Genetic continuity and change among the Indigenous peoples of California.

Before the colonial period, California harboured more language variation than all of Europe, and linguistic and archaeological analyses have led to many hypotheses to explain this diversity1. We report genome-wide data from 79 ancient individuals from California and 40 ancient individuals from Northern Mexico dating to 7,400-200 years before present (BP). Our analyses document long-term genetic continuity between people living on the Northern Channel Islands of California and the adjacent Santa Barbara mainland coast from 7,400 years BP to modern Chumash groups represented by individuals who lived around 200 years BP. The distinctive genetic lineages that characterize present-day and ancient people from Northwest Mexico increased in frequency in Southern and Central California by 5,200 years BP, providing evidence for northward migrations that are candidates for spreading Uto-Aztecan languages before the dispersal of maize agriculture from Mexico2-4. Individuals from Baja California share more alleles with the earliest individual from Central California in the dataset than with later individuals from Central California, potentially reflecting an earlier linguistic substrate, whose impact on local ancestry was diluted by later migrations from inland regions1,5. After 1,600 years BP, ancient individuals from the Channel Islands lived in communities with effective sizes similar to those in pre-agricultural Caribbean and Patagonia, and smaller than those on the California mainland and in sampled regions of Mexico.

Compatibility of medications with intravenous lipid emulsions: Effects of simulated Y-site mixing.

PURPOSE: To determine the physical intravenous Y-site compatibility of 19 commonly used medications at pediatric concentrations with 3 different types of lipid emulsion. METHODS: Medications at commonly used pediatric concentrations were mixed in a 1:1 ratio with lipid emulsions (Intralipid, Nutrilipid, and Smoflipid) and incubated at room temperature for 4 hours to simulate Y-site administration. Each sample was then diluted with particle-free water and analyzed using the analytical technique of light obscuration recommended in United States Pharmacopeia (USP) general information chapter 729 (USP <729>). Physical compatibility was determined by measuring the percentage of fat residing in globules larger than 5 µm (PFAT5) per USP <729> recommendations. RESULTS: Most combinations tested were physically compatible based on USP <729> regulations. Incompatibilities differed for the different brands of lipid emulsion. The two combinations that met USP <729> criteria for physical incompatibility were cisatracurium 2 mg/mL with Intralipid and gentamicin 2 mg/mL with Smoflipid. CONCLUSION: Three different lipid emulsions were physically compatible at the Y site with the majority of medications tested. Data regarding Y-site compatibility for one lipid emulsion product cannot be safely extrapolated to another without additional testing.

Living with epilepsy in adolescence-A qualitative study of young people's experiences in Singapore: Peer socialization, autonomy, and self-esteem.

BACKGROUND: Systematic reviews of quantitative research on the effects of childhood epilepsy have established its association with higher levels of psychiatric diagnosis, externalizing and internalizing problems, lower health-related quality of life, social competence, and poorer academic achievements, compared with their peers. However, much less is known about young people's experiences of living with epilepsy and its impact on their development from their own perspectives. METHODS: Semistructured interviews were conducted with 15 young people aged between 13 and 16 years. Participants were recruited as part of a larger mixed methods study examining individual and family influences on outcomes for young people with epilepsy. These young people attended an epilepsy clinic in KK Women's and Children's Hospital, Singapore. The framework approach to data management and analyses involved both inductive and deductive generation of themes. RESULTS: Findings from young people's interviews provided in-depth descriptions of stressful circumstances encountered. Interconnectedness between severity of the impairment and its impact on key developmental tasks, such as independence, autonomy, and social development, were emphasized. Seizures and illness-related demands disrupted their day-to-day functioning and challenged their abilities to meet these tasks. In addition to these impairment effects, young people's experiences of social exclusion were also affected by social and environmental factors, which act as systemic barriers to participation. In turn, this has an effect on their self-esteem. Nevertheless, young people reported positive experiences, such as support from both family and friends, which served as protective factors against the stress of living with a chronic medical condition. CONCLUSION: The demands of epilepsy affect various domains of young people's lives. In order to obtain a holistic understanding of young people's inclusion or exclusion to participation, it is necessary to consider impairment effects, barriers to doing, and barriers to being.

Immunogenicity of Structurally Perturbed Hen Egg Lysozyme Adsorbed to Silicone Oil Microdroplets in Wild-Type and Transgenic Mouse Models.

Silicone oil microdroplets may act as adjuvants, promoting unwanted immune responses against both foreign and self-proteins. Proteins often unfold upon adsorption to silicone oil microdroplets, but it is unclear how such unfolding might affect the immune response. In this study, we found that hen egg lysozyme (HEL) readily adsorbed to silicone oil microdroplets and perturbed the conformation of HEL. We compared the immune response to injections of HEL formulated in the presence and absence of silicone oil microdroplets in both wild-type mice and transgenic littermates that express a soluble form of HEL (sHEL), thus rendering them immunologically tolerant to this nominal self-antigen. Following 2 subcutaneous injections of a HEL formulation containing silicone oil microdroplets, wild-type mice exhibited a stronger IgG1 antibody response against HEL compared to the response in wild-type mice that administered an oil-free HEL formulation. However, when HEL was subcutaneously administered to sHEL-transgenic mice, immunological tolerance to sHEL was not broken in the presence of silicone oil microdroplets. Thus, although structural perturbations in proteins adsorbed to silicone oil microdroplets may augment the immune response, in the case of endogenously expressed proteins, such structural perturbations may not be sufficient to result in a breach of immunological tolerance.

Silicone Oil Microdroplets Can Induce Antibody Responses Against Recombinant Murine Growth Hormone in Mice.

Therapeutic protein products can cause adverse immune responses in patients. The presence of subvisible particles is a potential contributing factor to the immunogenicity of parenterally administered therapeutic protein formulations. Silicone oil microdroplets, which derive from silicone oil used as a lubricating coating on barrels of prefilled glass syringes, are often found in formulations. In this study, we investigated the potential of silicone oil microdroplets to act as adjuvants to induce an immune response in mice against a recombinant murine protein. Antibody responses in mice to subcutaneous injections of formulations of recombinant murine growth hormone (rmGH) that contained silicone oil microdroplets were measured and compared to responses to oil-free rmGH formulations. When rmGH formulations containing silicone oil microdroplets were administered once every other week, anti-rmGH antibodies were not detected. In contrast, mice exhibited a small IgG1 response against rmGH when silicone oil-containing rmGH formulations were administered daily, and an anti-rmGH IgM response was observed at later time points. Our findings showed that silicone oil microdroplets can act as an adjuvant to promote a break in immunological tolerance and induce antibody responses against a recombinant self-protein.

In Vivo Analysis of the Potency of Silicone Oil Microdroplets as Immunological Adjuvants in Protein Formulations.

Subvisible particles in a therapeutic protein product may act as adjuvants to promote unwanted immune responses against the protein. Silicone oil is used as a lubricant in prefilled syringes, and microdroplets of silicone oil are often detected in protein formulations expelled from prefilled syringes. In order to test the adjuvant potency of silicone oil microdroplets, antibody responses in mice to subcutaneous injections of formulations of ovalbumin (OVA) that contained silicone oil microdroplets were measured. These responses were compared against responses to oil-free OVA formulations and to OVA formulations that contained microparticulate aluminum hydroxide ("alum"), the common vaccine adjuvant. When administered with high concentrations of silicone oil microdroplets, OVA formulations elicited strong anti-OVA IgG1 and IgG2a antibody responses. These responses were equivalent to those observed when alum microparticles were added to OVA formulations, suggesting that silicone oil can act as a potent adjuvant. However, when OVA formulations were prepared with lower levels of silicone oil that had been obtained directly from commercial siliconized syringes, the anti-OVA antibody response was not enhanced significantly compared with responses against OVA alone.

Characterization and quantitation of aggregates and particles in interferon-ß products: potential links between product quality attributes and immunogenicity.

Interferon-ß (IFN-ß) products have been used for many years in the treatment of multiple sclerosis and include recombinant IFN-ß-1b (Betaseron®) and IFN-ß-1a (Avonex® and Rebif®). All three products lead to the formation of neutralizing antibodies (NAbs) and resulting loss of efficacy in patients but to different extents. Across several clinical trials, the reported rates of neutralizing-antibody formation were 22%-47% (Betaseron®), 5%-35% (Rebif®), and 2%-13% (Avonex®). In the current study, all products were purchased from the pharmacy and aggregates were characterized and/or quantified using size-exclusion chromatography (SEC), analytical ultracentrifugation, gel electrophoresis, and dot-blotting immunoassays. Particle characterization and counting were performed using microflow imaging, particle tracking analysis, and resonant mass measurement. Betaseron® and Rebif®, which are formulated with human serum albumin, had the greatest amount of aggregated protein and particles (e.g., 9%-15% high molecular weight species by SEC and >100,000 particles/mL by flow imaging). Avonex® was found to have the least amount of aggregated protein, with >95% monomer content by both SEC and analytical ultracentrifugation, and the particles detected in Avonex® were determined to be primarily silicone oil droplets. These results strongly suggest that protein aggregate and particle contents are key product quality attributes in a given product's propensity to elicit the production of NAbs in patients.

Dose effects of relaxation practice on immune responses in women newly diagnosed with breast cancer: an exploratory study.

PURPOSE/OBJECTIVES: To determine the dose effects of relaxation practice on immune responses and describe the types of relaxation techniques preferred and the extent of relaxation practice over 10 months. DESIGN: Descriptive, prospective, repeated measures. SETTING: An interdisciplinary breast clinic at a university-affiliated comprehensive cancer center in the United States. SAMPLE: 49 women with newly diagnosed breast cancer and undergoing adjuvant therapy who participated in a stress management intervention. METHODS: Relaxation practice was assessed twice a month for 10 months with immune measurements (e.g., natural killer cell activity; lymphocyte proliferation; interferon [IFN]-γ; interleukin [IL]-2, -4, -6, and -10) at the beginning and end of 10-month practice. MAIN RESEARCH VARIABLES: Relaxation practice (representing the concepts of stress and adherence), relaxation technique, and immune response. FINDINGS: After adjusting for covariates, the extent of relaxation practice significantly contributed to the variance of natural killer cell activity, lymphocyte proliferation, IL-4, and IL-10 responses in a positive direction; the higher the relaxation practice, the higher the immune responses. In comparison, IFN-γ, IL-2, and IL-6 responses were not affected. The deep-breathing method was most preferred by participants, followed by progressive relaxation and imagination or visualization. The mean weekly frequency of relaxation practice was 5.29 (SD = 3.35), and the mean duration of relaxation practice was 19.16 (SD = 10.81) minutes per session. CONCLUSIONS: Persistent relaxation practice may have positive effects on multiple immune responses in a dose-dependent manner. IMPLICATIONS FOR NURSING: Allowing the choice of preferred techniques and emphasizing the importance of long-term adherence, a relaxation program may need to be routinely offered to women under high stress.

Role of T2* magnetic resonance in monitoring iron chelation therapy.

The monitoring of chelation therapy is a very important part of the management of transfusion-dependent patients. Classical methods of monitoring iron loading are either unreliable or unable to detect important myocardial siderosis which can predispose to the development of cardiac complications such as heart failure. The development of the T2* technique using cardiovascular magnetic resonance has allowed clinicians to have a reliable method for measuring cardiac iron to guide chelation therapy. T2* can identify early those patients who are at risk of developing cardiac complications, enabling personalised, tailored therapy to avoid potential problems.

Influence of protein conformation and adjuvant aggregation on the effectiveness of aluminum hydroxide adjuvant in a model alkaline phosphatase vaccine.

The mechanism(s) of the enhancement of the immune response by addition of aluminum salt adjuvants to parenterally administered protein-based vaccines is still the subject of debate. It has been hypothesized, however, that destabilization of the antigen structure on the surface of the adjuvant may be important for eliciting immune response. Also, it has been suggested that immune response to adjuvanted vaccines is reduced if the adjuvant particles become aggregated before administration because of processing steps such as freeze-drying. In this study, we tested these hypotheses and examined the immune response in a murine model to various liquid, freeze-dried, and spray freeze-dried formulations of a model vaccine, bovine intestinal alkaline phosphatase adsorbed on aluminum hydroxide. Enzymatic activity of the alkaline phosphatase was used as a sensitive indicator of intact native antigen structure. By manipulating the secondary drying temperature during lyophilization, vaccines were produced with varying levels of alkaline phosphatase enzymatic activity and varying degrees of adjuvant aggregation, as assessed by particle size distribution. Anti-alkaline phosphatase titers observed in immunized mice were independent of both the antigen's retained enzymatic activity and the vaccine formulation's mean particle diameter.

Effects of solution conditions and surface chemistry on the adsorption of three recombinant botulinum neurotoxin antigens to aluminum salt adjuvants.

Botulinum neurotoxin (BoNT) is a biological warfare threat. Protein antigens have been developed against the seven major BoNT serotypes for the development of a recombinant protein vaccine. This study is an evaluation of adsorption profiles for three of the recombinant protein antigens to aluminum salt adjuvants in the development of a trivalent vaccine against BoNT. Adsorption profiles were obtained over a range of protein concentrations. The results document that charge-charge interactions dominate the adsorption of antigen to adjuvant. Optimal conditions for adsorption were determined. However, potency studies and solution stability studies indicated the necessity of using aluminum hydroxide adjuvant at low pH. To improve the adsorption profiles to AlOH adjuvant, phosphate ions were introduced into the adsorption buffers. The resulting change in the adjuvant chemistry led to an improvement of adsorption of the BoNT antigens to aluminum hydroxide adjuvant while maintaining potency. Competitive adsorption profiles were also determined, and showed changes in maximum adsorption from mixed solutions compared to adsorption from individual protein solutions. The adsorption profiles for each protein varied due to differences in adsorption mechanism and affinity for the adjuvant surface. These results emphasize the importance of evaluating competitive adsorption in the development of multivalent vaccine products.