Interleukin-7 receptor controls development and maturation of late stages of thymocyte subpopulations.

Interleukin (IL)-7 is a cytokine essential for T lymphocyte development and homeostasis. However, little is known about the roles of IL-7 receptor α-chain (IL-7Rα) in late stages of T-cell development. To address this question, we established IL-7Rα-floxed mice and crossed them with CD4-Cre transgenic mice. Resultant IL-7R conditional knockout (IL-7RcKO) mice exhibited marked reduction in CD8 single positive (SP) T cells, regulatory T cells (Tregs), and natural killer T (NKT) cells in thymus. The proportion and proliferation of both mature CD4SP and CD8SP thymocytes were decreased without affecting Runx expression. In addition, expression of the glucocorticoid-induced TNF receptor was reduced in CD4SP and CD8SP thymocytes, and expression of CD5 was decreased in CD8SP thymocytes. IL-7RcKO mice also showed impaired Treg and NKT cell proliferation and inhibition of NKT cell maturation. Bcl-2 expression was reduced in CD4SP and CD8SP thymocytes but not in Tregs and NKT cells, and introduction of a Bcl-2 transgene rescued frequency and CD5 expression of CD8SP thymocytes. Furthermore, IL-7RcKO mice exhibited greatly increased numbers of B cells and, to a lesser extent, γδ T and dendritic cells in thymus. Overall, this study demonstrates that IL-7Rα differentially controls development and maturation of thymocyte subpopulations in late developmental stages and suggests that IL-7R expression on αß T cells suppresses development of other cell lineages in thymus.

Identification of IL-7-producing cells in primary and secondary lymphoid organs using IL-7-GFP knock-in mice.

IL-7 is a cytokine crucial for development and maintenance of lymphocytes and other hematopoietic cells. However, how IL-7-expressing cells are distributed in lymphoid organs is not well known. To address this question, we established and analyzed IL-7-GFP knock-in mice. Thymic epithelial cells (TECs) expressed high GFP levels in the cortex and medulla, as detected with an anti-GFP Ab. Thymic mesenchymal cells also expressed GFP. Flow cytometry analysis suggested that cortical TECs expressed higher GFP levels than did medullary TECs. In bone marrow, immunohistochemistry indicated high levels of GFP in many VCAM-1(+) mesenchymal stromal cells and in some VCAM-1(-) cells. Additionally, half of the VCAM-1(+)CD31(-) stromal cells and some platelet-derived growth factor receptor α(+) stromal cells were GFP(+), as detected by flow cytometry. Moreover, we detected GFP expression in fibroblastic reticular cells in the T cell zone and cortical ridge of lymph nodes. Remarkably, lymphatic endothelial cells (LECs) expressed GFP at high levels within the lymph node medulla, skin epidermis, and intestinal tissues. Additionally, we detected abundant IL-7 transcripts in isolated LECs, suggesting that LECs produce IL-7, a heretofore unknown finding. Furthermore, GFP is expressed in a subpopulation of intestinal epithelial cells, and that expression was markedly upregulated in a dextran sulfate sodium-induced acute colitis model. Overall, IL-7-GFP knock-in mice serve as a unique and powerful tool to examine the identity and distribution of IL-7-expressing cells in vivo.

Medical costs of CKD in the Medicare population.

Estimates of the medical costs associated with different stages of CKD are needed to assess the economic benefits of interventions that slow the progression of kidney disease. We combined laboratory data from the National Health and Nutrition Examination Survey with expenditure data from Medicare claims to estimate the Medicare program's annual costs that were attributable to CKD stage 1-4. The Medicare costs for persons who have stage 1 kidney disease were not significantly different from zero. Per person annual Medicare expenses attributable to CKD were $1700 for stage 2, $3500 for stage 3, and $12,700 for stage 4, adjusted to 2010 dollars. Our findings suggest that the medical costs attributable to CKD are substantial among Medicare beneficiaries, even during the early stages; moreover, costs increase as disease severity worsens. These cost estimates may facilitate the assessment of the net economic benefits of interventions that prevent or slow the progression of CKD.

Schizosaccharomyces pombe cell division cycle under limited glucose requires Ssp1 kinase, the putative CaMKK, and Sds23, a PP2A-related phosphatase inhibitor.

Calcium/calmodulin-dependent protein kinase (CaMK) is required for diverse cellular functions, and similar kinases exist in fungi. Although mammalian CaMK kinase (CaMKK) activates CaMK and also evolutionarily-conserved AMP-activated protein kinase (AMPK), CaMKK is yet to be established in yeast. We here report that the fission yeast Schizosaccharomyces pombe Ssp1 kinase, which controls G2/M transition and response to stress, is the putative CaMKK. Ssp1 has a CaM binding domain (CBD) and associates with 14-3-3 proteins as mammalian CaMKK does. Temperature-sensitive ssp1 mutants isolated are defective in the tolerance to limited glucose, and this tolerance requires the conserved stretch present between the kinase domain and CBD. Sds23, multi-copy suppressor for mutants defective in type 1 phosphatase and APC/cyclosome, also suppresses the ssp1 phenotype, and is required for the tolerance to limited glucose. We demonstrate that Sds23 binds to type 2A protein phosphatases (PP2A) and PP2A-related phosphatase Ppe1, and that Sds23 inhibits Ppe1 phosphatase activity. Ssp1 and Ppe1 thus seem to antagonize in utilizing limited glucose. We also show that Ppk9 and Ssp2 are the catalytic subunits of AMPK and AMPK-related kinases, respectively, which bind to common beta-(Amk2) and gamma-(Cbs2) subunits.

A health policy model of CKD: 2. The cost-effectiveness of microalbuminuria screening.

BACKGROUND: Microalbuminuria screening may detect chronic kidney disease in its early stages, allowing for treatment that delays or prevents disease progression. The cost-effectiveness of microalbuminuria screening has not been determined. STUDY DESIGN: A cost-effectiveness model simulating disease progression and costs. SETTING & POPULATION: US patients. MODEL, PERSPECTIVE, AND TIMEFRAME: The microsimulation model follows up disease progression and costs in a cohort of simulated patients from age 50 to 90 years or death. Costs are evaluated from the health care system perspective. INTERVENTION: Microalbuminuria screening at 1-, 2-, 5-, or 10-year intervals followed by treatment with angiotensin-converting enzyme inhibitors or angiotensin II receptor blockers. We considered universal screening, as well as screening targeted at persons with diabetes, persons with hypertension but no diabetes, and persons with neither diabetes nor hypertension. OUTCOMES: Costs, quality-adjusted life-years (QALYs), and incremental cost-effectiveness ratios. RESULTS: For the full model population, universal screening increases costs and increases QALYs. Universal annual screening starting at age 50 years has a cost-effectiveness ratio of $73,000/QALY relative to no screening and $145,000/QALY relative to usual care. Cost-effectiveness ratios improved with longer screening intervals. Relative to no screening, targeted annual screening has cost-effectiveness ratios of $21,000/QALY, $55,000/QALY, and $155,000/QALY for persons with diabetes, those with hypertension, and those with neither current diabetes nor current hypertension, respectively. LIMITATIONS: Results necessarily are based on a microsimulation model because of the long time horizon appropriate for chronic kidney disease. The model includes only health care costs. CONCLUSIONS: Microalbuminuria screening is cost-effective for patients with diabetes or hypertension, but is not cost-effective for patients with neither diabetes nor hypertension unless screening is conducted at longer intervals or as part of existing physician visits.

A health policy model of CKD: 1. Model construction, assumptions, and validation of health consequences.

BACKGROUND: A cost-effectiveness model that accurately represents disease progression, outcomes, and associated costs is necessary to evaluate the cost-effectiveness of interventions for chronic kidney disease (CKD). STUDY DESIGN: We developed a microsimulation model of the incidence, progression, and treatment of CKD. The model was validated by comparing its predictions with survey and epidemiologic data sources. SETTING & POPULATION: US patients. MODEL, PERSPECTIVE, & TIMEFRAME: The model follows up disease progression in a cohort of simulated patients aged 30 until age 90 years or death. The model consists of 7 mutually exclusive states representing no CKD, 5 stages of CKD, and death. Progression through the stages is governed by a person's glomerular filtration rate and albuminuria status. Diabetes, hypertension, and other risk factors influence CKD and the development of CKD complications in the model. Costs are evaluated from the health care system perspective. INTERVENTION: Usual care, including incidental screening for persons with diabetes or hypertension. OUTCOMES: Progression to CKD stages, complications, and mortality. RESULTS: The model provides reasonably accurate estimates of CKD prevalence by stage. The model predicts that 47.1% of 30-year-olds will develop CKD during their lifetime, with 1.7%, 6.9%, 27.3%, 6.9%, and 4.4% ending at stages 1-5, respectively. Approximately 11% of persons who reach stage 3 will eventually progress to stage 5. The model also predicts that 3.7% of persons will develop end-stage renal disease compared with an estimate of 3.0% based on current end-stage renal disease lifetime incidence. LIMITATIONS: The model synthesizes data from multiple sources rather than a single source and relies on explicit assumptions about progression. The model does not include acute kidney failure. CONCLUSION: The model is well validated and can be used to evaluate the cost-effectiveness of CKD interventions. The model also can be updated as better data for CKD progression become available.

The association between health risks and medical expenditures in a Japanese corporation.

PURPOSE: To examine the relationship between health risks and medical care expenditures in an employer setting in Japan. DESIGN: A cross-sectional, correlational study. SETTING: A large Japanese corporation. SUBJECTS: A total of 6543 employees of a large Japanese electronics company, for whom medical expenditures, lifestyle risks and biometric data were available, were included in the analysis. Seventy-six Percent were male, and subjects were primarily white-collar workers. MEASURES: Medical expenditure data were available for fiscal year 2000, including inpatient, outpatient, and total expenditures, measured in Japanese yen. Binary expenditure indicators for those having no claims and those having high claims (90th percentile) were also created. Risk measures included biometric assessment of high blood pressure and high body mass index (BMI, body weight and height) and self-reported stress, lack of exercise, excess alcohol consumption, poor nutrition, current smoking, and recent quitting. High cholesterol and high blood glucose measures were also available for some subjects from company physicals. RESULTS: Average total expenditures were 48,017 yen (US$445). The 90th percentile of the expenditure distribution was approximately 111,750yen (US$1037). The most commonly reported risk factors were lack of exercise (52.9%), current smoking (35 %), stress (33%), and poor nutritional habits (23.6%). Least common were recently quitting smoking (2%), high blood pressure (4.1 %), and high blood glucose (9.4 %). The prevalence of overweight or obesity was 15.9%. High blood pressure and recent quitting were consistently related to high expenditures, after adjusting for the influence of other predictors. Adjusted expenditures were 76 % higher for recent quitters and 22.6% higher for employees with high blood pressure. Males and younger employees had consistently lower expenditures. Current smoking poor nutrition, and alcohol risk were also associated with lower expenditures. Those with multiple cardiovascular risk factors had adjusted medical expenditures that were 128% higher than those with no cardiovascular risks. Those who had multiple risk factors for stroke had expenditures that were 13% lower than those without stroke risk factors. CONCLUSIONS: This paper represents a first step in examining the association between health risks and medical expenditures in Japanese employees. The investigation uncovered some significant levels of risk for lack of exercise, smoking, and stress. Although results indicate some significant associations between health risks and medical expenditures, several unexpected assocations were noted that require further study. Such information provides a solid foundation for health promotion efforts in Japan and direction for subsequent investigations of health risks and medical expenditures. Future studies should address important issues of health risk measurement, data collection, and research design.

Synthesis and structural analysis of 6-deoxy-6-hydroxyphosphinyl-D-fructopyranose derivatives.

3,4-Di-O-benzyl-6-deoxy-6-diethoxyphosphinyl-1,2-O-isopropylidene-beta-D-fructofuranose (13) was prepared from the known 1,2-O-isopropylidene-6-O-tosyl-beta-D-fructofuranose in five steps. Reduction of 13 with sodium dihydrobis(2-methoxyethoxy)aluminate, followed by the action of hydrochloric acid and then hydrogen peroxide, afforded the 6-deoxy-6-hydroxyphosphinyl-D-fructopyranose derivative. This was converted into the 1,2,3,4,5-penta-O-acetyl-6-deoxy-6-methoxyphosphinyl-D-fructopyranoses, whose structure and conformation were established by 1H NMR spectroscopy.

Cost-effectiveness of a national population-based screening program for type 2 diabetes: the Brazil experience.

BACKGROUND: The cost-effectiveness of screening for type 2 diabetes mellitus (DM2) in developing countries remains unknown. The Brazilian government conducted a nationwide population screening program for type 2 diabetes mellitus (BNDSP) in which 22 million capillary glucose tests were performed in individuals aged 40 years and older. The objective of this study was to evaluate the life-time cost-effectiveness of a national population-based screening program for DM2 conducted in Brazil. METHODS: We used a Markov-based cost-effectiveness model to simulate the long-term costs and benefits of screening for DM2, compared to no screening program. The analysis was conducted from a public health care system perspective. Sensitivity analyses were conducted to examine the robustness of results to key model parameters. RESULTS: Brazilian National diabetes screening program will yield a large health benefit and higher costs. Compared with no screening, screen detection of undiagnosed diabetes resulted in US$ 31,147 per QALY gained. Results from sensitivity analyses found that screening targeted at hypertensive individuals would cost US$ 22,695/QALY. When benefits from early glycemic control on cardiovascular outcomes were considered, the cost per QALY gained would reduce significantly. CONCLUSIONS: In the base case analysis, not considering the intangible benefit of transferring diabetes management to primary care nor the benefit of using statin to treat eligible diabetic patients, CE ratios were not cost-effective considering thresholds proposed by the World Health Organization. However, significant uncertainty was demonstrated in sensitivity analysis. Our results indicate that policy-makers should carefully balance the benefit and cost of the program while considering using a population-based approach to screen for diabetes.

Secular trends in diabetes-related preventable hospitalizations in the United States, 1998-2006.

OBJECTIVE: To examine secular trends in diabetes-related preventable hospitalizations among adults with diabetes in the U.S. from 1998 to 2006. RESEARCH DESIGN AND METHODS: We used nationally representative data from the National Inpatient Sample to identify diabetes-related preventable hospitalizations. Based on the Agency for Healthcare Research and Quality's Prevention Quality Indicators, we considered that hospitalizations associated with the following four conditions were preventable: uncontrolled diabetes, short-term complications, long-term complications, and lower-extremity amputations. Estimates of the number of adults with diabetes were obtained from the National Health Interview Survey. Rates of hospitalizations among adults with diabetes were derived and tested for trends. RESULTS: Age-adjusted rates for overall diabetes-related preventable hospitalizations per 100 adults with diabetes declined 27%, from 5.2 to 3.8 during 1998-2006 (P(trend) < 0.01). This rate decreased significantly for all but not for short-term complication (58% for uncontrolled diabetes, 37% for lower-extremity amputations, 23% for long-term complications [all P < 0.01], and 15% for the short-term complication [P = 0.18]). Stratified by age-group and condition, the decline was significant for all age-condition groups (all P < 0.05) except short-term complications (P = 0.33) and long-term complications (P = 0.08) for the age-group 18-44 years. The decrease was significant for all sex-condition combination subgroups (all P < 0.01). CONCLUSIONS: We found a decrease in diabetes-related preventable hospitalizations in the U.S. from 1998 to 2006. This trend could reflect improvements in quality of primary care for individuals with diabetes.

The association of BMI with functional status and self-rated health in US adults.

OBJECTIVE: To examine the association of BMI with functional status and self-rated health among US adults and how the association differs by age and sex. METHODS AND PROCEDURES: All analyses are based on the National Health Interview Survey (NHIS), 1997-2005, a yearly, representative study of the US household population. We pooled all survey years and fitted logistic regression for the two sexes and three age strata (ages 18-44, 45-64, and > or =65). RESULTS: Our study found that although underweight and severe obesity are consistently associated with increased disability and poorer health status, overweight and moderate obesity show associations that vary considerably by age and sex. For men, the adjusted odds ratios (ORs) for disability and poor/fair self-rated health tended to be lowest among overweight persons, especially for ages > or =45. Among men with moderate obesity, the risk of disability was elevated for ages 18-44 but lower for ages > or =65. For women, the adjusted ORs for disability and poor/fair self-rated health tended to be lowest among normal-weight persons, particularly for ages < or =45. Compared to normal-weight counterparts, overweight women aged > or =65 had a lower risk of disability but a somewhat elevated risk of poor/fair self-rated health. DISCUSSION: The results suggest that the association of BMI with functional status and self-rated health varies significantly across ages and sexes. The variations in the association of BMI with functional status and self-rated health suggest that a single "ideal body weight category" may not be appropriate for all persons or all health outcomes.

The relationship between age and healthcare expenditure among persons with diabetes mellitus.

Few studies have examined how a person's age is related to healthcare expenditure among individuals with chronic conditions. The authors reviewed and examined the association between age and healthcare expenditure among persons with diabetes. Crude healthcare expenditure increases with age. Excluding expenditure associated with long-term and home healthcare, medical costs per person peaks at approximately 80 years of age. For males, persons aged 19-34 years had the lowest per-person medical costs, but, for females, those aged 0-18 years had the lowest per-person medical cost. Healthcare expenditure associated with long-term care and home care increased exponentially beyond 65 years of age. There were considerable differences between sexes in terms of the association of age with healthcare expenditure. Age is not a cause for increased healthcare costs; it is the ageing process and the increased likelihood of morbidity and mortality that comes with increasing age that lead to an increase in costs. The three dominant factors that mediate the positive relationship between age and healthcare expenditure are i) the high medical cost associated with death and the increasing likelihood of death with age; ii) increasing long-term and home care with age, particularly among the very elderly; and iii) the rising number and severity of diabetes-related complications with age. A person's age has no effect or a minimal positive effect on a person's demand for healthcare and total healthcare spending, after adjusting other covariates among persons with diabetes. The aging of populations should have a small impact on future healthcare expenditure. Including non-traditional factors in the cost model, such as proximity to death and prevalence of future diabetes-related complications, would improve the prediction of future healthcare expenditure for persons with diabetes.

The A-type cyclin CYCA2;3 is a key regulator of ploidy levels in Arabidopsis endoreduplication.

Plant cells frequently undergo endoreduplication, a process in which chromosomal DNA is successively duplicated in the absence of mitosis. It has been proposed that endoreduplication is regulated at its entry by mitotic cyclin-dependent kinase activity. However, the regulatory mechanisms for its termination remain unclear, although plants tightly control the ploidy level in each cell type. In the process of searching for regulatory factors of endoreduplication, the promoter of an Arabidopsis thaliana cyclin A gene, CYCA2;3, was revealed to be active in developing trichomes during the termination period of endoreduplication as well as in proliferating tissues. Taking advantage of the situation that plants encode highly redundant cyclin A genes, we were able to perform functional dissection of CYCA2;3 using null mutant alleles. Null mutations of CYCA2;3 semidominantly promoted endocycles and increased the ploidy levels achieved in mature organs, but they did not significantly affect the proportion of cells that underwent endoreduplication. Consistent with this result, expression of the CYCA2;3-green fluorescent protein fusion protein restrained endocycles in a dose-dependent manner. Moreover, a mutation in the destruction box of CYCA2;3 stabilized the fusion protein in the nuclei and enhanced the restraint. We conclude that CYCA2;3 negatively regulates endocycles and acts as a key regulator of ploidy levels in Arabidopsis endoreduplication.