A history of the renewal of the corneal epithelium : a 3D animation

Background: To compare the different schemes that have been proposed during the last thirteen years to explain the renewal of the corneal epithelium. Material and Methods:We analyzed all the data present in the literature to explain the renewal of the corneal epithelium in mammals. According to the schemes proposed in the literature we developed a 3D animation to facilitate the understanding of the different concepts. Results:Three different schemes have been proposed to explain the renewal of the corneal epithelium in mammals during the last thirteen years. 1950-1981: the corneal epithelium was thought being renewed by mitosis of cells located in the basal layer. At this time scientist were not talking about stem cells. 1981-1986 was the period of the "XYZ hypothesis" or the transdifferentiation paradigm. At this time the conjunctival epithelium renewed the corneal epithelium in a centripetal migration. 1986-2008: the limbal stem cell paradigm, there were no stem cells in the corneal epithelium, all the corneal stem cells were located in the limbus and renewed the central cornea after a migration of 6 to 7 mm of transient amplifying cells toward the centre of the cornea. 2008, epithelial stem cells were found in the central cornea in mammals (Nature, Majo et al. November 2008). Discussion:We thought that the renewal of the corneal epithelium was completely defined. According to the last results we published in Nature, the current paradigm will be revisited. The experiments we made were on animals and the final demonstration on human has still to be done. If we find the same results in human, a new paradigm will be define and will change the way we consider ocular surface therapy and reconstruction.

Evolutionary history of the greater white-toothed shrew (Crocidura russula) inferred from analysis of mtDNA, Y, and X chromosome markers.

We investigate the evolutionary history of the greater white-toothed shrew across its distribution in northern Africa and mainland Europe using sex-specific (mtDNA and Y chromosome) and biparental (X chromosome) markers. All three loci confirm a large divergence between eastern (Tunisia and Sardinia) and western (Morocco and mainland Europe) lineages, and application of a molecular clock to mtDNA divergence estimates indicates a more ancient separation (2.25 M yr ago) than described by some previous studies, supporting claims for taxonomic revision. Moroccan ancestry for the mainland European population is inconclusive from phylogenetic trees, but is supported by greater nucleotide diversity and a more ancient population expansion in Morocco than in Europe. Signatures of rapid population expansion in mtDNA, combined with low X and Y chromosome diversity, suggest a single colonization of mainland Europe by a small number of Moroccan shrews >38 K yr ago. This study illustrates that multilocus genetic analyses can facilitate the interpretation of species' evolutionary history but that phylogeographic inference using X and Y chromosomes is restricted by low levels of observed polymorphism.

Chromosomal versus mitochondrial DNA evolution: tracking the evolutionary history of the southwestern european populations of the Sorex araneus group (Mammalia Insectivora)

The shrews of the Sorer araneus group have undergone a spectacular chromosome evolution. The karyotype of Sorer granarius is generally considered ancestral to those of Sorer coronatus and S. araneus. However, a sequence of 777 base pairs of the cytochrome b gene of the mitochondrial DNA (mtDNA) produces a quite different picture: S. granarius is closely related to the populations of S. araneus from the Pyrenees and from the northwestern Alps, whereas S. coronatus and S. araneus from Italy and the southern Alps represent two well-separated lineages. It is suggested that mtDNA and chromosomal evolution are in this case largely independant processes. Whereas mtDNA haplotypes are closely linked to the geographical history of the populations, chromosomal mutations were probably transmitted from one population to another. Available data suggest that the impressive chromosome polymorphism of this group is quite a recent phenomenon.

A new perspective on the evolutionary history of western European Sorex araneus group revealed by paternal and maternal molecular markers.

The species of the common shrew (Sorex araneus) group are morphologically very similar, but have undergone a spectacular chromosomal evolution. We investigate here the evolutionary history of the Sorex araneus group distributed in western Europe. In particular, we clarify the position of a difficult species, S. granarius, using sex-specific (mtDNA and Y-chromosome) markers. The karyotype of S. granarius is generally considered similar to the common ancestor of the restricted group considered here. The mtDNA data (1.4 kb) confirms the close relationship between S. granarius and S. araneus sensu stricto (hereafter S. araneus s.s.), but the Y-chromosome (3.4 kb) produces a quite different picture: S. granarius is closely related to another species, S. coronatus. Comparison of mtDNA and Y-chromosome phylogenies suggests that the genetic and chromosomal evolution in this group are disconnected processes. The evolutionary history of the south-western European populations of the S. araneus group can only be understood considering secondary contacts between taxa after their divergence, implying genetic exchanges by means of hybridization and/or introgression.

Family history of cancer and the risk of cancer: a network of case-control studies.

BACKGROUND: The risk of many cancers is higher in subjects with a family history (FH) of cancer at a concordant site. However, few studies investigated FH of cancer at discordant sites. PATIENTS AND METHODS: This study is based on a network of Italian and Swiss case-control studies on 13 cancer sites conducted between 1991 and 2009, and including more than 12 000 cases and 11 000 controls. We collected information on history of any cancer in first degree relatives, and age at diagnosis. Odds ratios (ORs) for FH were calculated by multiple logistic regression models, adjusted for major confounding factors. RESULTS: All sites showed an excess risk in relation to FH of cancer at the same site. Increased risks were also found for oral and pharyngeal cancer and FH of laryngeal cancer (OR = 3.3), esophageal cancer and FH of oral and pharyngeal cancer (OR = 4.1), breast cancer and FH of colorectal cancer (OR = 1.5) and of hemolymphopoietic cancers (OR = 1.7), ovarian cancer and FH of breast cancer (OR = 2.3), and prostate cancer and FH of bladder cancer (OR = 3.4). For most cancer sites, the association with FH was stronger when the proband was affected at age <60 years. CONCLUSIONS: Our results point to several potential cancer syndromes that appear among close relatives and may indicate the presence of genetic factors influencing multiple cancer sites.

Reconstruction of the recent history of a large deep prealpine lake (Lake Bourget, France) using subfossil chironomids, diatoms, and organic matter analysis: towards the definition of a lake-specific reference state

This paper presents the recent history of a large prealpine lake (Lake Bourget) using chironomids, diatoms and organic matter analysis, and deals with the ability of paleolimnological approach to define an ecological reference state for the lake in the sense of the European Framework Directive. The study at low resolution of subfossil chironomids in a 4-m-long core shows the remarkable stability over the last 2.5 kyrs of the profundal community dominated by a Micropsectra-association until the beginning of the twentieth century, when oxyphilous taxa disappeared. Focusing on this key recent period, a high resolution and multiproxy study of two short cores reveals a progressive evolution of the lake's ecological state. Until AD 1880, Lake Bourget showed low organic matter content in the deep sediments (TOC less than 1%) and a well-oxygenated hypolimnion that allowed the development of a profundal oxyphilous chironomid fauna (Micropsectra-association). Diatom communities were characteristic of oligotrophic conditions. Around AD 1880, a slight increase in the TOC was the first sign of changes in lake conditions. This was followed by a first limited decline in oligotrophic diatom taxa and the disappearance of two oxyphilous chironomid taxa at the beginning of the twentieth century. The 1940s were a major turning point in recent lake history. Diatom assemblages and accumulation of well preserved planktonic organic matter in the sediment provide evidence of strong eutrophication. The absence of profundal chironomid communities reveals permanent hypolimnetic anoxia. From AD 1995 to 2006, the diatom assemblages suggest a reduction in nutrients, and a return to mesotrophic conditions, a result of improved wastewater management. However, no change in hypolimnion benthic conditions has been shown by either the organic matter or the subfossil chironomid profundal community. Our results emphasize the relevance of the paleolimnological approach for the assessment of reference conditions for modern lakes. Before AD 1900, the profundal Micropsectra-association and the Cyclotella dominated diatom community can be considered as the Lake Bourget reference community, which reflects the reference ecological state of the lake.

Increased salt sensitivity of ambulatory blood pressure in women with a history of severe preeclampsia.

Cardiovascular diseases are the principal cause of death in women in developed countries and are importantly promoted by hypertension. The salt sensitivity of blood pressure (BP) is considered as an important cardiovascular risk factor at any BP level. Preeclampsia is a hypertensive disorder of pregnancy that arises as a risk factor for cardiovascular diseases. This study measured the salt sensitivity of BP in women with a severe preeclampsia compared with women with no pregnancy hypertensive complications. Forty premenopausal women were recruited 10 years after delivery in a case-control study. Salt sensitivity was defined as an increase of >4 mm Hg in 24-hour ambulatory BP on a high-sodium diet. The ambulatory BP response to salt was significantly increased in women with a history of preeclampsia compared with that of controls. The mean (95% confidence interval) daytime systolic/diastolic BP increased significantly from 115 (109-118)/79 (76-82) mm Hg on low-salt diet to 123 (116-130)/80 (76-84) on a high-salt diet in women with preeclampsia, but not in the control group (from 111 [104-119]/77 [72-82] to 111 [106-116]/75 [72-79], respectively, P<0.05). The sodium sensitivity index (SSI=Δmean arterial pressure/Δurinary Na excretion×1000) was 51.2 (19.1-66.2) in women with preeclampsia and 6.6 (5.8-18.1) mm Hg/mol per day in controls (P=0.015). The nocturnal dip was blunted on a high-salt diet in women with preeclampsia. Our study shows that women who have developed preeclampsia are salt sensitive before their menopause, a finding that may contribute to their increased cardiovascular risk. Women with a history of severe preeclampsia should be targeted at an early stage for preventive measures of cardiovascular diseases.

Rationale and design of a randomized, double-blind, parallel-group study of terutroban 30 mg/day versus aspirin 100 mg/day in stroke patients: the prevention of cerebrovascular and cardiovascular events of ischemic origin with terutroban in patients with a history of ischemic stroke or transient ischemic attack (PERFORM) study.

BACKGROUND: Ischemic stroke is the leading cause of mortality worldwide and a major contributor to neurological disability and dementia. Terutroban is a specific TP receptor antagonist with antithrombotic, antivasoconstrictive, and antiatherosclerotic properties, which may be of interest for the secondary prevention of ischemic stroke. This article describes the rationale and design of the Prevention of cerebrovascular and cardiovascular Events of ischemic origin with teRutroban in patients with a history oF ischemic strOke or tRansient ischeMic Attack (PERFORM) Study, which aims to demonstrate the superiority of the efficacy of terutroban versus aspirin in secondary prevention of cerebrovascular and cardiovascular events. METHODS AND RESULTS: The PERFORM Study is a multicenter, randomized, double-blind, parallel-group study being carried out in 802 centers in 46 countries. The study population includes patients aged > or =55 years, having suffered an ischemic stroke (< or =3 months) or a transient ischemic attack (< or =8 days). Participants are randomly allocated to terutroban (30 mg/day) or aspirin (100 mg/day). The primary efficacy endpoint is a composite of ischemic stroke (fatal or nonfatal), myocardial infarction (fatal or nonfatal), or other vascular death (excluding hemorrhagic death of any origin). Safety is being evaluated by assessing hemorrhagic events. Follow-up is expected to last for 2-4 years. Assuming a relative risk reduction of 13%, the expected number of primary events is 2,340. To obtain statistical power of 90%, this requires inclusion of at least 18,000 patients in this event-driven trial. The first patient was randomized in February 2006. CONCLUSIONS: The PERFORM Study will explore the benefits and safety of terutroban in secondary cardiovascular prevention after a cerebral ischemic event.

Evolutionary and dispersal history of Eurasian house mice Mus musculus clarified by more extensive geographic sampling of mitochondrial DNA.

We examined the sequence variation of mitochondrial DNA control region and cytochrome b gene of the house mouse (Mus musculus sensu lato) drawn from ca. 200 localities, with 286 new samples drawn primarily from previously unsampled portions of their Eurasian distribution and with the objective of further clarifying evolutionary episodes of this species before and after the onset of human-mediated long-distance dispersals. Phylogenetic analysis of the expanded data detected five equally distinct clades, with geographic ranges of northern Eurasia (musculus, MUS), India and Southeast Asia (castaneus, CAS), Nepal (unspecified, NEP), western Europe (domesticus, DOM) and Yemen (gentilulus). Our results confirm previous suggestions of Southwestern Asia as the likely place of origin of M. musculus and the region of Iran, Afghanistan, Pakistan, and northern India, specifically as the ancestral homeland of CAS. The divergence of the subspecies lineages and of internal sublineage differentiation within CAS were estimated to be 0.37-0.47 and 0.14-0.23 million years ago (mya), respectively, assuming a split of M. musculus and Mus spretus at 1.7 mya. Of the four CAS sublineages detected, only one extends to eastern parts of India, Southeast Asia, Indonesia, Philippines, South China, Northeast China, Primorye, Sakhalin and Japan, implying a dramatic range expansion of CAS out of its homeland during an evolutionary short time, perhaps associated with the spread of agricultural practices. Multiple and non-coincident eastward dispersal events of MUS sublineages to distant geographic areas, such as northern China, Russia and Korea, are inferred, with the possibility of several different routes.

Oxygen-isotope thermometry of quartz-calcite veins - Unraveling the thermal-tectonic history of the subgreenschist facies Morcles nappe (Swiss Alps)

Combined structural analysis and oxygen isotope thermometry of syntectonic quartz-calcite fibrous veins can be used to correlate the thermal history of deformed rocks,vith specific structural and tectonic events. Results are presented for the Mercies nappe in the western Helvetic Alps, Switzerland, where mineral parageneses, illite `'crystallinity,'' and fluid inclusion chemistry record an apparent peak metamorphic temperature gradient that increased across the Morcles nappe from anchizonal conditions in the foreland to epizonal conditions in its hinterland root zone. Twenty-seven quartz-calcite veins were analyzed in this study in order to determine the temperatures of veining during formation and deformation of the nappe, Peak metamorphic temperatures ranged from approximate to 260 to 290 degrees C in the shallower, foreland localities and to approximate to 330 to 350 degrees C in the deeper, more hinterland localities at the end of S1-foliation formation, related to large-scale folding. Temperatures gradually decreased throughout the nappe during subsequent development of the S2 foliation and S3 crenulation cleavage, Uplift and erosion of the overlying nappe pile resulted in slow cooling of the Morcles nappe during the waning stages of the Alpine Orogeny. The dominant foliation-forming deformation of the Morcles nappe occurred at elevated temperatures over the course of 10 to 15 Ma. Combined structure-oxygen isotope analyses of quartz-calcite veins yield better temperature and temporal constraints on the thermal histories of subgreenschist vein-bearing tectonites than do other geothermometers.

History of cholelithiasis and cancer risk in a network of case-control studies.

Background We analyzed the relationship between cholelithiasis and cancer risk in a network of case-control studies conducted in Italy and Switzerland in 1982-2009. Methods The analyses included 1997 oropharyngeal, 917 esophageal, 999 gastric, 23 small intestinal, 3726 colorectal, 684 liver, 688 pancreatic, 1240 laryngeal, 6447 breast, 1458 endometrial, 2002 ovarian, 1582 prostate, 1125 renal cell, 741 bladder cancers, and 21 284 controls. The odds ratios (ORs) were estimated by multiple logistic regression models. Results The ORs for subjects with history of cholelithiasis compared with those without were significantly elevated for small intestinal (OR = 3.96), prostate (OR = 1.36), and kidney cancers (OR = 1.57). These positive associations were observed ≥10 years after diagnosis of cholelithiasis and were consistent across strata of age, sex, and body mass index. No relation was found with the other selected cancers. A meta-analysis including this and three other studies on the relation of cholelithiasis with small intestinal cancer gave a pooled relative risk of 2.35 [95% confidence interval (CI) 1.82-3.03]. Conclusion In subjects with cholelithiasis, we showed an appreciably increased risk of small intestinal cancer and suggested a moderate increased risk of prostate and kidney cancers. We found no material association with the other cancers considered.