Exclusion of BMP6 as a candidate gene for cleidocranial dysplasia

Cleidocranial dysplasia (CCD) is an autosomal dominant, generalized skeletal dysplasia in humans that has been mapped to the short arm of chromosome 6. We report linkage of a CCD mutation to 6p21 in a large family and exclude the bone morphogenetic protein 6 gene (BMP6) as a candidate for the disease by cytogenetic localization and genetic recombination. CCD was linked with a maximal two-point LOD score of 7.22 with marker D6S452 at theta = 0. One relative with a recombination between D6S451 and D6S459 and another individual with a recombination between D6S465 and CCD places the mutation within a 7 cM region between D6S451 and D6S465 at 6p21. A phage P1 genomic clone spanning most of the BMP6 gene hybridized to chromosome 6 in band region p23-p24 using FISH analysis, placing this gene cytogenetically more distal than the region of linkage for CCD. We derived a new polymorphic marker from this same P1 clone and found recombinations between the marker and CCD in this family. The results confirm the map position of CCD on 6p21, further refine the CCD genetic interval by identifying a recombination between D6S451 and D6S459, and exclude BMP6 as a candidate gene.     

Vasopressin receptor subtypes differentially modulate calcium-activated potassium currents in the horizontal limb of the diagonal band of Broca

Because many testicular toxicants cause damage to specific stages of spermatogenesis, the present study has investigated the utility of a model in which the testis is synchronized to contain only a few closely related spermatogenic stages. The susceptibility of different stages to 1,3-dinitrobenzene (1,3-DNB) toxicity was investigated in rats, the testes of which had been stage synchronized by a vitamin A depletion/repletion (VADR) procedure. 1,3-DNB (25 mg/kg, IP) or vehicle was injected 58, 61, or 78 d after vitamin A readministration, and testicular histopathology was evaluated 48 h later. At the time of sacrifice, testes in the three groups were synchronized to stages I-VI, VII-IX, or X-XIV+I. The data indicated that tubules in all stages of spermatogenesis, in both synchronized and unsynchronized animals, demonstrated histopathologic changes in response to 1,3-DNB. However, the lesion seen in synchronized animals was more severe and less stage specific than that seen in weight-matched, unsynchronized animals. This increase in degree of susceptibility could be partially explained by differences in toxicokinetics. Stage-synchronized testes could provide unique insights into stage-specific cellular and molecular events, especially for in vitro studies where the stage enrichment could be maximally exploited. However, results obtained from in vivo toxicity studies using animals subjected to VADR should be interpreted carefully in light of the confounding physiologic/metabolic perturbations potentially induced by the VADR procedure.     

An in vitro model for toxin-mediated vascular leak syndrome: ricin toxin A chain increases the permeability of human endothelial cell monolayers

Vascular leak syndrome (VLS) is the dose-limiting toxicity observed in clinical trials of immunotoxins containing ricin toxin A chain (RTA). RTA itself is thought to cause VLS by damaging vascular endothelial cells, but the exact mechanism remains unclear. This is partially due to the paucity of appropriate models. To study VLS, we developed an in vitro model in which human umbilical vein-derived endothelial cells were first grown to confluence on microporous supports and then cultured under low pressure in the presence or absence of RTA. Endothelial cell barrier function was assessed by measuring the volume of fluid that passed through each monolayer per unit time. We found that RTA significantly increased monolayer permeability at times and concentrations consistent with the onset of VLS in patients treated with RTA-based immunotoxins. Scanning electron microscopy showed that intercellular gaps formed in endothelial monolayers exposed to RTA. Intercellular gap formation followed endothelial cell death caused by the enzymatic activity of RTA. We conclude that RTA is directly toxic to endothelial cells in vitro and speculate that this contributes to VLS in vivo.     

Interdiffusion behavior of Hg in HgTe/CdTe superlattices grown on Cd0.96Zn0.04 Te (211)B substrates by molecular beam epitaxy

Double-crystal x-ray rocking curve (DCRC) and secondary-ion mass-spectroscopy (SIMS) measurements have been performed to investigate the effect of rapid thermal annealing on the interdiffusion behavior of Hg in HgTe/CdTe superlattices grown on Cd_0.96Zn_0.04Te (211)B substrates by molecular beam epitaxy. The sharp satellite peaks of the DCRC measurements on a 100-period HgTe/CdTe (100Å/100Å) superlattice show a periodic arrangement of the superlattice with high-quality interfaces. The negative direction of the entropy change obtained from the diffusion coefficients as a function of the reciprocal of the temperature after RTA indicates that the Hg diffusion for the annealed HgTe/CdTe superlattice is caused by an interstitial mechanism. The Cd and the Hg concentration profiles near the annealed HgTe/CdTe superlattice interfaces, as measured by SIMS, show a nonlinear behavior for Hg, originating from the interstitial diffusion mechanism of the Hg composition. These results indicate that a nonlinear interdiffusion behavior is dominant for HgTe/CdTe superlattices annealed at 190°C and that the rectangular shape of HgTe/CdTe superlattices may change to a parabolic shape because of the intermixing of Hg and Cd due to the thermal treatment.     

Acquired hemophilia and rheumatoid arthritis. Value of intravenous immunoglobulins

The authors report an exceedingly rare complication of rheumatoid arthritis, i.e. acquired hemophilia due to anti-factor VIII autoantibody production. Treatment with intravenous immune globulin ensured control of hemorrhagic manifestations by inducing a transient rise in factor VIII level.     

The crystal structure of an Fe-superoxide dismutase from the hyperthermophile Aquifex pyrophilus at 1.9 A resolution: structural basis for thermostability

The incidence of stress fractures is increasing among competitive and recreational athletes as well as among children and the elderly. By understanding the continuum of bone's response to stress and maintaining an appropriate index of suspicion, the health care provider can diagnose these injuries appropriately. An accurate history and examination is essential and will differentiate stress fractures from other stress reactions. The more common stress fractures are discussed.