CREB coactivators CRTC2 and CRTC3 modulate bone marrow hematopoiesis.

Populations of circulating immune cells are maintained in equilibrium through signals that enhance the retention or egress of hematopoietic stem cells (HSCs) from bone marrow (BM). Prostaglandin E2 (PGE2) stimulates HSC renewal and engraftment through, for example, induction of the cAMP pathway. Triggering of PGE2 receptors increases HSC survival in part via the PKA-mediated induction of the cAMP response element-binding protein (CREB) signaling pathway. PKA stimulates cellular gene expression by phosphorylating CREB at Ser133 and by promoting the dephosphorylation of the cAMP- responsive transcriptional coactivators (CRTCs). We show here that disruption of both CRTC2 and CRTC3 causes embryonic lethality, and that a single allele of either CRTC2 or CRTC3 is sufficient for viability. CRTC2 knockout mice that express one CRTC3 allele (CRTC2/3m mice) develop neutrophilia and splenomegaly in adulthood due to the up-regulation of granulocyte-colony stimulating factor (G-CSF); these effects are reversed following administration of neutralizing anti-G-CSF antiserum. Adoptive transfer of CRTC2/3m BM conferred the splenomegaly/neutrophilia phenotype in WT recipients. Targeted disruption of both CRTC2 and CRTC3 in stromal cells with a mesenchymal Prx1-Cre transgene also promoted this phenotype. Depletion of CRTC2/3 was found to decrease the expression of Suppressor of Cytokine Signaling 3 (SOCS3), leading to increases in STAT3 phosphorylation and to the induction of CEBPß, a key regulator of the G-CSF gene. As small molecule inhibition of JAK activity disrupted CEBPß induction and reduced G-CSF expression in CRTC2/3m stromal cells, our results demonstrate how cross-coupling between the CREB/CRTC and JAK/STAT pathways contributes to BM homeostasis.

CREB pathway links PGE2 signaling with macrophage polarization.

Obesity is thought to promote insulin resistance in part via activation of the innate immune system. Increases in proinflammatory cytokine production by M1 macrophages inhibit insulin signaling in white adipose tissue. In contrast, M2 macrophages have been found to enhance insulin sensitivity in part by reducing adipose tissue inflammation. The paracrine hormone prostaglandin E2 (PGE2) enhances M2 polarization in part through activation of the cAMP pathway, although the underlying mechanism is unclear. Here we show that PGE2 stimulates M2 polarization via the cyclic AMP-responsive element binding (CREB)-mediated induction of Krupple-like factor 4 (KLF4). Targeted disruption of CREB or the cAMP-regulated transcriptional coactivators 2 and 3 (CRTC2/3) in macrophages down-regulated M2 marker gene expression and promoted insulin resistance in the context of high-fat diet feeding. As re-expression of KLF4 rescued M2 marker gene expression in CREB-depleted cells, our results demonstrate the importance of the CREB/CRTC pathway in maintaining insulin sensitivity in white adipose tissue via its effects on the innate immune system.

Improving the long-term care referral process: insights from patients and caregivers.

Large increases in the need for long-term care (LTC) services are expected as baby boomers age. Little has been published about patient and caregiver preferences for information about LTC. However, our qualitative research findings suggest that potential consumers may find it difficult to obtain accurate and timely information about LTC programs and services. In-person, semistructured interviews were conducted with 47 subjects, including patients (n = 25) within 90 days of their referral to a LTC placement (including NH, assisted living, home care, and community) and their caregivers (n = 22). Interview questions addressed the events that seemed to trigger their need for a LTC referral, the resources they used to become more informed about LTC options and the issues they confronted with the LTC referral process. Qualitative analyses identified a number of patient and informal caregiver-reported barriers to making decisions about LTC services, including insufficient information about LTC programs and community resources, unclear funding requirements and inadequate funding, and difficulty knowing how to plan for LTC or make LTC decisions. A potential solution may be an online LTC Guide designed to provide accurate information about the range of LTC services, with an emphasis on home and community-based services. This Guide was developed to address the gap in comprehensive LTC information identified in the findings of this study.

Long-term effectiveness of screening for hearing loss: the screening for auditory impairment--which hearing assessment test (SAI-WHAT) randomized trial.

OBJECTIVES: To evaluate the effect of hearing screening on long-term hearing outcomes in a general population of older veterans. DESIGN: Hearing loss in the elderly is underdetected and undertreated. Routine hearing screening has been proposed, but it is not clear whether screening identifies patients who are sufficiently motivated to adhere to treatment. A four-arm randomized clinical trial was conducted to compare three screening strategies with no screening in 2,305 older veterans seeking general medical care. SETTING: Veterans Affairs Puget Sound Health Care System. INTERVENTIONS: The screening strategies were a tone-emitting otoscope, a widely used questionnaire about hearing handicap, and a combination of both tools. MEASUREMENTS: Hearing aid use 1 year after screening. RESULTS: Of participants who underwent screening with the tone-emitting otoscope, questionnaire, and combined testing, 18.6%, 59.2%, and 63.6%, respectively, screened positive for hearing loss (P<.01 for test of equality across three arms). Patients proceeded to formal audiology evaluation 14.7%, 23.0%, and 26.6% of the time in the same screening arms, compared with 10.8% in the control arm (P<.01 for test of equality across four arms). Hearing aid use 1 year after screening was 6.3%, 4.1%, and 7.4% in the same arms, compared with 3.3% in the control arm (P<.01). Hearing aid users experienced significant improvements in hearing-related function and communication ability. CONCLUSION: In older veterans, screening for hearing loss led to significantly more hearing aid use. Screening with the tone-emitting otoscope was more efficient. The results are most applicable to older populations with few cost barriers to hearing aids.

Targeted disruption of the CREB coactivator Crtc2 increases insulin sensitivity.

Under fasting conditions, increases in circulating concentrations of pancreatic glucagon maintain glucose homeostasis through induction of gluconeogenic genes by the CREB coactivator CRTC2. Hepatic CRTC2 activity is elevated in obesity, although the extent to which this cofactor contributes to attendant increases in insulin resistance is unclear. Here we show that mice with a knockout of the CRTC2 gene have decreased circulating glucose concentrations during fasting, due to attenuation of the gluconeogenic program. CRTC2 was found to stimulate hepatic gene expression in part through an N-terminal CREB binding domain that enhanced CREB occupancy over relevant promoters in response to glucagon. Deletion of sequences encoding the CREB binding domain in CRTC2 (-/-) mice lowered circulating blood glucose concentrations and improved insulin sensitivity in the context of diet-induced obesity. Our results suggest that small molecules that attenuate the CREB-CRTC2 pathway may provide therapeutic benefit to individuals with type 2 diabetes.

A pilot evaluation of the Family Caregiver Support Program.

The purposes of this study were to evaluate a federal and state-funded Family Caregiver Support Program (FCSP) and explore what types of caregiver support service are associated with what caregiver outcomes. Information was obtained on a sample of 164 caregivers' use of eleven different types of support service. Descriptive and comparative analyses were used to detect the differences between users and nonusers of caregiver support services. Six measures included were caregiving appraisal scale, caregiving burden, caregiving mastery, caregiving satisfaction, hour of care, and service satisfaction. Using consulting and education services is associated with lessening of subjective burden; using financial support services is associated with more beneficial caregiver appraisal, such as better caregiver mastery. The findings are practical and helpful for future caregiver service and program development and evaluation and policy making for supporting caregivers. In addition, the evaluation method demonstrated in the study provided a simple and moderately effective method for service agencies which would like to evaluate their family caregiver support services.

TORC2 regulates hepatic insulin signaling via a mammalian phosphatidic acid phosphatase, LIPIN1.

TORC2 is a major transcriptional coactivator for hepatic glucose production. Insulin impedes gluconeogenesis by inhibiting TORC2 via SIK2-dependent phosphorylation at Ser171. Interruption of this process greatly perturbs hepatic glucose metabolism, thus promoting hyperglycemia in rodents. Here, we show that hyperactivation of TORC2 would exacerbate insulin resistance by enhancing expression of LIPIN1, a mammalian phosphatidic acid phosphatase for diacylglycerol (DAG) synthesis. Diet-induced or genetic obesity increases LIPIN1 expression in mouse liver, and TORC2 is responsible for its transcriptional activation. While overexpression of LIPIN1 disturbs hepatic insulin signaling, knockdown of LIPIN1 ameliorates hyperglycemia and insulin resistance by reducing DAG and PKCvarepsilon activity in db/db mice. Finally, TORC2-mediated insulin resistance is partially rescued by concomitant knockdown of LIPIN1, confirming the critical role of LIPIN1 in the perturbation of hepatic insulin signaling. These data propose that dysregulation of TORC2 would further exaggerate insulin resistance and promote type 2 diabetes in a LIPIN1-dependent manner.

Mom and pop versus the big boys: adult family homes as providers of Medicaid-funded residential care.

This paper compares assisted living apartments (ALs), adult residential care facilities (ARCs), and small adult family homes (AFHs) for Medicaid residents in Washington State, with particular emphasis on the settings, staffing, services, and policies of AFHs. We targeted for enrollment all residents entering an AFH, ARC, or AL setting on Medicaid/state funding in a three-county area of Washington State. We obtained information on 199 settings, interviewing administrative and direct care providers. AFHs are smaller than ARCs and ALs and less likely to be part of a chain, with no significant difference in staffing ratios of registered nurses and licensed practical nurses. Sixty-four percent of AFH residents were receiving public funds compared to 32% of AL residents. AFHs report admitting residents with more activities of daily living needs, health conditions, and behavior problems. They are less likely to have autonomy-related policies, and they provide more services and fewer activities. While attention should continue to be paid to staff supports, policy and practice should support the continued role of AFHs, which are of special interest because of their potential to provide more homelike, less costly care but with possible trade-offs compared to larger facilities.

Barriers to home and community-based service referrals: the physician's role.

The purpose of this study was to obtain information about Department of Veteran Affairs (VA) long-term care (LTC) referrals that could be used to develop interventions that increase the likelihood of referrals to home and community-based services (HCBS) instead of institutional care. This primarily qualitative study was conducted at five VA Medical Centers. The study used three linked methods: interviews with patients and informal caregivers; focus groups with LTC administrators, providers, and social workers; and written rankings of the barriers to HCBS referrals. We unexpectedly identified a cluster of findings indicating the importance of physicians' role in the LTC referral process and the need for more LTC training, particularly about HCBS.

Assisted living pilot program: background, methods, and facility characteristics.

Objectives. The Department of Veterans Affairs (VA) funded assisted living (AL), adult family home (AFH), and residential care for the first time in the Assisted Living Pilot Program (ALPP). This article describes the background and methods of the ALPP evaluation and the characteristics and experiences of the facilities. Method. Facility data were collected from the contracting/inspection process and a survey of ALPP facilities and those contacted but not participating in ALPP. Results. Data on 131 participating facilities are presented: 41 AFHs, 47 assisted living facilities (ALFs), and 43 residential care facilities (RCFs). The average facility had 33 beds (about one quarter Medicaid beds), for-profit ownership, and private rooms for ALPP residents, and about half had private baths. About two thirds of ALPP AFH providers spoke a primary language other than English. Discussion. Findings indicate that a wide range of community facilities were willing to provide care to residents with heterogeneous needs on VA funding.

Assisted living pilot program: utilization and cost findings.

Objective. The Department of Veterans Affairs funded assisted living, adult family home, and adult residential care for the first time in the Assisted Living Pilot Program (ALPP). This article compares the use and cost for individuals that entered ALPP and a comparison group. Method. This was a nonrandomized study. The comparison group consisted of VA patients who were eligible but did not enter an ALPP facility. The ALPP (n = 393) and comparison (n = 259) groups were followed for 12 months to assess ALPP facility, case management, and health care costs. Results. ALPP facility and ALPP case management costs were respectively $5,560 and $2,830 per individual. Total health care costs, including ALPP costs, were $11,533 higher for the ALPP group compared to the comparison group after adjusting for baseline differences. Discussion. Although ALPP successfully helped individuals transition to longer term care in these facilities, it was more costly than the comparison group.

Assisted living pilot program: health outcomes.

Objectives. Assisted living programs demonstrate variation in structure and services. The Department of Veterans Affairs funded this care for the first time in the Assisted Living Pilot Program (ALPP). This article presents resident health outcomes and the relationship between facility characteristics and outcomes. Method. This article presents results on 393 ALPP residents followed for 12 months after admission to 95 facilities. Results. A total of 19.8% residents died, and the average activities of daily living impairment did not change significantly. Half of the residents remained in an ALPP facility, with the average resident spending 315 days in the community during the 12-month follow-up period. This article found a limited number of characteristics of structure and staffing to be significantly associated with outcomes. Discussion. If differences among facility characteristics are not clearly related to differences in outcomes, then choices among type of setting can be based on the match of needs to available services, location, or preferences.

A fasting inducible switch modulates gluconeogenesis via activator/coactivator exchange.

During early fasting, increases in skeletal muscle proteolysis liberate free amino acids for hepatic gluconeogenesis in response to pancreatic glucagon. Hepatic glucose output diminishes during the late protein-sparing phase of fasting, when ketone body production by the liver supplies compensatory fuel for glucose-dependent tissues. Glucagon stimulates the gluconeogenic program by triggering the dephosphorylation and nuclear translocation of the CREB regulated transcription coactivator 2 (CRTC2; also known as TORC2), while parallel decreases in insulin signalling augment gluconeogenic gene expression through the dephosphorylation and nuclear shuttling of forkhead box O1 (FOXO1). Here we show that a fasting-inducible switch, consisting of the histone acetyltransferase p300 and the nutrient-sensing deacetylase sirtuin 1 (SIRT1), maintains energy balance in mice through the sequential induction of CRTC2 and FOXO1. After glucagon induction, CRTC2 stimulated gluconeogenic gene expression by an association with p300, which we show here is also activated by dephosphorylation at Ser 89 during fasting. In turn, p300 increased hepatic CRTC2 activity by acetylating it at Lys 628, a site that also targets CRTC2 for degradation after its ubiquitination by the E3 ligase constitutive photomorphogenic protein (COP1). Glucagon effects were attenuated during late fasting, when CRTC2 was downregulated owing to SIRT1-mediated deacetylation and when FOXO1 supported expression of the gluconeogenic program. Disrupting SIRT1 activity, by liver-specific knockout of the Sirt1 gene or by administration of a SIRT1 antagonist, increased CRTC2 activity and glucose output, whereas exposure to SIRT1 agonists reduced them. In view of the reciprocal activation of FOXO1 and its coactivator peroxisome proliferator-activated receptor-gamma coactivator-1alpha (PGC-1alpha, encoded by Ppargc1a) by SIRT1 activators, our results illustrate how the exchange of two gluconeogenic regulators during fasting maintains energy balance.

Hepatic glucose sensing via the CREB coactivator CRTC2.

Chronic hyperglycemia contributes to the development of diabetes-associated complications. Increases in the concentration of circulating glucose activate the hexosamine biosynthetic pathway (HBP) and promote the O-glycosylation of proteins by O-glycosyl transferase (OGT). We show that OGT triggered hepatic gluconeogenesis through the O-glycosylation of the transducer of regulated cyclic adenosine monophosphate response element-binding protein (CREB) 2 (TORC2 or CRTC2). CRTC2 was O-glycosylated at sites that normally sequester CRTC2 in the cytoplasm through a phosphorylation-dependent mechanism. Decreasing amounts of O-glycosylated CRTC2 by expression of the deglycosylating enzyme O-GlcNAcase blocked effects of glucose on gluconeogenesis, demonstrating the importance of the HBP in the development of glucose intolerance.

Insulin modulates gluconeogenesis by inhibition of the coactivator TORC2.

During feeding, increases in circulating pancreatic insulin inhibit hepatic glucose output through the activation of the Ser/Thr kinase AKT and subsequent phosphorylation of the forkhead transcription factor FOXO1 (refs 1-3). Under fasting conditions, FOXO1 increases gluconeogenic gene expression in concert with the cAMP responsive coactivator TORC2 (refs 4-8). In response to pancreatic glucagon, TORC2 is de-phosphorylated at Ser 171 and transported to the nucleus, in which it stimulates the gluconeogenic programme by binding to CREB. Here we show in mice that insulin inhibits gluconeogenic gene expression during re-feeding by promoting the phosphorylation and ubiquitin-dependent degradation of TORC2. Insulin disrupts TORC2 activity by induction of the Ser/Thr kinase SIK2, which we show here undergoes AKT2-mediated phosphorylation at Ser 358. Activated SIK2 in turn stimulated the Ser 171 phosphorylation and cytoplasmic translocation of TORC2. Phosphorylated TORC2 was degraded by the 26S proteasome during re-feeding through an association with COP1, a substrate receptor for an E3 ligase complex that promoted TORC2 ubiquitination at Lys 628. Because TORC2 protein levels and activity were increased in diabetes owing to a block in TORC2 phosphorylation, our results point to an important role for this pathway in the maintenance of glucose homeostasis.

Characteristics of residents and providers in the assisted living pilot program.

PURPOSE: The number of residents in assisted living has rapidly increased, although these facilities still primarily serve people who can pay out of pocket. The U.S. Department of Veterans Affairs was authorized to provide this level of care for the first time in the Assisted Living Pilot Program (ALPP). We describe the residents and providers, comparing them across three facility types and other populations, to assess the characteristics and feasibility of this new approach. DESIGN AND METHODS: We assessed ALPP residents and providers across seven Veterans Affairs Medical Centers. We obtained information from medical records, assessment tools, and a provider survey. RESULTS: We report here on 743 residents placed from 2002 to 2004. The Department of Veterans Affairs contracted with 58 adult family homes, 56 assisted living facilities, and 46 residential care facilities. The average ALPP resident was a 70-year-old unmarried White man referred from an inpatient hospital and living in a private residence prior to placement. Adult family homes enrolled residents requiring greater levels of assistance with activities of daily living than other facility types. Assisted living facilities were less likely than adult family homes to admit residents with functional disabilities and less likely than either adult family homes or adult residential care facilities to admit residents with certain care needs. IMPLICATIONS: ALPP placed residents with a wide range of characteristics in community facilities that varied widely in size and services. This information can help determine the role of this type of care in and outside of the Department of Veterans Affairs.

Screening for Auditory Impairment-Which Hearing Assessment Test (SAI-WHAT): RCT design and baseline characteristics.

BACKGROUND: Effective screening programs should not merely detect presence of disease, but also lead to long-term benefit. We describe the rationale and design of the first randomized clinical trial to study the long-term effects of routine screening for hearing loss. We also describe the baseline characteristics of the randomized cohort. METHODS: We randomized 2305 veterans age 50 years or older to a control arm without screening, or to screening with: physiologic testing (AudioScope), a self-administered questionnaire (Hearing Handicap Inventory for the Elderly-Screening version [HHIE-S]), or both tests. The primary outcome measure will be hearing aid use one year after screening. We will also study a number of secondary outcomes, including appointments made with and visits to an audiologist, cases of aidable hearing loss, hearing aids dispensed, self-rated communication ability, and hearing-related quality of life. RESULTS: Baseline demographic and health status measures were evenly distributed across the screening arms. The percentage of patients who screened positive for hearing loss was 18.6%, 59.2%, and 63.6% for the AudioScope, HHIE-S, and combined screening arms, respectively. IMPLICATIONS: Long-term results are needed to gain insight into whether the AudioScope is associated with high rates of false negative screening, the HHIE-S is associated with high rates of false positive screening, or a combination of both. Identifying the best screening program will depend on determining which strategy leads to successful hearing aid use.

Psychotropic use in community residential care facilities: A prospective cohort study.

BACKGROUND: Psychotropic medication use in community residential care (CRC) facilities has been reported to be similar to that found in nursing homes before the implementation of the Omnibus Budget Reconciliation Act of 1987. OBJECTIVES: The objectives of this study were to (1) describe patterns of psychotropic medication use at baseline and after 1 year of follow-up in adult residents aged > or =65 years supported by Medicaid in CRC facilities, (2) describe the quality of psychotropic use, and (3) examine the relationship between psychotropic use and resident and facility characteristics. METHODS: This was a planned analysis of a larger prospective cohort study conducted in CRC facilities (assisted living, adult family home, adult residential care) in a 3-county area in the state of Washington. Interviews and state Medicaid databases were used to collect resident characteristics (demographic data, medication use, activities of daily living, self-reported health, and frequency of memory and behavior problems) and facility characteristics (type, staffing, and occupancy rates). Residents were classified as users or nonusers of psychotropic medications. Suboptimal psychotropic use was defined as use of agents with a higher side-effect profile (tertiary amine tricyclic antidepressants, long-acting benzodiazepines, and low-potency conventional antipsychotics). Logistic regression was used to examine characteristics associated with any psychotropic use at baseline. RESULTS: The typical resident was a white woman, aged 83 years, receiving 7 medications. Nearly half (46.8%) of all residents used > or =1 psychotropic medication at baseline, whereas 16.7% used multiple agents. Antidepressants accounted for the greatest amount of psychotropic use (31.2%). Suboptimal antidepressants, sedative/anxiolytics, and antipsychotics were used by 19.3%, 16.7%, and 7.3% of medication users in each class, respectively. Only age (odds ratio [OR] = 0.97; 95% CI, 0.35-1.00), number of medications (OR = 1.06; 95% CI, 1.00-1.11), and the Revised Memory and Behavior Problems Checklist score (OR = 2.03; 95% CI, 1.28-3.23) were associated with psychotropic use at baseline. CONCLUSIONS: Psychotropic medication use was high in CRC facilities (46.8%), with antidepressants being the most frequently used drugs. Use of suboptimal (19.3% of antidepressant users, 16.7% of sedative/anxiolytic users, 7.3% of antipsychotic users) and multiple psychotropics (16.7%) was low.

Identification of the tyrosine phosphatase PTP-MEG2 as an antagonist of hepatic insulin signaling.

Insulin resistance is a primary defect in type 2 diabetes characterized by impaired peripheral glucose uptake and insufficient suppression of hepatic glucose output. Insulin signaling inhibits liver glucose production by inducing nuclear exclusion of the gluconeogenic transcription factor FOXO1 in an Akt-dependent manner. Through the concomitant application of genome-scale functional screening and quantitative image analysis, we have identified PTP-MEG2 as a modulator of insulin-dependent FOXO1 subcellular localization. Ectopic expression of PTP-MEG2 in cells inhibited insulin-induced phosphorylation of the insulin receptor, while RNAi-mediated reduction of PTP-MEG2 transcript levels enhanced insulin action. Additionally, adenoviral-mediated depletion of PTP-MEG2 in livers of diabetic (db/db) mice resulted in insulin sensitization and normalization of hyperglycemia. These data implicate PTP-MEG2 as a mediator of blood glucose homeostasis through antagonism of insulin signaling, and suggest that modulation of PTP-MEG2 activity may be an effective strategy in the treatment of type 2 diabetes.

Quality of medication records and use of pharmacy resources in community residential care facilities.

BACKGROUND: In community residential care (CRC) facilities, medication administration is often performed by unlicensed personnel with minimal knowledge in medication use. Medication management is one of the top 3 quality-of-care issues facing these facilities. OBJECTIVE: To examine the type of medication assistance residents received, determine the proportion of facilities that used pharmacy resources, and examine the quality of facility medication records in CRC facilities (eg, adult family homes, adult residential care, assisted living facilities). METHODS: Baseline in-person interviews were conducted with 349 residents and 299 facility providers in the Puget Sound region of Washington. Information was also obtained from facility medication records at enrollment and state databases. A pharmacist determined quality of the records using a standardized form. RESULTS: The average resident was a 78-year-old white female taking 7 drugs. Medication records that were computer generated were significantly less likely to have misspelled names of drugs and errors in or absence of dose, directions for use, and route of administration. Overall, 26.3% of facilities reported that a consultant pharmacist reviewed residents' medication lists, 52.0% reported the use of preprinted lists, and 75.6% received prepackaged medications from the pharmacy. Adult family homes, the smallest facility type, were the least likely to use pharmacy-related services. CONCLUSIONS: The quality of handwritten medication records was a concern in CRC facilities. These facilities may benefit from services offered by pharmacies that may enhance medication management, many of which were underutilized.