Risk factors and 25 year risk of coronary heart disease in a male population with a high incidence of the disease: the Finnish cohorts of the seven countries study.

OBJECTIVE--To assess the efficacy of high serum cholesterol concentration, raised blood pressure, and smoking as predictors of coronary heart disease. DESIGN--Prospective cohort study of middle aged men conducted over 25 years. SETTING--Finish components of an ongoing international study (seven countries study). PARTICIPANTS--1520 Men who at age 40-59 in 1959 were free of clinically evident heart disease. INTERVENTIONS--At each follow up visit a detailed medical examination including resting electrocardiography was performed, blood pressure and serum total cholesterol concentration were measured, and smoking was assessed. MEASUREMENTS AND MAIN RESULTS--825 Deaths (54% of participants) occurred during follow up, of which 335 were due to coronary heart disease. The hazard ratio for death from coronary heart disease with respect to risk factors at entry were: for serum cholesterol concentrations above 8.4 mmol/l v below 5.2 mmol/l, 2.68 (95% confidence interval 1.62 to 4.42); for systolic blood pressure in the highest quintile v that in the lowest quintile, 2.46 (1.72 to 3.50); and for smoking 10 or more cigarettes daily v never smoking, 1.95 (1.36 to 2.79). The hazard ratios with respect to cholesterol concentrations and blood pressure remained constant during follow up but the ratio with respect to smoking diminished, mainly owing to men giving up the habit. The estimated conditional probability of a 50 year old man dying of coronary heart disease in the next 25 years ranged from 12% among those with the most favourable risk factor profile to 75% among those with the least favourable profile. CONCLUSIONS--High risk factor levels (as determined in this study) in middle aged men may greatly increase the absolute probability of death from coronary heart disease when the period of study is relevant to the human life span.     

Colonization and deterioration processes in Roman mortars by cyanobacteria,algae and lichens

The mortars covering some walls of the Roman city of Baelo Claudia (Cadiz, Spain) support an abundant colonization of cyanobacteria, algae and lichens. The distribution of these organisms is closely related to microclimatic parameters. Furthermore, the development, specific composition and biomass of algal cryptoendolithic communities are related to the wall orientation. The effect of these communities on mortar deterioration is discussed.     

The pineal gland of the mole-rat (Spalax ehrenbergi,Nehring)

Summary A comparative investigation of the distribution of monoaminergic neurons in non-malacostracan crustaceans was performed with the histochemical fluorescence method of Falck-Hillarp.Two fluorophores were found: the more widespread of the two emits a green fluorescence; and the more sparsely distributed emits a yellow to brown-yellow fluorescence.Specific green fluorescent areas were shown to exist in the protocerebrum. The central body and the optic ganglia of the compound eye (where present) are always fluorescent. Moreover, the centre of the nauplius eye may have a green fluorophore, as in ostracods, and a neuropile area, here called the frontal area. These neuropile centres are known from ordinary histological studies of the nervous system. In addition, there are specific monoaminergic centres, such as the so-called dorsal area of phyllopods and anostracans as well as the copepod specific areas. Specific monoaminergic areas appear in the deutocerebrum and the suboesophageal ganglion where they are particularly well developed.Presumed sensory neurons in the cavity receptor organ of Artemia salina are shown to be monoaminergic. Monoaminergic sensory neurons have not been described previously in Arthropods.Presumed motor innervation of hind-gut and trunk muscles is also found, and it is concluded that in crustaceans neurons of every type (sensory, internuncial, motor) may be monoaminergic.We have enjoyed unrestricted laboratory facilities at the Department of Histology, Faculty of Medicine, and with great pleasure express our sincere thanks to Prof. Bengt Falck. — Grants from the Swedish Natural Science Research Council (2760-007), the Swedish Medical Research Council (04X-712), the Royal Swedish Academy of Science (Hierta-Retzius), the Royal Physiographic Society of Lund, and the University of Lund supported the work.     

Anti-semaphorin 3A antibodies rescue retinal ganglion cells from cell death following optic nerve axotomy

Damage to the optic nerve in mammals induces retrograde degeneration and apoptosis of the retinal ganglion cell (RGC) bodies. The mechanisms that mediate the response of the neuronal cells to the axonal injury are still unknown. We have previously shown that semaphorins, axon guidance molecules with repulsive cues, are capable of mediating apoptosis in cultured neuronal cells (Shirvan, A., Ziv, I., Fleminger, G., Shina, R., He, Z., Brudo, I., Melamed, E., and Brazilai, A. (1999) J. Neurochem. 73, 961-971). In this study, we examined the involvement of semaphorins in an in vivo experimental animal model of complete axotomy of the rat optic nerve. We demonstrate that a marked induction of type III semaphorin proteins takes place in ipsilateral retinas at early stages following axotomy, well before any morphological signs of RGC apoptosis can be detected. Time course analysis revealed that a peak of expression occurred after 2-3 days and then declined. A small conserved peptide derived from semaphorin 3A that was previously shown to induce neuronal death in culture was capable of inducing RGC loss upon its intravitreous injection into the rat eye. Moreover, we demonstrate a marked inhibition of RGC loss when axotomized eyes were co-treated by intravitreous injection of function-blocking antibodies against the semaphorin 3A-derived peptide. Marked neuronal protection from degeneration was also observed when the antibodies were applied 24 h post-injury. We therefore suggest that semaphorins are key proteins that modulate the cell fate of axotomized RGC. Neutralization of the semaphorin repulsive function may serve as a promising new approach for treatment of traumatic injury in the adult mammalian central nervous system or of ophthalmologic diseases such as glaucoma and ischemic optic neuropathy that induce apoptotic RGC death.     

Lack of S-Adenosylmethionine Results in a Cell Division Defect in Escherichia coli

The enzyme S-adenosylmethionine (SAM) synthetase, the Escherichia coli metK gene product, produces SAM, the cell’s major methyl donor. We show here that SAM synthetase activity is induced by leucine and repressed by Lrp, the leucine-responsive regulatory protein. When SAM synthetase activity falls below a certain critical threshold, the cells produce long filaments with regularly distributed nucleoids. Expression of a plasmid-carried metK gene prevents filamentation and restores normal growth to the metK mutant. This indicates that lack of SAM results in a division defect.     

alpha2,6-Sialylation promotes binding of placental protein 14 via its Ca2+-dependent lectin activity: insights into differential effects on CD45RO and CD45RA T cells

Placental protein 14 (PP14; glycodelin) is a pregnancy-associated immunoregulatory protein that is known to inhibit T cells via T-cell receptor desensitization. The recent demonstration of PP14 as lectin has provided insight into how it may mediate its CD45 glycoprotein-dependent T-cell inhibition. In this study, we have investigated PP14's lectin-binding properties in detail. Significantly, PP14 reacts with N-acetyllactosamine (LacNAc) as was also found for members of the galectin family, such as the potent immunoregulatory protein, galectin-1. However, in contrast to galectin-1, PP14's binding is significantly enhanced by alpha2,6-sialylation and also by the presence of cations. This was demonstrated by preferential binding to fetuin as compared with its desialylated variant asialofetuin (ASF) and by using free alpha2,6- versus alpha2,3-sialylated forms of LacNAc in competitive inhibition and direct solid-phase binding assays. Interestingly, from immunological point of view, PP14 also binds differentially to CD45 isoforms known to differ in their degree of sialylation. PP14 preferentially inhibits CD45RA+, as compared with CD45RO+ T cells, and preferentially co-capped this variant CD45 on the T-cell surface. Finally, we demonstrate that PP14 promotes CD45 dimerization and clustering, a phenomenon that may regulate CD45 activity.     

Biochemical and Temporal Analysis of Events Associated with Apoptosis Induced by Lowering the Extracellular Potassium Concentration in Mouse Cerebellar Granule Neurons

Abstract: We analyzed biochemically and temporally the molecular events that occur in the programmed cell death of mouse cerebellar granule neurons deprived of high potassium levels. An hour after switching the neurons to a low extracellular K⁺ concentration ([K⁺]_o), a significant part of the genomic DNA was already cleaved to high-molecular-weight fragments. This phenomenon was intensified with the progression of the death process. Addition of cycloheximide to the neurons 4 h after high [K⁺]_o deprivation resulted in no cell loss and complete recovery of the damaged DNA. DNA margination and nuclear fragmentation as assessed by 4,6-diaminodiphenyl-2-phenylindole staining were observable in a few cells beginning ～4 h after the removal of high [K⁺]_o and developed to nuclear condensation 4 h later. Six hours after high [K⁺]_o deprivation, the DNA was fragmented into oligonucleosome-sized fragments. Within 6 h after removal of the extracellular K⁺, 50% of the neurons were committed to die and lost their ability to be rescued by readministration of 25 mM [K⁺]_o. Similar to high [K⁺]_o deprivation, inhibition of RNA or protein synthesis failed to halt neuronal degeneration of a similar percentage of cells 6 h after the onset of the death process. Mitochondrial function steadily decreased after [K⁺]_o removal. An ～40% decrease in RNA and protein synthesis was detected by 6 h of [K⁺]_o removal during the period of cell death commitment; rates continued to decline gradually thereafter. The temporal characteristics of the DNA damage and recovery, DNA cleavage to oligonucleosome-sized fragments, and the reduction in mitochondrial activity—events that occurred within the critical time—may indicate that these processes have an important part in the mechanism that committed the neurons to die.     

Deep sequencing reveals clonal evolution patterns and mutation events associated with relapse in B-cell lymphomas

Background

Molecular mechanisms associated with frequent relapse of diffuse large B-cell lymphoma (DLBCL) are poorly defined. It is especially unclear how primary tumor clonal heterogeneity contributes to relapse. Here, we explore unique features of B-cell lymphomas - VDJ recombination and somatic hypermutation - to address this question.

Results

We performed high-throughput sequencing of rearranged VDJ junctions in 14 pairs of matched diagnosis-relapse tumors, among which 7 pairs were further characterized by exome sequencing. We identify two distinctive modes of clonal evolution of DLBCL relapse: an early-divergent mode in which clonally related diagnosis and relapse tumors diverged early and developed in parallel; and a late-divergent mode in which relapse tumors developed directly from diagnosis tumors with minor divergence. By examining mutation patterns in the context of phylogenetic information provided by VDJ junctions, we identified mutations in epigenetic modifiers such as KMT2D as potential early driving events in lymphomagenesis and immune escape alterations as relapse-associated events.

Conclusions

Altogether, our study for the first time provides important evidence that DLBCL relapse may result from multiple, distinct tumor evolutionary mechanisms, providing rationale for therapies for each mechanism. Moreover, this study highlights the urgent need to understand the driving roles of epigenetic modifier mutations in lymphomagenesis, and immune surveillance factor genetic lesions in relapse.

Electronic supplementary material

The online version of this article (doi:10.1186/s13059-014-0432-0) contains supplementary material, which is available to authorized users.