Genome-wide DNA hydroxymethylation identifies potassium channels in the nucleus accumbens as discriminators of methamphetamine addiction and abstinence.

Epigenetic consequences of exposure to psychostimulants are substantial but the relationship of these changes to compulsive drug taking and abstinence is not clear. Here, we used a paradigm that helped to segregate rats that reduce or stop their methamphetamine (METH) intake (nonaddicted) from those that continue to take the drug compulsively (addicted) in the presence of footshocks. We used that model to investigate potential alterations in global DNA hydroxymethylation in the nucleus accumbens (NAc) because neuroplastic changes in the NAc may participate in the development and maintenance of drug-taking behaviors. We found that METH-addicted rats did indeed show differential DNA hydroxymethylation in comparison with both control and nonaddicted rats. Nonaddicted rats also showed differences from control rats. Differential DNA hydroxymethylation observed in addicted rats occurred mostly at intergenic sites located on long and short interspersed elements. Interestingly, differentially hydroxymethylated regions in genes encoding voltage (Kv1.1, Kv1.2, Kvb1 and Kv2.2)- and calcium (Kcnma1, Kcnn1 and Kcnn2)-gated potassium channels observed in the NAc of nonaddicted rats were accompanied by increased mRNA levels of these potassium channels when compared with mRNA expression in METH-addicted rats. These observations indicate that changes in differentially hydroxymethylated regions and increased expression of specific potassium channels in the NAc may promote abstinence from drug-taking behaviors. Thus, activation of specific subclasses of voltage- and/or calcium-gated potassium channels may provide an important approach to the beneficial treatment for METH addiction.

Open access follow-up care for early breast cancer: a randomised controlled quality of life analysis.

This study evaluated the acceptability of a supportive model of follow-up. One hundred and twelve women recovering from breast cancer were randomised to receive standard breast clinic aftercare (Control n = 56) or on demand by open access aftercare by breast care nurses (Intervention n = 56). Participants attended a support-based psycho-educational programme delivered in four half-day group sessions. Three quality of life questionnaires (EORTC QLQ-C30, QLQ-BR23, HADS) were administered at baseline and 6-monthly intervals for 2 years. Multilevel linear regression modelling methods were used for evaluation. Age was found to be a statistically significant predictor of quality of life in several sub-scales. Increasing age was negatively associated with sexual functioning, systematic therapy side effects and physical functioning, and positively associated with future perspective. Aftercare assignment was not found to be a statistically significant predictor. Women treated for early breast cancer were not disadvantaged by allocation to the open access supportive care model in terms of quality of life experienced. The model for follow-up was demonstrated to be a feasible alternative to routinised hospital-based follow-up and adds to the evidence for stratified follow-up for low-risk cancer patients, incorporating self-management education. Stratified follow-up pathways are viewed as a preferable approach.

Molecular dynamics of FMRP and other RNA-binding proteins in MEG-01 differentiation: the role of mRNP complexes in non-neuronal development.

Asymmetrically differentiating cells are formed with the aid of RNA-binding proteins (RBPs), which can bind, stabilize, regulate, and transport target mRNAs. The loss of RBPs in neurons may lead to severe neurodevelopmental diseases such as the Fragile X Syndrome with the absence of the Fragile X Mental Retardation Protein (FMRP). Because the latter is ubiquitous and shares many similarities with other RBPs involved in the development of peripheral cells, we suggest that FMRP would have a role in the differentiation of all tissues where it is expressed. A MEG-01 differentiation model was, therefore, established to study the global developmental functions of FMRP. PMA induction of MEG-01 cells causes important morphological changes driven by cytoskeletal dynamics. Cytoskeleton change and colocalization analyses were performed by confocal microscopy and sucrose gradient fractionation. Total cellular protein content and de novo synthesis were also analyzed. Microtubular transport mediates the displacement of FMRP and other RBP-containing mRNP complexes towards regions of the cell in development. De novo protein synthesis decreases significantly upon differentiation and total protein content composition is altered. Because those results are comparable with those obtained in neurons, the absence of FMRP would have significant consequences in cells everywhere in the body. The latter should be further investigated to give a better understanding of the systemic implications of imbalances of FMRP and other functionally similar RBPs.

Low stromal Foxp3+ regulatory T-cell density is associated with complete response to neoadjuvant chemoradiotherapy in rectal cancer.

BACKGROUND: Foxp3+ regulatory T cells (Tregs) play a vital role in preventing autoimmunity, but also suppress antitumour immune responses. Tumour infiltration by Tregs has strong prognostic significance in colorectal cancer, and accumulating evidence suggests that chemotherapy and radiotherapy efficacy has an immune-mediated component. Whether Tregs play an inhibitory role in chemoradiotherapy (CRT) response in rectal cancer remains unknown. METHODS: Foxp3+, CD3+, CD4+, CD8+ and IL-17+ cell density in post-CRT surgical samples from 128 patients with rectal cancer was assessed by immunohistochemistry. The relationship between T-cell subset densities and clinical outcome (tumour regression and survival) was evaluated. RESULTS: Stromal Foxp3+ cell density was strongly associated with tumour regression grade (P=0.0006). A low stromal Foxp3+ cell density was observed in 84% of patients who had a pathologic complete response (pCR) compared with 41% of patients who did not (OR: 7.56, P=0.0005; OR: 5.27, P=0.006 after adjustment for presurgery clinical factors). Low stromal Foxp3+ cell density was also associated with improved recurrence-free survival (HR: 0.46, P=0.03), although not independent of tumour regression grade. CONCLUSIONS: Regulatory T cells in the tumour microenvironment may inhibit response to neoadjuvant CRT and may represent a therapeutic target in rectal cancer.

A phase 1b clinical trial of the CD40-activating antibody CP-870,893 in combination with cisplatin and pemetrexed in malignant pleural mesothelioma.

BACKGROUND: Data from murine models suggest that CD40 activation may synergize with cytotoxic chemotherapy. We aimed to determine the maximum tolerated dose (MTD) and toxicity profile and to explore immunological biomarkers of the CD40-activating antibody CP-870,893 with cisplatin and pemetrexed in patients with malignant pleural mesothelioma (MPM). PATIENTS AND METHODS: Eligible patients had confirmed MPM, ECOG performance status 0-1, and measurable disease. Patients received cisplatin 75 mg/m(2) and pemetrexed 500 mg/m(2) on day 1 and CP-870,893 on day 8 of a 21-day cycle for maximum 6 cycles with up to 6 subsequent cycles single-agent CP-870,893. Immune cell subset changes were examined weekly by flow cytometry. RESULTS: Fifteen patients were treated at three dose levels. The MTD of CP-870,893 was 0.15 mg/kg, and was exceeded at 0.2 mg/kg with one grade 4 splenic infarction and one grade 3 confusion and hyponatraemia. Cytokine release syndrome (CRS) occurred in most patients (80%) following CP-870,893. Haematological toxicities were consistent with cisplatin and pemetrexed chemotherapy. Six partial responses (40%) and 9 stable disease (53%) as best response were observed. The median overall survival was 16.5 months; the median progression-free survival was 6.3 months. Three patients survived beyond 30 months. CD19+ B cells decreased over 6 cycles of chemoimmunotherapy (P < 0.001) with a concomitant increase in the proportion of CD27+ memory B cells (P < 0.001) and activated CD86+CD27+ memory B cells (P < 0.001), as an immunopharmacodynamic marker of CD40 activation. CONCLUSIONS: CP-870,893 with cisplatin and pemetrexed is safe and tolerable at 0.15 mg/kg, although most patients experience CRS. While objective response rates are similar to chemotherapy alone, three patients achieved long-term survival. AUSTRALIA NEW ZEALAND CLINICAL TRIALS REGISTRY NUMBER: ACTRN12609000294257.

Acute and chronic evolution of MRI findings in a case of posterior spinal cord ischemia.

STUDY DESIGN: Case report. OBJECTIVE: Reveal the evolution of the magnetic resonance imaging (MRI) pattern in a patient with a posterior spinal artery infarction, which belongs to a subgroup of spinal cord ischemia syndromes and presents a rare cause of spinal cord injury. Our report underlines that diagnosis of spinal cord ischemia and thus clinical decision making remains challenging. SETTING: University Hospital of Innsbruck and University Hospital of Salzburg, Austria. METHODS: Here we present clinical, electrophysiological and imaging data in the acute, subacute and chronic phase of a woman who developed signs and symptoms related to a bilateral posterior spinal cord infarction. RESULTS: At the clinical nadir (24 h after symptom onset), MRI did not exhibit T2 hyperintensities. However, such MRI changes were detected 8 days after symptom onset and persisted until the latest follow-up at 5 months. CONCLUSIONS: Repeated MRI constitutes an indispensable diagnostic and follow-up tool for spinal cord ischemia. The imaging data in accordance with the electrophysiological measurements correlated well with the clinical presentation in the subacute und chronic phase. Therefore, further studies might allow using MRI following spinal cord ischemia as a prognostic marker for an individual outcome.

Salmonella enterica causes more severe inflammatory disease in C57/BL6 Nramp1G169 mice than Sv129S6 mice.

Salmonella enterica serovar Typhimurium (S. Typhimurium) causes systemic inflammatory disease in mice by colonizing cells of the mononuclear leukocyte lineage. Mouse strains resistant to S. Typhimurium, including Sv129S6, have an intact Nramp1 (Slc11a1) allele and survive acute infection, whereas C57/BL6 mice, homozygous for a mutant Nramp1 allele, Nramp1(G169D) , develop lethal infections. Restoration of Nramp1 (C57/BL6 Nramp1(G169) ) reestablishes resistance to S. Typhimurium; mice survive at least 3 to 4 weeks postinfection. Since many transgenic mouse strains are on a C57/BL6 genetic background, C57/BL6 Nramp1(G169) mice provide a model to examine host genetic determinants of resistance to infection. To further evaluate host immune response to S. Typhimurium, we performed comparative analyses of Sv129S6 and C57/BL6 Nramp1(G169) mice 3 weeks following oral S. Typhimurium infection. C57/BL6 Nramp1(G169) mice developed more severe inflammatory disease with splenic bacterial counts 1000-fold higher than Sv129S6 mice and relatively greater splenomegaly and blood neutrophil and monocyte counts. Infected C57/BL6 Nramp1(G169) mice developed higher proinflammatory serum cytokine and chemokine responses (interferon-γ, tumor necrosis factor-α, interleukin [IL]-1ß, and IL-2 and monocyte chemotactic protein-1 and chemokine [C-X-C motif] ligand 1, respectively) and marked decreases in anti-inflammatory serum cytokine concentrations (IL-10, IL-4) compared with Sv129S6 mice postinfection. Splenic dendritic cells and macrophages in infected compared with control mice increased to a greater extent in C57/BL6 Nramp1(G169) mice than in Sv129S6 mice. Overall, data show that despite the Nramp1 gene present in both strains, C57/BL6 Nramp1(G169) mice develop more severe, Th1-skewed, acute inflammatory responses to S. Typhimurium infection compared with Sv129S6 mice. Both strains are suitable model systems for studying inflammation in the context of adaptive immunity.

Examining the relationship of concurrent obesity and tobacco use disorder on the development of substance use disorders and psychiatric conditions: Findings from the NESARC-III.

Background: Multimorbidity is linked to worse health outcomes than single health conditions. However, recent studies show that obesity may reduce the risk of developing substance use disorders (SUDs), particularly in vulnerable populations. We investigated how comorbid obesity and tobacco use disorder (TUD) relate to the risk of SUDs and psychiatric conditions. Methods: Data was used from 36,309 individuals who completed the National Epidemiological Survey on Alcohol and Related Conditions - Wave III. Individuals who met the DSM-5 criteria for TUD in the last year were defined as the TUD group. Obesity was defined as having a body mass index (BMI) greater than 30 kg/m2. Using this information, individuals were grouped into categories, with people being identified as either having obesity, TUD, both obesity and TUD, or not having either obesity or TUD (comparison). Groups were compared against their comorbid diagnoses of either an additional SUD or psychiatric conditions. Results: Controlling for demographic characteristics, we found that individuals with obesity including those individuals with TUD, had lower rates of comorbid SUD diagnosis than individuals with TUD alone. Additionally, individuals with combined TUD and obesity, and those with TUD alone, had the highest rates of comorbid psychiatric disorder diagnosis. Conclusions: The current study aligns with previous research suggesting that obesity may reduce risk of substance use disorders, even in individuals who have other risk factors promoting harmful substance use (e.g., tobacco use). These findings may inform targeted intervention strategies for this clinically relevant subpopulation.

Post-chemotherapy T-cell recovery is a marker of improved survival in patients with advanced thoracic malignancies.

BACKGROUND: There is increasing interest in combining chemotherapy with immunotherapy. However, the effects of chemotherapy on the human immune system are largely unknown. METHODS: Longitudinal changes in peripheral T-cell subsets in 40 patients with malignant mesothelioma (MM) or advanced non-small cell lung cancer (NSCLC) receiving platinum-based chemotherapy were assessed by flow cytometry and evaluated for associations with clinical outcome. RESULTS: Proliferating T cells of all subsets were almost entirely depleted at day 8 following chemotherapy, but rapidly recovered above baseline levels. Regulatory T cells (Treg) were most profoundly depleted at this time point. A greater increase in CD8(+) T-cell proliferation following one treatment cycle was associated with improved overall survival in univariate (hazard ratio (HR)=0.40; P<0.05) and multivariate (HR=0.17; P<0.01) analyses. A greater increase in the ratio of CD8(+) T cell to Treg proliferation was also predictive of better prognosis. CONCLUSION: Chemotherapy potentially provides a favourable environment for the development of anti-tumour immunity through transient Treg depletion and regeneration of the T-cell pool. Change in CD8(+) T-cell proliferation after one cycle of chemotherapy may represent a useful prognostic indicator in patients with MM and NSCLC.

Intramandibular course of the mandibular nerve; clinical significance for distraction and implantology.

OBJECTIVE: Loss of teeth is accompanied with loss of function and therefore reduction of alveolar bone height. Insufficient bone height can jeopardize the anchorage of implants or surgical procedures such as distraction osteogenesis, because of possible mandibular nerve damage. The goal of this investigation was to determine the exact course of the intramandibular nerve in edentulous mandibles. MATERIAL AND METHOD: The study samples included 37 dry human edentulous mandibles. A dental CT scan analysis was performed and four cross sectional views were investigated for each mandible. The Cawood classification was used to assess the grade of atrophy. Implantation simulation was performed in every case. RESULTS: There was no bilateral symmetry in edentulous mandibles, whatever the cross-section studied. A rate of 38.7% were classified Cawood class IV, the most common group in edentulous patients. Our study results led us to place the distraction osteogenesis device in the posterior edentulous mandible. Implant placement was not possible in every case. DISCUSSION: Our findings allow better understanding from the pathway of the mandibular canal close to the first and second molar in edentulous mandibles. This anatomical data and surgical techniques such as implant insertion and distraction osteogenesis allow finding solutions for "mandibular edentulism". Distraction is essential for a successful implantology.

Effect of precalving and postcalving dietary energy level on performance and blood metabolite concentrations of dairy cows throughout lactation.

The effects of the level of energy intake (high E and low E) offered before and after calving on body condition score at calving, production performance, and energy status in the first 250 d of lactation were evaluated in a 2 × 2 factorial design experiment involving 80 Holstein-Friesian dairy animals (40 primiparous and 40 multiparous). From d 80 until d 21 precalving, primiparous animals were offered either high or low pasture allowances. Thereafter, these animals were housed and had ad libitum access to a high energy density diet (high E) or restricted access [6 kg of dry matter (DM) per d] to a low energy density diet (low E), respectively, until calving. From d 100 until d 42 precalving, multiparous animals were offered either ad libitum or restricted (10 kg of DM/d) access to a late lactation diet, and thereafter, had ad libitum access to a high E diet or restricted access (7 kg of DM complete diet/d) to a low E diet, respectively, until calving. The forage to concentrate (F:C) ratios (DM basis) of these high E and low E diets [d 42 (d 21 in primiparous animals) until calving] were 64:36 and 83:17, respectively. Cows offered high E and low E precalving diets were allocated to either a high E or low E postcalving diet [F:C ratio (DM basis) of 30:70 and 70:30, respectively] and remained on these diets until d 250 of lactation. Multiparous animals offered a high E diet precalving had a significantly higher body condition score at calving than those offered the low E diet precalving. This effect was not evident in primiparous animals. Precalving diet had no significant effect on plasma nonesterified fatty acid concentrations during the last 3 wk precalving in primi- or multiparous animals. Primiparous animals offered a high E diet precalving had significantly higher postcalving plasma concentrations of nonesterified fatty acid, suggesting greater mobilization of body reserves. Primi- and multiparous animals offered a high E diet postcalving had a significantly higher dry matter intake, milk yield, and energy status postcalving compared with animals offered a low E diet postcalving. Milk yields of primiparous animals offered high E and low E diets postcalving were 29.7 and 24.8 kg/d, respectively, and milk yield of multiparous animals offered high E and low E diets postcalving were 33.5 and 28.2 kg/d, respectively. It is concluded that altering body condition score during the dry period is difficult but that specific dietary regimens applied precalving can have a significant influence on postcalving production and energy-related parameters.

Beneficial effects of a 3-week course of intramuscular glucocorticoid injections in patients with very early inflammatory polyarthritis: results of the STIVEA trial.

OBJECTIVE: To evaluate whether treating patients with very early inflammatory polyarthritis (IP) with a 3-week course of intramuscular (IM) methylprednisolone acetate may postpone the need for disease-modifying antirheumatic drugs (DMARDs) and prevent IP from evolving into rheumatoid arthritis (RA). METHODS: Patients with very early IP (4-10 weeks' duration) were randomised to receive three injections of either 80 mg IM methylprednisolone acetate or placebo, given at weekly intervals. Assessments were monthly until 6 months after the first injection, and then concluded at 12 months. The primary outcome was the need to start DMARDs by the 6-month assessment. Secondary outcomes included disease activity and final clinical diagnosis by the rheumatologist at 12 months. RESULTS: Patients in the placebo group (76%) were more likely to need DMARDs during the first 6 months of the trial than patients in the glucocorticoid group (61%) (adjusted OR = 2.11, 95% CI 1.16 to 3.85, p = 0.015). Disease activity did not differ between the two groups at 12 months, probably because many patients in the placebo group started DMARDs early in the study. After 12 months, the arthritis had resolved without the need for DMARDs in 9.9% (11/111) of the patients in the placebo group and in 19.8% (22/111) in the glucocorticoid-treated group (adjusted OR = 0.42, 95% CI 0.18 to 0.99, p = 0.048). CONCLUSION: Treatment of patients with very early IP with IM methylprednisolone acetate appears to postpone the prescription of DMARDs and prevent one in 10 patients from progressing into RA.

Chemoimmunotherapy: an emerging strategy for the treatment of malignant mesothelioma.

Whether the immune system can recognize malignant and premalignant cells and eliminate them to prevent the development of cancer is still a matter of open debate, but in our view, the balance of evidence favours this concept. Nonetheless, the International Agency for Research on Cancer has now predicted that cancer will overtake heart disease as the leading cause of death worldwide by 2010, showing that this protective mechanism often fails. Malignant mesothelioma has traditionally been considered a relatively non-immunogenic cancer. However, mesothelioma cells do express a set of well-defined tumour antigens that have been shown to engage with the host immune system. Mesothelioma should therefore be considered a target for immunotherapy. A variety of anticancer immunotherapies have been investigated in mesothelioma and in other malignancies, although these have been largely ineffective when used in isolation. Over recent years, there has been increasing interest in the possibility of combining immunotherapy with chemotherapy in the fight against cancer. Here, we discuss the rationale behind combining these two, long considered antagonistic, treatment options in the context of malignant mesothelioma.

Human c-Ki-ras2 proto-oncogene on chromosome 12.

A human colonic adenocarcinoma transforming gene, recently identified as a cellular homolog of the Kirsten sarcoma gene (v-ras), was used to assign the human cellular Kirsten ras2 gene to chromosome 12 by the Southern hybridization method. A single 640 base-pair Eco RI--Hind III fragment of the transforming gene, isolated by DNA transfection and molecular cloning, can detect a single Eco RI fragment (2.9 kilobase pairs) of DNA from phenotypically normal cells. The data suggest a constant chromosomal location of c-Ki-ras2.

The comparative responsiveness of the EQ-5D and SF-6D to change in patients with inflammatory arthritis.

PURPOSE: Comparative evidence regarding the responsiveness of the EQ-5D and SF-6D in arthritis patients is conflicting and insufficient across the range of disease severity. We examined the comparative responsiveness of the EQ-5D and SF-6D in cohorts of patients with early inflammatory disease through to severe rheumatoid arthritis (RA). METHODS: Responsiveness was tested using the effect size (ES) and standardised response mean (SRM). Correlation of change in EQ-5D and SF-6D with disease specific measures was tested using Pearson correlations and the Steiger's Z test. Treatment response and self-reported change were used as anchors of important change. RESULTS: The EQ-5D was more responsive to deterioration (ES ratio (EQ-5D/SF-6D): 1.6-3.0) and the SF-6D more responsive to improvement (ES ratio (SF-6D/EQ-5D): 1.1-1.8) in health. The SF-6D did not respond well to deterioration in patients with established severe RA (ES and SRM 0.08). The EQ-5D provided larger absolute mean change estimates but with greater variance compared to the SF-6D. CONCLUSIONS: The comparative responsiveness of the EQ-5D and SF-6D differs according to the direction of change. The level of mean change of the EQ-5D relative to the SF-6D has implications for cost-effectiveness analysis. Use of the SF-6D in patients with severe progressive disease may be inappropriate.

An evaluation of the efficacy of compound alpha and triclabendazole against two isolates of Fasciola hepatica.

Seventy indoor-reared sheep were divided into 10 groups to test the efficacy of the experimental fasciolicide, compound alpha (15mg/kg) against triclabendazole (TCBZ)-resistant and TCBZ-susceptible F. hepatica infections. Activity against the Sligo TCBZ-resistant isolate was tested at three time points post-infection (p.i.): 3 days, 4 weeks and 12 weeks (Groups 1-3, respectively). A parallel trial was carried out using TCBZ (10mg/kg) (Groups 5-7): this provided a direct comparison between the efficacies of the two drugs. Group 4 served as an untreated Sligo control. Groups 8 and 9 were setup to test the efficacy of TCBZ and compound alpha against 12-week-old and 4-week-old TCBZ-susceptible, Cullompton infections, respectively. Group 10 served as an untreated Cullompton control. Sheep were sacrificed at 16 weeks p.i. and efficacies were determined. All remaining flukes were collected and measured, before being processed for whole-mount staining to assess the condition of their reproductive structures (testis, vitellaria, ovary and uterus). A second study was carried out to test the activity of compound alpha (15mg/kg) against mature 12-week-old TCBZ-susceptible F. hepatica infections in sheep. Eighteen sheep were divided into two groups, A and B. Group A was treated and Group B served as an untreated control group. Efficacy was determined by reduction in faecal egg counts. The results showed that, whilst compound alpha was very active against adult TCBZ-susceptible flukes, producing a 100% reduction in faecal egg counts, it only caused a 62.5% reduction in fluke burden against juvenile flukes. Moreover, compound alpha was not effective against any stage of infection with TCBZ-resistant F. hepatica in sheep. Data from the trial also revealed biological differences between the two isolates. Thus, Sligo flukes were smaller in size and produced fewer eggs than the Cullompton flukes and their cysts were less infective to sheep. However, they reached the bile ducts more quickly and their eggs appeared in the faeces >2 weeks earlier.

Effects of breed and production system on lameness parameters in dairy cattle.

The aim of the present study was to assess the effects of Holstein-Friesian (HF) and Norwegian (N) dairy cattle genotypes on lameness parameters in dairy cattle within different production systems over the first 2 lactations. Following calving, HF (n = 39) and N (n = 45) heifers were allocated to 1 of 3 systems of production (high level of concentrate, low level of concentrate, and grass-based). High- and low-concentrate animals were continuously housed indoors on a rotational system so that they spent similar amounts of time on slatted and solid concrete floors. Animals on the grass treatment grazed from spring to autumn in both years of the study, so that most animals on this treatment grazed from around peak to late lactation. Claw health was recorded in both hind claws of each animal at 4 observation periods during each lactation as follows: 1) -8 to 70 d postcalving, 2) 71 to 150 d postcalving, 3) 151 to 225 d postcalving, and 4) 226 to 364 d postcalving. Sole lesions, heel erosion, axial wall deviation, sole length of the right lateral hind claw (claw length), right heel width, and right lateral hind heel height were recorded as well as the presence of digital dermatitis. The N cows had lower (better) white line and total lesion scores than HF cows. Cows on the high- and low-concentrate treatments had better sole and total lesion scores than cows on the grass treatment. The HF cows had better locomotion scores than N cows. Breed and production system differences were observed with respect to claw conformation, including claw length, heel width, and heel height. Digital dermatitis was associated with worse sole lesion scores and interacted with production system to influence white line lesion scores and maximum heel erosion scores. This study shows that genetic, environmental, and infectious factors are associated with hoof pathologies in dairy cows.

Effect of supplementation with barium selenate on the fertility, prolificacy and lambing performance of hill sheep.

Six weeks before mating, the ewes on six hill farms were randomly assigned to receive either a subcutaneous injection of a long-acting supplement containing 50 mg/ml selenium as barium selenate, or no injected selenium. Before the treatment, the mean activity of glutathione peroxidase (GSHPx) in the ewes on the six farms ranged from 166 to 592 U/g haemoglobin (Hb) and their plasma selenium concentrations ranged from 0.60 to 1.61 micromol/l. Treated ewes had higher plasma selenium concentrations and higher GSHPx activities than control ewes during the study. Conception rates were higher in the treated ewes than in the control ewes. At six weeks, the lambs born to the treated ewes had higher plasma selenium and GSHPx levels than the controls. The treated ewes reared 9 per cent more lambs than the control ewes. The treated ewes had lower abortion rates, and higher liveweights and body condition scores than the controls. There were weak but positive associations between the plasma selenium and GSHPx levels of the ewes and their reproductive performance.

Surface and internal tegumental changes in juvenile Fasciola hepatica following treatment in vivo with the experimental fasciolicide, compound alpha.

Eight indoor-reared, crossbred sheep with no pre-exposure to Fasciola hepatica were infected, by oral gavage, with 200 metacercarial cysts of the triclabendazole-susceptible, Cullompton isolate of F. hepatica. Anthelmintic dosing occurred at 4 weeks post-infection using 15mg/kg compound alpha. Two treated sheep per time period were euthanized at 24h, 48h and 72h post-treatment with compound alpha. The two sheep from the control group were euthanized alongside the 24h alpha-treated sheep. Juvenile flukes were recovered from each of the sheeps' liver and processed for examination by electron microscopy. The surface morphology of the flukes' tegument was assessed using scanning electron microscopy (SEM). The ultrastructure of the tegumental syncytium and underlying tegumental cells and connections and somatic musculature were investigated using transmission electron microscopy (TEM). Both the SEM and TEM results revealed a level of disruption that increased with time, culminating at 72h with extensive tegumental loss and substantial degeneration of the cell bodies. The effects of compound alpha on the surface morphology were not particularly apparent until 48h post-treatment, when disruption included swelling and blebbing of the tegument. At 72h post-treatment, SEM revealed loss of the entire syncytial layer over large areas of the flukes. In the areas where the syncytium was lost and the basal lamina exposed, lesions of varying sizes had developed, revealing underlying tissues. Though minor forms of disruption to the ultrastructure of the syncytium were observed using TEM 24h post-treatment, it was at 48h post-treatment that substantial stress responses occurred. They included the presence of autophagic vacuoles and 'open' bodies at the apex of the syncytium and swelling of the basal infolds. The mitochondria within the syncytium and tegumental cells became progressively more disrupted over the three time periods and, by 72h post-treatment, they were frequently distorted and swollen in appearance, and contained severely swollen cristae. By 72h, the number of secretory bodies, particularly T1 bodies, had become significantly depleted in their respective cell bodies, cytoplasmic processes and in the tegumental syncytium. Both the circular and longitudinal muscle bundles were severely disrupted 72h post-treatment. They frequently contained a reduced number of muscle fibres and, in more severe instances, there was an absence of fibres altogether.

Periprandial changes in metabolite and metabolic hormone concentrations in high-genetic-merit dairy heifers and their relationship to energy balance in early lactation.

Sixteen high-genetic-merit Holstein-Friesian heifers were offered a complete diet of grass silage, maize silage, and concentrates ad libitum through mo 1 to 3 postpartum. Open-circuit calorimetry and a 6-d digestibility balance were performed on each heifer at the end of each month, and energy balance (EB) was calculated. After each digestibility balance, heifers were blood sampled hourly from 1 h before to 9 h after feeding. Prefeed plasma and 3-h composites of postfeed plasmas were analyzed for selected metabolites and hormones. Levels of nonesterified fatty acids (NEFA) decreased, whereas those of beta-hydroxybutyrate (BHBA) increased after feeding in each month. Urea levels increased after feeding, whereas glucose levels decreased in each month. Insulin increased after feeding but with reducing significance as lactation progressed. Insulin was always lower before feeding, and mean insulin increased from mo 1 to mo 3. Levels of insulin-like growth factor-1 (IGF-I) increased across mo 1 to 3, but were unaffected by feeding except in mo 2, whereas leptin levels varied significantly on each sampling occasion, but showed no increase between mo 1 and mo 3. Multiple regression of all data showed no significant correlation between EB and either BHBA or NEFA levels. However, EB was negatively correlated with leptin levels (r = -0.632), which were themselves positively associated with IGF-I (r = 0.498) and glucose (r = 0.565). A relationship was established between overall mean EB and prefeed leptin, insulin, and urea (R(2) = 0.63) in the first 3 mo of lactation. A potentially useful relationship was also established between EB and prefeed concentrations of leptin, IGF-I, urea, and glucose (R(2) = 0.80) only in mo 1 of lactation.