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PubMed2002

Prevalence of the fragile X syndrome in African-Americans.

Since the development of a molecular diagnosis for the fragile X syndrome in the early 1990s, several population-based studies in Caucasians of mostly northern European descent have established that the prevalence is probably between one in 6,000 to one in 4,000 males in the general population. Reports of increased or decreased prevalence of the fragile X syndrome exist for a few other world populations; however, many of these are small and not population-based. We present here the final results of a 4-year study in the metropolitan area of Atlanta, Georgia, establishing the prevalence of the fragile X syndrome and the frequency of CGG repeat variants in a large Caucasian and African-American population. Results demonstrate that one-quarter to one-third of the children identified with the fragile X syndrome attending Atlanta public schools are not diagnosed before the age of 10 years. Also, a revised prevalence for the syndrome revealed a higher point estimate for African-American males (1/2,545; 95% CI: 1/5,208-1/1,289) than reported previously, although confidence intervals include the prevalence estimated for Caucasians from this (1/3,717; 95% CI: 1/7,692-1/1,869) and other studies. Further population-based studies in diverse populations are necessary to explore the possibility that the prevalence of the fragile X syndrome differs among world populations.

Alleles↗
PubMed2004

Ethical issues in identifying and recruiting participants for familial genetic research.

Family-based research is essential to understanding the genetic and environmental etiology of human disease. The success of family-based research often depends on investigators' ability to identify, recruit, and achieve a high participation rate among eligible family members. However, recruitment of family members raises ethical concerns due to the tension between protecting participants' privacy and promoting research quality, and guidelines for these activities are not well established. The Cancer Genetics Network Bioethics Committee assembled a multidisciplinary group to explore the scientific and ethical issues that arise in the process of family-based recruitment. The group used a literature review as well as expert opinion to develop recommendations about appropriate approaches to identifying, contacting, and recruiting family members. We conclude that there is no single correct approach, but recommend a balanced approach that takes into account the nature of the particular study as well as its recruitment goals. Recruitment of family members should be viewed as part of the research protocol and should require appropriate informed consent of the already-enrolled participant. Investigators should inform prospective participants why they are being contacted, how information about them was obtained, and what will happen to that information if they decide not to participate. The recruitment process should also be sensitive to the fact that some individuals from families at increased genetic risk will have no prior knowledge of their risk status. These recommendations are put forward to promote further discussion about the advantages and disadvantages of various approaches to family-based recruitment. They suggest a framework for considering alternative recruitment strategies and their implications, as well as highlight areas in need of further empirical research.

Bioethics↗
PubMed2006

Differential inhibition of Wnt-3a by Sfrp-1, Sfrp-2, and Sfrp-3.

Secreted frizzled related proteins (Sfrps) are extracellular attenuators of Wnt signaling that play important roles in both embryogenesis and oncogenesis. Although Sfrps are generally thought to bind and sequester Wnts away from active receptor complexes, very little is known about the specificity of Sfrp family members for various Wnts. In the developing chick neural tube, sfrp-1, 2, and 3 transcripts are expressed in and adjacent to the dorsal neural tube, where Wnt-1 and Wnt-3a are expressed. To better define the possible roles of Sfrp-1, 2, and 3 in the neural tube, we first tested the ability of purified Sfrps to inhibit Wnt-3a-induced accumulation of beta-catenin in L cells. We find that both Sfrp-1 and Sfrp-2 can inhibit Wnt-3a activity while Sfrp-3 cannot. To determine where Sfrp-1 and Sfrp-2 impinge on the Wnt signaling pathway, we tested the ability of these Sfrps to inhibit Wnt signaling induced by the addition of LiCl, an inhibitor of GSK-3. Sfrp-1 and Sfrp-2 are unable to inhibit the accumulation of beta-catenin in LiCl-treated cells, suggesting that the ability of Sfrps to inhibit the accumulation of beta-catenin is GSK-3 dependent. We have further shown that Sfrp-2 inhibits the ability of ectopic Wnt-3a to stimulate proliferation in the developing chick neural tube. These results provide the framework for understanding how Sfrps function to regulate Wnt-3a activity in developing embryos and in cancer.

Animals↗
PubMed2006

Age-related expression of molecular regulators of hypertrophy and maturation in articular cartilage.

The purpose of this study was to determine changes in the expression of regulatory molecules in normal equine articular cartilage throughout development up to 18 months of age. The hypothesis was that expression of these regulatory molecules would decrease from birth to postpubescence. Cartilage was harvested from normal femoropatellar or scapulohumeral joints from 34 fresh horse cadavers. Horses were placed in four age groups [prenatal (n = 5); prepubertal, 0-6 months (n = 11); pubertal, 7-14 months (n = 13); and postpubertal, 15-18 months (n = 5)]. Indian hedgehog (Ihh), Gli1, Gli3, Patched1 (Ptc1), Smoothened (Smo), Noggin, bone morphogenetic protein-6 (BMP-6), BMP-2, parathyroid hormone-related peptide (PTHrP), and PTH/PTHrP receptor mRNA expression levels were evaluated by real-time quantitative PCR. Spatial tissue mRNA and protein expression was determined by in situ hybridization and immunohistochemistry. The expression of PTHrP decreased (p = 0.002) in the pubertal group, while PTH/PTHrP receptor expression significantly increased (p = 0.001). No significant difference was found between groups for Ihh (p = 0.6) or Smo (p = 0.3) expression. In contrast, there was significantly increased expression of Ptc1 (p = 0.006), Gli1 (p = 0.04), and Gli3 (p = 0.007) in the pubertal group, and Gli3 (p = 0.007) remained elevated in the postpubertal group. The expression of BMP-6 significantly increased from prenatal to postnatal groups (p = 0.03) while BMP-2 expression increased during puberty and postpuberty (p = 0.03). The changes in expression of hedgehog and BMP signaling molecules in articular cartilage during postnatal development have not been shown previously. The increased expression of hedgehog receptor and transcription factors during puberty may indicate maturation of the deep articular layer during this time period.

Aging↗
PubMed2006

Predictors of responses to psychotherapy referral of WTC utility disaster workers.

This study examined male utility disaster workers' responses to referral for trauma-specific psychotherapy. Among 328 workers offered referral for symptoms related to the World Trade Center (WTC) attacks during psychological screening, approximately 48% chose to accept, 28% chose to consider only, and 24% chose to decline. Analyses examined predisposing factors, i.e., age, race/ethnicity, marital status, education, previous mental health treatment, and previous disorder; as well as illness level; i.e., posttraumatic stress disorder (PTSD), depression, and general psychiatric distress; current treatment; and time of referral as predictors of referral response. PTSD (specifically reexperiencing and hyperarousal symptoms), depressive symptoms, and previous mental health treatment were positively associated with workers' accepting referral. Implications and limitations of these findings are discussed.

Humans↗
PubMedDate not supplied

A pilot study of group exercise training (GET) for women with primary breast cancer: feasibility and health benefits.

Evidence is accumulating for physical activity as an effective, well-tolerated, highly rewarding complementary behavioral intervention for enhancing quality of life (QOL) as well as fitness among individuals with chronic and even terminal illnesses. However, relatively few studies have examined the feasibility and potential health benefits of supervised, structured exercise programs for sedentary women with primary breast cancer. Forty women over the age of 45 with primary breast cancer participated in a course of group exercise training (GET) delivered in a structured format three times per week for 16 weeks. GET emphasizes physical activities that promote aerobic fitness, strength, and flexibility. Assessments of fitness/vigor and QOL were conducted prior to, during, and upon completion of the program. Results demonstrated that GET was feasible, safe, and well-tolerated. Moreover, the participants experienced significant health benefits over the course of the intervention in multiple dimensions of fitness/vigor (aerobic capacity, strength, flexibility) as well as QOL (increased positive affect, decreased distress, enhanced well-being, and improved functioning). Discussion highlights the need for inclusion of physical activity programs in comprehensive, complementary treatment regimes for breast cancer patients.

Adaptation, Psychological↗
PubMed2004

Informed consent for screening sigmoidoscopy in a Veterans Administration population.

PURPOSE: This study was performed to test the hypotheses that current consent methods may not convey the data that we imagine that they do, and that many patients may not want the data that we believe that we ought to provide. We also argue that excessive and unthinking emphasis on informed consent documentation may ignore real and important issues. METHODS: Fifty-nine male patients consecutively scheduled for screening sigmoidoscopy were interviewed before and after the procedure in a tertiary care academic health center. Chi-squared analysis was used to determine if the three independent variables of ethnicity, educational level, and previous sigmoidoscopy experience were able to discriminate various components of the informed consent process. RESULTS: Thirty-nine percent of patients could describe no indication other than doctor recommendation for the procedure. Although 86 percent of patients had heard of the word "polyp," 16 percent could not define it. Fifteen percent of patients could not pick out from a list subsequent steps to be taken in case of an abnormal examination. Although most patients could describe discomforts associated with the procedure, only 19 percent of patients mentioned bleeding and perforation as possible complications. Only 5 percent of patients knew any alternatives to sigmoidoscopy. No patient could explain risks and benefits of alternatives. Eighty-eight percent of patients could not identify their endoscopist, but this only bothered 13 percent. Ninety-three percent of patients were given an opportunity to ask questions, but only 22 percent actually did so. All patients signed the consent form, but only 14 percent of patients actually read all of it. Most patients, 97 percent, thought that they had enough information to proceed with the endoscopy. CONCLUSIONS: By traditional and classic standards, the patients in this study did not give informed consent. Yet, surprisingly, despite this lack of informed consent, most of the patients failed to ask further questions of their physicians and claimed that they had sufficient information to proceed with the procedure. This was the case across the three independent variables of ethnicity, educational level, and previous sigmoidoscopy experience.

Aged↗
PubMed2005

Women's attitudes toward testing for fragile X carrier status: a qualitative analysis.

Fragile X syndrome (FXS) is primarily due to a repeat expansion mutation found in the FMR1 X-linked gene. We have conducted a qualitative analysis of responses from women concerning their attitudes toward testing for carrier status of the fragile X mutation among reproductive-age women. We obtained responses from focus groups including women with and without FXS in their families. We found the following themes: (1) mothers of children with FXS have difficulty formulating their opinions on population screening because of their unique experiences surrounding their own carrier diagnosis and their relationship with their children with FXS, (2) the motivation for carrier testing and need for information differ by family history of FXS and parental status, and (3) the timing of carrier testing with respect to a woman's life stage dictates whether carrier information will be viewed as beneficial or detrimental. There was evidence that non-carrier women from the general population would be wholly unprepared for positive carrier results. These findings have significant implications for genetic counseling as well as for population screening.

Attitude↗
PubMed2004

Cost-effectiveness of herpes simplex virus type 2 serologic testing and antiviral therapy in pregnancy.

OBJECTIVE: The purpose of this study was to determine whether serologic testing for herpes simplex virus type 2 (HSV-2) in pregnant women and their partners is cost-effective. STUDY DESIGN: A decision analysis model was developed to investigate the cost-effectiveness of providing type-specific serologic testing at week 15 of pregnancy for all women unaware of their HSV-2 status, and offering antiviral suppressive therapy from week 36 until delivery to all seropositive women. This scenario was compared with current care, in which only a minority of women diagnosed with genital herpes (GH) receives antiviral suppressive therapy (AST). In a third scenario, testing is offered to partners of pregnant women who test seronegative, and antiviral suppressive therapy is offered to the partners who test seropositive. RESULTS: Compared with current care, offering testing and antiviral suppressive therapy to 100,000 pregnant women resulted in an incremental cost of $3.1 million, 15.7 fewer cases of neonatal herpes, 186 fewer cesarean deliveries, and an incremental cost per quality-adjusted life- year gained (QALY) of $18,680. Offering testing and suppressive therapy to both the pregnant women and their partners resulted in an increased cost of $8.6 million, 16.8 fewer cases of neonatal herpes, 192 fewer cesarean deliveries, and an incremental cost per QALY of $48,946 compared with no testing. CONCLUSION: Compared with commonly accepted benchmarks for cost-effectiveness (<$50,000/QALY), type-specific HSV-2 serologic testing of pregnant women may be a cost-effective strategy.

Adolescent↗
PubMed2006

The newborn screening educational gap: what prenatal care providers do compared with what is expected.

OBJECTIVE: The purpose of this evaluation was to examine prenatal care providers' knowledge of, attitudes towards, and barriers for providing information about newborn screening and tandem mass spectrometry (MS/MS) screening. STUDY DESIGN: We mailed a 12-question survey to 6197 prenatal care providers in California asking about their experiences with newborn and prenatal screening services. RESULTS: Although 4/5 of respondents believe newborn screening is very important for their patients, only 1/3 discuss it with all their patients. Over half believe either pediatricians (38%) or hospital staff (36%) will discuss newborn screening. Only 61% of providers give their patients the newborn screening educational booklet, even though California law requires that the booklet be provided to all pregnant women. CONCLUSION: Pregnant women and state professionals rely on prenatal care providers to educate pregnant women about newborn screening; however, many providers do not appear to view it as part of their responsibility. Therefore, the state needs to improve communication with both providers and the public about newborn screening.

Female↗
PubMed2005

Predictors of psychosocial adaptation among people with spinal cord injury or disorder.

OBJECTIVE: To examine the influence of disability-related medical and psychologic variables on psychosocial adaptation to spinal cord injury or disorder (SCI/D). DESIGN: A structural equation modeling design linking 3 sets of predictive variables to an outcome measure of adaptation. SETTING: Two outpatient SCI clinics (1 veteran, 1 civilian) in Texas. PARTICIPANTS: Veterans (n=181) and civilians (n=132) with SCI/D. INTERVENTIONS: Not applicable. MAIN OUTCOME MEASURES: The adaptation outcome was measured by 2 subscales (acknowledgment, adjustment) of the Reactions to Impairment and Disability Inventory (RIDI) and by the Quality of Life Scale. The predictive variables were measured by a demographic questionnaire, 3 subscales (intrusion, re-experiencing, hyperarousal) of the Purdue Posttraumatic Stress Disorder-Revised scale, the McMordie-Templer Death Anxiety Scale, and 3 subscales (anxiety, depression, denial) of the RIDI. RESULTS: Goodness-of-fit indices suggested that a revised model of adaptation was a moderately good fit to the data. The revised model of adaptation indicated that there were medium total effects (direct plus indirect) on psychosocial adaptation by 2 latent variables (disability severity and impact, negative affectivity) and small total effects on psychosocial adaptation by disengagement coping. The latent factor of disengagement coping had the strongest direct effect on adaptation (although not statistically significant). Disability severity and impact had medium indirect effects and negative affectivity had small indirect effects on psychosocial adaptation. All of the aforementioned effects had a negative coefficient. CONCLUSIONS: Negative emotional responses (eg, depression, anxiety) to SCI/D, disengagement-type coping (eg, disability denial, avoidance), and the severity and impact of disability were related to lower levels of adaptation to SCI/D.

Adaptation, Psychological↗
PubMed2006

Genetic and dopaminergic modulation of reversal learning in a touchscreen-based operant procedure for mice.

Mice are uniquely suited as experimental subjects for various approaches to the study of the molecular and genetic basis of behavior, and there has been a corresponding explosion in the use of mice in behavioral neuroscience. Rats and monkeys, however, remain the preferred species for high-order cognitive models largely due to the unavailability of valid, reliable and translatable endpoint measures of behavior in the mouse. Here we present further development and validation of a touchscreen-based operant method for measuring cognition that is comparable to methods used in other species and human patients. C57BL/6J mice were found to show good performance on visual discrimination and reversal learning using this method. Demonstrating the sensitivity of the paradigm to genetic factors, C57BL/6J and DBA/2J mice exhibited marked differences in discrimination and reversal learning. Systemic treatment with the selective D1-like agonist, SKF81297, produced an impairment in the early phase of reversal learning, but did not alter visual discrimination, in C57BL/6J mice. The same treatment impaired spatial working memory on the T-maze delayed alternation task, but did not alter control measures of behavior including motivation and locomotor activity. These data demonstrate the sensitivity of visual discrimination and reversal learning measured by this method to genetic factors and pharmacological challenge, and thereby provide an extension and further validation of the method for measuring cognition in mice. When combined with emerging molecular techniques uniquely suited to this species such as genetic engineering and RNA modification this paradigm could provide a powerful new tool for behavioral neuroscience.

Analysis of Variance↗
PubMed2005

Structure-based design of isoquinoline-5-sulfonamide inhibitors of protein kinase B.

Structure-based drug design of novel isoquinoline-5-sulfonamide inhibitors of PKB as potential antitumour agents was investigated. Constrained pyrrolidine analogues that mimicked the bound conformation of linear prototypes were identified and investigated by co-crystal structure determinations with the related protein PKA. Detailed variation in the binding modes between inhibitors with similar overall conformations was observed. Potent PKB inhibitors from this series inhibited GSK3beta phosphorylation in cellular assays, consistent with inhibition of PKB kinase activity in cells.

Cell Line, Tumor↗
PubMed2026

Patient-derived models of prostate cancer: Capturing tumour complexity from initiation to metastasis.

Prostate cancer is a growing global health challenge. To identify new ways to improve patient care, researchers need a variety of preclinical models that faithfully recapitulate human tumours across the disease continuum, from initiation to metastasis. These complementary models include primary cultures of prostate epithelial cells (PrECs), co-cultures, patient-derived explants (PDEs), patient-derived organoids (PDOs) and patient-derived xenografts (PDXs). Collectively, these models enable researchers to study tumour biology and therapeutic responses in clinically relevant contexts. Yet, there is still a need to improve the fidelity of preclinical models to human tumours by integrating diverse cell types from the tumour microenvironment and mimicking biomechanical features. By improving culture methods with matrix components that resemble the tumour microenvironment and new formulations of media that imitate human plasma, in vitro models will more accurately reflect human physiology, nutrient availability, and metabolism. In time this may reduce the reliance on animal testing through organ-on-chip and related techniques. These more complex models are suited to more detailed experimental readouts, including single-cell and spatial analyses. Intravital imaging also enables dynamic visualisation of cell-cell interactions and treatment responses in vivo. Collectively, these approaches are facilitating a shift towards sophisticated models that capture patients' tumour heterogeneity, different cellular niches, and provide opportunities to carefully study tumorigenesis, metastasis, lineage plasticity, and therapy resistance. In this review, we discuss the current progress and future directions for patient-derived models of prostate cancer, highlighting how they can be generated, refined, characterised and shared to accelerate the worldwide effort in translational research.

Humans↗
PubMed2005

Journey to the Beacon Award: the Georgetown University Hospital perspective.

The medical intensive care unit (MICU) at Georgetown University Hospital in Washington, D.C., was among the first four hospitals to be awarded the Beacon Award from the American Association of Critical- Care Nurses. The Beacon Award is given to those units that prove, through a 42-question application, how they excel and serve as a guiding light to other intensive care units. The MICU's "journey" to the award prompted an introspective look into the unit, its policies, and its methods of providing the highest quality patient care, in an environment that is supportive to the nursing staff.

Attitude of Health Personnel↗
PubMed2005

The Methodist Hospital CCU: a Beacon unit of excellence.

This article features the Coronary Care Unit of The Methodist Hospital of Houston, Texas. This unit was one of the first Beacon Critical Care Units recognized by the American Association of Critical Care Nurses. This article focuses on how to achieve this award. The Coronary Care Unit nursing infrastructure is described, and specific unit examples are included.

Attitude of Health Personnel↗
PubMed2006

Single data extraction generated more errors than double data extraction in systematic reviews.

BACKGROUND AND OBJECTIVE: To conduct a pilot study to compare the frequency of errors that accompany single vs. double data extraction, compare the estimate of treatment effect derived from these methods, and compare the time requirements for these methods. METHODS: Reviewers were randomized to the role of data extractor or data verifier, and were blind to the study hypothesis. The frequency of errors associated with each method of data extraction was compared using the McNemar test. The data set for each method was used to calculate an efficacy estimate by each method, using standard meta-analytic techniques. The time requirement for each method was compared using a paired t-test. RESULTS: Single data extraction resulted in more errors than double data extraction (relative difference: 21.7%, P = .019). There was no substantial difference between methods in effect estimates for most outcomes. The average time spent for single data extraction was less than the average time for double data extraction (relative difference: 36.1%, P = .003). CONCLUSION: In the case that single data extraction is used in systematic reviews, reviewers and readers need to be mindful of the possibility for more errors and the potential impact these errors may have on effect estimates.

Data Interpretation, Statistical↗