Sodium/myo-Inositol Transporters: Substrate Transport Requirements and Regional Brain Expression in the TgCRND8 Mouse Model of Amyloid Pathology

Inositol stereoisomers, myo- and scyllo-inositol, are known to enter the brain and are significantly elevated following oral administration. Elevations in brain inositol levels occur across a concentration gradient as a result of active transport from the periphery. There are two sodium/myo-inositol transporters (SMIT1, SMIT2) that may be responsible for regulating brain inositol levels. The goals of this study were to determine the effects of aging and Alzheimer's disease (AD)-like amyloid pathology on transporter expression, to compare regional expression and to analyze substrate requirements of the inositol transporters. QPCR was used to examine expression of the two transporters in the cortex, hippocampus and cerebellum of TgCRND8 mice, a mouse model of amyloid pathology, in comparison to non-transgenic littermates. In addition, we examined the structural features of inositol required for active transport, utilizing a cell-based competitive uptake assay. Disease pathology did not alter transporter expression in the cortex or hippocampus (p>0.005), with only minimal effects of aging observed in the cerebellum (SMIT1: F2,26 = 12.62; p = 0.0002; SMIT2: F2,26 = 8.71; p = 0.0015). Overall, brain SMIT1 levels were higher than SMIT2, however, regional differences were observed. For SMIT1, at 4 and 6 months cerebellar SMIT1 levels were significantly higher than cortical and hippocampal levels (p<0.05). For SMIT2, at all three ages both cortical and cerebellar SMIT2 levels were significantly higher than hippocampal levels (p<0.05) and at 4 and 6 months of age, cerebellar SMIT2 levels were also significantly higher than cortical levels (p<0.05). Inositol transporter levels are stably expressed as a function of age, and expression is unaltered with disease pathology in the TgCRND8 mouse. Given the fact that scyllo-inositol is currently in clinical trials for the treatment of AD, the stable expression of inositol transporters regardless of disease pathology is an important finding

Pregnancy weight gain and breast cancer risk

BACKGROUND: Elevated pregnancy estrogen levels are associated with increased risk of developing breast cancer in mothers. We studied whether pregnancy weight gain that has been linked to high circulating estrogen levels, affects a mother's breast cancer risk. METHODS: Our cohort consisted of women who were pregnant between 1954–1963 in Helsinki, Finland, 2,089 of which were eligible for the study. Pregnancy data were collected from patient records of maternity centers. 123 subsequent breast cancer cases were identified through a record linkage to the Finnish Cancer Registry, and the mean age at diagnosis was 56 years (range 35 – 74). A sample of 979 women (123 cases, 856 controls) from the cohort was linked to the Hospital Inpatient Registry to obtain information on the women's stay in hospitals. RESULTS: Mothers in the upper tertile of pregnancy weight gain (>15 kg) had a 1.62-fold (95% CI 1.03–2.53) higher breast cancer risk than mothers who gained the recommended amount (the middle tertile, mean: 12.9 kg, range 11–15 kg), after adjusting for mother's age at menarche, age at first birth, age at index pregnancy, parity at the index birth, and body mass index (BMI) before the index pregnancy. In a separate nested case-control study (n = 65 cases and 431 controls), adjustment for BMI at the time of breast cancer diagnosis did not modify the findings. CONCLUSIONS: Our study suggests that high pregnancy weight gain increases later breast cancer risk, independently from body weight at the time of diagnosis

Evolutionary Rate Covariation Identifies New Members of a Protein Network Required for Drosophila melanogaster Female Post-Mating Responses

Seminal fluid proteins transferred from males to females during copulation are required for full fertility and can exert dramatic effects on female physiology and behavior. In Drosophila melanogaster, the seminal protein sex peptide (SP) affects mated females by increasing egg production and decreasing receptivity to courtship. These behavioral changes persist for several days because SP binds to sperm that are stored in the female. SP is then gradually released, allowing it to interact with its female-expressed receptor. The binding of SP to sperm requires five additional seminal proteins, which act together in a network. Hundreds of uncharacterized male and female proteins have been identified in this species, but individually screening each protein for network function would present a logistical challenge. To prioritize the screening of these proteins for involvement in the SP network, we used a comparative genomic method to identify candidate proteins whose evolutionary rates across the Drosophila phylogeny co-vary with those of the SP network proteins. Subsequent functional testing of 18 co-varying candidates by RNA interference identified three male seminal proteins and three female reproductive tract proteins that are each required for the long-term persistence of SP responses in females. Molecular genetic analysis showed the three new male proteins are required for the transfer of other network proteins to females and for SP to become bound to sperm that are stored in mated females. The three female proteins, in contrast, act downstream of SP binding and sperm storage. These findings expand the number of seminal proteins required for SP's actions in the female and show that multiple female proteins are necessary for the SP response. Furthermore, our functional analyses demonstrate that evolutionary rate covariation is a valuable predictive tool for identifying candidate members of interacting protein networks. © 2014 Findlay et al

Assessing patient-centered care in patients with chronic health conditions attending chiropractic practice: protocol for a mixed-methods study

BACKGROUND: The management of chronic health conditions increasingly requires an organized, coordinated, and patient-centered approach to care. The Chronic Care Model (CCM) has been adopted in primary care to improve care delivery for those with chronic health conditions. Chiropractors manage chronic health conditions; however, little is known if such care is patient-centered. The primary aim of this study is to determine to what extent chiropractic patients with chronic health conditions perceive their care is patient-centred. We will assess concordance with the CCM using the Patient Assessment of Chronic Illness Care (PACIC) survey in study patients. We will also explore perception of how patient-centered the care provided by chiropractors is for those with chronic health conditions according to patients and chiropractors. METHODS/DESIGN: We will use a sequential mixed methods design with quantitative priority. In the quantitative component patients will complete a written questionnaire providing sociodemographic, health status, and health care interaction information, all of which will serve as the independent variables. Patients will also complete a modified version of the PACIC; the average overall score will be the dependent variable. In the qualitative component semi-structured interviews and focus groups with patients and chiropractors will be conducted. A pilot study will be conducted to determine if the modified PACIC will perform adequately in measuring concordance with the CCM for chiropractic care. Pilot testing will also allow for assessment of the interview and focus groups guides. Variables found to be significantly associated will be included in a multivariate linear regression analysis to identify significant predictors of the dependent variable. Qualitative data will be analyzed using an inductive thematic analysis to provide meaning to the quantitative results. DISCUSSION: There is a paucity of research describing the extent to which chiropractic care for patients with chronic health conditions is concordant with the CCM. This study will examine this relationship and the perceptions and experiences of patients and chiropractors regarding how patient-centered chiropractic care is for these patients