Systematic mask synthesis for surface micromachined microelectromechanical systems

In the context of designing surface-micromachined microelectromechanical systems (MEMS), there does not appear to be systematic means, with the exception of parametrized layout models, to generate the mask data after the geometric model of a MEMS device is refined through behavioral simulations. This paper focuses on automatically generating masks, given a geometric model of the MEMS device and the process sequence (referred to here as the inverse problem). This necessitates a systematic solution of the forward problem, which involves automatically generating a geometric model of the MEMS device given the masks. A systematic and implementation-independent framework for the geometric modeling of MEMS is presented in order to solve the forward and inverse problems for general surface-micromachined devices. In particular, the geometric problem of mask synthesis is reduced to a system of linear equations.Peer Reviewedhttp://deepblue.lib.umich.edu/bitstream/2027.42/49041/2/jm3616.pd

Polyol pathway and modulation of ischemia-reperfusion injury in Type 2 diabetic BBZ rat hearts

We investigated the role of polyol pathway enzymes aldose reductase (AR) and sorbitol dehydrogenase (SDH) in mediating injury due to ischemia-reperfusion (IR) in Type 2 diabetic BBZ rat hearts. Specifically, we investigated, (a) changes in glucose flux via cardiac AR and SDH as a function of diabetes duration, (b) ischemic injury and function after IR, (c) the effect of inhibition of AR or SDH on ischemic injury and function. Hearts isolated from BBZ rats, after 12 weeks or 48 weeks diabetes duration, and their non-diabetic littermates, were subjected to IR protocol. Myocardial function, substrate flux via AR and SDH, and tissue lactate:pyruvate (L/P) ratio (a measure of cytosolic NADH/NAD+), and lactate dehydrogenase (LDH) release (a marker of IR injury) were measured. Zopolrestat, and CP-470,711 were used to inhibit AR and SDH, respectively. Myocardial sorbitol and fructose content, and associated changes in L/P ratios were significantly higher in BBZ rats compared to non-diabetics, and increased with disease duration. Induction of IR resulted in increased ischemic injury, reduced ATP levels, increases in L/P ratio, and poor cardiac function in BBZ rat hearts, while inhibition of AR or SDH attenuated these changes and protected hearts from IR injury. These data indicate that AR and SDH are key modulators of myocardial IR injury in BBZ rat hearts and that inhibition of polyol pathway could in principle be used as a therapeutic adjunct for protection of ischemic myocardium in Type 2 diabetic patients

Acute Administration of n-3 Rich Triglyceride Emulsions Provides Cardioprotection in Murine Models after Ischemia-Reperfusion

Dietary n-3 fatty acids (FAs) may reduce cardiovascular disease risk. We questioned whether acute administration of n-3 rich triglyceride (TG) emulsions could preserve cardiac function and decrease injury after ischemia/reperfusion (I/R) insult. We used two different experimental models: in vivo, C57BL/6 mice were exposed to acute occlusion of the left anterior descending coronary artery (LAD), and ex-vivo, C57BL/6 murine hearts were perfused using Langendorff technique (LT). In the LAD model, mice treated with n-3 TG emulsion (1.5g/kg body weight), immediately after ischemia and 1h later during reperfusion, significantly reduced infarct size and maintained cardiac function (p<0.05). In the LT model, administration of n-3 TG emulsion (300mgTG/100ml) during reperfusion significantly improved functional recovery (p<0.05). In both models, lactate dehydrogenase (LDH) levels, as a marker of injury, were significantly reduced by n-3 TG emulsion. To investigate the mechanisms by which n-3 FAs protects hearts from I/R injury, we investigated changes in key pathways linked to cardioprotection. In the ex-vivo model, we showed that n-3 FAs increased phosphorylation of AKT and GSK3β proteins (p<0.05). Acute n-3 TG emulsion treatment also increased Bcl-2 protein level and reduced an autophagy marker, Beclin-1 (p<0.05). Additionally, cardioprotection by n-3 TG emulsion was linked to changes in PPARγ protein expression (p<0.05). Rosiglitazone and p-AKT inhibitor counteracted the positive effect of n-3 TG; GSK3β inhibitor plus n-3 TG significantly inhibited LDH release. We conclude that acute n-3 TG injection during reperfusion provides cardioprotection. This may prove to be a novel acute adjunctive reperfusion therapy after treating patients with myocardial infarction

Morphological Changes and Immunohistochemical Expression of RAGE and its Ligands in the Sciatic Nerve of Hyperglycemic Pig (Sus Scrofa)

The aim of our project was to study the effect of streptozotocin (STZ)—induced hyperglycemia on sciatic nerve morphology, blood plasma markers and immunohistochemical expression of RAGE (the Receptor for Advanced Glycation End-products), and its ligands—S100B and Carboxymethyl Lysine (CML)-advanced glycation endproduct (AGE) in the laboratory pig. Six months after STZ—injections, blood plasma measurements, morphometric analysis of sciatic nerve fiber density, immunofluorescent distribution of potential molecular neuropathy contributors, ELISA measurement of plasma AGE level and HPLC analysis of sciatic nerve levels of one of the pre-AGE and the glycolysis intermediate products—methyl-glyoxal (MG) were performed. The results of our study revealed that STZ—injected animals displayed elevated levels of plasma glucose, gamma glutamyl transferase (GGT) and triglycerides. The sciatic nerve of STZ-injected pigs revealed significantly lower numbers of small-diameter myelinated fibers, higher immunoreactivity for RAGE and S100B and increased levels of MG as compared to control animals. Our results correspond to clinical findings in human patients with hyperglycemia/diabetes-evoked peripheral neuropathy and suggest that the domestic pig may be a suitable large animal model for the study of mechanisms underlying hyperglycemia-induced neurological complications in the peripheral nerve and may serve as a relevant model for the pre-clinical assessment of candidate drugs in neuropathy

Radical Roles for RAGE in the Pathogenesis of Oxidative Stress in Cardiovascular Diseases and Beyond

Oxidative stress is a central mechanism by which the receptor for advanced glycation endproducts (RAGE) mediates its pathological effects. Multiple experimental inquiries in RAGE-expressing cultured cells have demonstrated that ligand-RAGE interaction mediates generation of reactive oxygen species (ROS) and consequent downstream signal transduction and regulation of gene expression. The primary mechanism by which RAGE generates oxidative stress is via activation of NADPH oxidase; amplification mechanisms in the mitochondria may further drive ROS production. Recent studies indicating that the cytoplasmic domain of RAGE binds to the formin mDia1 provide further support for the critical roles of this pathway in oxidative stress; mDia1 was required for activation of rac1 and NADPH oxidase in primary murine aortic smooth muscle cells treated with RAGE ligand S100B. In vivo, in multiple distinct disease models in animals, RAGE action generates oxidative stress and modulates cellular/tissue fate in range of disorders, such as in myocardial ischemia, atherosclerosis, and aneurysm formation. Blockade or genetic deletion of RAGE was shown to be protective in these settings. Indeed, beyond cardiovascular disease, evidence is accruing in human subjects linking levels of RAGE ligands and soluble RAGE to oxidative stress in disorders such as doxorubicin toxicity, acetaminophen toxicity, neurodegeneration, hyperlipidemia, diabetes, preeclampsia, rheumatoid arthritis and pulmonary fibrosis. Blockade of RAGE signal transduction may be a key strategy for the prevention of the deleterious consequences of oxidative stress, particularly in chronic disease

Successfully Engaging Private Providers to Improve Diagnosis, Notification, and Treatment of TB and Drug-Resistant TB: The EQUIP Public-Private Model in Chennai, India.

Private physicians in India see and treat more than half of all people with tuberculosis (TB) each year and thus have potential to make significant contributions to TB control. The EQUIP project was designed as a prospective cohort study to assess the potential of private providers to diagnose and appropriately treat drug-resistant TB (DR-TB) in the Central and South districts of Chennai, India. The private-sector engagement model consisted of free access to rapid diagnostics; choice of free daily or thrice-weekly treatment regimens; support for notification of patients; and patient support including directly observed therapy through EQUIP centers staffed by a community-based interface agency. Data were collected on provider participation; referral results; treatment regimens prescribed; and treatment outcomes. From October 2015 through June 2017, 227 of the 466 (48.7%) private providers approached referred at least 1 patient to an EQUIP center for evaluation. A total of 2,621 patients received testing and 1,232 (47.0%) were diagnosed with TB. Of those, 727 (59.0%) were bacteriologically confirmed, including 694 (56.3%) using GeneXpert and 33 (2.7%) using smear microscopy. A total of 26 (3.7% of GeneXpert diagnosed) patients were confirmed as rifampicin-resistant cases. EQUIP-related notifications comprised approximately 10% of TB and DR-TB notifications in Chennai during the project period. The project initiated 1,167 (96.8%) drug-sensitive TB patients on treatment. Of those, 691 (59.2%) received standard daily regimens with EQUIP support and 288 (24.7%) received standard intermittent regimens. At the time of writing, 89.4% of 868 drug-susceptible TB patients receiving EQUIP support had treatment success. Of the 26 rifampicin-resistant TB cases notified, 20 (77%) started and continued on second-line treatment; 2 died and 4 were lost to follow-up prior to treatment initiation. Private providers can make a substantial contribution to detection and appropriate treatment of patients with TB and DR-TB in India when provided with access to rapid diagnostics, support for notification and patient treatment through interface agencies, and free, quality anti-TB drugs