revealed increased immunoreactivity within trophoblastic epithelial cells which was most extensive in IV vaccinated cattle with vaccine induced placentitis. These results indicate that SRB51 is less abortifacient than previously published reports with S19; however, SRB51 can infect the bovine placenta and fetus, can induce placentitis, and in some cases, lead to preterm expulsion of the fetus. Undesireable effects of SRB51 are dependent on dose and route of administration as SC vaccination with a lower dose does not result in placental or fetal infection

To see or not to see: a qualitative interview study of patients' views on their own diagnostic images

Objectives To ascertain what meaning individuals attach to perceiving images of their own interior body and how the images and their meanings affect the clinical consultation. Design Face-to-face semistructured interviews. Participants 25 adult patients in southern England who, within the preceding 12 months, had been referred for diagnostic imaging. Setting Community. Results For patients, being shown their own X-rays, MRIs or CT images creates a variety of effects: (1) a sense of better understanding of the diagnosis; (2) validation of their sensory and emotional response to the illness or injury and (3) an alteration to the tenor and nature of the clinical encounter between patient and physician. In addition to meanings attached to these images, patients also impute meaning to the physician's decision not to share an image with them. The desire to see their image was greater in those patients with a skeletal injury; patients are less keen on viewing abdominal or other soft tissue images. Conclusions Viewing images of one's interior, invisible body is powerful and resonant in a number of ways. The experience of not seeing, whether through the patient's or the physician's choice, is also fraught with meaning

First-principles calculation of the intrinsic aqueous solubility of crystalline druglike molecules

We demonstrate that the intrinsic aqueous solubility of crystalline druglike molecules can be estimated with reasonable accuracy from sublimation free energies calculated using crystal lattice simulations and hydration free energies calculated using the 3D Reference Interaction Site Model (3D-RISM) of the Integral Equation Theory of Molecular Liquids (IET). The solubilities of 25 crystalline druglike molecules taken from different chemical classes are predicted by the model with a correlation coefficient of R = 0.85 and a root mean square error (RMSE) equal to 1.45 log(10) S units, which is significantly more accurate than results obtained using implicit continuum solvent models. The method is not directly parametrized against experimental solubility data, and it offers a full computational characterization of the thermodynamics of transfer of the drug molecule from crystal phase to gas phase to dilute aqueous solution.PostprintPeer reviewe

Multiple locus VNTR analysis highlights that geographical clustering and distribution of Dichelobacter nodosus, the causal agent of footrot in sheep, correlates with inter-country movements

Dichelobacter nodosus is a Gram-negative, anaerobic bacterium and the causal agent of footrot in sheep. Multiple locus variable number tandem repeat (VNTR) analysis (MLVA) is a portable technique that involves the identification and enumeration of polymorphic tandem repeats across the genome. The aims of this study were to develop an MLVA scheme for D. nodosus suitable for use as a molecular typing tool, and to apply it to a global collection of isolates. Seventy-seven isolates selected from regions with a long history of footrot (GB, Australia) and regions where footrot has recently been reported (India, Scandinavia), were characterised. From an initial 61 potential VNTR regions, four loci were identified as usable and in combination had the attributes required of a typing method for use in bacterial epidemiology: high discriminatory power (D > 0.95), typeability and reproducibility. Results from the analysis indicate that D. nodosus appears to have evolved via recombinational exchanges and clonal diversification. This has resulted in some clonal complexes that contain isolates from multiple countries and continents; and others that contain isolates from a single geographic location (country or region). The distribution of alleles between countries matches historical accounts of sheep movements, suggesting that the MLVA technique is sufficiently specific and sensitive for an epidemiological investigation of the global distribution of D. nodosus

Phenotypic and molecular assessment of seven patients with 6p25 deletion syndrome: Relevance to ocular dysgenesis and hearing impairment

BACKGROUND: Thirty-nine patients have been described with deletions involving chromosome 6p25. However, relatively few of these deletions have had molecular characterization. Common phenotypes of 6p25 deletion syndrome patients include hydrocephalus, hearing loss, and ocular, craniofacial, skeletal, cardiac, and renal malformations. Molecular characterization of deletions can identify genes that are responsible for these phenotypes. METHODS: We report the clinical phenotype of seven patients with terminal deletions of chromosome 6p25 and compare them to previously reported patients. Molecular characterization of the deletions was performed using polymorphic marker analysis to determine the extents of the deletions in these seven 6p25 deletion syndrome patients. RESULTS: Our results, and previous data, show that ocular dysgenesis and hearing impairment are the two most highly penetrant phenotypes of the 6p25 deletion syndrome. While deletion of the forkhead box C1 gene (FOXC1) probably underlies the ocular dysgenesis, no gene in this region is known to be involved in hearing impairment. CONCLUSIONS: Ocular dysgenesis and hearing impairment are the two most common phenotypes of 6p25 deletion syndrome. We conclude that a locus for dominant hearing loss is present at 6p25 and that this locus is restricted to a region distal to D6S1617. Molecular characterization of more 6p25 deletion patients will aid in refinement of this locus and the identification of a gene involved in dominant hearing loss

Obese father's metabolic state, adiposity, and reproductive capacity indicate son's reproductive health

ObjectiveTo determine whether dietary and exercise regimes in obese males can provide a novel intervention window for improving the reproductive health of the next generation.DesignExperimental animal study.SettingUniversity research facilities.Animal(s)C57BL6 male and female mice.Intervention(s)Mice were fed a control diet (6% fat) or high-fat diet (21% fat) for 9 weeks. After the initial feeding, high-fat-diet males were allocated to diet and/or exercise interventions for a further 9 weeks. After intervention males were mated with females fed standard chow (4% fat) before and during pregnancy.Main outcome measure(s)F1 sperm motility, count, morphology, capacitation, mitochondrial function, and sperm binding and weight of reproductive organs.Result(s)Our primary finding was that diet intervention alone in founders improved offspring sperm motility and mitochondrial markers of sperm health (decreased reactive oxygen species and mitochondrial membrane potential), ultimately improving sperm binding. Sperm binding and capacitation was also improved in F1 males born to a combined diet and exercise intervention in founders. Founder sperm parameters and metabolic measures as a response to diet and/or exercise (i.e., lipid/glucose homeostasis, sperm count and morphology) correlated with offspring's sperm function, independent of founder treatment. This implicates paternal metabolic and reproductive status in predicting male offspring's reproductive function.Conclusion(s)This is the first study to show that improvements to both metabolic (lipids, glucose and insulin sensitivity) and reproductive function (sperm motility and morphology) in obese fathers via diet and exercise interventions can improve subsequent reproductive health in offspring.Nicole O. McPherson, Tod Fullston, Hassan W. Bakos, Brian P. Setchell and Michelle Lan

Editorial Message

We compare a range of computational methods for the prediction of sublimation thermodynamics (enthalpy, entropy and free energy of sublimation). These include a model from theoretical chemistry that utilizes crystal lattice energy minimization (with the DMACRYS program) and QSPR models generated by both machine learning (Random Forest and Support Vector Machines) and regression (Partial Least Squares) methods. Using these methods we investigate the predictability of the enthalpy, entropy and free energy of sublimation, with consideration of whether such a method may be able to improve solubility prediction schemes. Previous work has suggested that the major source of error in solubility prediction schemes involving a thermodynamic cycle via the solid state is in the modeling of the free energy change away from the solid state. Yet contrary to this conclusion other work has found that the inclusion of terms such as the enthalpy of sublimation in QSPR methods does not improve the predictions of solubility. We suggest the use of theoretical chemistry terms, detailed explicitly in the methods section, as descriptors for the prediction of the enthalpy and free energy of sublimation. A dataset of 158 molecules with experimental sublimation thermodynamics values and some CSD refcodes has been collected from the literature and is provided with their original source references

Genetic risk factors for ischaemic stroke and its subtypes (the METASTROKE Collaboration): a meta-analysis of genome-wide association studies

<p>Background - Various genome-wide association studies (GWAS) have been done in ischaemic stroke, identifying a few loci associated with the disease, but sample sizes have been 3500 cases or less. We established the METASTROKE collaboration with the aim of validating associations from previous GWAS and identifying novel genetic associations through meta-analysis of GWAS datasets for ischaemic stroke and its subtypes.</p> <p>Methods - We meta-analysed data from 15 ischaemic stroke cohorts with a total of 12 389 individuals with ischaemic stroke and 62 004 controls, all of European ancestry. For the associations reaching genome-wide significance in METASTROKE, we did a further analysis, conditioning on the lead single nucleotide polymorphism in every associated region. Replication of novel suggestive signals was done in 13 347 cases and 29 083 controls.</p> <p>Findings - We verified previous associations for cardioembolic stroke near PITX2 (p=2·8×10−16) and ZFHX3 (p=2·28×10−8), and for large-vessel stroke at a 9p21 locus (p=3·32×10−5) and HDAC9 (p=2·03×10−12). Additionally, we verified that all associations were subtype specific. Conditional analysis in the three regions for which the associations reached genome-wide significance (PITX2, ZFHX3, and HDAC9) indicated that all the signal in each region could be attributed to one risk haplotype. We also identified 12 potentially novel loci at p<5×10−6. However, we were unable to replicate any of these novel associations in the replication cohort.</p> <p>Interpretation - Our results show that, although genetic variants can be detected in patients with ischaemic stroke when compared with controls, all associations we were able to confirm are specific to a stroke subtype. This finding has two implications. First, to maximise success of genetic studies in ischaemic stroke, detailed stroke subtyping is required. Second, different genetic pathophysiological mechanisms seem to be associated with different stroke subtypes.</p&gt