Prostate cancer specific survival in the Prostate,Lung, Colorectal,and Ovarian (PLCO) Cancer Screening Trial

Background: The prostate component of the Prostate, Lung, Colorectal, and Ovarian (PLCO) randomized screening trial demonstrated no mortality effect of screening. Here we analyze prostate cancer specific survival in PLCO and its relation to screening. Methods: 76,693 men aged 55–74 were randomized to usual care (n = 38,350) or intervention (n = 38,343). Intervention arm men received annual prostate-specific antigen (6 years) and digital rectal exam (4 years). Men were followed for cancer diagnosis and mortality through 13 years. Medical record abstractors confirmed prostate cancer diagnoses, stage and grade. Prostate-specific survival in PLCO cases was analyzed using Kaplan–Meier analysis and proportional hazards modeling. We utilized data from the Surveillance, Epidemiology and End Results (SEER) program to compute expected survival in PLCO and compared this to observed. Results: There was no significant difference in prostate-specific survival rates between arms; 10 year survival rates were 94.7% (intervention, n = 4250 cases) versus 93.5% (usual care, n = 3815 cases). Within the intervention arm, cases never screened in PLCO had lower 10 year survival rates (82%) than screen detected or interval (following a negative screen) cases, both around 95.5%. The ratio of observed to expected 10 year prostate-specific death (1-survival) rates was 0.59 (95% CI: 0.51–0.68) for all PLCO cases, 0.66 (95% CI: 0.51–0.81) for Gleason 5–7 cases and 1.07 (95% CI: 0.87–1.3) for Gleason 8–10 cases. Conclusion: Prostate cancer specific survival in PLCO was comparable across arms and significantly better than expected based on nationwide population data. How much of the better survival is due to a healthy volunteer effect and to lead-time and overdiagnosis biases is not readily determinable.     

Metal enrichment in water and fish in a semi-urban Nigerian lake,and their associated risks

Trace metal (Zn, Pb, Cu, Cr and Cd) concentrations in the water column and in the liver, muscle and gill tissues of Parachanna obscura and Clarias gariepinus in Agulu Lake, Nigeria, were investigated in June 2014 and compared with WHO and FAO safe limits for water and fish. Hazard index (HI) values were estimated to assess the potential public health risk of consuming contaminated fish. Lead and cadmium exceeded WHO guideline values for drinking water. In most cases, variations in concentration of the metals in organs were liver > muscle > gill. Differences in tissue-specific concentrations between species were not significant, except for zinc in muscles and gills. Cadmium and chromium were not detected in the fish, but lead was above the FAO maximum value for consumption. Hazard index values were below 1, indicating a low risk to public health. However, trace metal contamination in Agulu Lake is increasing.     

Genomic prediction of genetic merit using LD-based haplotypes in the Nordic Holstein population

Background

A haplotype approach to genomic prediction using high density data in dairy cattle as an alternative to single-marker methods is presented. With the assumption that haplotypes are in stronger linkage disequilibrium (LD) with quantitative trait loci (QTL) than single markers, this study focuses on the use of haplotype blocks (haploblocks) as explanatory variables for genomic prediction. Haploblocks were built based on the LD between markers, which allowed variable reduction. The haploblocks were then used to predict three economically important traits (milk protein, fertility and mastitis) in the Nordic Holstein population.

Results

The haploblock approach improved prediction accuracy compared with the commonly used individual single nucleotide polymorphism (SNP) approach. Furthermore, using an average LD threshold to define the haploblocks (LD≥0.45 between any two markers) increased the prediction accuracies for all three traits, although the improvement was most significant for milk protein (up to 3.1 % improvement in prediction accuracy, compared with the individual SNP approach). Hotelling’s t-tests were performed, confirming the improvement in prediction accuracy for milk protein. Because the phenotypic values were in the form of de-regressed proofs, the improved accuracy for milk protein may be due to higher reliability of the data for this trait compared with the reliability of the mastitis and fertility data. Comparisons between best linear unbiased prediction (BLUP) and Bayesian mixture models also indicated that the Bayesian model produced the most accurate predictions in every scenario for the milk protein trait, and in some scenarios for fertility.

Conclusions

The haploblock approach to genomic prediction is a promising method for genomic selection in animal breeding. Building haploblocks based on LD reduced the number of variables without the loss of information. This method may play an important role in the future genomic prediction involving while genome sequences.     

Skeletal muscle [(V)\dot]O2 \dot V_{O_2 } in rat and lemming: Effect of blood flow rate

Summary The rate of oxygen consumption ( ) by skeletal muscle was investigated in isolated perfused hindlimbs of laboratory rats and lemmings (Lemmus). In both species, increased in proportion to blood flow rate, even at flow rates 4–5 times above resting level. The slope of the line relating to skeletal muscle blood flow was significantly greater in the lemming than in the rat. This may be related to the inverse relationship between body weight and metabolic rate. These data support the hypothesis that in small animals a dependent relationship exists between blood flow and skeletal muscle .     

Antibody to the phosphomannosyl receptor inhibits recycling of receptor in fibroblasts

The 215-kd phosphomannosyl receptor is involved in the transport of newly synthesized acid hydrolases to lysosomes and also mediates the pinocytosis of lysosomal enzymes by fibroblasts in culture. Recycling of receptors to the sorting sites is an integral part of both these processes. In this report, we describe the inhibition in human fibroblasts of both functions of the phosphomannosyl receptor by a rabbit antiserum to the bovine liver receptor. This inhibition cannot be completely accounted for by inhibition of ligand-receptor interaction. Rather the antibody appears to cross-link receptors and cause a removal of receptors from the sorting sites (plasma membrane and Golgi apparatus) and their accumulation in a compartment from which they do not recycle. Removal of receptors from the recycling pool by antibody is irreversible, and return of receptors requires synthesis of new protein. Degradation of "trapped receptors" is enhanced (t1/2 = 7.5 hr), but much more gradual than their removal from the functional receptor pool (t1/2 = 30 min).     

Alpha Adrenergic Induction of Transport of Lysosomal Enzyme across the Blood-Brain Barrier

The impermeability of the adult blood-brain barrier (BBB) to lysosomal enzymes impedes the ability to treat the central nervous system manifestations of lysosomal storage diseases.Here, we found that simultaneous stimulation of the alpha1 and alpha2 adrenoreceptor restores in adult mice the high rate of transport for the lysosomal enzyme P-GUS that is seen in neonates but lost with development. Beta adrenergics, other monoamines, and acetylcholine did not restore this transport. A high dose (500 microg/mouse) of clonidine, a strong alpha2 and weak alpha1 agonist, was able to act as monotherapy in the stimulation of P-GUS transport. Neither use of alpha1 plus alpha2 agonists nor the high dose clonidine disrupted the BBB to albumin. In situ brain perfusion and immunohistochemistry studies indicated that adrengerics act on transporters already at the luminal surface of brain endothelial cells. These results show that adrenergic stimulation, including monotherapy with clonidine, could be key for CNS enzyme replacement therapy.     

Mutational analysis of a patient with mucopolysaccharidosis type VII, and identification of pseudogenes.

PCR of cDNA produced from patient fibroblasts allowed us to determine the paternal mutation in the first patient reported with beta-glucuronidase-deficiency mucopolysaccharidosis type VII (MPS VII). The G-->T transversion 1,881 bp downstream of the ATG translation initiation codon destroys an MboII restriction site and converts Trp627 to Cys (W627C). Digestion of genomic DNA PCR fragments with MboII indicated that the patient and the father were heterozygous for this missense mutation in exon 12. Failure to find cDNAs from patient RNA which did not contain this mutation suggested that the maternal mutation leads to greatly reduced synthesis or reduced stability of mRNA from the mutant allele. In order to identify the maternal mutation, it was necessary to analyze genomic sequences. This approach was complicated by the finding of multiple unprocessed pseudogenes and/or closely related genes. Using PCR with a panel of human/rodent hybrid cell lines, we found that these pseudogenes were present over chromosomes 5-7, 20, and 22 and the Y chromosome. Conditions were defined which allowed us to amplify and characterize genomic sequences for the true beta-glucuronidase gene despite this background of related sequences. The patient proved to be heterozygous for a second mutation, in which a C-->T transition introduces a termination codon (R356STOP) in exon 7. The mother was also heterozygous for this mutation. Expression of a cDNA containing the maternal mutation produced no enzyme activity, as expected. Expression of the paternal mutation in COS-7 cells produced a surprisingly high (65% of control) level of activity. However, activity was 13% of control in transiently transfected murine MPS VII cells. The level of activity of this mutant allele appears to correlate with the level of overexpression, suggesting that high concentrations of mutant monomers can drive the folding and tetramerization of mutant enzyme to produce an active and stable enzyme.     

The ecology of very small-seeded shade-tolerant trees and shrubs in lowland rain forest in Singapore

A study was made in Bukit Timah Nature Reserve of niche differentiation among 11 woody species that have very small seeds (22–460 µg) and establish in deep shade, i.e., where the indirect site factor (isf) under cloudy conditions is 2%, and one taxonomically related light-demander (seed mass 33 µg). Comparative observations were made on changing light requirement with age. The species varied from shrubs and treelets (Urophyllum) via small to medium-height trees (Ficus, Pternandra) to tall trees (Gynotroches and Pellacalyx). In general, the shorter species fruited in deep shade while the taller needed direct irradiance. All produced ripe fruit at least once a year.In 1–3% isf seedling mortality over 11 months was 24% for Urophyllum hirsutum and 57% for Pternandra echinata (two strongly shade-tolerant species); survivors produced appreciable new stem and leaf tissue. For two more light-demanding species (Ficus grossularioides and F. fistulosa) mean lamina area was much larger in small gaps (10% isf) than in the understorey (<3% isf), while for Urophyllum hirsutum it was much smaller. These three species showed the greatest difference in SLA. There were few significant intraspecific differences between gaps and understorey in concentrations of N, P or K. In a valley where there was no significant difference in isf between a path and adjacent understorey, seedlings of species with seeds <1 mg mean dry mass were five times as dense on transects along steep pathside banks as in the understorey 5 m upslope. The mean mid-bank slope was 66° (cf. 20° upslope). On mid-bank transects litter had a cover of 36% (cf. 95% upslope), and was thinner (0.8 vs 3.2 cm). The soil at 0–7 cm depth into the mid-bank had much lower concentrations of organic matter, total N and P (but not total K) and fine roots than that of upslope transects. All species were found to have vesicular-arbuscular mycorrhiza when 1–2 m tall in deep shade, several having very dense infections. Seedling form and responses are discussed in relation to potential adaptive value and possible evolutionary origin.