Current Areas Of Investigation Research Articles

Using Administrative Data to Better Treat Chronic Limb Threatening Ischemia

Chronic limb threatening ischemia (CLTI) is the most severe manifestation of peripheral arterial disease and represents a particularly high-risk subgroup of patients. As such, efforts to better understand this complex patient population through well-designed clinical research studies are critical to improving CLTI care. Prospective randomized clinical trials (RCTs) remain the gold standard in clinical research, but these trials are resource-intensive and have highly selective patient populations, which limit their feasibility and generalizability. Alternatively, retrospective studies are less expensive than RCTs, have a larger sample size, and are more generalizable owing to a broader patient population. Health care administrative data provide rich sources of information that may be used for research purposes and are increasingly being used for the study of vascular surgery conditions, including CLTI. Although administrative data are collected for billing purposes, they may be leveraged to study a broad range of topics in vascular surgery including those related to health care delivery, epidemiology, health disparities, and outcomes. This review provides an overview of administrative data available for CLTI research, the strengths and limitations of these data sources, current areas of investigation, and future opportunities for further study with the goal of improving outcomes in this high-risk population.

The Future of Facial Fat Grafting.

Fat grafting was first described in the early 20th century but for many years remained a relatively underused technique due to the unreliability of long-term volume expansion. Significant improvements in reliability have been made in the last 2 decades and there is a large body of literature pertaining to extraction, processing and injection methods to obtain more lasting effects. However, volume loss and graft resorption remain a major challenge in the long term and lead to unpredictability in results. Enriching adipose graft with stromal vascular fraction, ex vivo cultured adipose stem cells and platelet-derived growth factor among others is one method under active investigation which may assist graft survival through a range of mechanisms including increased angiogenesis. Breaking adipose graft into smaller fragments such that engrafted cells have greater access to donor-site oxygenation and nutrition is another method which in theory may promote survival. Presently, adipose grafting in the face is usually for the addition of volume to fill defects. However, the stem-cell containing fraction of adipose grafting (stromal vascular fraction) appears to exert a rejuvenating effect on overlying skin and soft tissue when administered alone. The application of these low-volume injections represents a significant shift in thinking away from mere volume expansion. These techniques have been tested in a range of animal models and some human studies. In this review, the authors provide a broad overview of present research and highlight both limitations in previous research and current areas of investigation.

Design and analysis of automotive composite propeller shaft using fea

The last few years have seen the increasing use of composite materials in many fields of engineering applications. Polymer composites are today widely used to design the automobile components in view of their outstanding specific stiffness and strength properties. Composite shafts for automotive applications are among the most current areas of investigation. Weight reduction can be primarily achieved by the introduction of better material. The conventional system uses metallic shaft, has inherent limitations like heavy weight, corrosion, flexibility problems, vibrations, bearing and manufacturing problems, which magnifies with increase in shaft diameter. Advanced composite materials offer the potential to improve propulsion shafting, by reducing weight, bearing loads, alignment problems, life- cycle cost by using strategic materials, by increasing allowable fatigue stress, flexibility, and vibration damping characteristics.This paper is related to investigations on Carbon Reinforced plastics (CFRP) and Glass Fiber Reinforced Plastics (GFRP) composite hollow shafts for automobiles. Failure analysis has been carried out using maximum stress criteria and it is found that the failure torque is well above the design torque level.For accurate design solution, the propeller shaft was analyzed using FEM techniques (ANSYS package). The propeller shaft was geometrically modeled using FEM “3D-shell99 element and solid46 layered element”. To check all failure modes, linear static analysis, vibration Eigen value analysis, buckling analysis and harmonic analysis were done.

High Frequency Deep Brain Stimulation and Neural Rhythms in Parkinson's Disease.

High frequency (HF) deep brain stimulation (DBS) is an established therapy for the treatment of Parkinson's disease (PD). It effectively treats the cardinal motor signs of PD, including tremor, bradykinesia, and rigidity. The most common neural target is the subthalamic nucleus, located within the basal ganglia, the region most acutely affected by PD pathology. Using chronically-implanted DBS electrodes, researchers have been able to record underlying neural rhythms from several nodes in the PD network as well as perturb it using DBS to measure the ensuing neural and behavioral effects, both acutely and over time. In this review, we provide an overview of the PD neural network, focusing on the pathophysiological signals that have been recorded from PD patients as well as the mechanisms underlying the therapeutic benefits of HF DBS. We then discuss evidence for the relationship between specific neural oscillations and symptoms of PD, including the aberrant relationships potentially underlying functional connectivity in PD as well as the use of different frequencies of stimulation to more specifically target certain symptoms. Finally, we briefly describe several current areas of investigation and how the ability to record neural data in ecologically-valid settings may allow researchers to explore the relationship between brain and behavior in an unprecedented manner, culminating in the future automation of neurostimulation therapy for the treatment of a variety of neuropsychiatric diseases.

Combinatorial RNA-based gene therapy for the treatment of HIV/AIDS

Introduction: HIV/AIDS continues to be a worldwide health problem and viral eradication has been an elusive goal. HIV+ patients are currently treated with combination antiretroviral therapy (cART) which is not curative. For many patients, cART is inaccessible, intolerable or unaffordable. Therefore, a new class of therapeutics for HIV is required to overcome these limitations. Cell and gene therapy for HIV has been proposed as a way to provide a functional cure for HIV in the form of a virus/infection resistant immune system.Areas covered: In this review, the authors describe the standard therapy for HIV/AIDS, its limitations, current areas of investigation and the potential of hematopoietic stem cells modified with anti-HIV RNAs as a means to affect a functional cure for HIV.Expert opinion: Cell and gene therapy for HIV/AIDS is a promising alternative to antiviral drug therapy and may provide a functional cure. In order to show clinical benefit, multiple mechanisms of inhibition of HIV entry and lifecycle are likely to be required. Among the most promising antiviral strategies is the use of transgenic RNA molecules that provide protection from HIV infection. When these molecules are delivered as gene-modified hematopoietic stem and progenitor cells, long-term repopulation of the patient's immune system with gene-modified progeny has been observed.

A little statistical mechanics for the graph theorist

In this survey, we give a friendly introduction from a graph theory perspective to the q -state Potts model. The Potts model is an important statistical mechanics tool for analyzing complex systems in which nearest neighbor interactions determine the aggregate behavior of the system. We present the surprising equivalence of the Potts model partition function and one of the most renowned graph invariants, the Tutte polynomial. This relationship has resulted in a remarkable synergy between the two fields of study. We highlight some of these interconnections, such as computational complexity results that have alternated between the two fields. The Potts model captures the effect of temperature on the system and plays an important role in the study of thermodynamic phase transitions. We discuss the equivalence of the chromatic polynomial and the zero-temperature antiferromagnetic partition function, and how this has led to the study of the complex zeros of these functions. We also briefly describe Monte Carlo simulations commonly used for Potts model analysis of complex systems. The Potts model has applications in areas as widely varied as magnetism, tumor migration, foam behaviors, and social demographics, and we provide a sampling of these that also demonstrates some variations of the Potts model. We conclude with some current areas of investigation that emphasize graph theoretic approaches.

Emerging drugs for colorectal cancer

Background: The past 5 years have shown major advances in the treatment of colorectal cancer. Our understanding of existing drugs, such as oxaliplatin and irinotecan, has become more refined. The incorporation of newer drugs such as bevacizumab and cetuximab has expanded treatment options as well. Objective: Our goals are to review the evidence for currently approved drugs, with particular attention to the most recent studies highlighting the ideal conditions for each. In addition, we discuss current areas of investigation – particularly, specific pathway inhibitors – that are most relevant for colorectal cancer. Methods: We have used existing literature as well as abstracts and oral presentations from ASCO and AACR meetings. Results/conclusion: We report current thinking on the use of existing drugs, and present the most promising novel pathway inhibitors that are now being developed for colorectal cancer.

PL-02-02: Beta-secretase as a therapeutic target

Finding inhibitors of Aβ42 generation is a major goal of Alzheimer's disease drug development. Two target protease activities, β–and γ–secretase, were operationally defined in the early 90s, but progress in this area was slow, because the actual enzymes were not understood at the molecular level. Some years ago we identified a novel membrane bound aspartic protease, BACE1, as β–secretase. This finding has been confirmed and BACE1 and its homolog BACE2 have been characterized in detail by many groups. Major progress has been made in two areas: First, the x–ray crystal structure, which is critical for rational inhibitor design, has been solved and shown to be similar to that of other pepsin family members. Second, knockout studies show that BACE1 is critical for Aβ generation, but the knockout mice show an otherwise normal phenotype, raising the possibility that therapeutic BACE1 inhibition could be accomplished without major mechanism based toxicity. However, target–mediated toxicity of β–secretase inhibition cannot be ruled out based on the currently available data alone. While various peptidic β–secretase inhibitors have been published, the key challenge now is the generation of more drug–like compounds that could be developed for therapeutic purposes. Other current areas of investigation, including identification of additional BACE1 substrates, the potential role of BACE1 overexpression in AD and the phenotype of BACE2 knockout mice will be discussed.

Haemophilus somnus virulence factors and resistance to host immunity.

Haemophilus somnus ('Histophilus somni) is a Gram-negative bacterium and opportunistic pathogen associated with multisystemic diseases of bovines. Some strains of H. somnus are relatively avirulent, but are biochemically and antigenically similar to the virulent strains. Several virulence factors have been identified in H. somnus, of which lipo-oligosaccharide phase variation, induction of apoptosis, intraphagocytic survival and immunoglobulin Fc binding proteins have been well studied. The sequencing of the genomes of two strains of H. somnus has facilitated the identification of genes responsible for distinctive attributes within this species and related bacteria. The genetic characterization of this bacterium will enhance our understanding of H. somnus virulence factors and facilitate the development of new and improved vaccines. This review presents an overview of H. somnus virulence factors, their role in resistance to host defenses and pathogenesis, and the host immune response to this bacterium. Current areas of investigation in the post-genomic era and recent insights into new pathogenic mechanisms are also discussed.

Haemophilus somnus virulence factors and resistance to host immunity

Haemophilus somnus (‘Histophilus somni’) is a Gram-negative bacterium and opportunistic pathogen associated with multisystemic diseases of bovines. Some strains of H. somnus are relatively avirulent, but are biochemically and antigenically similar to the virulent strains. Several virulence factors have been identified in H. somnus, of which lipo-oligosaccharide phase variation, induction of apoptosis, intraphagocytic survival and immunoglobulin Fc binding proteins have been well studied. The sequencing of the genomes of two strains of H. somnus has facilitated the identification of genes responsible for distinctive attributes within this species and related bacteria. The genetic characterization of this bacterium will enhance our understanding of H. somnus virulence factors and facilitate the development of new and improved vaccines. This review presents an overview of H. somnus virulence factors, their role in resistance to host defenses and pathogenesis, and the host immune response to this bacterium. Current areas of investigation in the post-genomic era and recent insights into new pathogenic mechanisms are also discussed.

Food Webs of Shallow Subtidal Marine Ecosystems

To some ecologists, food webs and the diagrams associated with them represent the underpinnings of a grand unifying theory of ecology, the culmination of years of field study by numerous investigators, and a gateway to the creation of synthetic models and other predictive tools for resource management; but for others, they are naive and dangerous oversimplifications and the associated diagrams and models are merely the Tinkertoys of reductive, impatient investigators. Clearly, both views have their merits. Like many paradigms and heuristic tools in ecology, the popularity of food webs has waxed and waned. Nevertheless, the dynamic debate arising from the intellectual tension between these two positions could foster the progress in ecological research needed to produce a holistic approach that would enable ecologists to deliver the sound predictions demanded by resource users and managers. However conscientious, any rush to abandon these tools, and thereby avoid the simplification of complex processes, would only serve to delay the development of the holism needed to improve the management of our natural resources. Consequently, we need to periodically revisit and revise our conceptualization of the food webs we study, to consider anew the insights they might generate, and to assess their relevance to the twofold task of improving our understanding of the impact of human activities on global and regional ecosystems and then determining how best to manage them. In the past few decades, investigation into the ecology of shallow subtidal ecosystems has increased greatly, thanks to the advent and popularization of SCUBA diving and our consequent ability to conduct field studies in these physically challenging environments. These studies have expanded our understanding of the enormous impact of human activities on these ecosystems, as well as the long-term consequences of resource extraction. Without such studies, the impact of humans on these cryptic ecosystems would remain largely unknown and the observed changes in resources would seem mysterious and often inexplicable. In many cases, this new recognition of the strong effect of human activities became the impetus to create protected areas that maintain the food web or re-create new webs that minimize human influences. To stimulate further development of ecological holism, I invited several investigators working in disparate subtidal ecosystems to present a brief description of their research on the food webs in their study areas and to place these concepts into the historical context of ecological investigation. Authors were asked to identify the important issues in this arena that are not well understood and to focus on current areas of investigation. They were to assume that food webs would be revised as additional information became available. The papers that follow are the result of this initiative and offer a simple overview of our understanding of some of the most well-studied subtidal food webs. Changes in the ecological view of these food webs and the web structures themselves over time under natural and human influences are also presented. The early insights into human influences on subtidal ecosystems are important. However, given the short-term nature of most of these studies, it is difficult to determine to what extent natural variability contributes to the changes and what the resilience and recovery potential of these ecosystems may be. The coral reefs of the eastern Pacific, as described by Glynn (this issue), are a good exReceived 22 April 2003; accepted 23 April 2003; published online 27 April 2004. Corresponding author; e-mail: crcp@africaonline.co.ke Ecosystems (2004) 7: 321–322 DOI: 10.1007/s10021-004-0065-3 ECOSYSTEMS

Isoproterenol Inhibits Bacterial Lipopolysaccharide-Stimulated Release of Tumor Necrosis Factor-α from Human Heart Tissue

Recent evidence suggests that inflammatory cytokines, particularly tumor necrosis factor a (TNF-α), may play a role in heart disease. Elevated plasma levels of the cytokine have been reported in congestive heart failure and severe angina and after myocardial infarction. The exact role of TNF-α in heart disease and how production is stimulated and regulated in the heart are current areas of investigation. Regarding regulation of production, isoproterenol elevates cyclic AMP and inhibits TNF-α release in macrophages. Therefore we hypothesized that stimulation of β-adrenergic receptors of the sympathetic nervous system would inhibit release of the cytokine from heart tissue. With Institutional Review Board approval and patient consent atrial tissue was obtained during preparation for cardiac bypass. The tissue was divided into segments, placed in culture medium, and incubated for various times in the presence or absence of lipopolysaccharide (LPS) (20 μg/mL) and/or isoproterenol (1 μM). The medium was removed and analyzed for biologically active TNF-α by the L929 cell cytotoxicity assay. Tissue samples were weighed and TNF-α release was expressed as pg TNF-α/mg tissue. Initially, to determine the time course of release, measurements were made at 2, 5, 10, 15, 30, 60, 120, 180, and 360 minutes after the addition of LPS. Elevated TNF-α levels in the culture medium were reliably detected at 360 minutes after exposure to LPS. In atrial tissue obtained from seven patients TNF-α released into the culture medium at 360 minutes was 6 ± 3 pg/mg tissue. In the presence of LPS, levels of the cytokine in the culture medium increased to 604 ± 233 pg/mg tissue ( P < 0.05 vs LPS alone). When isoproterenol and LPS were simultaneously added to the culture medium release of TNF-α was reduced by 87 per cent to 82 ± 40 pg/mg tissue ( P < 0.05 vs LPS alone). Our results show that activation of the β-adrenergic receptor inhibits myocardial production of TNF-α. This finding suggests that the sympathetic nervous system inhibits production of the cytokine and that impaired sympathetic function in heart failure may play a role in the elevated levels of TNF-α.

Engineering and Material Considerations in Islet Cell Transplantation

The successful application and optimization of cell transplantation will require quantitative engineering design and analysis of cells and materials in which relevant biological processes remain complex and incompletely defined. This report primarily reviews the engineering and material considerations in islet cell transplantation, including established biological constraints and biohybrid devices for cell delivery, as well as available barrier materials and the associated processing strategies directed at the control of solute transport, barrier permeability, and host responses at the biological-material interface. Also described are current areas of investigation with particular promise as enabling technologies for accelerating the clinical effectiveness of islet cell transplantation.

Preconditioning

Preconditioning

Drug Treatment of Colorectal Cancer

Drug therapy is most often used in colorectal cancer for palliation of metastatic disease. Current data also support the use of adjuvant chemotherapy following complete surgical resection in patients with locoregional lymph node metastases. The agent most widely used in the treatment of colorectal cancer is the antimetabolite fluorouracil (5-fluorouracil; 5-FU). This fluoridated pyrimidine has been available for over 30 years, yet to date no other single agent has proven to be more efficacious. Controversy exists about the most desirable schedule for administration of fluorouracil. Efforts have been made to improve upon its therapeutic index and efficacy by using the concept of biomodulation, in which chemicals which are not themselves active antineoplastic agents against colorectal cancer are administered with fluorouracil in an attempt to enhance the sensitivity of the cancer cell to fluorouracil. Biomodulation agents currently in use in clinical practice include leucovorin (calcium folinate), methotrexate, and interferon-alpha. Other biomodulation strategies are currently under investigation. Adding putatively active antineoplastic agents to fluorouracil to form combination chemotherapy regimens has not yielded convincingly superior results to treatment with fluorouracil alone, and the toxicities of many of these combination regimens have been formidable. Secondary therapies following failure of fluorouracil-based regimens have been similarly disappointing. Current areas of investigation into the chemotherapy of colorectal cancer include development of new agents, locoregional administration of chemotherapy, and manipulation of intrinsic drug resistance mechanisms of the cancer cells.

Overview of hemodynamic and non-hemodynamic factors associated with left ventricular hypertrophy

The role of the heart in hypertension has finally emerged as a major issue of cardiovascular concern by the clinician, physiologist, pharmacologist, biochemist, and molecular biologist. This discussion provides an overview of the present state of knowledge and current areas of investigation in this active area of broad interest. Generally, these relate to: the active participation of the heart (e.g. hemodynamic, humoral, autocrine/paracrine); the adaptive response of the heart (i.e. hemodynamic); non-hemodynamic relationships (vis-a-vis, age, race, gender, humoral, coexistent disease); and current thoughts on mechanisms of so-called regression of left ventricular hypertrophy. Several antihypertensive classes of compounds are characterized by decreasing cardiac mass and left ventricular wall thicknesses. The angiotensin converting enzyme inhibitors are included among these agents; their physiological effects in producing "regression" are under active study as are the mechanisms responsible for these changes. These concerns are no longer of incidental or theoretical interest but have major impact on selection of antihypertensive therapy and the management of the patient with hypertension. Thus, the heart may participate actively in the pathogenesis and maintenance of the disease; it adapts to the vascular disease hemodynamically; but in this regard the response has both positive beneficial concerns as well as negative implications as an independent risk factor. These latter concerns should be explored in great depth before conclusions are made with respect to the long-term implications of antihypertensive therapy on the heart.

Eicosanoids and heart disease

The discovery of prostaglandins over 5 decades ago heralded a new era in the study of mediators or factors involved in physiological and pathophysiological processes. Prostaglandins, however, do not represent the sole products derived from arachidonic acid or other fatty acid precursors; instead these fatty acids can undergo metabolism to numerous bioactive compounds derived from cyclooxygenase, lipoxygenase, as well as the recently discovered epoxygenase cytochrome P-450 dependent pathways. Collectively, these products are commonly referred to as eicosanoids and have been implicated in numerous biological phenomena. It has long been hypothesized that the prostaglandins play an important role in cardiovascular regulation. For instance, the concept of a balance between the vasoconstrictor, prothrombotic properties of some arachidonic acid derived products and the opposing actions of others led to the development of drug therapies against thromboembolic disorders. Aspirin, for example, a well-known cyclooxygenase inhibitor, has been shown to be efficacious against myocardial infarction and stroke of embolic origin. Moreover, cyclooxygenase- and lipoxygenase-derived products have been implicated in various types of cardiac dysfunction including coronary constriction, arrhythmogenesis, anaphylactic reactions, or ischemic and reperfusion injury.In view of the evolving complexity of arachidonic acid metabolism and increasing evidence that eicosanoids, either alone, or through interaction with other substances, represent important mediators in either the development of heart disease or the myocardial response to injury, we organized this symposium entitled Eicosanoids and Heart Disease concurrent with the 31st Annual Meeting of the Canadian Federation of Biological Societies. A one-half day symposium precludes the possibility of detailed coverage of the many areas in cardiovascular disease in which eicosanoid participation could be implicated and which ideally one would hope to cover. The organizers' aim was to address, in the form of research presentations or reviews, current areas of investigation dealing with selected topics in heart disease.The success of this symposium was made possible by the participation of several distinguished scientists. We would also like to thank the Pharmacological Society of Canada, the Canadian Heart Foundation, Upjohn Canada, Sterling Drug, and Ciba-Geigy U.S. A. for financial support. The organizers thank Dr. J. Burka for serving as Guest Editor and Mrs. L. Hendrickson of this Journal for coordinating the submission of the manuscripts.

Stroke and microcirculation

Cervos-Navarro and Ferszt have assembled 85 scientific articles, under the broad heading of cerebral microcirculation, which are of interest primarily to those working in experimental cerebral ischemia. The articles are divided into six main sections: ischemia; edema; hydrocephalus; intracranial pressure; subarachnoid hemorrhage; and diffuse cerebrovascular disease. A brief summary of each article is provided grouped by sections. The vast majority of articles deal with experimental work although the sections on subarachnoid hemorrhage and diffuse cerebrovascular disease include clinical papers as well. The book is not intended nor is it a comprehensive review of the topics comprising the main sections. The book does cover a wide range of issues, including ischemic thresholds, the influence of rheologic factors and hyperglycemia on ischemia, the role of inflammatory response in cerebral edema, cerebral vasospasm and its response to calcium antagonists, and vascular dementia. This broad approach obviously precludes dealing with a particular topic in any degree of depth. Nonetheless, many current areas of investigation in cerebrovascular disease are addressed. In their preface, the editors ask whether recent experimental research has anything to offer patients with cerebrovascular disease. Therefore, it is somewhat surprising that treatment is not a major emphasis in any section. This deficiency is all the more surprising given the recent work being done both experimentally and clinically with thrombolytic agents, calcium antagonists, and N-methyl -D-aspartate (NMDA) receptor antagonists in cerebral ischemia. Nonetheless, by focusing on understanding basic mechanisms of processes, such as ischemia and edema, the authors are taking a necessary step in the development of treatment regimens.

Male Sexual Dysfunction

This multiauthor book seeks to pull together several specialties that deal with male sexual dysfunction. As the editors point out, the urologist has, in many instances, become the primary coordinator for the patient with impotence, ejaculatory disturbance, or whatever may be altering normal sexual function. Also, because of the development of penile prostheses, it is important to know the cause of the sexual dysfunction so as to pick the proper operative candidates. The book consists of 25 chapters, the first four presenting the physiology of normal male sexual function. Current areas of investigation are covered in these chapters, including studies on the sympathetic innervation and receptors. The remaining chapters cover the various neurological, endocrine, pharmacologic, vascular, and behavioral factors that affect sexual function. Unfortunately, the book probably went to print before the publication of Brindley, which describes the technique of producing an erection by the injection of sympathetic α-blocking agent

Software metrics

Software metrics, an area of software engineering, is concerned with various measurements of computer software and its development. Software metrics, its importance, some current areas of investigation, and problems are described. An annotated bibliography of work in software metrics is included.I often say that when you can measure what you are speaking about, and express it in numbers, you know something about it; but when you cannot measure it, when you cannot express it in numbers, your knowledge is of a meagre and unsatisfactory kind: it may be the beginning of knowledge, but you have scarcely, in you thoughts, advanced to the stage of science , whatever the matter may be.---Lord Kelvin, Popular Lectures and Addresses , volume 1, 1889