CD36 deficiency leads to choroidal involution via COX2 down-regulation in rodents.

BACKGROUND: In the Western world, a major cause of blindness is age-related macular degeneration (AMD). Recent research in angiogenesis has furthered the understanding of choroidal neovascularization, which occurs in the "wet" form of AMD. In contrast, very little is known about the mechanisms of the predominant, "dry" form of AMD, which is characterized by retinal atrophy and choroidal involution. The aim of this study is to elucidate the possible implication of the scavenger receptor CD36 in retinal degeneration and choroidal involution, the cardinal features of the dry form of AMD. METHODS AND FINDINGS: We here show that deficiency of CD36, which participates in outer segment (OS) phagocytosis by the retinal pigment epithelium (RPE) in vitro, leads to significant progressive age-related photoreceptor degeneration evaluated histologically at different ages in two rodent models of CD36 invalidation in vivo (Spontaneous hypertensive rats (SHR) and CD36-/- mice). Furthermore, these animals developed significant age related choroidal involution reflected in a 100%-300% increase in the avascular area of the choriocapillaries measured on vascular corrosion casts of aged animals. We also show that proangiogenic COX2 expression in RPE is stimulated by CD36 activating antibody and that CD36-deficient RPE cells from SHR rats fail to induce COX2 and subsequent vascular endothelial growth factor (VEGF) expression upon OS or antibody stimulation in vitro. CD36-/- mice express reduced levels of COX2 and VEGF in vivo, and COX2-/- mice develop progressive choroidal degeneration similar to what is seen in CD36 deficiency. CONCLUSIONS: CD36 deficiency leads to choroidal involution via COX2 down-regulation in the RPE. These results show a novel molecular mechanism of choroidal degeneration, a key feature of dry AMD. These findings unveil a pathogenic process, to our knowledge previously undescribed, with important implications for the development of new therapies.

Effect of antiretroviral therapy on apoptosis markers and morphology in peripheral lymph nodes of HIV-infected individuals.

BACKGROUND: CD4+ T cell depletion and destruction and the involution of the lymphoid tissue are hallmarks of HIV infection. Although the underlying mechanisms are still unclear, apoptosis appears to play a central role. The objective of this study was to investigate the effect of antiretroviral therapy on the lymph node tissue, particularly with respect to morphology and apoptosis. PATIENTS AND METHODS: Between 1997 and 1999, two inguinal lymph nodes were excised from 31 previously untreated individuals who were in an early stage of HIV infection, the first one prior to treatment and the second after 16 to 20 months of treatment. Paraffin sections were investigated for lymph node architecture, distribution of cellular and viral markers, apoptosis, and expression of apoptotic key molecules which indirectly reflect apoptotic processes. RESULTS: After 16-20 months of antiretroviral therapy, a significant decrease in highly activated HIV-driven immune response was observed in the lymph node tissue as a marked reduction in follicular hyperplasia, a normalization of the follicular dendritic cell network, a significant increase in the number of CD4+ T cells, and a significant decrease in the number of CD8+ T cells. The expression of several proapoptotic (Fas, TRAIL, and active caspase 3) and antiapoptotic (Bcl-2 and IL-7Ralpha) molecules that were reconstituted in the tissues during therapy resembled their expression in lymph nodes of HIV-negative individuals. Limitations of the study are (a) the lack of untreated patients in the late stages, (b) for ethical reasons, the lack of a control group with untreated patients, and (c) for methodological reasons, the restriction of sequential measurements of apotpotic markers to one-third of the patients. CONCLUSION: Antiretroviral therapy initiated in the early stages in HIV infection may halt the irreversible destruction of the lymph node tissue and may partially normalize apoptotic processes.

Revision of the genus acrochordiceras hyatt, 1877 (Ammonoidea, Middle Triassic): Morphology, biometry, biostratigraphy and intra-specific variability

The family Acrochordiceratidae Arthaber, 1911 ranges in age from latest Spathian to the middle/late Anisian boundary, and it represents a major component of ammonoid faunas during that time. The middle Anisian genus Acrochordiceras Hyatt, 1877 is the most widespread taxon of the family and occurs abundantly worldwide within the low paleolatitude belt. However, there is a profusion of species names available for Acrochordiceras. This excessive diversity at the species level essentially results from the fact that sufficiently large samples were not available, thus leading to a typological approach to its taxonomy. Based on new extensive collections obtained from the Anisian (Middle Triassic) Fossil Hill Member (Star Peak Group, north-west Nevada) for which a high resolution biostratigraphic frame is available, the taxonomy and biostratigraphy of the genus Acrochordiceras Hyatt, 1877 is herein revised with respect to its intra-specific variation. Morphological and biometric studies (c. 550 bedrock-controlled specimens were measured) show that only one species occurs in each stratigraphic level. Continuous ranges of intra-specific variation of studied specimens enable us to synonymize Haydenites Diener, 1907, Silesiacrochordiceras Diener, 1916 and Epacrochordiceras Spath, 1934 with Acrochordiceras Hyatt, 1877. Three stratigraphically successive species are herein recognized in the low paleolatitude middle Anisian faunas from Nevada: A. hatschekii (Diener, 1907), A. hyatti Meek, 1877 and A. carolinae Mojsisovics, 1882. Moreover, an assessment of intra-specific variation of the adult size range does not support recognition of a dimorphic pair (Acrochordiceras and Epacrochordiceras) as previously suggested by other workers (Epacrochordiceras is the compressed and weakly ornamented end-member variant of Acrochordiceras). The successive middle Anisian species of Acrochordiceras form an anagenetic lineage characterized by increasing involution, adult size and intra-specific variation. This taxonomic revision based on new bedrock-controlled collections is thus an important prerequisite before studying the evolution of the group.

Large-scale evolutionary trends of Acrochordiceratidae Arthaber, 1911 (Ammonoidea, Middle Triassic) and Cope's rule

Directed evolution of life through millions of years, such as increasing adult body size, is one of the most intriguing patterns displayed by fossil lineages. Processes and causes of such evolutionary trends are still poorly understood. Ammonoids (externally shelled marine cephalopods) are well known to have experienced repetitive morphological evolutionary trends of their adult size, shell geometry and ornamentation. This study analyses the evolutionary trends of the family Acrochordiceratidae Arthaber, 1911 from the Early to Middle Triassic (251228 Ma). Exceptionally large and bed-rock-controlled collections of this ammonoid family were obtained from strata of Anisian age (Middle Triassic) in north-west Nevada and north-east British Columbia. They enable quantitative and statistical analyses of its morphological evolutionary trends. This study demonstrates that the monophyletic clade Acrochordiceratidae underwent the classical evolute to involute evolutionary trend (i.e. increasing coiling of the shell), an increase in its shell adult size (conch diameter) and an increase in the indentation of its shell suture shape. These evolutionary trends are statistically robust and seem more or less gradual. Furthermore, they are nonrandom with the sustained shift in the mean, the minimum and the maximum of studied shell characters. These results can be classically interpreted as being constrained by the persistence and common selection pressure on this mostly anagenetic lineage characterized by relatively moderate evolutionary rates. Increasing involution of ammonites is traditionally interpreted by increasing adaptation mostly in terms of improved hydrodynamics. However, this trend in ammonoid geometry can also be explained as a case of Copes rule (increasing adult body size) instead of functional explanation of coiling, because both shell diameter and shell involution are two possible paths for ammonoids to accommodate size increase.

Ontogeny and covariation in the Toarcian genus Osperleioceras (Ammonoidea)

Starting from embryonic (protoconch-ammonitella) and early juvenile shells, which are indistinguishable at the species level, growth curves of Osperleioceras from the Reynesi Subzone (Upper Toarcian) of the Causses Basin (Aveyron, France) show a continuous radiating range of correlated variation in dimensional and ornamental characters, such as involution, whorl compression, rib strength and rib density. This covariation pattern can be observed among single-horizon assemblages, as well as during individual ontogenetic development. The existence of a continuous intergradational series of shells, ranging from stout coarsely ribbed to smooth suboxycone morphologies, rules out functional or ecological selectivity to explain this non-random variability pattern. The complex interdependence of shape and sculpture can be simulated by a model in which sculpture intensity depends on mantle curvature [GUEX, 1999]. The expression of covariation in subadult specimens since the base of Upper Toarcian reveals a rise in variability, concomitant with a size decrease, both contemporaneous with environmental instability. It developed in successive bursts from a fairly long low variability period spanning the whole Middle Toarcian.

A generalization of Cope's rule

For numerous shelly invertebrates, Cope's rule is shown in this paper to merely describe the particular case where volume increase is strictly coupled with diameter or length. Allometries, which are frequently observed in the evolution of the shells' geometry, mean that their size, volume and surface can vary independently. The consequences of this can be summarized as follows : 1) volume increase not coupled with an increase of diameter or length of the organisms generates increasing involution and/or lateral width in the shell of cephalopods, foraminifera and radiolarians; 2) an increase of the biomineralizing surface, not coupled with volume increase, generates increasing apparent complexity in the sutures and growth lines in ammonites, and an increase in the complexity and number of chambers in foraminifera.

Estimation of reference curves for the urinary steroid metabolome in the first year of life in healthy children : Tracing the complexity of human postnatal steroidogenesis.

CONTEXT: Complex steroid disorders such as P450 oxidoreductase deficiency or apparent cortisone reductase deficiency may be recognized by steroid profiling using chromatographic mass spectrometric methods. These methods are highly specific and sensitive, and provide a complete spectrum of steroid metabolites in a single measurement of one sample which makes them superior to immunoassays. The steroid metabolome during the fetal-neonatal transition is characterized by (a) the metabolites of the fetal-placental unit at birth, (b) the fetal adrenal androgens until its involution 3-6 months postnatally, and (c) the steroid metabolites produced by the developing endocrine organs. All these developmental events change the steroid metabolome in an age- and sex-dependent manner during the first year of life. OBJECTIVE: The aim of this study was to provide normative values for the urinary steroid metabolome of healthy newborns at short time intervals in the first year of life. METHODS: We conducted a prospective, longitudinal study to measure 67 urinary steroid metabolites in 21 male and 22 female term healthy newborn infants at 13 time-points from week 1 to week 49 of life. Urine samples were collected from newborn infants before discharge from hospital and from healthy infants at home. Steroid metabolites were measured by gas chromatography-mass spectrometry (GC-MS) and steroid concentrations corrected for urinary creatinine excretion were calculated. RESULTS: 61 steroids showed age and 15 steroids sex specificity. Highest urinary steroid concentrations were found in both sexes for progesterone derivatives, in particular 20α-DH-5α-DH-progesterone, and for highly polar 6α-hydroxylated glucocorticoids. The steroids peaked at week 3 and decreased by ∼80% at week 25 in both sexes. The decline of progestins, androgens and estrogens was more pronounced than of glucocorticoids whereas the excretion of corticosterone and its metabolites and of mineralocorticoids remained constant during the first year of life. CONCLUSION: The urinary steroid profile changes dramatically during the first year of life and correlates with the physiologic developmental changes during the fetal-neonatal transition. Thus detailed normative data during this time period permit the use of steroid profiling as a powerful diagnostic tool.