Maternal Genetic Variants of IL4/IL13 Pathway Genes on IgE With "Western or Eastern Environments/Lifestyles"

Purpose

We investigated maternal genetic effects of four IL-4/IL-13 pathway genes as well as their interactions with the "Western or Eastern lifestyles/environments" on IgE in Karelian children.

Methods

This study included 609 children and their mothers. Total IgE levels in children and mothers were measured and 10 single nucleotide polymorphisms (SNPs) in IL-4, IL-4Ra, IL-13, and STAT6 were genotyped in mothers and their children.

Results

The maternal G allele of IL-13 130 (rs20541) was significantly (P=0.001) associated with decreased IgE in children in the Karelian population (Pooling Finnish and Russian children), as well as in Finnish (P=0.030) and Russian children (P=0.018). The IgE levels were significantly (P=0.001) higher in Russian children whose mothers were homozygous for the G allele of the IL-4Ra 50 (rs1805010) SNP than that in Russian children of mothers who were AG heterozygotes or AA homozygotes. After accounting for children''s genotypes, we observed interactive effects on children''s IgE for maternal IL-13 130 genotypes (P=0.014) and maternal IL-4Ra 50 genotypes (P=0.0003) with "Western or Eastern" lifestyles/environments. With the adjustment for multiple comparisons using a false discovery rate (FDR) of 0.05, the interactive effect of the maternal IL-4Ra50 SNP was significant.

Conclusion

Maternal genetic variants in IL-4/IL-13 pathway genes, such as IL-13 130 and IL-4Ra50, influenced IgE levels in school children that were independent of the children''s genetic effects. These effects differ in "Western or Eastern" environments.     

Apolipoprotein B gene variants are involved in the determination of serum cholesterol levels: a study in normo- and hyperlipidaemic individuals

We have investigated the frequencies of 3 restriction fragment length polymorphisms (RFLPs) of the apolipoprotein B (apo B) gene in normo- and hyperlipidaemic individuals. In individuals with type III hyperlipidaemia, the allele frequency for the RFLP detected with XbaI was significantly different from the allele frequency in normolipidaemic individuals and in those with other types of hyperlipidaemia. No significant difference in allele frequency was found among these groups for the RFLPs detected with MspI or EcoRI. Within a sample of 62 normolipidaemic individuals, homozygotes for the X2 allele (cutting site) of the XbaI RFLP had a significantly higher serum cholesterol level than homozygotes for the XI allele, with individuals of the genotype X1X2 having an intermediate value (X2X2 mean 5.71 mmol/l, X1X1 mean 4.81 mmol/l, X1X2 mean 5.30 mmol/l). There were also significant differences in serum triglyceride levels in individuals with different XbaI genotypes. In these normolipidaemic individuals there was no correlation between the EcoRI and MspI RFLP genotypes and levels of any serum lipid variable. Information from the XbaI and EcoRI RFLPs was used in conjunction to define apo B haplotypes. These haplotypes are a more precise measure of the genotypic variation, and they explain a greater fraction of the serum cholesterol and triglyceride levels than the single-site polymorphisms considered separately. This study suggests that variations in the gene for apo B are associated with the determination of serum cholesterol and triglyceride levels both in patients with type III hyperlipidaemia and in the normal population.     

Activity in orbitofrontal neuronal ensembles reflects inhibitory control

Stopping, or inhibition, is a form of self‐control that is a core element of flexible and adaptive behavior. Its neural origins remain unclear. Some views hold that inhibition decisions reflect the aggregation of widespread and diverse pieces of information, including information arising in ostensible core reward regions (i.e., outside the canonical executive system). We recorded activity of single neurons in the orbitofrontal cortex (OFC) of macaques, a region associated with economic decisions, and whose role in inhibition is debated. Subjects performed a classic inhibition task known as the stop signal task. Ensemble decoding analyses reveal a clear firing rate pattern that distinguishes successful from failed inhibition and that begins after the stop signal and before the stop signal reaction time (SSRT). We also found a different and orthogonal ensemble pattern that distinguishes successful from failed stopping before the beginning of the trial. These signals were distinct from, and orthogonal to, value encoding, which was also observed in these neurons. The timing of the early and late signals was, respectively, consistent with the idea that neuronal activity in OFC encodes inhibition both proactively and reactively.     

Executive summary from American Radium Society’s appropriate use criteria on neurocognition after stereotactic radiosurgery for multiple brain metastases

BackgroundThe American Radium Society (ARS) Appropriate Use Criteria brain malignancies panel systematically reviewed (PRISMA [Preferred Reporting Items for Systematic Reviews and Meta-Analyses]) published literature on neurocognitive outcomes after stereotactic radiosurgery (SRS) for patients with multiple brain metastases (BM) to generate consensus guidelines.MethodsThe panel developed 4 key questions (KQs) to guide systematic review. From 11 614 original articles, 12 were selected. The panel developed model cases addressing KQs and potentially controversial scenarios not addressed in the systematic review (which might inform future ARS projects). Based upon quality of evidence, the panel confidentially voted on treatment options using a 9-point scale of appropriateness.ResultsThe panel agreed that SRS alone is usually appropriate for those with good performance status and 2–10 asymptomatic BM, and usually not appropriate for >20 BM. For 11–15 and 16–20 BM there was (between 2 case variants) agreement that SRS alone may be appropriate or disagreement on the appropriateness of SRS alone. There was no scenario (among 6 case variants) in which conventional whole-brain radiotherapy (WBRT) was considered usually appropriate by most panelists. There were several areas of disagreement, including: hippocampal sparing WBRT for 2–4 asymptomatic BM; WBRT for resected BM amenable to SRS; fractionated versus single-fraction SRS for resected BM, larger targets, and/or brainstem metastases; optimal treatment (WBRT, hippocampal sparing WBRT, SRS alone to all or select lesions) for patients with progressive extracranial disease, poor performance status, and no systemic options.ConclusionsFor patients with 2–10 BM, SRS alone is an appropriate treatment option for well-selected patients with good performance status. Future study is needed for those scenarios in which there was disagreement among panelists.     

The Effect of a Hypertension Self-Management Intervention on Diabetes and Cholesterol Control

Background

Most patient chronic disease self-management interventions target single-disease outcomes. We evaluated the effect of a tailored hypertension self-management intervention on the unintended targets of glycosylated hemoglobin (HbA_1c) and low-density lipoprotein cholesterol (LDL-C).

Methods

We evaluated patients from the Veterans Study to Improve the Control of Hypertension, a 2-year randomized controlled trial. Patients received either a hypertension self-management intervention delivered by a nurse over the telephone or usual care. Although the study focused on hypertension self-management, we compared changes in HbA_1c among a subgroup of 216 patients with diabetes and LDL-C among 528 patients with measurements during the study period. Changes in these laboratory values over time were compared between the 2 treatment groups using linear mixed-effects models.

Results

For the patients with diabetes, the hypertension self-management intervention resulted in a 0.46% reduction in HbA_1c over 2 years compared with usual care (95% confidence interval, 0.04%-0.89%; P = .03). For LDL-C, there was a minimal 0.9 mg/dL between-group difference that was not statistically significant (95% confidence interval, −7.3-5.6 mg/dL; P = .79).

Conclusions

There was a significant effect of the self-management intervention on the unintended target of HbA_1c,but not LDL-C. Chronic disease self-management interventions might have “spill-over” effects on patients' comorbid chronic conditions.     

Development of an automated closed system for generation of human lymphokine-activated killer (LAK) cells for use in adoptive immunotherapy

Immunotherapy utilizing the adoptive transfer of lymphokine-activated killer (LAK) cells in conjunction with recombinant interleukin-2 (IL-2) can mediate tumor regression in some patients with advanced cancer. The activation of large numbers of LAK cells was performed in roller bottles in a research laboratory setting and required meticulous aseptic technique, at least one skilled technician per patient and one laminar flow hood per patient. To reduce the complexity and expense of LAK cell generation for human immunotherapy trials we have developed a closed-system automated procedure using a continuous flow blood cell separator. PBL were obtained by standard apheresis techniques. Platelets and plasma were elutriated using countercentrifugal flow of saline in the cell separator machine. The washed PBL were underlaid with Ficoll-Hypaque (FH) in the original separation bag. Lymphocytes were then flushed into a collection bag where they were concentrated and washed with 2 liters of saline. Mean recovery from the automated FH technique was 54.6 +/- 4.3% compared to 62.3 +/- 4.0% using manual methods in 50 ml tubes (P greater than 0.05). Cells were diluted in the collection bag with RPMI 1640 +/- 2% human AB serum and could be dispensed in an automated fashion to polyolefin bags via a sample port with 1000-1500 U/ml IL-2. After 3-4 days of culture in 5% CO2 at 37 degrees C, activated cells from the bags were harvested and washed in a closed system using the continuous flow cell separator. Cell yield from the harvest was 79.2 +/- 5.4% in the automated system compared to 64.9 +/- 5.0% in the standard procedure using manual harvest of roller bottles (P less than 0.01). Lytic capacity of the cells against fresh human tumor in a 4 h 51Cr release assay was equivalent in cells processed either by the automated or the conventional manual method. The advantages of a closed system include decreased potential for microbial contamination and reduced labor and capital equipment costs. This technique may be easily adapted for use with other cell collection and culture systems.     

Virtual Rhesus Labyrinth Model Predicts Responses to Electrical Stimulation Delivered by a Vestibular Prosthesis

Journal of the Association for Research in Otolaryngology - To better understand the spread of prosthetic current in the inner ear and to facilitate design of electrode arrays and stimulation...     

Antibody competition studies with gold-labelling immunoelectron microscopy

Competitive studies, involving neutralizing monoclonal antibodies (NTmAbs) to outercoat proteins of Akabane virus were performed by immunoelectron microscopy. The experiments were designed to determine whether the NTmAbs were directed against the same or spatially different epitopes. Characteristics of NTmAbs in direct and indirect gold-labelling studies were determined. It was found that the protein A method gave cross-contamination of the immuno-gold complexes whereas direct conjugation of the NTmAbs to gold probes gave clean, specific and intense labelling. Analysis of dilution curves confirmed that saturation of antigenic sites did not occur and secondly determined the optimum working dilutions for the conjugated probes. The data generated in the preliminary studies enabled reliable results to be obtained from the double-labelling competitive experiment. We found that the 2 NTmAbs were directed to either the same epitope or to 2 separate but neighbouring epitopes where the binding of one NTmAb inhibited the binding of the second. The results demonstrate that if reliable data is to be obtained in double-labelling immunoelectron microscopical studies then experiments must be meticulously designed.     

Subtalar dislocation: Evaluation and management in the emergency department

Subtalar dislocations are sufficiently uncommon to be unfamiliar but require appropriate recognition and management to effect a good outcome. These dislocations benefit from urgent reduction that is essential to limiting sustained disability. Most can be reduced by closed manipulation at the time of presentation. Three cases of subtalar dislocations are presented followed by a discussion of the subject.     

Cyclic AMP levels in purified rat adrenal zonae fasciculata and reticularis cells and the effect of adrenocorticotrophic hormone

Cyclic AMP levels were measured in combined cells and supernatant fraction from incubations of dispersed rat adrenal zona fasciculata and zona reticularis cell preparations purified by unit gravity sedimentation. These measurements were correlated with deoxycorticosterone (DOC) and corticosterone outputs from the cells in the presence or absence of ACTH. Similar measurements of cyclic AMP outputs were made for unpurified dispersed, decapsulated rat adrenal cell preparations and they were found to correspond to previously reported measurements made by other workers on such preparations. The response of the purest zona reticularis cells to ACTH in terms of cyclic AMP output was 28-fold lower than that of the purest zona fasciculata cells (compared with a fivefold lower DOC output and a 20-fold lower corticosterone output) and the response to ACTH of the mixed-cell preparations was related to the number of zona fasciculata cells in the preparation, i.e. the greater the proportion of zona fasciculata cells in the preparation the greater the response in terms of both outputs of cyclic AMP and of either of the two steroids measured. This correlation is in accordance with the theory that cyclic AMP may be the secondary messenger for both zona fasciculata and zona reticularis cells of the rat adrenal cortex in mediating the response to an ACTH stimulus.