Skin cancer after X-ray treatment for scalp ringworm

Some 2,224 children given X-ray therapy for tinea capitis (ringworm of the scalp) have been followed for up to 50 years to determine cancer incidence, along with a control group of 1,380 tinea capitis patients given only topical medications. The study found a relative risk (RR) of 3.6 (95% confidence interval, 2.3-5.9) for basal cell skin cancer (BCC) of the head and neck among irradiated Caucasians (124 irradiated cases and 21 control cases), in response to a scalp dose of about 4.8 Gy. No melanomas of the head and neck have been seen, and only a few squamous cell carcinomas. About 40% of irradiated cases have had multiple BCCs, for a total of 328 BCCs. Although 25% of both the irradiated and control groups are African-American, only 3 skin cancers have been seen among them, all in the irradiated group, indicating the importance of susceptibility to UV radiation as a cofactor. Light complexion, severe sunburning and North European ancestry were predictive of BCC risk in the irradiated group, but chronic sun exposure was not. Children irradiated at young ages had the highest BCC risk. The RR for BCC risk is approximately constant with time since exposure, suggesting that risk will probably last for a lifetime.     

New evidence for hominid presence in the Lower Pleistocene of the Southern Levant

The site of 'Ubeidiya is located in the Jordan Valley, Israel and has been biochronologically dated to 1.5 m.y.a. It exhibits large lithic and faunal assemblages. Previous published hominid material includes a molar (UB 1701) and I(2) (UB 1700). A recent review of the faunal material from previous excavations has revealed a highly worn hominid right lateral lower incisor (UB 335). The tooth was found in situ in the Lower Pleistocene deposits of stratum I-26a, which is comprised of sand and conglomerates of flint, limestone and basalt indicative of a pebbled lakeshore environment. Taphonomic analysis of the macromammal assemblage indicates high-energy fluvial transport. Paleoecological reconstruction suggests a large woodland fauna with a small percent of open steppe species.UB 335 did not differ significantly from the Lower Pleistocene hominid and modern populations but did differ significantly from all other fossil populations. Two-tailed Student t -test and single classification Model II ANOVA of the buccolingual diameter did not distinguish between Lower Pleistocene species: Homo habilis, H. ergaster and H. cf. erectus. Thus, UB 335 can be identified as a Lower Pleistocene hominid although it cannot be securely assigned to any particular species within that time frame. The current date of the 'Ubeidiya deposits and the location of the site within the Levantine corridor suggests a tenative identification as H. ergaster.     

Nesprin-1alpha self-associates and binds directly to emerin and lamin A in vitro

The mitogen-stimulated protein kinase p70(s6k)/p85(s6k) (S6K) plays an essential role in cell proliferation and growth, with inhibitors of the S6K signalling pathway showing promise as anti-tumour therapeutics. Here, we report that the bisindolylmaleimide derivative Ro 31-6045, previously reported to be inactive as a kinase inhibitor, inhibited S6K activity in vivo with an IC50=8 microM. Structure/function analysis using mutant forms of S6K indicates that Ro 31-6045 inhibition is independent of the upstream activator mTOR. Ro 31-6045 will prove useful in elucidating the complex activation mechanism of S6K and its independence from mTOR will allow confirmation of functional data obtained using the mTOR inhibitor rapamycin.     

Phylogenetic analysis shows that the OXA beta-lactamase genes have been on plasmids for millions of years

The OXA genes encode a class of b-lactamases that confer resistance to a wide range of b-lactam antibiotics. To determine whether the diversity of the OXA b-lactamases is the result of recent or ancient events, and to determine whether mobilization of the OXA genes from chromosomes to plasmids occurred recently or long ago, we have constructed a Bayesian phylogeny of the OXA b-lactamase genes. Analysis of that phylogeny shows that much of the diversity is the result of ancient events and that the OXA genes were mobilized from chromosomes to plasmids on at least two independent occasions that occurred millions of years ago. That observation contradicts the commonly held impression that mobilization of antibiotic resistance genes is strictly the result of modern use of antibiotics.     

Overlapping and specific patterns of GDNF,c-ret and GFR alpha mRNA expression in the developing chicken retina

GDNF and the GDNF receptors, c-Ret, GFR alpha 1 and 2 mRNA is expressed in the developing chicken retina. GDNF labelling was mainly found in embryonic day 4-5 retina but weak labelling could also be found over scattered retinal cells at later stages. c-ret labelling was found over ganglion cells, amacrine and horizontal cells; the preferred GDNF receptor (GFR alpha 1) over amacrine and horizontal cells; and the less preferred GDNF receptor (GFR alpha 2) over ganglion cells, amacrine cells and photoreceptors.     

Pre-implantational timetable of embryonal development of Myocastor coypus (Coypu)

The purpose of the present study was to determine the chronology of the pre-implantation embryonic development in Myocastor coypus (coypu). It was carried out by daily colpocytological examination and controlled mating of 33 females. Oocytes and embryos were obtained by flushing from day 0 to day 10 post-coitus (p.c.). On day 1 p.c., oocytes predominated whereas on day 2 p.c. zygotes were predominant. The cleavage period was from day 3 to day 6 p.c.. Morulae were collected from day 6 to day 9 p.c., whereas blastocysts were collected on days 8 and 9. From oviduct flushing, the embryos in the zygote stage and up to the morula stage with less than a 30-cell stage were recovered. Embryos in the morula stage with 30 or more cells and up to the growing blastocyst stage were collected from the flushing of hemiuteri.     

Variant heparan sulfates synthesized in developing mouse brain differentially regulate FGF signaling

Heparan sulfates (HSs) exert critical regulatory actions on many proteins, including growth factors, and are essential for normal development. Variations in their specific sulfation patterns are known to regulate binding and signaling of fibroblast growth factors (FGFs) via tyrosine kinase receptors (FGFRs). We previously reported differences in sulfation patterns between HS species expressed by embryonic day 10 (E10) and E12 mouse neural precursor cells. We have examined the abilities of the different HS species to support signaling of the relevant FGF-FGFR combinations expressed early during brain development. For FGF8, which only functions early (E8-E11), E10 HS showed preferential activation. The most potent signaling for FGF8 was via FGFR3c, for which E10 HS was strongly active and E12 HS had no activity. For FGF2, which functions from E10 to E13, HS from both stages showed similar activity and were more potent at activating FGFR1c than the other receptors. Thus, we find a stage-specific correlation with activation. To explore the potential mechanisms for the generation of these stage-specific HS species, we investigated the expression of the HS sulfotransferase (HSST) isozymes responsible for creating diverse sulfation motifs in HS chains. We find that there are stage-specific combinations of HSST isozymes that could underlie the synthesis of different HS species at E10 and E12. Collectively, these data lead us to propose a model in which differential expression of HSSTs results in the synthesis of variant HS species that form functional signaling complexes with FGFs and FGFRs and orchestrate proliferation and differentiation in the developing brain.     

Chondrodysplasias due to proteoglycan defects

The proteoglycans, especially the large chondroitin sulfate proteoglycan aggrecan, have long been viewed as important components of the extracellular matrix of cartilage. The drastic change in expression during differentiation from mesenchyme to cartilage, the loss of tissue integrity associated with proteoglycan degradation in several disease processes and, most important, the demonstration of abnormalities in proteoglycan production concomitant with the aberrant growth patterns exhibited by the brachymorphic mouse, the cartilage matrix deficient mouse, and the nanomelic chick provide the strongest evidence that the proteoglycan aggrecan is essential during differentiation and for maintenance of the skeletal elements. More recently, mutations associated with proteoglycans other than aggrecan, especially the heparan sulfate proteoglycans, glypican and perlecan, suggest an important role for these molecules in skeletal development as well. This review focuses on the molecular bases of the hereditary proteoglycan defects in animal models, as well as of some human chondrodysplasias, that collectively are providing a better understanding of the role of proteoglycans in the development and maintenance of the skeletal elements.     

Regulation of airway tight junctions by proinflammatory cytokines

Epithelial tight junctions (TJs) provide an important route for passive electrolyte transport across airway epithelium and provide a barrier to the migration of toxic materials from the lumen to the interstitium. The possibility that TJ function may be perturbed by airway inflammation originated from studies reporting (1) increased levels of the proinflammatory cytokines interleukin-8 (IL-8), tumor necrosis factor alpha (TNF-alpha), interferon gamma (IFN-gamma), and IL-1beta in airway epithelia and secretions from cystic fibrosis (CF) patients and (2) abnormal TJ strands of CF airways as revealed by freeze-fracture electron microscopy. We measured the effects of cytokine exposure of CF and non-CF well-differentiated primary human airway epithelial cells on TJ properties, including transepithelial resistance, paracellular permeability to hydrophilic solutes, and the TJ proteins occludin, claudin-1, claudin-4, junctional adhesion molecule, and ZO-1. We found that whereas IL-1beta treatment led to alterations in TJ ion selectivity, combined treatment of TNF-alpha and IFN-gamma induced profound effects on TJ barrier function, which could be blocked by inhibitors of protein kinase C. CF bronchi in vivo exhibited the same pattern of expression of TJ-associated proteins as cultures exposed in vitro to prolonged exposure to TNF-alpha and IFN-gamma. These data indicate that the TJ of airway epithelia exposed to chronic inflammation may exhibit parallel changes in the barrier function to both solutes and ions.