Neutron source reconstruction using a generalized expectation-maximization algorithm on one-dimensional neutron images from the Z facility.

Magnetized Liner Inertial Fusion experiments have been performed at the Z facility at Sandia National Laboratories. These experiments use deuterium fuel, which produces 2.45 MeV neutrons on reaching thermonuclear conditions. To study the spatial structure of neutron production, the one-dimensional imager of neutrons diagnostic was fielded to record axial resolved neutron images. In this diagnostic, neutrons passing through a rolled edge aperture form an image on a CR-39-based solid state nuclear track detector. Here, we present a modified generalized expectation-maximization algorithm to reconstruct an axial neutron emission profile of the stagnated fusion plasma. We validate the approach by comparing the reconstructed neutron emission profile to an x-ray emission profile provided by a time-integrated pinhole camera.

Polarisation of equine pregnancy outcome associated with a maternal MHC class I allele: Preliminary evidence.

Identification of risk factors which are associated with severe clinical signs can assist in the management of disease outbreaks and indicate future research areas. Pregnancy loss during late gestation in the mare compromises welfare, reduces fecundity and has financial implications for horse owners. This retrospective study focussed on the identification of risk factors associated with pregnancy loss among 46 Thoroughbred mares on a single British stud farm, with some but not all losses involving equid herpesvirus-1 (EHV-1) infection. In a sub-group of 30 mares, association between pregnancy loss and the presence of five common Thoroughbred horse haplotypes of the equine Major Histocompatibility Complex (MHC) was assessed. This involved development of sequence specific, reverse transcriptase polymerase chain reactions and in several mares, measurement of cytotoxic T lymphocyte activity. Of the 46 mares, 10 suffered late gestation pregnancy loss or neonatal foal death, five of which were EHV-1 positive. Maternal factors including age, parity, number of EHV-1 specific vaccinations and the number of days between final vaccination and foaling or abortion were not significantly associated with pregnancy loss. In contrast, a statistically significant association between the presence of the MHC class I B2 allele and pregnancy loss was identified, regardless of the fetus/foal's EHV-1 status (p=0.002). In conclusion, this study demonstrated a significantly positive association between pregnancy loss in Thoroughbred mares and a specific MHC class I allele in the mother. This association requires independent validation and further investigation of the mechanism by which the mare's genetic background contributes to pregnancy outcome.

A racing start in life? The hurdles of equine feto-placental pathology.

Significant progress has been made in understanding and monitoring the causes of equine abortion over past decades. However, not all in utero pathology results in abortion. It has long been recognised that some in utero pathology, such as twinning or chronic placentitis, can result in the birth of live but growth-retarded foals and there is historical evidence that birth weight may influence future athletic performance. Clinical experience (e.g. from twins) and experimental studies (pony-Thoroughbred embryo transfer) have highlighted the importance of reduced functional placental area in limiting growth in utero in horses. Many other nonfatal in utero pathologies (e.g. umbilical cord-related circulatory compromise) can potentially affect either placental function or other organ systems. Their influence on the short- and long-term health of the foal and its future athletic performance is in many cases poorly documented or understood. This review summarises the main causes of in utero pathology and reflects on how these may potentially affect the foal if born alive, highlighting the need for long-term studies on this important subject.

Serum cardiac troponin I in dogs with primary immune-mediated haemolytic anaemia.

OBJECTIVES: The assessment of serum cardiac troponin I concentrations in dogs with a range of nonprimary cardiac illnesses has revealed that cardiac myocyte damage is commonplace in many canine diseases. Whilst it is well established that dogs with fatal immune-mediated haemolytic anaemia frequently have cardiac pathology based on post-mortem examinations, there is limited information on the incidence of cardiac myocyte damage in this population of dogs. METHODS: Serum cardiac troponin I concentrations were measured in 11 healthy dogs, 27 dogs with primary haemolytic anaemia and 49 hospitalised dogs without primary cardiac or haematological disorders. RESULTS: Dogs with primary haemolytic anaemia have higher serum concentrations of cardiac troponin I than hospitalised ill dogs (P<0.005) and healthy dogs (P<0.01). Using a cut-off of less than 0.1 ng/mL, 20 of 27 dogs with primary haemolytic anaemia had increased serum cardiac troponin I concentrations, which was a significantly higher proportion compared to the hospitalised ill dogs (P<0.001, 16 out of 49 dogs) and healthy dogs (P<0.05, 3 out of 11 dogs). CLINICAL SIGNIFICANCE: Dogs with primary haemolytic anaemia have a higher incidence of subclinical myocyte damage than healthy dogs or dogs with non-haematological or primary cardiac illnesses. The prognostic significance of increased serum cardiac troponin I concentrations in dogs with primary haemolytic anaemia merits further investigation.

Bayesian methods for meta-analysis of causal relationships estimated using genetic instrumental variables.

Genetic markers can be used as instrumental variables, in an analogous way to randomization in a clinical trial, to estimate the causal relationship between a phenotype and an outcome variable. Our purpose is to extend the existing methods for such Mendelian randomization studies to the context of multiple genetic markers measured in multiple studies, based on the analysis of individual participant data. First, for a single genetic marker in one study, we show that the usual ratio of coefficients approach can be reformulated as a regression with heterogeneous error in the explanatory variable. This can be implemented using a Bayesian approach, which is next extended to include multiple genetic markers. We then propose a hierarchical model for undertaking a meta-analysis of multiple studies, in which it is not necessary that the same genetic markers are measured in each study. This provides an overall estimate of the causal relationship between the phenotype and the outcome, and an assessment of its heterogeneity across studies. As an example, we estimate the causal relationship of blood concentrations of C-reactive protein on fibrinogen levels using data from 11 studies. These methods provide a flexible framework for efficient estimation of causal relationships derived from multiple studies. Issues discussed include weak instrument bias, analysis of binary outcome data such as disease risk, missing genetic data, and the use of haplotypes.

Serum cardiac troponin I concentrations in cattle with cardiac and noncardiac disorders.

BACKGROUND: Making a clinical diagnosis of pericarditis in cattle is difficult and additional diagnostic tests are needed to evaluate cattle with suspected pericarditis. Serum cardiac troponin I (cTnI) concentrations are increased in cattle with pericarditis, but the utility of measuring serum cTnI concentrations in cattle with suspected pericarditis in cattle remains unclear. OBJECTIVES: To determine if serum cTnI concentrations in cattle can be used to differentiate pericarditis from other cardiac disorders and noncardiac thoracic diseases. ANIMALS: Seventy-seven clinically diseased cattle and 19 healthy control cattle. METHODS: Serum cTnI concentrations were measured using an Immunlite Troponin I immunometric chemiluminescent assay in consecutive cases of postmortem-confirmed pericarditis (n=18), endocarditis (n=15), chronic suppurative pneumonia (n=13), congenital heart disease (n=10), reticulitis (n=3), mediastinal abscess (n=7), thymic lymphoma (n=6), and caudal vena cava thrombosis (n=5). Serum cTnI concentrations were measured in 19 healthy cattle. RESULTS: Although serum cTnI concentrations were significantly higher in cattle with pericarditis compared with healthy cattle, they were not significantly different from concentrations in cattle with endocarditis, congenital cardiac disease, mediastinal abscess, reticulitis, caudal vena cava thrombosis, or chronic suppurative pneumonia. CONCLUSIONS: Serum cTnI cannot be used to distinguish cattle with pericarditis from cattle with other primary cardiac diseases. In addition, serum cTnI concentrations cannot distinguish between cattle with primary cardiac diseases and those with other noncardiac, intrathoracic disorders.

An investigation into the suitability of a commercial real-time PCR assay to screen for Taylorella equigenitalis in routine prebreeding equine genital swabs.

REASONS FOR PERFORMING STUDY: Standard bacteriological methods for identifying Taylorella equigenitalis in cervical smears are time consuming. Therefore, a more rapid real-time PCR assay was evaluated for its suitability in screening swabs. OBJECTIVE: To compare the results of a commercially available real-time PCR assay with routine microbiological culture for the identification of T. equigenitalis, the causative organism of contagious equine metritis, in equine genital swab samples, under 'field trial' conditions. MATERIALS AND METHODS: Routine prebreeding genital swabs (n=2072) collected from Thoroughbred mares and stallions during 2009 were examined together with stored T. equigenitalis positive material. Swabs were cultured for T. equigenitalis using standard microbiological techniques. Bacterial lysates were isolated from the swabs and examined for the presence of a 16S DNA fragment of T. equigenitalis, using a commercial multiplex real-time PCR assay system. RESULTS: There was complete concordance between positive and negative results obtained by the 2 methods. Real-time PCR also detected T. equigenitalis DNA from swabs that were negative using standard microbiological culture after 6 months' storage at +4 degrees C but from which T. equigenitalis had been isolated following collection. The sensitivities of real-time PCR and bacterial culture were both 10(-3) (equivalent to 3 colony-forming units). CONCLUSION AND CLINICAL RELEVANCE: Routine bacterial culture of T. equigenitalis requires an incubation period of not less than 7 days before a conclusive negative result can be obtained, whereas bacterial extraction and real-time PCR assay can be completed in less than 6 h. The commercially-available PCR assay tested provided a rapid and reliable method for the identification of T. equigenitalis from equine genital swabs and could be usefully employed for the screening of mares and stallions for preseason Horserace Betting Levy Board (HBLB) Code of Practice and in other situations such as for bloodstock sales screening requirements, overcoming the current delays imposed by bacterial culture requirements. Its use could be quality assured by the existing HBLB biannual testing scheme for designated laboratories.

The development and distribution of the interstitial cells of Cajal in the intestine of the equine fetus and neonate.

This study set out to determine the pattern of development and distribution of the interstitial cells of Cajal (ICC) in the intestinal tract of the equine fetus and neonate. Intestinal tissue samples from 12 naturally aborted equine fetuses and three euthanized neonates were collected and fixed in formalin prior to applying standard immunohistochemical labelling techniques targeting the c-Kit protein of the ICC. At 6 months of gestation, a network of ICC was present in the myenteric plexus region of both the small and the large intestine. ICC were also present within the circular muscle layer. In the large intestine, a proximal to distal gradient of distribution was evident, with few ICC observed in the more distal parts of the large intestine in the younger fetuses compared with the near-term animals. A transmural gradient of distribution was also evident within the large intestine, with the most luminal part of the muscularis externa being the last area to be colonized by ICC. This region did not appear fully developed until the early neonatal period. An increased density of ICC was noted throughout the large intestine in the regions of the taenial bands in all animals. This study is the first to describe ICC development and distribution in the equine fetus and neonate.

Biochemical markers of bone metabolism in growing thoroughbreds: a longitudinal study.

This study describes longitudinal changes in serum levels of biochemical markers of bone cell activity in a group of 24 thoroughbred foals from birth to 18 months of age. The markers of bone formation included the type I collagen carboxy-terminal propeptide (PICP), the bone-specific isoenzyme of alkaline phosphatase (BAP), and osteocalcin (OC). Levels of the cross-linked telopeptide of type I collagen (ICTP), a marker of bone resorption, and the N-terminal propeptide of type III collagen (PNIIIP), a marker of soft tissue turnover, were also measured. Levels of all markers fell significantly between birth and 18 months of age (70-80 per cent); this decrease being most marked between 0 and 6 months. However, a transient increase in levels of the markers then occurred between 6 and 14 months of age. The timing of this increase was specific for each parameter. ICTP and OC concentrations increased between October and December. PICP concentrations increased between December and April whereas the increase in PIIINP was coincident with the peak in weight gain between April and June. Changes in BAP concentration were less distinct at this time. Season was shown to have significant effects on the biochemical markers independent from the effect of age. Concentrations of all markers decreased with increasing body weight and at any given age heavier horses had lower marker levels. These results show that biochemical markers of bone cell activity and soft tissue turnover follow characteristic patterns of change in growing thoroughbreds influenced by age, season and bodyweight. The demonstration that the reference ranges for the biochemical markers change from month to month means that single samples from individuals are of little value for monitoring bone cell activity in growing thoroughbreds.

Increased anterior cingulate and caudate activity in bipolar mania.

BACKGROUND: Executive control of cognition, emotion, and behavior are disrupted in the manic state of bipolar disorder. Whereas frontal systems are implicated in such dysfunction, the localization of functional brain abnormalities in the manic state is not well understood. METHODS: We utilized a high-sensitivity H(2)(15)0 positron emission tomography technique to investigate regions of increased brain activity in mania, compared to euthymia, in bipolar disorder. RESULTS: The principal findings were manic state-related increased activity in left dorsal anterior cingulate, and left head of caudate. CONCLUSIONS: The findings suggest that the manic state of bipolar disorder may be associated with heightened activity in a frontal cortical-subcortical neural system that includes the anterior cingulate and caudate.

Rostral and orbital prefrontal cortex dysfunction in the manic state of bipolar disorder.

OBJECTIVE: This study investigated prefrontal cortex function in the manic state of bipolar disorder. METHOD: High-sensitivity [15O]H2O positron emission tomography and a word generation activation paradigm were used to study regional cerebral blood flow in five manic and six euthymic individuals with bipolar disorder and in five healthy individuals. RESULTS: Decreased right rostral and orbital prefrontal cortex activation during word generation and decreased orbitofrontal activity during rest were associated with mania. CONCLUSIONS: The data support the presence of rostral and orbital prefrontal dysfunction in primary mania. These findings, when seen in the context of the human brain lesion and the behavioral neuroanatomic literatures, may help to explain some of the neurobehavioral abnormalities characteristic of the manic state.

Legal system involvement and costs for persons in treatment for severe mental illness and substance use disorders.

OBJECTIVE: Persons with co-occurring severe mental illness and substance use disorders were followed for three years to better understand how they are involved with the legal system and to identify factors associated with different kinds of involvement. METHODS: Data came from a three-year study of 203 persons enrolled in specialized treatment for dual disorders. Cost and utilization data were collected from multiple data sources, including police, sheriffs and deputies, officers of the court, public defenders, prosecutors, private attorneys, local and county jails, state prisons, and paid legal guardians. RESULTS: Over three years 169 participants (83 percent) had contact with the legal system, and 90 (44 percent) were arrested at least once. Participants were four times more likely to have encounters with the legal system that did not result in arrest than they were to be arrested. Costs associated with nonarrest encounters were significantly less than costs associated with arrests. Mean costs per person associated with an arrest were $2,295, and mean costs associated with a nonarrest encounter were $385. Combined three-year costs averaged $2,680 per person. Arrests and incarcerations declined over time. Continued substance use and unstable housing were associated with a greater likelihood of arrest. Poor treatment engagement was associated with multiple arrests. Men were more likely to be arrested, and women were more likely to be the victims of crime. CONCLUSIONS: Effective treatment of substance use among persons with mental illness appears to reduce arrests and incarcerations but not the frequency of nonarrest encounters. Stable housing may also reduce the likelihood and number of arrests.

Induction of rat WT1 gene expression correlates with human chromosome 11p11.2-p12-mediated suppression of tumorigenicity in rat liver epithelial tumor cell lines.

We have previously identified and mapped a locus within human chromosome 11p11.2-p12 that suppresses the tumorigenic potential of some rat liver tumor cell lines. In the present study, possible molecular mechanisms of human 11p11.2-p12-mediated liver tumor suppression were investigated by examining gene expression patterns in suppressed and non-suppressed microcell hybrid (MCH) cell lines. The parental rat liver tumor cell lines (GN6TF and GP7TB) express moderate levels of p53 mRNA and protein, overexpress mRNAs for c-H-ras, c-myc, and TGFá, and do not express detectable levels of WT1 mRNA or protein. Suppression of tumorigenicity by human chromosome 11p11.2-p12 was not accompanied by significant alterations in the levels of expression of p53, c-myc, or TGFá. Expression of c-H-ras was decreased significantly in both suppressed and non-suppressed MCH cell lines, suggesting that down-regulation of c-H-ras is not directly responsible for tumor suppression. In contrast, the level of expression of WT1 correlated precisely with tumor suppression in this model system. All suppressed MCH cell lines expressed WT1 mRNA and protein at levels comparable to that of untransformed rat liver epithelial cells (WB-F344), whereas only trace WT1 mRNA and protein were detected in a non-suppressed MCH cell line. PCR analysis demonstrated that two suppressed MCH cell lines do not carry the human WT1 gene, indicating that WT1 expression in these lines originates from the rat locus. Furthermore, RT-PCR analysis showed that each of the four known splice variants of the WT1 mRNA are expressed in these suppressed MCH cell lines, recapitulating the expression pattern observed in the untransformed rat liver epithelial cells. Re-expression of tumorigenicity by suppressed MCH cell lines was accompanied by the coordinate loss of human chromosome 11p11.2-p12 and of WT1 gene expression, suggesting that one or more human 11p11.2-p12 genes are required for sustained expression of WT1 in these cell lines. Together, these results suggest that the molecular mechanism governing human chromosome 11p11.2-p12-mediated liver tumor suppression may involve induction of rat WT1 gene expression under the direct or indirect transcriptional regulation of a genetic locus (or loci) on human 11p11.2-p12.

Quantitative analysis of the development of experimentally induced post surgical adhesions: a microstereological study.

The aim of this study was to quantitatively define the development of post surgical adhesions (PSAs) in a well characterized experimental model and identify possible windows of pathogenesis where pharmaceutical intervention may be most effective. PSAs were induced, in an established rabbit uterine horn model, using standardized reproducible injury, in 17 experimental groups, each with 8 experimental sites and these PSAs were sampled from 30 seconds to 42 days post surgery. Using design based, unbiased stereology, mean volumes of PSAs and associated tissue damage and reaction per experimental site were calculated for each sample time point. PSA development followed the normal pattern of wound healing with surrounding adjacent tissue having a profound influence and interaction. There was a direct relationship between volume of damage (initial and subsequent) and the volume of injury tissue generated. In vivo weak fibrinous PSAs were present from 10 min following injury, with tenacious fibrinous PSAs present from 1 h and onwards. PSA development can be classified into two distinct stages: (i) PSA modelling - occurring during the first 16 h, in which maximum rate of PSA construction is achieved; and (ii) PSA remodelling - from 16 h onwards. Considering this, PSA prevention should ideally be initiated immediately post injury to prevent PSA modelling or, alternatively, during PSA modelling.

Plasticity of the neoplastic phenotype in vivo is regulated by epigenetic factors.

Age of host and transplantation-site microenvironment influence the tumorigenic potential of neoplastically transformed liver epithelial cells. Tumorigenic BAG2-GN6TF rat liver epithelial cells consistently form tumors at ectopic sites, but differentially express tumorigenicity or hepatocytic differentiation in the liver depending on host age and route of cell transplantation into the liver. Direct inoculation into host livers concentrates tumor cells locally, resulting in undifferentiated tumors near the transplantation site in both young (3-month-old) and old (18-month-old) rats. Transplantation-site tumors regress within 1 month in the livers of young rats, but grow progressively in old rats. However, inoculation of cells into the spleen distributes transplanted cells individually throughout the liver, resulting in hepatocytic differentiation by tumor cells with concomitant suppression of their tumorigenicity in young rats. When transplanted into livers of old rats by splenic inoculation, or when young hepatic-transplant recipients are allowed to age, hepatocytic progeny of BAG2-GN6TF cells proliferate to form foci, suggesting that the liver microenvironment of old rats incompletely regulates the proliferation and differentiation of tumor cell-derived hepatocytes. Upon removal from the liver, BAG2-GN6TF-derived hepatocytes revert to an undifferentiated, aggressively tumorigenic phenotype. We posit that the spectrum between normal differentiation and malignant potential of these cells reflects the dynamic interaction of the specific transformation-related genotype of the cells and the characteristics of the tissue microenvironment at the transplantation site. Changes in the tissue milieu, such as those that accompany normal aging, may determine the ability of a genetically aberrant cell to produce a tumor.

Cost-effectiveness of assertive community treatment versus standard case management for persons with co-occurring severe mental illness and substance use disorders.

OBJECTIVE: To determine the cost-effectiveness of Assertive Community Treatment (ACT) in comparison to Standard Case Management (SCM) for persons with severe mental illness and substance use disorders. DATA SOURCES AND STUDY SETTING: Original data on the effectiveness and social costs of ACT and SCM that were collected between 1989 and 1995. Seven community mental health centers in New Hampshire provided both types of treatment. STUDY DESIGN: Persons with schizophrenia, schizoaffective disorder, or bipolar disorder and a concurrent substance use disorder were randomly assigned to ACT or SCM and followed for three years. The primary variables assessed were substance use, psychiatric symptoms, functioning, quality of life, and social costs. DATA COLLECTION METHODS: Effectiveness data were obtained from interviews at six-month intervals with persons enrolled in treatment and with their service providers. Social cost and service utilization data came from client reports; interviews with informal caregivers; provider information systems and Medicaid claims; law enforcement agencies; courts; and community service providers. PRINCIPAL FINDINGS: Participants in both groups showed significant reductions in substance use over time. Focusing on quality of life and substance use outcomes, ACT and SCM were not significantly different in cost-effectiveness over the entire three-year study period. Longitudinal analyses showed that SCM tended to be more efficient during the first two years but that ACT was significantly more efficient than SCM during the final year of the study. CONCLUSIONS: In an adequately funded system, ACT is not more cost-effective than SCM. However, ACT efficiency appears to improve over time.

Downregulation of right ventricular phosphodiesterase PDE-3A mRNA and protein before the development of canine heart failure.

Phosphodiesterase III (PDE-3) inhibitors are inotropes used to treat congestive heart failure (HF). Previous studies showed PDE-3A mRNA levels were reduced in the left ventricle (LV) in dogs subjected to pacing-induced HF. The present study evaluated a time-course for RV-specific changes in PDE-3A mRNAs and proteins after pacing for 3 wk (n = 4) or in HF (4-5 wk; n = 4-6). Total RNA from LV/RV tissues was isolated for Northern analyses; cytosolic and microsomal proteins were prepared for PDE-3A immunoblots. PDE-3A mRNAs (7-8 and 10 kb) were normalized against glyceraldehyde-3-phosphodehydrogenase (GAPDH) or ribosomal 18s with similar results. PDE-3A/GAPDH ratios in 3 wk were unchanged in LV, but significantly (p < 0.05) reduced by 48% in RV vs unpaced controls (n = 8). In contrast, PDE-3A (7-8 kb)/GAPDH ratios were significantly reduced in HF by 50-59% in both ventricles. Consistent with mRNA levels, significant reductions in microsomal 135 kDa (93-96%) and cytosolic 120 kDa PDE-3A (57-69%) were seen in both ventricles in HF or in the RV at 3 wk; an LV-specific reduction (50%) in cytosolic 80 kDa PDE-3A in HF was also detected. In summary, RV-specific downregulation of PDE-3A mRNA/protein(s) at 3 wk suggests that hemodynamic rather than humoral mechanisms are responsible, and provides a molecular basis for the limited efficacy of milrinone in the progression of HF.

Development of decompensated dilated cardiomyopathy is associated with decreased gene expression and activity of the milrinone-sensitive cAMP phosphodiesterase PDE3A.

BACKGROUND: Phosphodiesterase III (PDE3) inhibitors are inotropic agents used to treat congestive heart failure (CHF) and are less effective in patients with severe CHF. Little is known about relative changes in PDE3 activity or gene expression during the evolution of cardiomyopathy. METHODS AND RESULTS: In the present study, we evaluated temporal changes in PDE3A gene expression before and after pacing-induced CHF in nine mongrel dogs. Three weeks of left ventricular (LV) pacing produced LV end-diastolic pressures of 15+/-1.7 mm Hg, whereas overt CHF at 4 to 5 weeks was associated with LV end-diastolic pressures of 24+/-1.7 mm Hg; prepacing values were 6.6+/-0.6 mm Hg. Total RNA isolated from LV tissues was analyzed on Northern blots; 10 unpaced normal hearts served as tissue controls. Signals for PDE3A mRNAs (7, 8, and 10 kb) or PDE4D (7.6 kb) were normalized against glyceraldehyde-3-phosphate dehydrogenase (GAPDH) or ribosomal 18S RNA. Before the onset of CHF, PDE3A/GAPDH ratios were not different between the control and 3-week paced groups. In contrast, all PDE3A/GAPDH ratios were selectively reduced by 52%, and PDE3A/18S was reduced by 70% (P<.05) in CHF; PDE4D/GAPDH (or 18S) was unchanged. LV tissues from four control and four CHF dogs were also processed to isolate cytosolic and microsomal membrane protein for cAMP PDE3 activity assays. CHF was associated with a significant 54% reduction (P<.05) in microsomal but not cytosolic PDE3 activity. CONCLUSIONS: Selective downregulation of PDE3A may account in part for the ineffectiveness of milrinone in the treatment of severe CHF.