Cardiorenal End Points in a Trial of Aliskiren for Type 2 Diabetes

BACKGROUND: This study was undertaken to determine whether use of the direct renin inhibitor aliskiren would reduce cardiovascular and renal events in patients with type 2 diabetes and chronic kidney disease, cardiovascular disease, or both. METHODS: In a double-blind fashion, we randomly assigned 8561 patients to aliskiren (300 mg daily) or placebo as an adjunct to an angiotensin-converting-enzyme inhibitor or an angiotensin-receptor blocker. The primary end point was a composite of the time to cardiovascular death or a first occurrence of cardiac arrest with resuscitation; nonfatal myocardial infarction; nonfatal stroke; unplanned hospitalization for heart failure; end-stage renal disease, death attributable to kidney failure, or the need for renal-replacement therapy with no dialysis or transplantation available or initiated; or doubling of the baseline serum creatinine level. RESULTS: The trial was stopped prematurely after the second interim efficacy analysis. After a median follow-up of 32.9 months, the primary end point had occurred in 783 patients (18.3%) assigned to aliskiren as compared with 732 (17.1%) assigned to placebo (hazard ratio, 1.08; 95% confidence interval [CI], 0.98 to 1.20; P=0.12). Effects on secondary renal end points were similar. Systolic and diastolic blood pressures were lower with aliskiren (between-group differences, 1.3 and 0.6 mm Hg, respectively) and the mean reduction in the urinary albumin-to-creatinine ratio was greater (between-group difference, 14 percentage points; 95% CI, 11 to 17). The proportion of patients with hyperkalemia (serum potassium level, ≥6 mmol per liter) was significantly higher in the aliskiren group than in the placebo group (11.2% vs. 7.2%), as was the proportion with reported hypotension (12.1% vs. 8.3%) (P<0.001 for both comparisons). CONCLUSIONS: The addition of aliskiren to standard therapy with renin-angiotensin system blockade in patients with type 2 diabetes who are at high risk for cardiovascular and renal events is not supported by these data and may even be harmful. (Funded by Novartis; ALTITUDE ClinicalTrials.gov number, NCT00549757.).

New natural noncannabinoid ligands for cannabinoid type-2 (CB2) receptors

Since the discovery that Delta 9-tetrahydrocannabinol and related cannabinoids from Cannabis sativa L. act on specific physiological receptors in the human body and the subsequent elucidation of the mammalian endogenous cannabinoid system, no other natural product class has been reported to mimic the effects of cannabinoids. We recently found that N-alkyl amides from purple coneflower (Echinacea spp.) constitute a new class of cannabinomimetics, which specifically engage and activate the cannabinoid type-2 (CB2) receptors. Cannabinoid type-1 (CB1) and CB2 receptors belong to the family of G protein-coupled receptors and are the primary targets of the endogenous cannabinoids N-arachidonoyl ethanolamine and 2-arachidonoyl glyerol. CB2 receptors are believed to play an important role in distinct pathophysiological processes, including metabolic dysregulation, inflammation, pain, and bone loss. CB2 receptors have, therefore, become of interest as new targets in drug discovery. This review focuses on N-alkyl amide secondary metabolites from plants and underscores that this group of compounds may provide novel lead structures for the development of CB2-directed drugs.

Hypofibrinolysis in type 2 diabetes: the role of the inflammatory pathway and complement C3

AIMS/HYPOTHESIS Plasminogen activator inhibitor-1 (PAI-1) has been regarded as the main antifibrinolytic protein in diabetes, but recent work indicates that complement C3 (C3), an inflammatory protein, directly compromises fibrinolysis in type 1 diabetes. The aim of the current project was to investigate associations between C3 and fibrinolysis in a large cohort of individuals with type 2 diabetes. METHODS Plasma levels of C3, C-reactive protein (CRP), PAI-1 and fibrinogen were analysed by ELISA in 837 patients enrolled in the Edinburgh Type 2 Diabetes Study. Fibrin clot lysis was analysed using a validated turbidimetric assay. RESULTS Clot lysis time correlated with C3 and PAI-1 plasma levels (r = 0.24, p < 0.001 and r = 0.22, p < 0.001, respectively). In a multivariable regression model involving age, sex, BMI, C3, PAI-1, CRP and fibrinogen, and using log-transformed data as appropriate, C3 was associated with clot lysis time (regression coefficient 0.227 [95% CI 0.161, 0.292], p < 0.001), as was PAI-1 (regression coefficient 0.033 [95% CI 0.020, 0.064], p < 0.05) but not fibrinogen (regression coefficient 0.003 [95% CI -0.046, 0.051], p = 0.92) or CRP (regression coefficient 0.024 [95% CI -0.008, 0.056], p = 0.14). No correlation was demonstrated between plasma levels of C3 and PAI-1 (r = -0.03, p = 0.44), consistent with previous observations that the two proteins affect different pathways in the fibrinolytic system. CONCLUSIONS/INTERPRETATION Similarly to PAI-1, C3 plasma levels are independently associated with fibrin clot lysis in individuals with type 2 diabetes. Therefore, future studies should analyse C3 plasma levels as a surrogate marker of fibrinolysis potential in this population.

Quality of care for uninsured type 2 diabetic patients in a financial assistance medical home model

The medically uninsured population in the United States is 16% or 42 million people and consists of a significant number of Type 2 diabetic patients which is the predominant form of diabetes with 798,000 new cases diagnosed each year. There is limited health services research on uninsured populations concerning health system measures or specific disease conditions. ^ The purpose of this investigation was to determine the impact a newly implemented health care program had on the quality of care provided to patients with Type 2 diabetes. The primary study objective was to compare the quality of care while controlling for utilization, and health status of patients in the new program to their status during the previous financial assistance program. The research design was a retrospective matched-pairs design. The study population consisted of 225 patients who received medical care during 1996 and 1997 at the University Health System in San Antonio, Texas. ^ Six quality of care measures individually failed to demonstrate a statistically significant difference when compared between the two periods. However, an index measure reflecting the number of patients who received all six of the quality of care measures demonstrated a statistically significant increase in 1997 (p-value < 0.05). In 1996, 8 patients (2.6%) received all six medical management components. In 1997, 38 patients (16.8%) received all six medical management components. Four regression models were analyzed; two out of the four models demonstrated inconsistent results based on the program membership variable. ^ It is concluded that there has been a small effect of the Carelink program demonstrated by an increase from 8 to 38 patients receiving all quality of care components for Type 2 diabetics at the UHS. It is recommended that additional research be conducted in order to evaluate the quality of care provided to Type 2 diabetic patients. ^

Outcomes and cost effectiveness of treating type 2 diabetes with a nurse case manager following treatment algorithms versus primary care physicians

Background. Diabetes places a significant burden on the health care system. Reduction in blood glucose levels (HbA1c) reduces the risk of complications; however, little is known about the impact of disease management programs on medical costs for patients with diabetes. In 2001, economic costs associated with diabetes totaled $100 billion, and indirect costs totaled $54 billion. ^ Objective. To compare outcomes of nurse case management by treatment algorithms with conventional primary care for glycemic control and cardiovascular risk factors in type 2 diabetic patients in a low-income Mexican American community-based setting, and to compare the cost effectiveness of the two programs. Patient compliance was also assessed. ^ Research design and methods. An observational group-comparison to evaluate a treatment intervention for type 2 diabetes management was implemented at three out-patient health facilities in San Antonio, Texas. All eligible type 2 diabetic patients attending the clinics during 1994–1996 became part of the study. Data were obtained from the study database, medical records, hospital accounting, and pharmacy cost lists, and entered into a computerized database. Three groups were compared: a Community Clinic Nurse Case Manager (CC-TA) following treatment algorithms, a University Clinic Nurse Case Manager (UC-TA) following treatment algorithms, and Primary Care Physicians (PCP) following conventional care practices at a Family Practice Clinic. The algorithms provided a disease management model specifically for hyperglycemia, dyslipidemia, hypertension, and microalbuminuria that progressively moved the patient toward ideal goals through adjustments in medication, self-monitoring of blood glucose, meal planning, and reinforcement of diet and exercise. Cost effectiveness of hemoglobin AI, final endpoints was compared. ^ Results. There were 358 patients analyzed: 106 patients in CC-TA, 170 patients in UC-TA, and 82 patients in PCP groups. Change in hemoglobin A1c (HbA1c) was the primary outcome measured. HbA1c results were presented at baseline, 6 and 12 months for CC-TA (10.4%, 7.1%, 7.3%), UC-TA (10.5%, 7.1%, 7.2%), and PCP (10.0%, 8.5%, 8.7%). Mean patient compliance was 81%. Levels of cost effectiveness were significantly different between clinics. ^ Conclusion. Nurse case management with treatment algorithms significantly improved glycemic control in patients with type 2 diabetes, and was more cost effective. ^

The economic cost of type 2 diabetes attributable to physical inactivity in the United States and Texas in 2007

Type 2 diabetes has grown to epidemic proportions in the U.S., and its prevalence has been steadily increasing in Texas. The physical activity levels in the population have remained low despite it being one of the primary preventive strategies for type 2 diabetes. The objectives of this study were to estimate the direct medical costs of type 2 diabetes attributable to not meeting physical activity Guidelines and to physical inactivity in the U.S. and Texas in 2007. This was a cross sectional study that used physical activity prevalence data from the 2007 Behavioral Risk Factor Surveillance System (BRFSS) to estimate the population attributable risk percentage (PAR%) for type 2 diabetes. These data were combined with the prevalence and cost data of type 2 diabetes to estimate the cost of type 2 diabetes attributable to not meeting Guidelines and to inactivity in the U.S. and Texas in 2007.^ The cost of type 2 diabetes in the U.S. in 2007, attributable to not meeting physical activity Guidelines was estimated to be $13.29 billion, and that attributable to physical inactivity (no leisure time physical activity) was estimated to be $3.32 billion. Depending on various assumptions, these estimates ranged from $7.61 billion to $41.48 billion for not meeting Guidelines, and $1.90 billion to $13.20 billion for physical inactivity in the U.S. in 2007. The cost of type 2 diabetes in Texas in 2007 attributable to not meeting physical activity Guidelines was estimated to be $1.15 billion, and that attributable to physical inactivity (no leisure time physical activity) was estimated to be $325 million. Depending on various assumptions, these estimates ranged from $800 million to $3.47 billion for not meeting Guidelines, and $186 million to $1.28 billion for physical inactivity in Texas in 2007. These results illustrate how much money could be saved annually just in terms of type 2 diabetes cost in the U.S. and Texas, if the entire adult population was active enough to meet physical activity Guidelines. Physical activity promotion, particularly at the environmental and policy level should be a priority in the population. ^

Control of a solar dryer through using a fuzzy logic and low-cost model-based sensor

Solar drying is one of the important processes used for extending the shelf life of agricultural products. Regarding consumer requirements, solar drying should be more suitable in terms of curtailing total drying time and preserving product quality. Therefore, the objective of this study was to develop a fuzzy logic-based control system, which performs a ?human-operator-like? control approach through using the previously developed low-cost model-based sensors. Fuzzy logic toolbox of MatLab and Borland C++ Builder tool were utilized to develop a required control system. An experimental solar dryer, constructed by CONA SOLAR (Austria) was used during the development of the control system. Sensirion sensors were used to characterize the drying air at different positions in the dryer, and also the smart sensor SMART-1 was applied to be able to include the rate of wood water extraction into the control system (the difference of absolute humidity of the air between the outlet and the inlet of solar dryer is considered by SMART-1 to be the extracted water). A comprehensive test over a 3 week period for different fuzzy control models has been performed, and data, obtained from these experiments, were analyzed. Findings from this study would suggest that the developed fuzzy logic-based control system is able to tackle difficulties, related to the control of solar dryer process.

UAS See-and-Avoid Strategy using a Fuzzy Logic Controller Optimized by Cross-Entropy in Scaling Factors and Membership Functions

This work aims to develop a novel Cross-Entropy (CE) optimization-based fuzzy controller for Unmanned Aerial Monocular Vision-IMU System (UAMVIS) to solve the seeand- avoid problem using its accurate autonomous localization information. The function of this fuzzy controller is regulating the heading of this system to avoid the obstacle, e.g. wall. In the Matlab Simulink-based training stages, the Scaling Factor (SF) is adjusted according to the specified task firstly, and then the Membership Function (MF) is tuned based on the optimized Scaling Factor to further improve the collison avoidance performance. After obtained the optimal SF and MF, 64% of rules has been reduced (from 125 rules to 45 rules), and a large number of real flight tests with a quadcopter have been done. The experimental results show that this approach precisely navigates the system to avoid the obstacle. To our best knowledge, this is the first work to present the optimized fuzzy controller for UAMVIS using Cross-Entropy method in Scaling Factors and Membership Functions optimization.

UAS See-and-Avoid Strategy using a Fuzzy Logic Controller Optimized by Cross-Entropy in Scaling Factors and Membership Functions.

This work aims to develop a novel Cross-Entropy (CE) optimization-based fuzzy controller for Unmanned Aerial Monocular Vision-IMU System (UAMVIS) to solve the seeand-avoid problem using its accurate autonomous localization information. The function of this fuzzy controller is regulating the heading of this system to avoid the obstacle, e.g. wall. In the Matlab Simulink-based training stages, the Scaling Factor (SF) is adjusted according to the specified task firstly, and then the Membership Function (MF) is tuned based on the optimized Scaling Factor to further improve the collison avoidance performance. After obtained the optimal SF and MF, 64% of rules has been reduced (from 125 rules to 45 rules), and a large number of real flight tests with a quadcopter have been done. The experimental results show that this approach precisely navigates the system to avoid the obstacle. To our best knowledge, this is the first work to present the optimized fuzzy controller for UAMVIS using Cross-Entropy method in Scaling Factors and Membership Functions optimization.

The Balanced Cross-Layer Design Routing Algorithm in Wireless Sensor Networks Using Fuzzy Logic

Recently, the cross-layer design for the wireless sensor network communication protocol has become more and more important and popular. Considering the disadvantages of the traditional cross-layer routing algorithms, in this paper we propose a new fuzzy logic-based routing algorithm, named the Balanced Cross-layer Fuzzy Logic (BCFL) routing algorithm. In BCFL, we use the cross-layer parameters’ dispersion as the fuzzy logic inference system inputs. Moreover, we give each cross-layer parameter a dynamic weight according the value of the dispersion. For getting a balanced solution, the parameter whose dispersion is large will have small weight, and vice versa. In order to compare it with the traditional cross-layer routing algorithms, BCFL is evaluated through extensive simulations. The simulation results show that the new routing algorithm can handle the multiple constraints without increasing the complexity of the algorithm and can achieve the most balanced performance on selecting the next hop relay node. Moreover, the Balanced Cross-layer Fuzzy Logic routing algorithm can adapt to the dynamic changing of the network conditions and topology effectively.

Quantitative insight into proliferation and differentiation of oligodendrocyte type 2 astrocyte progenitor cells in vitro

As part of our attempts at understanding fundamental principles that underlie the generation of nondividing terminally differentiated progeny from dividing precursor cells, we have developed approaches to a quantitative analysis of proliferation and differentiation of oligodendrocyte type 2 astrocyte (O-2A) progenitor cells at the clonal level. Owing to extensive previous studies of clonal differentiation in this lineage, O-2A progenitor cells represent an excellent system for such an analysis. Previous studies have resulted in two competing hypotheses; one of them suggests that progenitor cell differentiation is symmetric, the other hypothesis introduces an asymmetric process of differentiation. We propose a general model that incorporates both such extreme hypotheses as special cases. Our analysis of experimental data has shown, however, that neither of these extreme cases completely explains the observed kinetics of O-2A progenitor cell proliferation and oligodendrocyte generation in vitro. Instead, our results indicate that O-2A progenitor cells become competent for differentiation after they complete a certain number of critical mitotic cycles that represent a period of symmetric development. This number varies from clone to clone and may be thought of as a random variable; its probability distribution was estimated from experimental data. Those O-2A cells that have undergone the critical divisions then may differentiate into an oligodendrocyte in each of the subsequent mitotic cycles with a certain probability, thereby exhibiting the asymmetric type of differentiation.

Reduced growth, abnormal kidney structure, and type 2 (AT2) angiotensin receptor-mediated blood pressure regulation in mice lacking both AT1A and AT1B receptors for angiotensin II

The classically recognized functions of the renin–angiotensin system are mediated by type 1 (AT1) angiotensin receptors. Whereas man possesses a single AT1 receptor, there are two AT1 receptor isoforms in rodents (AT1A and AT1B) that are products of separate genes (Agtr1a and Agtr1b). We have generated mice lacking AT1B (Agtr1b −/−) and both AT1A and AT1B receptors (Agtr1a −/−Agtr1b −/−). Agtr1b −/− mice are healthy, without an abnormal phenotype. In contrast, Agtr1a −/−Agtr1b −/− mice have diminished growth, vascular thickening within the kidney, and atrophy of the inner renal medulla. This phenotype is virtually identical to that seen in angiotensinogen-deficient (Agt−/−) and angiotensin-converting enzyme-deficient (Ace −/−) mice that are unable to synthesize angiotensin II. Agtr1a −/−Agtr1b −/− mice have no systemic pressor response to infusions of angiotensin II, but they respond normally to another vasoconstrictor, epinephrine. Blood pressure is reduced substantially in the Agtr1a −/− Agtr1b −/− mice and following administration of an angiotensin converting enzyme inhibitor, their blood pressure increases paradoxically. We suggest that this is a result of interruption of AT2-receptor signaling. In summary, our studies suggest that both AT1 receptors promote somatic growth and maintenance of normal kidney structure. The absence of either of the AT1 receptor isoforms alone can be compensated in varying degrees by the other isoform. These studies reaffirm and extend the importance of AT1 receptors to mediate physiological functions of the renin–angiotensin system.

Urocortin II: A member of the corticotropin-releasing factor (CRF) neuropeptide family that is selectively bound by type 2 CRF receptors

Here we describe the cloning and initial characterization of a previously unidentified CRF-related neuropeptide, urocortin II (Ucn II). Searches of the public human genome database identified a region with significant sequence homology to the CRF neuropeptide family. By using homologous primers deduced from the human sequence, a mouse cDNA was isolated from whole brain poly(A)+ RNA that encodes a predicted 38-aa peptide, structurally related to the other known mammalian family members, CRF and Ucn. Ucn II binds selectively to the type 2 CRF receptor (CRF-R2), with no appreciable activity on CRF-R1. Transcripts encoding Ucn II are expressed in discrete regions of the rodent central nervous system, including stress-related cell groups in the hypothalamus (paraventricular and arcuate nuclei) and brainstem (locus coeruleus). Central administration of 1–10 μg of peptide elicits activational responses (Fos induction) preferentially within a core circuitry subserving autonomic and neuroendocrine regulation, but whose overall pattern does not broadly mimic the CRF-R2 distribution. Behaviorally, central Ucn II attenuates nighttime feeding, with a time course distinct from that seen in response to CRF. In contrast to CRF, however, central Ucn II failed to increase gross motor activity. These findings identify Ucn II as a new member of the CRF family of neuropeptides, which is expressed centrally and binds selectively to CRF-R2. Initial functional studies are consistent with Ucn II involvement in central autonomic and appetitive control, but not in generalized behavioral activation.

A potential pathogenetic mechanism for multiple endocrine neoplasia type 2 syndromes involves ret-induced impairment of terminal differentiation of neuroepithelial cells.

Germ-line missense mutations of the receptor-like tyrosine kinase ret are the causative genetic event of the multiple endocrine neoplasia (MEN) type 2A and type 2B syndromes and of the familial medullary thyroid carcinoma. We have used the rat pheochromocytoma cell line, PC12, as a model system to investigate the mechanism or mechanisms by which expression of activated ret alleles contributes to the neoplastic phenotype in neuroendocrine cells. Here we show that stable expression of ret mutants (MEN2A and MEN2B alleles) in PC12 cells causes a dramatic conversion from a round to a flat morphology, accompanied by the induction of genes belonging to the early as well as the delayed response to nerve growth factor. However, in the transfected PC12 cells, the continuous expression of neuronal specific genes is not associated with the suppression of cell proliferation. Furthermore, expression of ret mutants renders PC12 cells unresponsive to nerve growth factor-induced inhibition of proliferation. These results suggest that induction of an aberrant pattern of differentiation, accompanied by unresponsiveness to growth-inhibitory physiological signals, may be part of the mechanism of action of activated ret alleles in the pathogenesis of neuroendocrine tumors associated with MEN2 syndromes.

High frequency of inactivating mutations in the neurofibromatosis type 2 gene (NF2) in primary malignant mesotheliomas.

Malignant mesotheliomas (MMs) are aggressive tumors that develop most frequently in the pleura of patients exposed to asbestos. In contrast to many other cancers, relatively few molecular alterations have been described in MMs. The most frequent numerical cytogenetic abnormality in MMs is loss of chromosome 22. The neurofibromatosis type 2 gene (NF2) is a tumor suppressor gene assigned to chromosome 22q which plays an important role in the development of familial and spontaneous tumors of neuroectodermal origin. Although MMs have a different histogenic derivation, the frequent abnormalities of chromosome 22 warranted an investigation of the NF2 gene in these tumors. Both cDNAs from 15 MM cell lines and genomic DNAs from 7 matched primary tumors were analyzed for mutations within the NF2 coding region. NF2 mutations predicting either interstitial in-frame deletions or truncation of the NF2-encoded protein (merlin) were detected in eight cell lines (53%), six of which were confirmed in primary tumor DNAs. In two samples that showed NF2 gene transcript alterations, no genomic DNA mutations were detected, suggesting that aberrant splicing may constitute an additional mechanism for merlin inactivation. These findings implicate NF2 in the oncogenesis of primary MMs and provide evidence that this gene can be involved in the development of tumors other than nervous system neoplasms characteristic of the NF2 disorder. In addition, unlike NF2-related tumors, MM derives from the mesoderm; malignancies of this origin have not previously been associated with frequent alterations of the NF2 gene.