Increased metabolic rate and insulin sensitivity in male mice lacking the carcino-embryonic antigen-related cell adhesion molecule 2.

AIMS/HYPOTHESIS: The carcino-embryonic antigen-related cell adhesion molecule (CEACAM)2 is produced in many feeding control centres in the brain, but not in peripheral insulin-targeted tissues. Global Ceacam2 null mutation causes insulin resistance and obesity resulting from hyperphagia and hypometabolism in female Ceacam2 homozygous null mutant mice (Cc2 [also known as Ceacam2](-/-)) mice. Because male mice are not obese, the current study examined their metabolic phenotype. METHODS: The phenotype of male Cc2(-/-) mice was characterised by body fat composition, indirect calorimetry, hyperinsulinaemic-euglycaemic clamp analysis and direct recording of sympathetic nerve activity. RESULTS: Despite hyperphagia, total fat mass was reduced, owing to the hypermetabolic state in male Cc2(-/-) mice. In contrast to females, male mice also exhibited insulin sensitivity with elevated ß-oxidation in skeletal muscle, which is likely to offset the effects of increased food intake. Males and females had increased brown adipogenesis. However, only males had increased activation of sympathetic tone regulation of adipose tissue and increased spontaneous activity. The mechanisms underlying sexual dimorphism in energy balance with the loss of Ceacam2 remain unknown. CONCLUSIONS/INTERPRETATION: These studies identified a novel role for CEACAM2 in the regulation of metabolic rate and insulin sensitivity via effects on brown adipogenesis, sympathetic nervous outflow to brown adipose tissue, spontaneous activity and energy expenditure in skeletal muscle.

Stimulation of human 8-oxoguanine-DNA glycosylase by AP-endonuclease: potential coordination of the initial steps in base excision repair.

8-Oxoguanine-DNA glycosylase 1 (OGG1), with intrinsic AP lyase activity, is the major enzyme for repairing 7,8-dihydro-8-oxoguanine (8-oxoG), a critical mutagenic DNA lesion induced by reactive oxygen species. Human OGG1 excised the damaged base from an 8-oxoG. C-containing duplex oligo with a very low apparent k(cat) of 0.1 min(-1) at 37 degrees C and cleaved abasic (AP) sites at half the rate, thus leaving abasic sites as the major product. Excision of 8-oxoG by OGG1 alone did not follow Michaelis-Menten kinetics. However, in the presence of a comparable amount of human AP endonuclease (APE1) the specific activity of OGG1 was increased approximately 5-fold and Michaelis-Menten kinetics were observed. Inactive APE1, at a higher molar ratio, and a bacterial APE (Nfo) similarly enhanced OGG1 activity. The affinity of OGG1 for its product AP.C pair (K:(d) approximately 2.8 nM) was substantially higher than for its substrate 8-oxoG.C pair (K:(d) approximately 23. 4 nM) and the affinity for its final ss-elimination product was much lower (K:(d) approximately 233 nM). These data, as well as single burst kinetics studies, indicate that the enzyme remains tightly bound to its AP product following base excision and that APE1 prevents its reassociation with its product, thus enhancing OGG1 turnover. These results suggest coordinated functions of OGG1 and APE1, and possibly other enzymes, in the DNA base excision repair pathway.

Multiple DNA glycosylases for repair of 8-oxoguanine and their potential in vivo functions.

8-Oxoguanine (8-oxoG) is a critical mutagenic lesion because of its propensity to mispair with A during DNA replication. All organisms, from bacteria to mammals, express at least two types of 8-oxoguanine-DNA glycosylase (OGG) for repair of 8-oxoG. The major enzyme class (OGG1), first identified in Escherichia coli as MutM (Fpg), and later in yeast and humans, excises 8-oxoG when paired with C, T, and G but rarely with A. In contrast, a distinct and less abundant OGG, OGG2, prefers 8-oxoG when paired with G and A as a substrate, and has been characterized in yeast and human cells. Recently, OGG2 activity was detected in E. coli which was subsequently identified to be Nei (Endo VIII). In view of the ubiquity of OGG2, we have proposed a model named "bipartite antimutagenic processing of 8-oxoguanine" and is an extension of the original "GO model." The GO model explains the presence of OGG1 (MutM) that excises 8-oxoG from nonreplicated DNA. If 8-oxoG mispairs with A during replication, MutY excises A and provides an opportunity for insertion of C opposite 8-oxoG during subsequent repair replication. Our model postulates that whereas OGG1 (MutM) is responsible for global repair of 8-oxoG in the nonreplicating genome, OGG2 (Nei) repairs 8-oxoG in nascent or transcriptionally active DNA. Interestingly, we observed that MutY and MutM reciprocally inhibited each other's catalytic activity but observed no mutual interference between Nei and MutY. This suggests that the recognition sites on the same substrate for Nei and MutY are nonoverlapping. Human OGG1 is distinct from other oxidized base-specific DNA glycosylases because of its extremely low turnover, weak AP lyase activity, and nonproductive affinity for the abasic (AP) site, its first reaction product. OGG1 is activated nearly 5-fold in the presence of AP-endonuclease (APE) as a result of its displacement by the latter. These results support the "handoff" mechanism of BER in which the enzymatic steps are coordinated as a result of displacement of the DNA glycosylase by APE, the next enzyme in the pathway. The physiological significance of multiple OGGs and their in vivo reaction mechanisms remain to be elucidated by further studies.

Regulation of hypothalamic neuropeptide Y Y1 receptor gene expression during the estrous cycle: role of progesterone receptors.

Neuropeptide Y (NPY) stimulates the release of GnRH in an estrogen (E2)-dependent manner, which is important in generating preovulatory GnRH surges. We tested the hypothesis that E2 up-regulates NPY's actions by stimulating NPY Y1 receptor (Y1r) gene expression through a mechanism mediated by E2's ability to induce progesterone (P) receptors (PRs). In initial experiments, a specific Y1r antagonist BIBP3226 was used to confirm the involvement of Y1r in the stimulatory effects of NPY on in vivo GnRH release. Hypothalamic Y1r messenger RNA (mRNA) levels were then measured using competitive RT-PCR and were found to be significantly increased at 1000, 1200, and 1400 h on proestrus compared with other times of the day or cycle stage. Ovariectomy eliminated these increases, and E2 treatment restored them. Additional P treatment produced even larger increases in Y1r mRNA levels. To assess the role of PRs in stimulating Y1r expression, proestrous rats were treated with PR antagonist or oil vehicle and killed at 1200 h. Treatment with PR antagonist completely blocked the proestrous rise in Y1r gene expression. In parallel experiments, the same in vivo PR antagonist treatments also blocked NPY stimulation of GnRH release in vitro. Together our findings reveal that 1) Y1r mRNA levels are increased during the late morning and afternoon of proestrus; 2) Y1r mRNA levels are similarly increased by E2, and to an even greater extent by additional P; and 3) PR antagonism blocks both increased Y1r mRNA and induction of GnRH responsiveness to NPY. These observations support the idea that E2 up-regulates GnRH neuronal responses to NPY through stimulation of Y1r gene expression, and that E2's actions are mediated by the induction and subsequent activation of PRs.

Alzheimer's disease and related dementias increase costs of comorbidities in managed Medicare.

OBJECTIVES: To analyze the relationship between comorbid conditions and costs for patients with AD and related dementias (ADRD) in a Medicare managed care organization (MCO). To derive implications for improving management of patients with ADRD. METHODS: Retrospective analysis was carried out on administrative data for 3,934 patients with ADRD and 19,300 age/sex-matched control subjects enrolled in a large Medicare MCO. Patients with ADRD were identified from diagnoses on medical claims and encounter data for a 2-year period. Control subjects were selected from health plan members without dementia. Comorbid conditions were based on the diagnostic classifications from the Charlson comorbidity index. Health care costs and utilization for MCO-covered services for cases were compared with those of control subjects. RESULTS: Prevalence of ADRD was 4.4%, substantially higher than reported in previous studies of Medicare managed care and similar to population-based estimates. After controlling for comorbid conditions, age, and sex, annual costs were $4,134 higher for ADRD patients, resulting in excess costs of $16 million to the MCO. For the 10 most prevalent comorbidities in ADRD patients, adjusted costs were higher for ADRD patients compared with control subjects with the same condition. Higher costs were attributable to higher inpatient and skilled nursing facility utilization. CONCLUSIONS: In this study, prevalence rates for ADRD mirrored population estimates. Costs for patients with ADRD in this Medicare MCO varied considerably by comorbid condition and were substantially higher for patients with both AD and comorbid diseases commonly targeted for disease management, indicating that AD increases costs through effects on the management of comorbid illnesses. These findings indicate that better treatment and care management of AD could reduce the costs of comorbid illnesses commonly experienced by the frail elderly.

"Single-exposure" dual energy digital radiography in the detection of pulmonary nodules and calcifications.

We studied the detectability of mineralized and non-mineralized simulated pulmonary nodules with dual energy digital radiography. "Soft tissue" and "bone" images (pixel size = 0.2 mm, 10 bits deep) were obtained with subtraction image processing after a single simultaneous exposure (100 kVp, 8 mAs, 17 mR skin exposure dose) of two storage phosphors with an interleaved 0.9 mm copper wafer. Three classes of paraffin-based nodules (0.5 to 3.0 cm) of varying mineral concentration (0, 120 and 190 mg/cm3 K2HPO4) were randomly positioned on the chest wall of two healthy volunteers to simulate calcified and non-calcified nodules. The average receiver operating characteristics (ROC) area of six readers (n = 2880 observations) showed that digital "bone" images (ROC area: 0.77 +/- 0.03) were significantly better (P less than 0.04) than conventional radiographs (OC Film, Lanex medium screens, 141 kVp, 19 mR skin exposure dose) (ROC area: 0.71 +/- 0.05) in detecting calcification in nodules. The unsubtracted digital images of lower kilovoltage were not superior to the 141 kVp conventional radiographs in a subgroup of two readers (ROC area: 0.73 +/- 0.02). Digital "soft tissue" images were equivalent to conventional chest radiographs in detecting soft tissue pulmonary nodules (ROC areas: 0.92 +/- 0.04 and 0.92 +/- 0.05, respectively.

Satisfaction and choice: a view from the plans.

Community-wide surveys have demonstrated that managed care enrollees tend to express higher satisfaction with their health plan if they have been given the opportunity to make a choice between managed care and fee-for-service plans. This DataWatch shows similar results with plan-specific data, even for enrollees whose plan benefits include coverage for out-of-network services. That is, what matters seems to be choice at the time of enrollment, not at the point of service. Further, in the practical application of ranking plans on overall enrollee satisfaction, choice appears to be a more important influence than other factors that may receive attention, including enrollees' health status. We discuss this phenomenon with respect to competition and strategy in the managed care marketplace.

Characterization of lipoprotein a by capillary zone electrophoresis.

Lipoprotein a [Lp(a)] has been recognized as a significant marker for premature coronary heart disease (CHD). In this paper, we present the results of Lp(a) analysis based on capillary zone electrophoresis (CZE). CZE separation of Lp(a) and its reduced species, lipoprotein a- [Lp(a-)] and apolipoprotein a [apo(a)], was accomplished using 50 mM borate buffer containing 3.5 mM sodium dodecyl sulfate (SDS) and 20% (v/v) acetonitrile (ACN). Low density lipoprotein (LDL) and high density lipoprotein (HDL) were separated under the same buffer conditions. The electrophoretic mobilities of both Lp(a) and Lp(a-) were found to be different from that of LDL. Benzyl alcohol (BA) and methanol (MeOH) were used as electroosmotic flow markers. BA molecules associated with Lp(a-) and LDL to enhance their UV absorbance, but did not change their effective electrophoretic mobilities. Our results show that CE is a very efficient and effective technique for lipoprotein analysis.

Do health maintenance organizations work for Medicare?

Since 1985, the Health Care Financing Administration (HCFA) has encouraged health maintenance organizations (HMOs) to provide Medicare coverage to enrolled beneficiaries for fixed prepaid premiums. Our evaluation shows that the risk program achieves some of its goals while not fulfilling others. We find that HMOs provide care of comparable quality to that delivered by free-for-service (FFS) providers using fewer health care resources. Enrollees experience substantially reduced out-of-pocket costs and greater coverage. However, because the capitation system does not account for the better health of those who enroll, the program does not save money for Medicare.

Aspirin treatment after myocardial infarction: are health maintenance organization members, women, and the elderly undertreated?

In April 1996, we surveyed 539 patients who had suffered a myocardial infarction in 1995 to determine whether the prescription and use of aspirin after myocardial infarction differs by patient age, sex, and type of health insurance. Patients who were insured through one of four health maintenance organizations in major metropolitan areas or by an indemnity plan in 40 states completed the survey. Among the 502 patients with no contraindications to use, 93.8% were prescribed aspirin. Among patients with a prescription and no subsequent contraindications to use, 96.4% were taking aspirin when surveyed. Among aspirin users, 96.5% reported taking aspirin daily. Controlling for other characteristics, 75-year-old patients were 5 percentage points less likely to receive a prescription for aspirin than were 50-year-old patients (P = 0.05). Although not significant at conventional levels, point estimates revealed a prescription rate for women that was 6 percentage points higher than that for men (P = 0.054) and a rate for health maintenance organization members that was 4 percentage points lower than that for patients with indemnity insurance (P = 0.10). Aspirin use was lower among older patients (P = 0.02) but did not differ by gender or type of insurance plan. Health maintenance organization members were just as likely to receive a prescription from a specialist as were those with indemnity insurance (P = 0.92). Based on these results, the rate of aspirin treatment after myocardial infarction may be much higher than previous studies indicate. Concerns that managed care patients and women may be undertreated are not supported by our findings. Although older patients are at risk for undertreatment, this risk is low. Once aspirin is prescribed, selfreported patient compliance with a daily regimen of aspirin is high.

Family relationships in survivors of childhood cancer: resource or restraint?

Family relationships may be an important mediator between childhood cancer and psychosocial adjustment in adult life. This paper focuses on the developmental task of the transition from adolescence to adulthood, with regard to the cancer survivor's family relationships. Theories, concepts and findings relevant to this specific focus are considered in relation to whether these relationships may prove a resource or a restraint in this process. Potential aspects of family relationships that may be of interest to research are discussed, and clinical implications drawn.

Exercise prescription.

Exercise seems to be an effective, safe and cost effective treatment modality for mildly depressed and anxious patients. The exercise should be aerobic in nature. Individuality of prescription and frequent follow-up with attainable, reasonable goals are important. Physician interest should be high, and the patient should feel ownership of the program. Progression should be slow to lessen drop-out frequency.

Benefit-cost analysis of supported competitive employment for persons with mental retardation.

A review of the literature on unemployment rates among adults with mental retardation is presented and the societal impact of the number of adults with mental retardation who remain unemployed is discussed. The supported competitive employment model is presented as illustrative of a habilitation program allowing greater monetary returns to society than traditional adult service programs. A benefit-cost analysis of our supported competitive employment program, occurring during the period from 1978 to 1986, is presented from two perspectives: that of the consumer (i.e., the adult with severe disabilities) and that of the taxpayer. Results of the benefit-cost analysis indicate that supported competitive employment is a financially prosperous venture from both perspectives. That is, from the consumers' perspective, for every $1.00 relinquished in taxes, supplemental security income (SSI), and forgone workshop earnings, $1.97 was received in increased income; the net benefit per year was $3,894 consumer. From the taxpayers' perspective, for every $1.00 expended for the funding of supported competitive employment programs and in lost tax revenues realized by the provision of targeted jobs tax credits, $1.87 was accumulated in benefits; the net yearly benefit to the taxpayer was $4,063 per consumer. The authors conclude that supported competitive employment is a financially profitable venture for both consumers and taxpayers.

How does HEDIS affect quality improvement strategies in an HMO?

To meet the demands of the marketplace, health plans devote considerable resources to comply with Health Plan Employer Data and Information Set (HEDIS) reporting standards and to improve performance along those measures. Given HEDIS's growing prominence, one might question whether it plays a major role in the formulation of an HMO's quality improvement strategies. The experience at NYLCare Health Plans, Inc., suggests that quality improvement strategies should focus on strengthening the ability of HMOs to meet the more general agenda of quality measurement and improvement, and not just requirements specific to HEDIS.

Advanced telepresence surgery system development.

SRI International is currently developing a prototype remote telepresence surgery system, for the Advanced Research Projects Agency (ARPA), that will bring life-saving surgical care to wounded soldiers in the zone of combat. Remote surgery also has potentially important applications in civilian medicine. In addition, telepresence will find wide medical use in local surgery, in endoscopic, laparoscopic, and microsurgery applications. Key elements of the telepresence technology now being developed for ARPA, including the telepresence surgeon's workstation (TSW) and associated servo control systems, will have direct application to these areas of minimally invasive surgery. The TSW technology will also find use in surgical training, where it will provide an immersive visual and haptic interface for interaction with computer-based anatomical models. In this paper, we discuss our ongoing development of the MEDFAST telesurgery system, focusing on the TSW man-machine interface and its associated servo control electronics.

Telepresence interface with applications to microsurgery and surgical simulation.

To address the needs for performing microsurgical procedures, the SRI telepresence surgery workstation has been combined with a pair of micromanipulator arms. The prototype microsurgery system has been tested with ex-vivo tasks similar to those required for surgical procedures, such as cutting, grasping, suturing, and knot tying. Initial animal testing has been done on a rat model in which end-to-end anastomosis of the femoral artery (approximately 1 millimeter in diameter) was completed with ten rats, and 100% patency was obtained. To address the needs of surgical training, SRI has begun to develop a system that uses a 6-DOF telepresence workstation. A computer-generated stereo image is reflected in a mirror and appears to be superimposed on the surgeon's hands, creating an immersive and realistic environment. Tools held in the surgeon's hands are connected to left- and right-hand manipulators that both continuously measure tool position/orientation and apply force/torque to the tools. Furthermore, the visual image and tool locations are registered, so that the user perceives that he or she is looking at and moving the simulated tools in the visual image.

Intranuclear matrix metalloproteinases promote DNA damage and apoptosis induced by oxygen-glucose deprivation in neurons.

Degradation of the extracellular matrix by elevated matrix metalloproteinase (MMP) activity following ischemia/reperfusion is implicated in blood-brain barrier disruption and neuronal death. In contrast to their characterized extracellular roles, we previously reported that elevated intranuclear MMP-2 and -9 (gelatinase) activity degrades nuclear DNA repair proteins and promotes accumulation of oxidative DNA damage in neurons in rat brain at 3-h reperfusion after ischemic stroke. Here, we report that treatment with a broad-spectrum MMP inhibitor significantly reduced neuronal apoptosis in rat ischemic hemispheres at 48-h reperfusion after a 90-min middle cerebral artery occlusion (MCAO). Since extracellular gelatinases in brain tissue are known to be neurotoxic during acute stroke, the contribution of intranuclear MMP-2 and -9 activities in neurons to neuronal apoptosis has been unclear. To confirm and extend our in vivo observations, oxygen-glucose deprivation (OGD), an in vitro model of ischemia/reperfusion, was employed. Primary cortical neurons were subjected to 2-h OGD with reoxygenation. Increased intranuclear gelatinase activity was detected immediately after reoxygenation onset and was maximal at 24h, while extracellular gelatinase levels remained unchanged. We detected elevated levels of both MMP-2 and -9 in neuronal nuclear extracts and gelatinase activity in neurons co-localized primarily with MMP-2. We found a marked decrease in PARP1, XRCC1, and OGG1, and decreased PARP1 activity. Pretreatment of neurons with selective MMP-2/9 inhibitor II significantly decreased gelatinase activity and downregulation of DNA repair enzymes, decreased accumulation of oxidative DNA damage, and promoted neuronal survival after OGD. Our results confirm the nuclear localization of gelatinases and their nuclear substrates observed in an animal stroke model, further supporting a novel role for intranuclear gelatinase activity in an intrinsic apoptotic pathway in neurons during acute stroke injury.

Hemoglobin decline in chemotherapy patients prior to and after policy changes affecting use of erythropoiesis-stimulating agents: 2006-2009.

OBJECTIVE: Since 2007, the use of erythropoiesis-stimulating agents (ESAs) to treat anemia in cancer patients receiving chemotherapy has been increasingly restricted in the USA. This study assessed hemoglobin (Hb) decline over time among chemotherapy patients. METHODS: Episodes of chemotherapy care were identified in a large US-oncology electronic medical record database; weekly Hb levels were computed in the first 8 weeks. Unadjusted and adjusted proportions of patient-weeks with Hb decline>1 g/dl (i.e. representing clinically significant decline) within 1 or 2 weeks were analyzed. RESULTS: Between 2006 and 2009, unadjusted proportions of patient-weeks with Hb decline>1 g/dl increased (1-week, from 12.7% to 14.9%; 2-week, from 19.3% to 26.3%). Adjusted 1-week proportions in 2007 were similar to 2006, but increased in 2008 (odds ratio [OR] 1.135; 95% confidence intervals [CI] 1.067, 1.208) and in 2009 (OR 1.235; 95% CI 1.094, 1.395). Adjusted 2-week proportions had the same pattern. CONCLUSIONS: Since restrictions on ESA use were introduced in the USA, more patients have experienced a clinically significant Hb decline after chemotherapy initiation. Initiating anemia therapy at the earliest indicated opportunity may help reduce the risk of such declines.

ApoA-1 mimetic restores adiponectin expression and insulin sensitivity independent of changes in body weight in female obese mice.

BACKGROUND: We examined the ability of the apolipoprotein AI mimetic peptide L-4F to improve the metabolic state of female and male ob mice and the mechanisms involved. METHODS: Female and male lean and obese (ob) mice were administered L-4F or vehicle for 6 weeks. Body weight was measured weekly. Fat distribution, serum cytokines and markers of cardiovascular dysfunction were determined at the end of treatment. RESULTS: L-4F significantly decreased serum interleukin (IL)-6, tumor necrosis factor-α and IL-1ß. L-4F improved vascular function, and increased serum adiponectin levels and insulin sensitivity compared with untreated mice. In addition, L-4F treatment increased heme oxygenase (HO)-1, pAKT and pAMPK levels in kidneys of ob animals. pAKT and pAMPK levels were significantly reduced in the presence of an HO inhibitor. Interestingly, L4F did not alter body weight in female mice, but caused a significant reduction in males. CONCLUSIONS: L-4F treatments reduced cardiovascular risk factors and improved insulin sensitivity in female ob mice independent of body fat changes. Reduced inflammatory cytokine levels accompanied by increased HO activity, serum adiponectin and improved insulin sensitivity suggest that L-4F may promote the conversion of visceral fat to a healthier phenotype. Therefore, L-4F appears to be a promising therapeutic strategy for treating both cardiovascular risk factors and insulin resistance in obese patients of either gender.