Four-dimensional address topology for circuits with stacked multilayer crossbar arrays

We present a topological framework that provides a simple yet powerful electronic circuit architecture for constructing and using multilayer crossbar arrays, allowing a significantly increased integration density of memristive crosspoint devices beyond the scaling limits of lateral feature sizes. The truly remarkable feature of such circuits, which is an extension of the CMOL (Cmos + MOLecular-scale devices) concept for an area-like interface to a three-dimensional system, is that a large-feature-size complimentary metal-oxide-semiconductor (CMOS) substrate can provide high-density interconnects to multiple crossbar layers through a single set of vertical vias. The physical locations of the memristive devices are mapped to a four-dimensional logical address space such that unique access from the CMOS substrate is provided to every device in a stacked array of crossbars. This hybrid architecture is compatible with digital memories, field-programmable gate arrays, and biologically inspired adaptive networks and with state-of-the-art integrated circuit foundries.     

Image-guided enzyme/prodrug cancer therapy.

PURPOSE: The success of enzyme/prodrug cancer therapy is limited by the uncertainty in the delivery of the enzyme in vivo. This study shows the use of noninvasive magnetic resonance (MR) and optical imaging to image the delivery of a prodrug enzyme. With this capability, prodrug administration can be timed so that the enzyme concentration is high in the tumor and low in systemic circulation and normal tissue, thereby minimizing systemic toxicity without compromising therapeutic efficiency. EXPERIMENTAL DESIGN: The delivery of a multimodal imaging reporter functionalized prodrug enzyme, cytosine deaminase, was detected by MR and optical imaging in MDA-MB-231 breast cancer xenografts. Stability of the enzyme in the tumor was verified by (19)F MR spectroscopy, which detected conversion of 5-fluorocytosine to 5-flurouracil. The optimal time window for prodrug injection determined by imaging was validated by immunohistochemical, biodistribution, and high-performance liquid chromatographic studies. The therapeutic effect and systemic toxicity of this treatment strategy were investigated by histologic studies and tumor/body weight growth curves. RESULTS: The delivery of the functionalized enzyme in tumors was successfully imaged in vivo. The optimal time window for prodrug administration was determined to be 24 h, at which time the enzyme continued to show high enzymatic stability in tumors but was biodegraded in the liver. Significant tumor growth delay with tolerable systemic toxicity was observed when the prodrug was injected 24 h after the enzyme. CONCLUSION: These preclinical studies show the feasibility of using a MR-detectable prodrug enzyme to time prodrug administration in enzyme/prodrug cancer therapy.     

Numerical simulation of local pharmacokinetics of a drug after intravascular delivery with an eluting stent

We use mathematical modelling to delineate the influence of two important factors on local pharmacokinetics of a drug delivered via an eluting stent, namely: (1) diffusional resistance of a stent coating, and (2) reversible binding of a drug to the vascular tissue. A system of differential equations that describes diffusion of the drug out of the polymeric coating of the stent into the vascular tissue and into the bloodstream, as well as reversible binding of the drug within the vascular tissue, was solved numerically and the spatial profiles of the concentration of the drug at various points of time were produced and analysed. Also, kinetic curves of the spatial average concentration of the drug within the wall were constructed, and the areas under those curves (AUC) were calculated. The simulations showed that AUC might be enhanced, if the stent is coated with a continuous layer of a drug-releasing medium with a high diffusional resistance. Both the residence time and the average concentration of the drug within the vascular wall increase in this case mainly because the coating imposes a diffusional barrier between the vascular tissue and the bloodstream, thereby reducing the wash-out. If the drug reversibly binds to the tissue, the residence time increases greatly, but the AUC for the free (unbound) drug remains unchanged, implying that the presence of the drug in the vessel is prolonged at the expense of a proportional reduction in concentration of a free drug within the tissue. These findings justify the design of eluting stents with continuous coatings with enhanced diffusional resistance and the engineering of drugs with enhanced affinity to the vascular matrix. Reversible binding to tissue may be beneficial for prolonging the presence of the drug in the target tissue, and for avoiding potential toxic peak effects of high concentrations of the free (unbound) drug.     

Choosing general surgery: insights into career choices of current medical students

HYPOTHESIS: The number of unfilled general surgery programs in the United States increased from 4 in 1999 to 41 in 2001. This study seeks to determine if changes in student attitudes occurring during their medical school careers and during the third-year general surgery clerkship contribute to a decline in interest in a surgical career. DESIGN: Prospective survey of medical students at a public medical school in California. PARTICIPANTS AND METHODS: Each medical student received a survey via the Internet. Responses were anonymous. Once quantified, chi(2) analysis was used for comparison and analysis of survey results. Comparisons were made between individual class years and on the basis of whether the respondent completed the third-year general surgery clerkship. RESULTS: Of 368 surveys sent, 232 (63%) were successfully completed and included in the study. Comparison of students' attitudes before and after completion of their general surgery clerkship showed that following surgical course exposure more students believed surgery lacked breadth of expertise, limitations over stress, control over one's time, regularity of schedule, adequacy of leisure time, and income commensurate to workload (P<.05). These results are also consistent in comparisons between individual class years. CONCLUSIONS: Data suggest that medical students seem to be more concerned with issues of "controllable lifestyle" such as adequacy of family and/or leisure time, high level of stress, and amount of work and commitment. The erosion of income differential between demanding and less taxing specialties was also an important cause cited for the flagging interest in surgical disciplines.     

Expression and distribution of id helix-loop-helix proteins in human astrocytic tumors

The Id family of helix-loop-helix proteins is involved in a variety of processes, such as development, proliferation, and angiogenesis. In this study, we investigated the expression pattern of Id1, Id2, and Id3 in surgical specimens of human glial tumors. Western blot analysis demonstrated that all three Id proteins were expressed in astrocytic tumors. Expression levels in high-grade tumors were higher than in low-grade tumors. Immunohistochemical analysis confirmed that many of the tumor astrocytes exhibited strong Id1-3 IR. In contrast, in adult human normal brain, Id expression was low both in resting astrocytes and in endothelial cells. In tumor cells, Id proteins displayed cytoplasmic as well as nuclear localization. Id1-3 IR scores in tumor cells were positively correlated with proliferation indices. Moreover, Id1-3 IR was detected in endothelial cells of the astrocytic tumor blood vessels. The vascular Id1-3 expression correlated positively with tumor vascularity and grade. These results support the role of the Id gene family in the enhanced proliferative potential of tumor astrocytes. The evidence also supports the involvement of the Id gene family in tumor angiogenesis, a process that critically influences the malignant behavior of glial tumors.     

Role of ACE Inhibitors in treating hypertensive diabetic patients

Cardiovascular disease (CVD) is a major determining factor of morbidity and mortality in type 2 diabetic patients. Hypertension, which accompanies diabetes in more than 70% of cases, contributes to increased prevalence of CVD events in this group of patients. Results from the United Kingdom Prospective Diabetes Study (UKPDS) indicated that reduction of elevated blood pressure might decrease CVD morbidity and mortality more than reduction of hyperglycemia. Activation of circulating and tissue renin-angiotensin system (RAS) contributes to the development of both hypertension and insulin resistance in patients with the cardiometabolic syndrome. Angiotensin-converting enzyme (ACE) inhibitor therapy in patients with the cardio-metabolic syndrome may improve insulin action as well as lessen CVD. In clinical trials, ACE inhibitors have been shown to be more efficient than other antihypertensive medications (ie, calcium channel blockers) in the reduction of CVD morbidity and mortality in hypertensive diabetics. In this article, we summarize possible mechanisms by which ACE inhibition may improve insulin resistance, coagulation/ clotting, and vascular function abnormalities, and postpone or even prevent the development of type 2 diabetes in hypertensive patients.     

Large recursive partitioning analysis of complex disease pharmacogenetic studies. II. Statistical considerations

Identifying genetic variations predictive of important phenotypes, such as disease susceptibility, drug efficacy, and adverse events, remains a challenging task. There are individual polymorphisms that can be tested one at a time, but there is the more difficult problem of the identification of combinations of polymorphisms or even more complex interactions of genes with environmental factors. Diseases, drug responses or side effects can result from different mechanisms. Identification of subgroups of people where there is a common mechanism is a problem for diagnosis and prescribing of treatment. Recursive partitioning (RP) is a simple statistical tool for segmenting a population into non-overlapping groups where the response of interest, disease susceptibility, drug efficacy and adverse events are more homogeneous within the segments. We suggest that the use of RP is not only more technically feasible than other search methods but it is less susceptible to multiple-testing problems. The numbers of combinations of gene-gene and gene-environment interactions is potentially astronomical and RP greatly reduces the effective search and inference space. Moreover, the certain reliance of RP on the presence of marginal effects is justifiable as was found by using analytical and numerical arguments. In the context of haplotype analysis, results suggest that the analysis of individual SNPs is likely to be successful even when susceptibilities are determined by haplotypes. Retrospective clinical studies where cases and controls are collected will be a common design. This report provides methods that can be used to adjust the RP analysis to reflect the population incidence of the response of interest. Confidence limits on the incidence of the response in the segmented subgroups are also discussed. RP is a straightforward way to create realistic subgroups, and prediction intervals for the within-subgroup disease incidence are easily obtained.     

Staged Laparoscopic Roux-en-Y: A Novel Two-Stage Bariatric Operation as an Alternative in the Super-Obese with Massively Enlarged Liver

In a subset of super-obese patients, the one-stage laparoscopic Roux-en-Y gastric bypass (RYGBP) can be associated with significant morbidity and mortality. In a previous effort to reduce the perioperative risks associated with the super-obese, a two-stage operation was devised. This two-stage operation consisted of a sleeve gastrectomy (1st stage) followed by a RYGBP or duodenal switch procedure (2nd stage). We find that the primary limiting factor making laparoscopic gastric bypass challenging in the super-obese is the volume of the left lobe of the liver. A greatly thickened left lobe of the liver obscures visualization of the gastroesophageal junction and angle of His so that a sleeve gastrectomy is difficult to construct. In this report, we describe a novel method utilizing a staged Roux-en-Y procedure. Instead of performing a restrictive operation (sleeve gastrectomy) as the initial procedure, we fashion a modified Roux-en-Y with a low gastrojejunal anastomosis and a larger gastric pouch encompassing the gastric fundus. The low anastomosis obviates the need for exposure of the gastro-esophageal junction and angle of His. At the 2nd stage procedure, completion sleeve gastrectomy of the gastric fundus is performed at an interval of 6-12 months after the 1st stage operation.