Overexpression of Key Sterol Pathway Enzymes in Two Model Marine Diatoms Alters Sterol Profiles in <i>Phaeodactylum tricornutum</i>.

Sterols are a class of triterpenoid molecules with diverse functional roles in eukaryotic cells, including intracellular signaling and regulation of cell membrane fluidity. Diatoms are a dominant eukaryotic phytoplankton group that produce a wide diversity of sterol compounds. The enzymes 3-hydroxy-3-methyl glutaryl CoA reductase (HMGR) and squalene epoxidase (SQE) have been reported to be rate-limiting steps in sterol biosynthesis in other model eukaryotes; however, the extent to which these enzymes regulate triterpenoid production in diatoms is not known. To probe the role of these two metabolic nodes in the regulation of sterol metabolic flux in diatoms, we independently over-expressed two versions of the native HMGR and a conventional, heterologous SQE gene in the diatoms Thalassiosira pseudonana and Phaeodactylum tricornutum. Overexpression of these key enzymes resulted in significant differential accumulation of downstream sterol pathway intermediates in P. tricornutum. HMGR-mVenus overexpression resulted in the accumulation of squalene, cycloartenol, and obtusifoliol, while cycloartenol and obtusifoliol accumulated in response to heterologous NoSQE-mVenus overexpression. In addition, accumulation of the end-point sterol 24-methylenecholesta-5,24(24')-dien-3β-ol was observed in all P. tricornutum overexpression lines, and campesterol increased three-fold in P. tricornutum lines expressing NoSQE-mVenus. Minor differences in end-point sterol composition were also found in T. pseudonana, but no accumulation of sterol pathway intermediates was observed. Despite the successful manipulation of pathway intermediates and individual sterols in P. tricornutum, total sterol levels did not change significantly in transformed lines, suggesting the existence of tight pathway regulation to maintain total sterol content

Genetic Variants at Chromosomes 2q35, 5p12, 6q25.1, 10q26.13, and 16q12.1 Influence the Risk of Breast Cancer in Men

Male breast cancer accounts for approximately 1% of all breast cancer. To date, risk factors for male breast cancer are poorly defined, but certain risk factors and genetic features appear common to both male and female breast cancer. Genome-wide association studies (GWAS) have recently identified common single nucleotide polymorphisms (SNPs) that influence female breast cancer risk; 12 of these have been independently replicated. To examine if these variants contribute to male breast cancer risk, we genotyped 433 male breast cancer cases and 1,569 controls. Five SNPs showed a statistically significant association with male breast cancer: rs13387042 (2q35) (odds ratio (OR)  = 1.30, p = 7.98×10−4), rs10941679 (5p12) (OR = 1.26, p = 0.007), rs9383938 (6q25.1) (OR = 1.39, p = 0.004), rs2981579 (FGFR2) (OR = 1.18, p = 0.03), and rs3803662 (TOX3) (OR = 1.48, p = 4.04×10−6). Comparing the ORs for male breast cancer with the published ORs for female breast cancer, three SNPs—rs13387042 (2q35), rs3803662 (TOX3), and rs6504950 (COX11)—showed significant differences in ORs (p<0.05) between sexes. Breast cancer is a heterogeneous disease; the relative risks associated with loci identified to date show subtype and, based on these data, gender specificity. Additional studies of well-defined patient subgroups could provide further insight into the biological basis of breast cancer development

Prescriptive variability of drugs by general practitioners

<div><p>Prescription drug spending is growing faster than any other sector of healthcare. However, very little is known about patterns of prescribing and cost of prescribing between general practices. In this study, we examined variation in prescription rates and prescription costs through time for 55 GP surgeries in Northern Ireland Western Health and Social Care Trust. Temporal changes in variability of prescribing rates and costs were assessed using the Mann–Kendall test. Outlier practices contributing to between practice variation in prescribing rates were identified with the interquartile range outlier detection method. The relationship between rates and cost of prescribing was explored with Spearman's statistics. The differences in variability and mean number of prescribing rates associated with the practice setting and socioeconomic deprivation were tested using t-test and <i>F</i>-test respectively. The largest between-practice difference in prescribing rates was observed for Apr-Jun 2015, with the number of prescriptions ranging from 3.34 to 8.36 per patient. We showed that practices with outlier prescribing rates greatly contributed to between-practice variability. The largest difference in prescribing costs was reported for Apr-Jun 2014, with the prescription cost per patient ranging from £26.4 to £64.5. In addition, the temporal changes in variability of prescribing rates and costs were shown to undergo an upward trend. We demonstrated that practice setting and socio-economic deprivation accounted for some of the between-practice variation in prescribing. Rural practices had higher between practice variability than urban practices at all time points. Practices situated in more deprived areas had higher prescribing rates but lower variability than those located in less deprived areas. Further analysis is recommended to assess if variation in prescribing can be explained by demographic characteristics of patient population and practice features. Identification of other factors contributing to prescribing variability can help us better address potential inappropriateness of prescribing.</p></div

The role of dietary fibre in pig production, with a particular emphasis on reproduction

Abstract Fibres from a variety of sources are a common constituent of pig feeds. They provide a means to utilise locally-produced plant materials which are often a by-product of the food or drink industry. The value of a high fibre diet in terms of producing satiety has long been recognised. However the addition of fibre can reduce feed intake, which is clearly detrimental during stages of the production cycle when nutrient needs are high, for example in growing piglets and during lactation. More recently, fibre has been found to promote novel benefits to pig production systems, particularly given the reduction in antimicrobial use world-wide, concern for the welfare of animals fed a restricted diet and the need to ensure that such systems are more environmentally friendly. For example, inclusion of dietary fibre can alter the gut microbiota in ways that could reduce the need for antibiotics, while controlled addition of certain fibre types may reduce nitrogen losses into the environment and so reduce the environmental cost of pig production. Of particular potential value is the opportunity to use crude fibre concentrates as ‘functional’ feed additives to improve young pig growth and welfare. Perhaps the greatest opportunity for the use of high fibre diets is to improve the reproductive efficiency of pigs. Increased dietary fibre before mating improves oocyte maturation, prenatal survival and litter size; providing a consumer-acceptable means of increasing the amount of saleable meat produced per sow. The mechanisms responsible for these beneficial effects remain to be elucidated. However, changes in plasma and follicular fluid concentrations of key hormones and metabolites, as well as effects of the hypothalamic satiety centre on gonadotrophin secretion and epigenetic effects are strong candidates

Mucopolysaccharidosis VI

Mucopolysaccharidosis VI (MPS VI) is a lysosomal storage disease with progressive multisystem involvement, associated with a deficiency of arylsulfatase B leading to the accumulation of dermatan sulfate. Birth prevalence is between 1 in 43,261 and 1 in 1,505,160 live births. The disorder shows a wide spectrum of symptoms from slowly to rapidly progressing forms. The characteristic skeletal dysplasia includes short stature, dysostosis multiplex and degenerative joint disease. Rapidly progressing forms may have onset from birth, elevated urinary glycosaminoglycans (generally >100 μg/mg creatinine), severe dysostosis multiplex, short stature, and death before the 2nd or 3rd decades. A more slowly progressing form has been described as having later onset, mildly elevated glycosaminoglycans (generally <100 μg/mg creatinine), mild dysostosis multiplex, with death in the 4th or 5th decades. Other clinical findings may include cardiac valve disease, reduced pulmonary function, hepatosplenomegaly, sinusitis, otitis media, hearing loss, sleep apnea, corneal clouding, carpal tunnel disease, and inguinal or umbilical hernia. Although intellectual deficit is generally absent in MPS VI, central nervous system findings may include cervical cord compression caused by cervical spinal instability, meningeal thickening and/or bony stenosis, communicating hydrocephalus, optic nerve atrophy and blindness. The disorder is transmitted in an autosomal recessive manner and is caused by mutations in the ARSB gene, located in chromosome 5 (5q13-5q14). Over 130 ARSB mutations have been reported, causing absent or reduced arylsulfatase B (N-acetylgalactosamine 4-sulfatase) activity and interrupted dermatan sulfate and chondroitin sulfate degradation. Diagnosis generally requires evidence of clinical phenotype, arylsulfatase B enzyme activity <10% of the lower limit of normal in cultured fibroblasts or isolated leukocytes, and demonstration of a normal activity of a different sulfatase enzyme (to exclude multiple sulfatase deficiency). The finding of elevated urinary dermatan sulfate with the absence of heparan sulfate is supportive. In addition to multiple sulfatase deficiency, the differential diagnosis should also include other forms of MPS (MPS I, II IVA, VII), sialidosis and mucolipidosis. Before enzyme replacement therapy (ERT) with galsulfase (Naglazyme®), clinical management was limited to supportive care and hematopoietic stem cell transplantation. Galsulfase is now widely available and is a specific therapy providing improved endurance with an acceptable safety profile. Prognosis is variable depending on the age of onset, rate of disease progression, age at initiation of ERT and on the quality of the medical care provided

Factors Associated with Height Catch-Up and Catch-Down Growth Among Schoolchildren

In developed countries, children with intrauterine growth restriction (IUGR) or born preterm (PT) tend to achieve catch-up growth. There is little information about height catch-up in developing countries and about height catch-down in both developed and developing countries. We studied the effect of IUGR and PT birth on height catch-up and catch-down growth of children from two cohorts of liveborn singletons. Data from 1,463 children was collected at birth and at school age in Ribeirão Preto (RP), a more developed city, and in São Luís (SL), a less developed city. A change in z-score between schoolchild height z-score and birth length z-score≥0.67 was considered catch-up; a change in z-score≤−0.67 indicated catch-down growth. The explanatory variables were: appropriate weight for gestational age/PT birth in four categories: term children without IUGR (normal), IUGR only (term with IUGR), PT only (preterm without IUGR) and preterm with IUGR; infant's sex; maternal parity, age, schooling and marital status; occupation of family head; family income and neonatal ponderal index (PI). The risk ratio for catch-up and catch-down was estimated by multinomial logistic regression for each city. In RP, preterms without IUGR (RR = 4.13) and thin children (PI<10th percentile, RR = 14.39) had a higher risk of catch-down; catch-up was higher among terms with IUGR (RR = 5.53), preterms with IUGR (RR = 5.36) and children born to primiparous mothers (RR = 1.83). In SL, catch-down was higher among preterms without IUGR (RR = 5.19), girls (RR = 1.52) and children from low-income families (RR = 2.74); the lowest risk of catch-down (RR = 0.27) and the highest risk of catch-up (RR = 3.77) were observed among terms with IUGR. In both cities, terms with IUGR presented height catch-up growth whereas preterms with IUGR only had height catch-up growth in the more affluent setting. Preterms without IUGR presented height catch-down growth, suggesting that a better socioeconomic situation facilitates height catch-up and prevents height catch-down growth

Adaptive robot training for the treatment of incoordination in Multiple Sclerosis

<p>Abstract</p> <p>Background</p> <p>Cerebellar symptoms are extremely disabling and are common in Multiple Sclerosis (MS) subjects. In this feasibility study, we developed and tested a robot therapy protocol, aimed at the rehabilitation of incoordination in MS subjects.</p> <p>Methods</p> <p>Eight subjects with clinically defined MS performed planar reaching movements while grasping the handle of a robotic manipulandum, which generated forces that either reduced (error-reducing, ER) or enhanced (error-enhancing, EE) the curvature of their movements, assessed at the beginning of each session. The protocol was designed to adapt to the individual subjects' impairments, as well as to improvements between sessions (if any). Each subject went through a total of eight training sessions. To compare the effect of the two variants of the training protocol (ER and EE), we used a cross-over design consisting of two blocks of sessions (four ER and four EE; 2 sessions/week), separated by a 2-weeks rest period. The order of application of ER and EE exercises was randomized across subjects. The primary outcome measure was the modification of the Nine Hole Peg Test (NHPT) score. Other clinical scales and movement kinematics were taken as secondary outcomes.</p> <p>Results</p> <p>Most subjects revealed a preserved ability to adapt to the robot-generated forces. No significant differences were observed in EE and ER training. However over sessions, subjects exhibited an average 24% decrease in their NHPT score. The other clinical scales showed small improvements for at least some of the subjects. After training, movements became smoother, and their curvature decreased significantly over sessions.</p> <p>Conclusions</p> <p>The results point to an improved coordination over sessions and suggest a potential benefit of a short-term, customized, and adaptive robot therapy for MS subjects.</p

The Effect of Performance-Based Financial Incentives on Improving Patient Care Experiences: A Statewide Evaluation

Patient experience measures are central to many pay-for-performance (P4P) programs nationally, but the effect of performance-based financial incentives on improving patient care experiences has not been assessed. The study uses Clinician &amp; Group CAHPS data from commercially insured adult patients (n = 124,021) who had visits with 1,444 primary care physicians from 25 California medical groups between 2003 and 2006. Medical directors were interviewed to assess the magnitude and nature of financial incentives directed at individual physicians and the patient experience improvement activities adopted by groups. Multilevel regression models were used to assess the relationship between performance change on patient care experience measures and medical group characteristics, financial incentives, and performance improvement activities. Over the course of the study period, physicians improved performance on the physician-patient communication (0.62 point annual increase, p &lt; 0.001), care coordination (0.48 point annual increase, p &lt; 0.001), and office staff interaction (0.22 point annual increase, p = 0.02) measures. Physicians with lower baseline performance on patient experience measures experienced larger improvements (p &lt; 0.001). Greater emphasis on clinical quality and patient experience criteria in individual physician incentive formulas was associated with larger improvements on the care coordination (p &lt; 0.01) and office staff interaction (p &lt; 0.01) measures. By contrast, greater emphasis on productivity and efficiency criteria was associated with declines in performance on the physician communication (p &lt; 0.01) and office staff interaction (p &lt; 0.001) composites. In the context of statewide measurement, reporting, and performance-based financial incentives, patient care experiences significantly improved. In order to promote patient-centered care in pay for performance and public reporting programs, the mechanisms by which program features influence performance improvement should be clarified