Twelve-year follow-up of a population-based primary care diabetes program in Israel.

OBJECTIVE: To describe the effects of a long-term intervention including 72% of Israeli diabetes patients, aimed at improving diabetes care in a primary care setting. DESIGN: A retrospective periodic population-based cross-sectional study. SETTING: Two health maintenance organizations (HMOs) in Israel-intervention and control. PARTICIPANTS: All diagnosed diabetes patients enrolled in both HMOs. INTERVENTION: Multifaceted interventions directed toward primary care providers, including educational strategies, registries, clinical pathways, care quality indicators, computerized reminders and feedback. MAIN OUTCOME MEASURES: Performance in quality indicators, compared with an HMO that did not implement an intervention program. RESULTS: The prevalence of diabetes increased from 20.2/1000 in 1995 to 63.7/1000 in 2007. Annual testing of hemoglobin A1c (HbA1c) rose from 22% in 1995 to 88% in 2007. The corresponding figures for low-density lipoprotein (LDL) were 23 and 89%, and for microalbumin 10 and 69%, respectively (P< 0.0001 for all comparisons). The proportion of HbA1c ≤7% increased from 10 to 53%, while HbA1c >9% decreased from 40 to 13% (P< 0.0001). Good control of LDL ≤100 mg/dl increased from 26 to 59% (P< 0.0001). In the comparison HMO, subtle increases in the performance of HbA1c (55.8-63.4%), LDL (59.7-67.0%) and microalbumin (55.1-67.6%) were noted between 2005 and 2007, respectively. HbA1c ≤7 and >9% remained stable (36 and 13%, respectively), while LDL ≤100 mg/dl rose from 38 to 44% in the control HMO. CONCLUSION: A community-oriented program for diabetes care led to improvements in performance of tests, as well as control of HbA1c and LDL among 72% of diabetes patients in Israel.

Beta-catenin phosphorylated at serine 45 is spatially uncoupled from beta-catenin phosphorylated in the GSK3 domain: implications for signaling.

C. elegans and Drosophila generate distinct signaling and adhesive forms of beta-catenin at the level of gene expression. Whether vertebrates, which rely on a single beta-catenin gene, generate unique adhesive and signaling forms at the level of protein modification remains unresolved. We show that beta-catenin unphosphorylated at serine 37 (S37) and threonine 41 (T41), commonly referred to as transcriptionally Active beta-Catenin (ABC), is a minor nuclear-enriched monomeric form of beta-catenin in SW480 cells, which express low levels of E-cadherin. Despite earlier indications, the superior signaling activity of ABC is not due to reduced cadherin binding, as ABC is readily incorporated into cadherin contacts in E-cadherin-restored cells. Beta-catenin phosphorylated at serine 45 (S45) or threonine 41 (T41) (T41/S45) or along the GSK3 regulatory cassette S33, S37 or T41 (S33/37/T41), however, is largely unable to associate with cadherins. Beta-catenin phosphorylated at T41/S45 and unphosphorylated at S37 and T41 is predominantly nuclear, while beta-catenin phosphorylated at S33/37/T41 is mostly cytoplasmic, suggesting that beta-catenin hypophosphorylated at S37 and T41 may be more active in transcription due to its enhanced nuclear accumulation. Evidence that phosphorylation at T41/S45 can be spatially separated from phosphorylations at S33/37/T41 suggests that these phosphorylations may not always be coupled, raising the possibility that phosphorylation at S45 serves a distinct nuclear function.

Beta-catenin/T-cell factor signaling is activated during lung injury and promotes the survival and migration of alveolar epithelial cells.

The Wnt/beta-catenin signaling cascade activates genes that allow cells to adopt particular identities throughout development. In adult self-renewing tissues like intestine and blood, activation of the Wnt pathway maintains a progenitor phenotype, whereas forced inhibition of this pathway promotes differentiation. In the lung alveolus, type 2 epithelial cells (AT2) have been described as progenitors for the type 1 cell (AT1), but whether AT2 progenitors use the same signaling mechanisms to control differentiation as rapidly renewing tissues is not known. We show that adult AT2 cells do not exhibit constitutive beta-catenin signaling in vivo, using the AXIN2(+/LacZ) reporter mouse, or after fresh isolation of an enriched population of AT2 cells. Rather, this pathway is activated in lungs subjected to bleomycin-induced injury, as well as upon placement of AT2 cells in culture. Forced inhibition of beta-catenin/T-cell factor signaling in AT2 cultures leads to increased cell death. Cells that survive show reduced migration after wounding and reduced expression of AT1 cell markers (T1alpha and RAGE). These results suggest that AT2 cells may function as facultative progenitors, where activation of Wnt/beta-catenin signaling during lung injury promotes alveolar epithelial survival, migration, and differentiation toward an AT1-like phenotype.

Issues associated with assessing nuclear localization of N-terminally unphosphorylated beta-catenin with monoclonal antibody 8E7.

BACKGROUND: Beta-catenin is a dual function adhesion/transcriptional co-activator protein, and both functions are critical for normal tissue homeostasis. Since the transcriptional functions of beta-catenin are more often implicated in various disease processes, there is much interest in the development and use of reagents to interrogate spatial and temporal evidence of beta-catenin nuclear signaling in cells and tissues. An important study demonstrated that the signaling form of beta-catenin is specifically unphosphorylated at residues S37 and T41, and suggested that this form exhibits a propensity for cytosolic/nuclear accumulation relative to the total pool of beta-catenin. RESULTS: We show that monoclonal antibody, 8E7, which recognizes the signaling form of beta-catenin specifically unphosphorylated at S37 and T41 (Active B-Catenin, ABC), also cross-reacts with a widely expressed, variably accessible nuclear antigen that is not beta-catenin. In cell types commonly used to study Wnt activation, this non-specific nuclear staining can be robust, obscuring the ABC signal. Definitive detection of nuclear localized ABC can be confirmed through an ability of classical cadherins to sequester ABC to cell junctions. In tissues, milder antigen retrieval methods can reduce the accessibility of mAb 8E7 to this cross-reacting nuclear antigen. CONCLUSION: These findings reveal that interpretation of nuclear, signaling active beta-catenin using monoclonal antibody 8E7 should be considered judiciously, and in conjunction with independent methods.

Attitudes of Israeli primary care physicians towards mental health care.

Rates of depression and anxiety are increasing all over the world in developed and developing countries as well and Israel is no exception to this trend. People suffering from depression and anxiety disorders tend not to turn for professional help to mental health clinics but to primary care. This cross-sectional study examines the attitudes and barriers of primary care physicians in the southern region of Israel toward providing care for depression and anxiety in their practices. In 2002 we sent a questionnaire concerning attitudes and barriers toward depression and anxiety to 99 primary care physicians from 14 primary care clinics with a response rate of 67.7% (67 physicians); 80.6% of the participants agreed with the statement that depression and anxiety are frequent problems in primary care and they should be treated in primary care clinics, but 37.3% reported to have little interest in treating mental disorders, 47.7% thought depression and anxiety should be treated in mental health clinics; 43.3% of the participants declared that they experienced a personal difficulty in taking care of patients with depression and anxiety, and 85% identified time constraint as a major barrier to care of depression and anxiety in primary care. This study suggests that in order to improve treatment of depression and anxiety in primary care, there is a need for a change of attitudes of the primary care providers.