CHARACTERIZATION AND TREATMENT OF A NOVEL MOUSE MODEL OF TSC-ASSOCIATED AUTISM

Tuberous sclerosis complex (TSC) is a dominant tumor suppressor disorder caused by mutations in either TSC1 or TSC2. The proteins of these genes form a complex to inhibit the mammalian target of rapamycin complex 1 (mTORC1), which controls protein translation and cell growth. TSC causes substantial neuropathology, often leading to autism spectrum disorders (ASDs) in up to 60% of patients. The anatomic and neurophysiologic links between these two disorders are not well understood. However, both disorders share cerebellar abnormalities. Therefore, we have characterized a novel mouse model in which the Tsc2 gene was selectively deleted from cerebellar Purkinje cells (Tsc2f/-;Cre). These mice exhibit progressive Purkinje cell degeneration. Since loss of Purkinje cells is a well-reported postmortem finding in patients with ASD, we conducted a series of behavior tests to assess if Tsc2f/-;Cre mice displayed autistic-like deficits. Using the three chambered social choice assay, we found that Tsc2f/-;Cre mice showed behavioral deficits, exhibiting no preference between a stranger mouse and an inanimate object, or between a novel and a familiar mouse. Tsc2f/-;Cre mice also demonstrated increased repetitive behavior as assessed with marble burying activity. Altogether, these results demonstrate that loss of Tsc2 in Purkinje cells in a haploinsufficient background lead to behavioral deficits that are characteristic of human autism. Therefore, Purkinje cells loss and/or dysfunction may be an important link between TSC and ASD. Additionally, we have examined some of the cellular mechanisms resulting from mutations in Tsc2 leading to Purkinje cell death. Loss of Tsc2 led to upregulation of mTORC1 and increased cell size. As a consequence of increased protein synthesis, several cellular stress pathways were upregulated. Principally, these included altered calcium signaling, oxidative stress, and ER stress. Likely as a consequence of ER stress, there was also upregulation of ubiquitin and autophagy. Excitingly, treatment with an mTORC1 inhibitor, rapamycin attenuated mTORC1 activity and prevented Purkinje cell death by reducing of calcium signaling, the ER stress response, and ubiquitin. Remarkably, rapamycin treatment also reversed the social behavior deficits, thus providing a promising potential therapy for TSC-associated ASD.

"I understood what she meant when she said '21st century medicine'": A qualitative analysis of patient responses for plans for colorectal cancer screening following a recommendation from their physician

Although physician recommendation has been significantly associated with colorectal cancer screening (CRCS), it still does not motivate all patients to get CRCS. Although improved physician recommendation for CRCS has been shown to increase patient CRCS screening, questions remain about what elements of that discussion may lead to screening. The objective of this study is to describe patients' perceptions and interpretations about their physician's recommendation for CRCS during their annual wellness exam. A subset of patients (n=51) participating in a supplement study of a behavioral intervention trial designed to increase CRCS completed a follow-up, open-ended interview two to four weeks after their annual wellness visit. Using qualitative methods, transcripts of these interviews were analyzed. Findings suggest that most patients would follow their physician's recommendation for CRCS despite not engaging in much discussion. Patients may refrain from CRCS discussion because of a commitment to CRCS, awareness of screening guidelines, and trust in physician's honesty and beneficence. Yet many patients left their wellness exams with questions, refraining because of future plans to consult with their physicians, perceived time constraints or a lack of a patient-physician relationship. If patients are leaving their wellness exams with unanswered questions, interventions should prepare physicians for patient reticence, teaching physicians how to assure patients that CRCS is a primary care activity where all questions and concerns, including cost and scheduling, may be resolved.^

Measuring Service Effectiveness for Families

While most professionals do not dispute the fact that evaluation is necessary to determine whether agencies and practitioners are truly providing services that meet clients’ needs, information regarding consistent measures on service effectiveness in human service organizations is sparse. A national survey of 250 not-for-profit family service organizations in the United States (52.8% return rate) yielded results relevant to client identified needs and agency effectiveness measures in serving today’s families. On an open-ended survey item, 52.3% agencies indicated that poverty represented the most pressing problem among today’s families because other psychological needs also take priority. Over two thirds of these agencies used multiple methods to evaluate their services. Clients’ feedback and outcome measures are the most popular methods. The findings reveal agencies' difficulties in determining what or who decides if the most appropriate services are being provided for the target population. Limited data collected on outcomes and impact may impose additional difficulties in program design and planning.

Translating knowledge into action: Information needs of decision-makers in healthcare

Purpose: The purpose of this study was to assess the healthcare information needs of decision-makers in a local US healthcare setting in efforts to promote the translation of knowledge into action. The focus was on the perceptions and preferences of decision-makers regarding usable information in making decisions as to identify strategies to maximize the contribution of healthcare findings to policy and practice. Methods: This study utilized a qualitative data collection and analysis strategy. Data was collected via open-ended key-informant interviews from a sample of 37 public and private-sector healthcare decision-makers in the Houston/Harris County safety net. The sample was comprised of high-level decision-makers, including legislators, executive managers, service providers, and healthcare funders. Decision-makers were asked to identify the types of information, the level of collaboration with outside agencies, useful attributes of information, and the sources, formats/styles, and modes of information preferred in making important decisions and the basis for their preferences. Results: Decision-makers report acquiring information, categorizing information as usable knowledge, and selecting information for use based on the application of four cross-cutting thought processes or cognitive frameworks. In order of apparent preference, these are time orientation, followed by information seeking directionality, selection of validation processes, and centrality of credibility/reliability. In applying the frameworks, decision-makers are influenced by numerous factors associated with their perceptions of the utility of information and the importance of collaboration with outside agencies in making decisions as well as professional and organizational characteristics. Conclusion: An approach based on the elucidated cognitive framework may be valuable in identifying the reported contextual determinants of information use by decision-makers in US healthcare settings. Such an approach can facilitate active producer/user collaborations and promote the production of mutually valued, comprehensible, and usable findings leading to sustainable knowledge translation efforts long-term.^

Correlates of prenatal care initiation among low -income Hispanic women

Because Hispanic women are even less likely than women of other ethnic groups to receive early prenatal care, the purpose of this study was to identify factors that may influence these women to initiate care. After giving consent, 300 Hispanic women (100 who initiated first trimester care, 100 who initiated second trimester care, and 100 who initiated third trimester care or received no care) were interviewed in the post partum unit of a local public hospital. The interview included recollection of events leading to the first prenatal appointment, including first physical indicators of pregnancy, confirmation of pregnancy, feelings about the pregnancy, appointment making behavior, and system barriers encountered. The Health Belief Model was used as the theoretical framework for determining psychosocial variables. Using this model, perceived susceptibility to problems during pregnancy, perceived seriousness of possible problems, perceived benefits of prenatal care, perceived barriers to care, and cues to action were assessed. Time of entry into prenatal care was assessed by interview.^ In this sample of low-income Hispanic women, a higher perception of barriers to care was associated with later initiation of care and non-use of care, higher perceived benefits of care for the baby were associated with earlier care, especially in women without a card to access hospital district services, and having a card to access hospital district services was associated with earlier care. Several barriers to care were mentioned by women on open-ended questioning including long waiting times, embarrassment, and lack of transportation.^ Recommendations for practice included decreasing the number of visits for low-risk women while increasing the time spent with the provider, decreasing the number of vaginal exams for low-risk women, increasing the use of midwives, training lay workers to do risk assessment, giving specific messages about benefits of care to baby, and increasing general health motivation through community intervention methods. More research on the psychosocial and cultural factors associated with initiation of care is needed. In the meantime, the recommendations for practice can be implemented now to increase the use of prenatal care by low-income Hispanic women. ^