Unilateral vestibular schwannoma and meningiomas in a patient with PIK3CA-related segmental overgrowth: Co-occurrence of mosaicism for 2 rare disorders.

A 28-year-old female with PIK3CA-related segmental overgrowth presented with headaches. She also had a unilateral vestibular schwannoma (VS), as well as 3 small (<2 cm) meningiomas, which according to the Manchester consensus diagnostic criteria for neurofibromatosis 2 (NF2) is sufficient for a clinical diagnosis. Analysis of blood revealed a mosaic PIK3CA c.2740G>A (p.Gly914Arg) mutation, confirming the diagnosis of PIK3CA-related overgrowth, but no mutations in NF2 were detected. Although VS has not previously been reported in PIK3CA-related segmental overgrowth, meningiomas have, raising the question of whether this patient's VS and meningiomas represent coincidental NF2 or phenotypic extension of her overgrowth syndrome. Genetic analysis of the VS revealed a heterozygous NF2 mutation c.784C>T (p.Arg262Ter) and loss of a portion of 22q, including NF2, SMARCB1, and LZTR1 genes. These results suggest that the patient has 2 different mosaic disorders, NF2 and PIK3CA-related overgrowth. The PIK3CA mutation was also present in the VS. Confirmation of the clinical diagnosis of mosaic NF2 in this patient has implications for monitoring and highlights the possibility of co-occurrence of mosaicism for multiple rare disorders in a single patient.

Computational design of mechanically coupled axle-rotor protein assemblies.

Natural molecular machines contain protein components that undergo motion relative to each other. Designing such mechanically constrained nanoscale protein architectures with internal degrees of freedom is an outstanding challenge for computational protein design. Here we explore the de novo construction of protein machinery from designed axle and rotor components with internal cyclic or dihedral symmetry. We find that the axle-rotor systems assemble in vitro and in vivo as designed. Using cryo-electron microscopy, we find that these systems populate conformationally variable relative orientations reflecting the symmetry of the coupled components and the computationally designed interface energy landscape. These mechanical systems with internal degrees of freedom are a step toward the design of genetically encodable nanomachines.

Bacillus cereus induces permeability of an in vitro blood-retina barrier.

Most Bacillus cereus toxin production is controlled by the quorum-sensing-dependent, pleiotropic global regulator plcR, which contributes to the organism's virulence in the eye. The purpose of this study was to analyze the effects of B. cereus infection and plcR-regulated toxins on the barrier function of retinal pigment epithelium (RPE) cells, the primary cells of the blood-retina barrier. Human ARPE-19 cells were apically inoculated with wild-type or quorum-sensing-deficient B. cereus, and cytotoxicity was analyzed. plcR-regulated toxins were not required for B. cereus-induced RPE cytotoxicity, but these toxins did increase the rate of cell death, primarily by necrosis. B. cereus infection of polarized RPE cell monolayers resulted in increased barrier permeability, independent of plcR-regulated toxins. Loss of both occludin and ZO-1 expression occurred by 8 h postinfection, but alterations in tight junctions appeared to precede cytotoxicity. Of the several proinflammatory cytokines analyzed, only interleukin-6 was produced in response to B. cereus infection. These results demonstrate the deleterious effects of B. cereus infection on RPE barrier function and suggest that plcR-regulated toxins may not contribute significantly to RPE barrier permeability during infection.

Sulfotransferase gene copy number variation: pharmacogenetics and function.

Pharmacogenetics is the study of the role of inheritance in variation to drug response. Drug response phenotypes can vary from adverse drug reactions at one end of the spectrum to equally serious lack of the desired effect of drug therapy at the other. Many of the current important examples of pharmacogenetics involve inherited variation in drug metabolism. Sulfate conjugation catalyzed by cytosolic sulfotransferase (SULT) enzymes, particularly SULT1A1, is a major pathway for drug metabolism in humans. Pharmacogenetic studies of SULT1A1 began over a quarter of a century ago and have advanced from biochemical genetic experiments to include cDNA and gene cloning, gene resequencing, and functional studies of the effects of single nucleotide polymorphisms (SNPs). SNP genotyping, in turn, led to the discovery of functionally important copy number variations (CNVs) in the SULT1A1 gene. This review will briefly describe the evolution of our understanding of SULT1A1 pharmacogenetics and CNV, as well as challenges involved in utilizing both SNP and CNV data in an attempt to predict SULT1A1 function. SULT1A1 represents one example of the potential importance of CNV for the evolving disciplines of pharmacogenetics and pharmacogenomics.

Fructose and behavior: does fructose influence food intake and macronutrient selection?

Fructose, as compared with other sugars, may have a suppressant effect on subsequent food intake and may result in a different selection of macronutrients. The research investigating these effects and the possible underlying mechanisms of action is reviewed. These mechanisms include fructose's effects on the rate of gastric emptying, concentrations of plasma glucose and insulin, and hepatic metabolism. The research is not conclusive. Questions that remain to be examined more thoroughly are the time course of fructose's effects on food intake and macronutrient selection in the short-term, and effects of long-term administration of fructose on these appetitive processes.

Psychosocial outcomes of breast-conserving surgery versus mastectomy: a meta-analytic review.

Effective breast-conserving surgical techniques for early-stage disease were developed to improve breast cancer patients' quality of life. The literature comparing the psychosocial sequelae of these newer treatments with mastectomy is ambiguous and shows an unexpected lack of substantial benefits. To clarify these inconsistencies, meta-analytic methods were used to summarize the findings of 40 investigations. Mean weighted effect sizes were calculated for 6 psychosocial outcomes. Modest advantages for breast-conserving surgery were identified for psychological, marital-sexual, and social adjustment; body/self-image; and cancer-related fears and concerns. Method of assignment to treatment and timing of assessment were relevant for some outcomes.

The effects of message framing on mammography utilization.

This experiment compared the effectiveness of gain-versus loss-framed messages to persuade women to obtain mammography screening. One hundred and thirty-three women 40 years and older and not adhering to current guidelines for obtaining mammography screening were assigned randomly to view either gain-framed (emphasizing the benefits of obtaining mammography) or loss-framed (emphasizing the risks of not obtaining mammography) persuasive videos that were factually equivalent. Attitudes and beliefs were measured before and immediately following the intervention. Mammography utilization was assessed 6 and 12 months later. Consistent with predictions based on prospect theory, women who viewed the loss-framed message were more likely to have obtained a mammogram within 12 months of the intervention. These findings suggest that loss-framed messages may have an advantage in the promotion of detection behaviors such as mammography.

Can methodological features account for patient-treatment matching findings in the alcohol field?

OBJECTIVE: Despite enthusiasm for the potential of matching patients to alcohol treatments to improve outcomes, consistent findings have not emerged. This review considers the extent to which methodological factors may account for the pattern of findings from research on Patient x Alcohol Treatment interactions. METHOD: We focused on 55 studies that compared more than one type of alcohol treatment and included formal statistical tests for interactions. We examined four predictors of the number of significant interactions found in the 55 studies: (1) the number of statistical tests for interactions conducted, (2) the average number of participants, (3) whether or not participants were randomized to treatment and (4) the proportion of tested interactions that were hypothesis- or rationale-driven, as opposed to exploratory. RESULTS: Only the number of statistical tests for interactions predicted the number of patient-treatment interactions identified per study (zero-order r = 0.47; r2 = 0.22). A substantial number of tests for interactions (43) was conducted, on average, per study. Only a minority of the studies (33%) included enough participants to have a reasonable probability (0.80) of identifying a medium-sized matching effect. CONCLUSIONS: Drawing general conclusions regarding matching patients to alcohol treatments is hampered because Type I error has contributed to the matches identified, studies in this area are often underpowered, and the combinations of patient and treatment variables that have been tested are few relative to the numerous possible combinations. To be productive, future research will need to focus on patients at the extremes of matching dimensions and on distinct treatments. (J Stud. Alcohol 62: 62-73, 2001)

Development of bovine and porcine embryonic teratomas in athymic mice.

Inner cell masses (ICM) and embryonic discs from bovine and porcine blastocysts of various ages were transplanted under the kidney capsule of athymic (nude) mice to evaluate growth of teratocarcinomas containing both differentiated tissues and undifferentiated stem cells. Inner cell masses were isolated immunosurgically from Day 8, Day 9 and Day 10 porcine blastocysts and from Day 8, Day 10 and Day 12 bovine blastocysts. Embryonic discs were mechanically dissected from Day 11 and Day 12 porcine embryos and from Day 14 bovine embryos. Day 6 egg cylinders were dissected from BALB/C embryos and from hybrid embryos of a cross between BALB/C and an outbred strain of mouse. Two to four ICM, embryonic discs or egg cylinders were transplanted under the kidney capsule of each athymic host. After 8 weeks, graft hosts were killed and their tumors removed, fixed and prepared for histological and immunohistochemical examination. Embryonic teratomas developed at high frequency from murine egg cylinders and from Day 11 and Day 12 porcine and Day 14 bovine embryos. Tumors were observed only infrequently from younger bovine and porcine blastocysts. Murine embryonic tumors were composed of numerous differentiated cell types of ectodermal, mesodermal and endodermal origins, but representation of the three embryonic germ layers was somewhat more restricted in bovine and porcine embryonic tumors. No undifferentiated stem cells were detected in tumors of any of the three species. These results demonstrate that teratomas will develop from bovine and porcine embryos when grafted to an immunocompromised host, but the presence of undifferentiated teratocarcinoma stem cells from these species has yet to be achieved.

Facilitating the shift to population-based public health programs: innovation through the use of framework and logic model tools.

Program planning and evaluation are critical steps in using a population health approach. This paper outlines how logic models have been adapted within a health promotion framework to guide public health programs and facilitate program description. It is important that we take the time to describe clearly what we are doing, reflect on practice and elaborate the conceptual base for the new public health programs so that we can evaluate the impact of our work. Ongoing research is required to identify appropriate and measurable indicators that capture the process, as well as the outcome, of population-based health promotion.

Evidence against humoral immune attack as the cause of sheep-goat interspecies and hybrid pregnancy failure in the doe.

The failure of interspecies and hybrid pregnancies between the domestic sheep (Ovis aries) and goat (Capra hircus) is not completely understood. The sheep-goat hematopoietic chimera is a unique model for studying the role of the maternal immune response in failure of interspecies and hybrid pregnancies between these species. Hematopoietic chimeras were created by in utero transplantation of sheep fetal liver cells into goat fetuses. The resulting chimeric females were recipients of sheep demi-embryos genetically identical to their sheep cells and/or were bred to a ram to create a hybrid pregnancy. Pregnancy sera were analyzed for the presence of anti-species antibodies (Ab) using a lymphocyte microcytotoxicity assay. None of the concepti survived to term. Gross and histological evaluations of two interspecies sheep concepti revealed abnormal placentome formation. The humoral immune response of several hematopoietic chimeras to the challenging concepti differed from control animals. We observed delayed onset of Ab production, low and absent titers, and persistent Ab titers with delayed fetal death. Ultrasonography typically revealed normal fetal development associated with high volumes of placental fluids and retarded placentome development. We conclude that fetal death was associated with abnormal placental development that was not the result of maternal humoral immune attack.

Fetal leukocyte trafficking as a stimulus for the production of maternal antibodies in the goat.

The production of antibodies during pregnancy or after parturition is a natural occurrence in many mammalian species. Fetal cells have been detected in the peripheral blood of women and mice and are thought to be the immune stimulus for antibody production. The aim of this study was to investigate if the production of maternal anti-fetal antibodies during ruminant pregnancy is the result of fetal leukocyte trafficking across the placenta. Maternal pregnancy serum was collected from 94 does whose fetuses received sheep hematopoietic stem cells via in utero transplantation at 49 to 62 d of gestation. Serum samples were collected before surgery and at weekly intervals throughout gestation. A lymphocyte microcytotoxicity assay was used to screen the serum samples from does that carried chimeric fetuses to term (n = 75). Of these 75 does, 28 parous does had presurgery serum that contained alloreactive antibodies. Nine of the 75 does had nonreactive presurgery serum, but they produced alloreactive antibody titers during gestation. Xenoreactive antibodies were detected in the pregnancy sera from 2 of the 75 does tested. Hemolytic assays confirmed the species-specificity of the xenoreactive serum from these 2 does. In view of the fact that hematopoietic cells were the only source of anti-sheep antibody stimulation in this model, we propose that fetal leukocyte trafficking does take place across the caprine placenta.

Successful pregnancy in goats carrying their genetically identical conceptus.

Mammalian pregnancies are naturally allogeneic, but syngeneic pregnancies have been carried to term in laboratory animal species. The need for maternal immune recognition during mammalian pregnancy is still unclear. Allogeneic pregnancies are protected from maternal immune attack by the nature of the trophoblast and its interactions with maternal tissues at the maternal-fetal interface. Syngeneic pregnancy models and the success of pregnancies in immunosuppressed mice challenge the necessity of a maternal immune response in mammals. This study was designed to investigate if outbred, domestic sheep and goats can successfully establish and maintain a syngeneic pregnancy. Embryo splitting and cryopreservation techniques were used to enable sheep and goat demi-embryos to be transferred to genetically identical females. Allogeneic pregnancies were established from the transfer of demi-embryos subjected to the same manipulations to assess demi-embryo survival and pregnancy rates under conventional immune compatibility conditions. Syngeneic pregnancies were established and carried to term in goats (2/11) but not in sheep (0/24). Microsatellite and DNA fingerprinting analyses confirmed that each kid was a genetically identical twin to the female that carried it to term. Our results demonstrated that genetic disparity is not required for the establishment and maintenance of pregnancy in goats, but our results were inconclusive for sheep.

Progestin implants can rescue demi-embryo pregnancies in goats: a case study.

Survival after transfer of demi-embryos (i.e., half-embryos produced by embryo splitting) to recipients usually is lower than survival after transfer of intact embryos. Reduced survival after demi-embryo transfer could be due to loss of viability after splitting, failure of a viable demi-embryo to prevent corpus luteum (CL) regression in the recipient female, or a combination of factors. From a retrospective analysis of pregnancy and embryo survival rates after demi-embryo transfer in sheep and goats, we report the rescue of caprine demi-embryo pregnancies in which CL regression occurred at the end of diestrus despite the presence of a viable conceptus in the uterus with progestin implants. Day 5 or 6 morulae and blastocysts were flushed from superovulated ewes and does and split into demi-embryos of approximately equal halves. Demi-embryos were either transferred fresh to synchronized recipients of the homologous species or frozen in liquid nitrogen. Approximately half of the recipient does and ewes were treated with norgestomet implants on Day 10 of the embryo transfer cycle and again 2 wk later. Serum collected on Day 25 from recipients with implants was assayed for progesterone to determine if a CL of pregnancy had been maintained. Pregnancy was diagnosed by ultrasonography on Day 35 of gestation. Corpus luteum regression occurred despite the presence of a viable conceptus in the uterus in 6 of 55 progestin-treated caprine demi-embryo recipients and in 0 of 66 ovine demi-embryo recipients. Five of the caprine pregnancies were maintained to term with norgestomet implants and produced 5 live kids. The sixth fetus, which was carried by a progestin implant-treated 8-mo-old doeling, died at approximately 50 d of gestation. These results suggest that, at least in goats, some demi-embryos may provide inadequate signaling for maternal recognition of pregnancy, and such pregnancies can be rescued with progestin treatment to the doe.

Predictors of social support and psychological distress in women with breast cancer.

This investigation sought to understand previous well-cited and worrisome findings that women treated for breast cancer with breast-conserving surgery compared to mastectomy experience less social support and more mood disturbance, and that social support from significant others erodes over time. Ninety-three women with breast cancer and a subset of their partners completed assessments at the time of surgical treatment and at 3 and 13 months post-treatment. Contrary to the previous findings, type of surgical treatment was not related to perceptions of social support or psychological functioning. Perceptions of social support and psychological distress decreased over time, and the discrepancy between recipients' and providers' judgments of available support increased over time. Low levels of physical functioning led to relative increases in social support, whereas high levels of psychological distress led to relative decreases in social support. Social support as rated by patients (but not their partners) was a significant predictor of changes in psychological distress.

Transdisciplinary work with psychology from a population health perspective: an illustration.

One of the important implications of a population health perspective in public health is an increase in the need for transdisciplinary ways of working. The Community Health Research Unit (CHRU) is presented as an example of an environment where psychology and psychologists work with other disciplines to conduct applied research in population health. Research activities were examined to identify how the disciplines collaborate and to provide evidence of successful interdisciplinary and transdisciplinary approaches which incorporate health psychology. The strengths and challenges of multi-, inter-, and transdisciplinary approaches were examined through a poll of CHRU members. Further, members' views about the contributions of psychology to their work were gathered. Issues of working with different disciplines in a transdisciplinary approach are highlighted and future directions are suggested.

Evaluation of a midwifery birthing center in the Canadian north.

An evaluation of a midwife-operated community birthing center was conducted to identify whether it would be safe, cost-effective, and psychologically and socially satisfying for Inuit women in one community in the Northwest Territories. Two nurse-midwives provided antenatal and postnatal care to all pregnant women and delivered those designated as 'low risk' for complications. Another community similar in size but with no community birthing was used for comparison of the three indices. Data were gathered on reproductive histories and pregnancy risk profiles of all women giving birth in a one-year period. The financial costs were calculated for those women transferred out to hospital for delivery and compared with those who stayed in the community. Pregnant women and their partners in both communities, health staff, and community members were interviewed for their feelings and concerns about the birthing services. Preliminary findings suggest that with experienced midwives community births are safe. A minimum of 25 births is required in the community for this project to be cost effective. The women who had their infants in the community expressed satisfaction for a number of reasons.