Magnetite nanoparticles as a kinetically favorable source of iron to enhance GBM response to chemoradiosensitization with pharmacological ascorbate.

Ferumoxytol (FMX) is an FDA-approved magnetite (Fe3O4) nanoparticle used to treat iron deficiency anemia that can also be used as an MR imaging agent in patients that can't receive gadolinium. Pharmacological ascorbate (P-AscH-; IV delivery; plasma levels ≈ 20 mM) has shown promise as an adjuvant to standard of care chemo-radiotherapy in glioblastoma (GBM). Since ascorbate toxicity mediated by H2O2 is enhanced by Fe redox cycling, the current study determined if ascorbate catalyzed the release of ferrous iron (Fe2+) from FMX for enhancing GBM responses to chemo-radiotherapy. Ascorbate interacted with Fe3O4 in FMX to produce redox-active Fe2+ while simultaneously generating increased H2O2 fluxes, that selectively enhanced GBM cell killing (relative to normal human astrocytes) as opposed to a more catalytically active Fe complex (EDTA-Fe3+) in an H2O2 - dependent manner. In vivo, FMX was able to improve GBM xenograft tumor control when combined with pharmacological ascorbate and chemoradiation in U251 tumors that were unresponsive to pharmacological ascorbate therapy. These data support the hypothesis that FMX combined with P-AscH- represents a novel combined modality therapeutic approach to enhance cancer cell selective chemoradiosentization in the management of glioblastoma.

Maturation of coordinated immediate early gene expression by cocaine during adolescence.

Adolescence may be a critical period for drug addiction. Young adolescent male rats have greater locomotor responses than adults after acute low dose cocaine administration. Further, repeated cocaine administration produces as much or more conditioned place preference but reduced locomotor sensitization in adolescents compared to adults. Acute activation of neurons by cocaine induces long-term changes in behavior by activating transcriptional complexes. The purpose of the present study was to correlate cocaine-induced locomotor activity with neuronal activation in subregions of the striatum and cortex by acute cocaine in young adolescent (postnatal (PN) 28) and adult (PN 65) male rats by measuring the induction of the plasticity-associated immediate early genes (IEGs) c-fos and zif268 using in situ hybridization. Animals were treated with saline, low (10 mg/kg), or high (40 mg/kg) dose cocaine in locomotor activity chambers and killed 30 min later. Low dose cocaine induced more locomotor activity and striatal c-fos expression in adolescents than adults whereas high dose cocaine induced more locomotor activity, striatal c-fos, and striatal zif268 expression in adults. Locomotor activity correlated with the expression of both genes in adults but correlated with striatal c-fos only in adolescents. Finally, there was a significant correlation between the expression of c-fos and zif268 in the adult striatum but not in adolescents. Our results suggest that the coordinated expression of transcription factors by cocaine continues to develop during adolescence. The immature regulation of transcription factors by cocaine could explain why adolescents show unique sensitivity to specific long-term behavioral alterations following cocaine treatment.

Relationship between youth and parent perceptions of family environment and social anxiety.

This study concurrently examined the relationship between adolescents' perceptions of their parents' child-rearing styles and family environment and their reports of social anxiety. Adolescents reporting higher levels of social anxiety perceived their parents as being more socially isolating, overly concerned about others' opinions, ashamed of their shyness and poor performance, and less socially active than did youth reporting lower levels of social anxiety. Parent perceptions of child-rearing styles and family environment, however, did not differ between parents of socially anxious and nonsocially anxious adolescents. Results are comparable to studies using adult retrospective reports and are discussed with regard to the role of the family environment in the development of social anxiety.

Peripheral retinopathy in offspring of carriers of Norrie disease gene mutations. Possible transplacental effect of abnormal Norrin.

BACKGROUND: The Norrie disease (ND) gene (Xp11.3) (McKusick 310600) consists of one untranslated exon and two exons partially translated as the Norrie disease protein (Norrin). Norrin has sequence homology and computer-predicted tertiary structure of a growth factor containing a cystine knot motif, which affects endothelial cell migration and proliferation. Norrie disease (congenital retinal detachment), X-linked primary retinal dysplasia (congenital retinal fold), and X-linked exudative vitreoretinopathy (congenital macular ectopia) are allelic disorders. METHODS: Blood was drawn for genetic studies from members of two families to test for ND gene mutations. Sixteen unaffected family members were examined ophthalmologically. If any retinal abnormality were identified, fundus photography and fluorescein angiography was performed. RESULTS: Family A had ND (R109stp), and family B had X-linked exudative vitreoretinopathy (R121L). The retinas of 11 offspring of carrier females were examined: three of seven carrier females, three of three otherwise healthy females, and one of one otherwise healthy male had peripheral inner retinal vascular abnormalities. The retinas of five offspring of affected males were examined: none of three carrier females and none of two otherwise healthy males had this peripheral retinal finding. CONCLUSIONS: Peripheral inner retinal vascular abnormalities similar to regressed retinopathy of prematurity were identified in seven offspring of carriers of ND gene mutations in two families. These ophthalmologic findings, especially in four genetically healthy offspring, strongly support the hypothesis that abnormal Norrin may have an adverse transplacental (environmental) effect on normal inner retinal vasculogenesis.

Microscopic polyangiitis with ocular involvement.

Microscopic polyangiitis is an exclusively small-vessel (arterioles, capillaries, or venules) vasculitis that primarily involves the kidney and often involves the lungs, skin, or nervous system. Characteristic features include focal segmental glomerulonephritis, nongranulomatous necrotizing vasculitis, and serum positive for perinuclear-staining antineutrophil cytoplasmic antibodies (P-ANCA). We report a case of microscopic polyangiitis with previously unreported eyelid and conjunctival manifestations that responded well to immunosuppressive therapy.

Accuracy of lower extremity arterial duplex mapping.

We performed lower extremity arterial duplex mapping from the aortic bifurcation to the ankle in 150 consecutive patients evaluated for aortic and lower extremity arterial reconstruction and compared lower extremity arterial duplex mapping in a blinded fashion to angiography. On the basis of history, physical examination, and four-cuff segmental Doppler pressures individual lower extremities were classified as normal, isolated aortoiliac disease, infrainguinal disease, and multilevel inflow and outflow disease. For vessels proximal to the tibial arteries, lower extremity arterial duplex mapping was analyzed for its ability to insonate individual arterial segments, detect a 50% or greater stenosis, and distinguish stenosis from occlusion. In the tibial arteries lower extremity arterial duplex mapping was evaluated for its ability to visualize tibial vessels and to predict interruption of tibial artery patency from origin to ankle. Lower extremity arterial duplex mapping visualized 99% of arterial segments proximal to the tibial vessels, with overall sensitivities for detecting a 50% or greater lesion ranging from 89% in the iliac vessels to 67% at the popliteal artery. Stenosis was successfully distinguished from occlusion in 98% of cases. In the tibial vessels lower extremity arterial duplex mapping was better at visualizing anterior tibial and posterior tibial artery segments (94% and 96%) than peroneal artery segments (83%), (p less than 0.001). Overall sensitivities for predicting interruption of tibial artery patency were 90% for the anterior tibial, 90% for the posterior tibial, and 82% for the peroneal. Clinical disease category did not influence in a major way the accuracy of lower extremity arterial duplex mapping in either above-knee or below-knee vessels.

MacGeneRisk and MacMedRisk--HyperCard programs which tutor Bayesian risk assessment.

Programs have been devised for the Macintosh computer which tutor medical students in the solution of risk assessment problems in human genetics and clinical test interpretation, using Bayesian probability.

Competence Mutant of Haemophilus influenzae with Abnormal Ratios of Marker Efficiencies in Transformation.

In studies of competence-deficient mutants of Haemophilus influenzae which absorb deoxyribonucleic acid (DNA) but fail to produce transformants, it was observed that in some mutants the residual transforming activity for different markers varied widely, i.e., produced a ratio effect. One of these mutants, com(-56), was studied intensively to determine the cause of the residual efficiency of transformation and the reason for the ratio effect. The residual frequency of transformation was higher for markers considered single-site mutations (like naladixic acid resistance), whereas the least efficient markers tested were those conferring resistance to high levels of streptomycin or novobiocin which are more complex than single-site mutations. Measurement of frequencies of cotransformation indicated that overall genetic linkage was reduced. Transfection was fairly efficient with phage S2 DNA, but not prophage DNA. Donor marker activity could be detected in transformed cell lysates, but not linked to recipient markers in recombinant molecules. Sucrose gradient analysis of such lysates revealed that donor material was associated with recipient DNA in at least normal quantities, but lacked detectable genetic activity. Material from donor DNA labeled with heavy isotopes was incorporated into recipient chromosomal fragments having a density indistinguishable from normal density, unlike the hybrid density recombinant material found in normal cells. No excessive solubilization or nicking of unincorporated donor was detected. It is postulated that this strain contains a hyperactive nuclease, which reduces the effective size of the input DNA during the integration process.

Requirements for macromolecular synthesis in the establishment of beta-galactosidase repression in zygotes.

Inhibitors of protein synthesis do not consistently prevent formation of the lac operon repressor, according to several published reports, although direct evidence indicates that the repressor is a protein. Inhibition of ribonucleic acid (RNA) synthesis has never been shown to block lactose repression. These results have raised the possibility that repressor is synthesized in some unusual fashion. We have studied the effect of various inhibitors upon the establishment of repression in zygotes, utilizing conditions which minimize catabolite repression. Inhibition of protein synthesis by either chloramphenicol treatment or tryptophan deprivation blocked repressor formation in our experiments. Sodium borate and 6-azauracil are compounds reported to be specific inhibitors of RNA synthesis, and their behavior in control experiments is consistent with this specificity. Both delayed the establishment of repression. Thymine deprivation, either by starvation of a thymine auxotroph or by treatment with 5-fluorodeoxyuridine, did not delay the onset of repression. We conclude that repressor formation requires RNA synthesis and probably utilizes the usual protein-forming mechanisms.