The distribution of infectivity in blood components and plasma derivatives in experimental models of transmissible spongiform encephalopathy

BACKGROUND: The administration of blood components from donors who subsequently develop Creutzfeldt-Jakob disease has raised the issue of blood as a possible vehicle for iatrogenic disease. STUDY DESIGN AND METHODS: We examined infectivity in blood components and Cohn plasma fractions in normal human blood that had been "spiked" with trypsinized cells from a scrapie-infected hamster brain, and in blood of clinically ill mice that had been inoculated with a mouse-adapted strain of human transmissible spongiform encephalopathy. Infectivity was assayed by intracerebral inoculation of the blood specimens into healthy animals. RESULTS: Most of the infectivity in spiked human blood was associated with cellular blood components; the smaller amount present in plasma, when fractionated, was found mainly in cryoprecipitate (the source of factor VIII) and fraction I+II+III (the source of fibrinogen and immunoglobulin); almost none was recovered in fraction IV (the source of vitamin-K-dependent proteins) and fraction V (the source of albumin). Mice infected with the human strain of spongiform encephalopathy had very low levels of endogenous infectivity in buffy coat, plasma, cryoprecipitate, and fraction I+II+III, and no detectable infectivity in fractions IV or V. CONCLUSION: Convergent results from exogenous spiking and endogenous infectivity experiments, in which decreasing levels of infectivity occurred in cellular blood components, plasma, and plasma fractions, suggest a potential but minimal risk of acquiring Creutzfeldt-Jakob disease from the administration of human plasma protein concentrates.     

The metabolite 1 alpha,25-dihydroxyvitamin D3 enhances lymphokine- mediated activation of the oxidative metabolism of the U937 cell line and phosphorylation of a 48-kD respiratory burst-associated protein

U937 cells respond to a variety of stimuli with increased differentiation as manifested by reduced growth, increased adherence, increased expression of several surface receptors, and increased capacity for phagocytosis and formation of reactive oxygen intermediates. In the present study the effects of lymphocyte conditioned media, recombinant interferon-gamma (IFN-gamma), and 1 alpha,25-dihydroxyvitamin D3 (1,25(OH)2D3) on the ability to form reactive oxygen intermediates by U937 cells were measured by using the luminol-dependent luminescence (LDL) assay. Neither 1,25(OH)2D3 alone nor IFN-gamma alone enhanced competence for phorbol myristate acetate- stimulated LDL. Cells were capable of moderate LDL after exposure to lymphocyte conditioned media, and this was enhanced by 1,25(OH)2D3 (10(- 8) mol/L) and other vitamin D metabolites at higher concentrations. This effect was not secondary to accelerated production of myeloperoxidase, which is important in the LDL assay. Enhanced phorbol myristate acetate-stimulated phosphorylation of a 48-kd substrate was observed in 32P-labeled intact cells treated with 1,25(OH)2D3 alone or in combination with IFN-gamma. Treatment of cells with IFN-gamma or lymphocyte conditioned media did not alter phosphorylation. These results support the concept that 1,25(OH)2D3 plays a role in phagocyte differentiation and activation beyond the effects of lymphokines. Protein kinase C-mediated phosphorylation reactions may be necessary for the ability of U937 cells to reduce O2 and required for maximal activity under some conditions of incubation.     

Factors Associated with HIV Viral Load in a Respondent Driven Sample in Los Angeles

This study used a modified version of the Behavioral Model for Vulnerable Populations to examine the predisposing, enabling, and need factors associated with detectable viral load (VL). HIV status was measured using saliva and confirmed by blood. Of 797 persons enrolled, 193 were HIV positive and provided VL counts. A hierarchical multivariate logistic regression approach demonstrated that the predisposing factors of homelessness and recent substance abuse, particularly methamphetamine abuse, had a negative association with VL. The negative association of homelessness on VL was weakened with the introduction of enabling and need utilization factors. Mediation analysis indicated homelessness and HIV medication taking significantly associated with methamphetamine use as a predictor of detectable viral load. Guided policy to address substance abuse among those who are HIV positive is needed to improve biological outcomes.     

A defective signal peptide in the maize high-lysine mutant floury 2.

The maize floury 2 (fl2) mutation enhances the lysine content of the grain, but the soft texture of the endosperm makes it unsuitable for commercial production. The mutant phenotype is linked with the appearance of a 24-kDa alpha-zein protein and increased synthesis of binding protein, both of which are associated with irregularly shaped protein bodies. We have cloned the gene encoding the 24-kDa protein and show that it is expressed as a 22-kDa alpha-zein with an uncleaved signal peptide. Comparison of the deduced N-terminal amino acid sequence of the 24-kDa alpha-zein protein with other alpha-zeins revealed an alanine to valine substitution at the C-terminal position of the signal peptide, a histidine insertion within the seventh alpha-helical repeat, and an alanine to threonine substitution with the same alpha-helical repeat of the protein. Structural defects associated with this alpha-zein explain many of the phenotypic effects of the fl2 mutation.     

Clinical features and outcome of T-cell acute lymphoblastic leukemia in childhood with respect to alterations at the TAL1 locus: a Pediatric Oncology Group study

Alteration of the TAL1 locus is the most common nonrandom genetic defect in childhood T-cell acute lymphoblastic leukemia (T-ALL). To determine if rearrangements of the TAL1 proto-oncogene confer a distinct leukemic phenotype, we studied leukemic peripheral blood or bone marrow samples from 182 children with newly diagnosed T-ALL enrolled on Pediatric Oncology Group treatment protocols. Forty-eight (26%) of the samples had a local rearrangement of the TAL1 locus. Demographic and clinical features were compared for patient subgroups with and without TAL1 rearrangements. The only clinical correlates that were significantly associated with TAL1 gene rearrangements were higher white blood cell count (P = .017) and higher hemoglobin (P = .007) at diagnosis. Immunophenotypically, samples with altered TAL1 were more likely to be CD2+ (P = .001) and lack CD10 (cALLa) expression (P = .007) than those without the rearrangement. There was a trend toward improved event-free survival (EFS) in patients with TAL1 rearrangements (4-year EFS was 44% +/- 7% for patients without the rearrangements v 59% +/- 11% for those with rearrangements), but the difference was not significant (P = .34). The role of TAL1 in leukemogenesis has yet to be clearly defined, and the prognostic significance of TAL1 gene rearrangements in T-ALL deserves further study.     

Prevalence of comorbidities and management of gout in a tropical city in Australia

To examine the management of gout in general practice in Townsville, Australia, and to explore comorbid conditions in patients with gout. Study will also explore how closely guidelines are being followed in managing gout. Retrospective chart review was conducted from May to November 2014 in three general practices in Townsville. Registers for patients were established by searching “gout” and “gouty arthritis”. Three hundred and twenty-one patients were included in the study after excluding inactive patients, patients below age of 18 and patients with cancer. Main outcome measures were prevalence of comorbidities in gout patients, gout medications and adequate serum urate control (≤0.36 mmol/l). Multivariate logistic regression was used to study the relationship between serum urate level, comorbid conditions and lifestyle factors. Hypertension was the most common comorbid condition with 60.8 % of patients followed by obesity and dyslipidaemia. In terms of medication, 46.7 % of patients were on allopurinol, 12.8 % on indomethacin and 13.4 % on diuretics. Eighty-six percentage of patients had serum urate level (sUA) recorded in the previous year. Of these, 32.2 % had a serum urate level below or equal to 0.36 mmol/l. Moreover, 17.4 % of patients had lifestyle advice documented in chart. Male gender was the most influential factor in having poor uric acid control (p < 0.01), followed by not being on allopurinol (p < 0.01) and patients older than 50 years (p = 0.02). Management of gout in this study sample was not entirely concordant with guidelines. The study also suggests a need for possible tighter monitoring and allopurinol dosing regime in older, male patients.     

Inhibition by propranolol of 3,5,3'-triiodothyronine formation from thyroxine in isolated rat renal tubules: an effect independent of beta-adrenergic blockade

Recent studies in man have shown a decrease in serum L-T3 (T3) levels in subjects treated with DL-propranolol, but the mechanism of this effect is unknown. Isolated rat renal tubules were used to study the effect of propranolol and related drugs on the formation of T3 from L-T4 (T4). Racemic (DL) propranolol at 100 microM inhibited the net formation of T3 from T4 by 35% (P less than 0.01). The D- and L-isomers of propranolol were also potent in inhibiting T3 formation, but the beta-blockers atenolol and sotalol, which have no significant membrane-stabilizing activity, had no effect at similar concentrations. Quinidine inhibited T3 formation, with a dose-response curve which was similar over the concentrations studied to that of DL-propranolol. L-Epinephrine and L-isoproterenol had no effect on T3 formation, and equimolar amounts of L-isoproterenol did not prevent the inhibition of T3 formation by DL-propranolol. cAMP production was stimulated by 200 micro M L-isoproterenol, and this was blocked by an equimolar concentration of DL-propranolol but not of D-propranolol. It is concluded that DL-propranolol directly inhibits net T3 formation from T4 in this system by a direct membrane-stabilizing or quinidine-like action and not by specific beta-blockade.