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Progress in gynecologic cancer detection and treatment.

Slow but steady progress has been made in the earlier diagnosis and better treatment of gynecological cancers, particularly over the last 50 years. Cervical cytology screening programs, where implemented, have led to a remarkable reduction in both the incidence and mortality from clinically invasive cervical cancer. This relatively simple technology has been truly one of the major success stories of modern medicine, but unfortunately this technique has not been uniformly applied to all women in the world, particularly to women in developing countries. New research into cervical cancer etiology, the role of HPV, and the development of vaccines against this virus offer a great hope particularly for developing countries. In addition, the combination of radiotherapy and chemotherapy has resulted in a marked improvement in outcome results for women with advanced cervical cancer. Ovarian cancer has seen the development of effective chemotherapy strategies for this disease. Currently this disease remains one of the major scourges in industrialized countries but the continued evolution of knowledge with regard to optimum sequencing of chemotherapeutic agents and surgery offers the prospect for better outcomes, less morbidity and a better quality of life. Ongoing research into the development of newer chemotherapeutic agents and a better understanding of the actual mechanisms regarding the efficacy of chemotherapy and drug resistance offers great promise for the future. Endoscopic surgery for staging and also for therapy shows promise for improved quality of life as well as outcomes for patients in the future and offers the challenge of trying to make this technology readily available to all women in the world. As we gain a better understanding of the molecular basis of disease and health we will truly be able to intervene in a preventive mode in the new millennium.

Breast Neoplasms↗

Multiple parallel synthesis of peptides on SynPhase grafted supports.

The Multipin peptide synthesis approach originated as an immunological tool for epitope mapping. However, continuing evolution of the basic technology has permitted the synthesis of peptides at scales up to 25 micromol per modular grafted surface. At this loading, the methodology can no longer be considered just a screening tool and is now used for the synthesis of micromoles of peptide and other small drug-like molecules for high throughput compound screening. Recent developments such as the introduction of novel grafted polymeric surfaces, new linkers, as well as novel cleavage formats has extended the scope of applications for modular grafted surfaces. This review summarizes the important achievements over the last 15 years of applications of the Multipin synthesis approach and also introduces a new modular grafted surface for peptide and small molecule synthesis called the SynPhase Lantern.

Combinatorial Chemistry Techniques↗

Mechanical characterization of regenerated osseous tissue during callotasis and its related biological phenomenon.

The mechanical characteristics of the regenerated osseous tissue and osteoblastic activities during callotasis were studied using Chinese mountain goat as the animal model. Open osteotomy of the left tibiae was done in 24 goats. Distraction started 6 days after the operation with the rate of 1 mm per day for 4 weeks. The bone regeneration was monitored with serial X-ray films. The tension generated during distraction was measured with the strain gauges mounted on the distraction apparatus. The osteoblastic activities were monitored by measuring plasma bone specific alkaline phosphatase activity. The results showed that the average lengthening was 22.9 +/- 2.8 mm in each animal. The newly formed osseous tissue becomes stiffer during the course of distraction lengthening. The continuous evolution of the tensile behaviour of the newly formed osseous tissue correlates with the plasma bone specific alkaline phosphatase activities. The radiological appearance of a physis like structure took place at 12 mm lengthening. Its appearance corresponds to the changes in the tensile behaviour as well as the biological activities of the osteoblasts and may serve as a useful radiological marker in monitoring the process of callotasis in clinical practice.

Alkaline Phosphatase↗

Hodgkin's disease.

The outlook for patients with Hodgkin's disease has improved dramatically over the past 20 years. The question is no longer whether cure is possible, but rather, how can cure be best achieved. With better understanding of the biology of Hodgkin's disease and with continued evolution of treatment approaches, the goal of curing all patients with Hodgkin's disease is clearly within reach. This article provides a summary of current concepts in the biology and management of Hodgkin's disease. Staging, treatment options, and complications of therapy are discussed.

Adolescent↗

Economic effects of managed care.

There have been substantial changes in the way health care has been paid for in the last half of this century. The original contract between a physician and a patient has evolved to insurance companies paying usual and customary costs for physician services. Now, the medical care of a whole population is bid to organizations willing to insure the risk for managing the care of the population for a prospectively determined fee. The rising cost of health care has imposed new strategies to manage these escalating costs for physician, facilities, and patients. Despite the changes that have radically altered health care delivery, costs continue to rise. This fact ensures that there will be continuing evolution of strategies to decrease the rising rate of health care. Trauma care management traditionally has involved looking at the entire spectrum of the patient's disease process from the prehospital phase to his or her rehabilitation. The discipline that was necessary to identify each component of the system and quantify the cost associated with it has made trauma care a potential model for managed care. There are now systems of care in place that are fully dedicated to trauma. The facilities in them are verified by the American College of Surgeons or a similar professional body. These facilities are designated by a regulatory body, such as the state. It will become more common for payors to require that patients be enrolled in some trauma system of care because this will provide the most cost-effective management, especially for severely injured patients. Surgeons should clearly understand the historic and present strategies for cost-management and how they have evolved. A clear understanding of these forces will allow rational plans to be developed that will deliver the best, most cost effective care to trauma victims.

Certification↗

Assessment of the retinal nerve fiber layer in clinical trials of glaucoma neuroprotection.

Assessment of the retinal nerve fiber layer (RNFL) is appealing for use in clinical trials of glaucoma neuroprotection, as it is directly correlated with loss of ganglion cells, which is assumed to be a primary event in glaucomatous damage. Qualitative assessment of the RNFL includes ophthalmoscopy, color stereophotography, and red-free monochromatic photography. In contrast, confocal scanning laser ophthalmoscopy (CSLO), scanning laser polarimetry (GDx), optical coherence tomography (OCT), and retinal thickness analysis (RTA) objectively and quantitatively measure the RNFL thickness. These latter techniques are still in evolution. Continuing meticulous objective validation is necessary to assess the usefulness and limitations of these powerful tools. Nevertheless, there are excellent prospects for using longitudinal assessment of the RNFL in clinical trials of glaucoma neuroprotection.

Cell Survival↗

Phacoemulsification and modern cataract surgery.

The techniques and results of cataract surgery have changed dramatically during the past three decades. In the USA, we have moved from intracapsular cataract extraction as the preferred technique to almost exclusively extracapsular techniques. Smaller incisions have become the standard, with phacoemulsification now being the method of choice for most surgeons. Along with these advances have come improved intraocular lens materials and designs, especially well suited for use with smaller incisions. Phacoemulsification as a method to remove the cataractous lens was first proposed more than 20 years ago. Advances in techniques and equipment have led to a dramatic increase in the popularity of phacoemulsification with increased safety and efficiency. Viscoelastic agents have been developed synchronously with modern phacoemulsification techniques, playing an integral role in the success of this new technology. Improved surgical techniques for removing the anterior lens capsule have decreased the incidence of both intraoperative and postoperative capsular complications. Nucleus removal, formerly performed primarily in the anterior chamber, is now performed in the posterior chamber, decreasing damage to the corneal endothelium. Improved wound construction allows many wounds to be left unsutured, and smaller wounds allow shorter recovery time and greater intraoperative control and safety. Intraocular lenses can have smaller optic sizes and still maintain accurate centration. Foldable intraocular lenses can take advantage of the smaller incision, even further shortening the time to visual recovery. Continual evolution of this technology promises to further improve patient outcomes after cataract surgery.

Anesthesia, Local↗

The role of partial nephrectomy for renal cell carcinoma in contemporary practice.

Partial nephrectomy has proved to be a safe and effective treatment modality, even for patients with normal contralateral kidneys. The indications for elective partial nephrectomy continue to evolve as contemporary series demonstrate low morbidity approaching that of radical nephrectomy. Furthermore, patients who undergo partial nephrectomy have a significantly decreased risk of future renal insufficiency. As such, a rationale exists for expanding indications in an era of excellent technical outcomes and increased patient longevity. Characterization of newer diagnostic (three-dimensional imaging) and treatment (laparoscopic partial nephrectomy, cryosurgery) modalities will allow continued evolution of nephron-sparing techniques.

Carcinoma, Renal Cell↗

From quality assurance to quality management in long term care.

This article describes the continuing evolution of the quality assurance program at Crown Nursing Home, a privately owned, skilled long-term care facility in Brooklyn, New York, into quality management. Activities are intended to improve the systems and processes of resident care, develop and implement practice guidelines, integrate suppliers and vendors into the facility processes, use information systems for indicator monitoring, encourage residents and family participation, provide care through a team approach, and promote human resource management and staff enhancement.

Clinical Protocols↗

Chromatography and electrophoresis on chips: critical elements of future integrated, microfluidic analytical systems for life science.

Liquid chromatography and electrophoresis played a major role in the life-science revolution, most strikingly in protein purification, peptide fractionation and sequencing, amino acid analysis, and DNA sequencing. The objective of this article is to examine the potential role of separation systems in the continuing evolution of biochemistry, biotechnology and molecular biology. Very small chip-based systems may change how chemical analyses in biology, medical research and health care evolve over the next decade.

Biological Science Disciplines↗

Canine parvovirus.

Canine parvovirus is a truly new pathogen of dogs that emerged in the late 1970s. Initially seen as epidemic disease in all dogs, parvoviral enteritis is now primarily a disease of 1- to 6-month-old dogs. Maternal antibody interference with immunization accounts for the vast majority of vaccine "breaks." Molecular virologic methods have revealed continued evolution of the virus, but this appears to be of greater academic than practical interest. Clinical diagnosis can be definitive in fulminant cases but requires laboratory support--usually demonstration of virus in the feces--in less clear-cut cases. Treatment remains symptomatic, based simply on principles of good supportive care. As the virus is firmly entrenched in both the wild and domestic canine population, elimination of the virus is impossible, and CPV-2 will remain a concern for the small animal practitioner indefinitely.

Animals↗

Expanded divalent metal-ion tolerance of evolved ligase ribozymes.

Class I ligases are artificial ribozymes that catalyze the joining of two single-stranded RNAs. These ribozymes are between 120 and 160 nucleotides in length, making them intermediate in size for catalytic RNAs. Previous characterization of the b1-207 ribozyme suggests that it behaves similar to larger ribozymes in terms of divalent metal-ion dependence. This molecule displays a strong preference for magnesium for catalysis, and is inactive in any other metal except manganese, which actually inhibits its operation in magnesium. Here, we sought to examine the metal-ion usages of two ligases that were obtained through continuous evolution in vitro from the b1-207 sequence framework. We found an expanded catalytic range for the E(100)(#3) and B(16)(#19) ribozymes, as they are both catalytically active in calcium and strontium, and less inhibited by manganese. Though not selected for activity in these salts, the evolved ribozymes exhibit several adaptations to in vitro catalysis, and their ability to accommodate metals other than magnesium can be viewed as an example of a molecular exaptation.

Base Sequence↗

The pH dependence of proton-deuterium exchange, hydrogen production and uptake catalyzed by hydrogenases from sulfate-reducing bacteria.

Different patterns have been found in the pH dependence of hydrogenase activity with enzymes purified from different species of Desulfovibrio. With the cytoplasmic hydrogenase from Desulfovibrio baculatus strain 9974, the pH optima in H2 production and uptake were respectively 4.0 and 7.5 with a higher activity in production than in uptake. The highest D2-H+ exchange activity was found also at pH 4.0 but the optima differed for the HD and the H2 components. Both similarly rose when the pH decreased from 9.0 to 4.5, but the rate of H2 evolution slowed whereas the HD evolution continued rising till pH values around 3.0 were reached. The H2 to HD ratio at pH above 4.5 was higher than one. With the periplasmic hydrogenase from Desulfovibrio vulgaris Hildenborough, the highest exchange activity was near pH 5.5, the same value as in hydrogen production. The periplasmic hydrogenase from Desulfovibrio gigas had in contrast the same pH optimum in the exchange (7.5-8.0) as in the H2 uptake. The ratio of H2 to HD was below one for both enzymes. These different patterns may be related to functional and structural differences in the three hydrogenases so far studied, particularly in the composition of their catalytic centers.

Cytoplasm↗

Codon reassignment in Candida species: an evolutionary conundrum.

A number of Candida species translate the standard leucine CUG codon as serine rather than as leucine. Such codon reassignment in nuclear-encoded mRNAs is unusual and raises a number of important questions about the origin of the genetic code and its continuing evolution. In particular we must establish how a codon can come to be reassigned without extinction of the species and what, if any, selective pressure drives such potentially catastrophic changes. Recent studies on the structure and identity of the novel CUG-decoding tRNA(Ser) from several different Candida species have begun to shed light on possible evolutionary mechanisms which could have facilitated such changes to the genetic code. These findings are reviewed here and a possible molecular mechanism proposed for how the standard leucine CUG codon could have become reassigned as a serine codon.

Base Sequence↗

Advances in ultrasound biomicroscopy.

The visualisation of living tissues at microscopic resolution is attracting attention in several fields. In medicine, the goals are to image healthy and diseased tissue with the aim of providing information previously only available from biopsy samples. In basic biology, the goal may be to image biological models of human disease or to conduct longitudinal studies of small-animal development. High-frequency ultrasonic imaging (ultrasound biomicroscopy) offers unique advantages for these applications. In this paper, the development of ultrasound biomicroscopy is reviewed. Aspects of transducer development, systems design and tissue properties are presented to provide a foundation for medical and biological applications. The majority of applications appear to be developing in the 40-60-MHz frequency range, where resolution on the order of 50 microm can be achieved. Doppler processing in this frequency range is beginning to emerge and some examples of current achievements will be highlighted. The current state of the art is reviewed for medical applications in ophthalmology, intravascular ultrasound, dermatology, and cartilage imaging. Ultrasound biomicroscopic studies of mouse embryonic development and tumour biology are presented. Speculation on the continuing evolution of ultrasound biomicroscopy will be discussed.

Animals↗

A computational model of symbiotic composition in evolutionary transitions.

Several of the major transitions in evolutionary history, such as the symbiogenic origin of eukaryotes from prokaryotes, share the feature that existing entities became the components of composite entities at a higher-level of organization. This composition of pre-adapted extant entities into a new whole is a fundamentally different source of variation from the gradual accumulation of small random variations, and it has some interesting consequences for issues of evolvability. Intuitively, the pre-adaptation of sets of features in reproductively independent specialists suggests a form of 'divide and conquer' decomposition of the adaptive domain. Moreover, the compositions resulting from one level may become the components for compositions at the next level, thus scaling-up the variation mechanism. In this paper, we explore and develop these concepts using a simple abstract model of symbiotic composition to examine its impact on evolvability. To exemplify the adaptive capacity of the composition model, we employ a scale-invariant fitness landscape exhibiting significant ruggedness at all scales. Whilst innovation by mutation and by conventional evolutionary algorithms becomes increasingly more difficult as evolution continues in this landscape, innovation by composition is not impeded as it discovers and assembles component entities through successive hierarchical levels.

Adaptation, Physiological↗

Medicaid managed care and the emergency department: the first one hundred days.

Spurred by concerns over increasing costs and variable quality, public and private third-party payors are moving their subscribers into managed care plans. A central feature of many of these plans is coordination of patient care through a primary care provider (PCP). In exchange for easy access to the PCP, patients are expected to limit their use of emergency services for episodic, primary, and urgent care problems. The State of Connecticut has begun a transition from a fee-for-service Medicaid plan into a managed care product. Because many Medicaid patients had freely used emergency services under the fee-for-service arrangement, urban teaching hospital emergency departments rapidly became a focus of efforts to control cost and change care-seeking behavior. The Hartford Hospital Emergency Department (ED) began screening, education, and referral of managed Medicaid patients in the fall of 1995 and recorded experiences with patients, administrators, and health care providers involved in the implementation of the managed care program. The first 3 mo following plan implementation were chaotic and frustrating for all parties, with many difficulties due to an unprepared infrastructure. Changes in ED operations and maturation of the payor and health care provider network eventually resulted in a reasonably smooth system accompanied by reductions in ED visit volumes of at least 15%. Continual evolution of role and goals will be necessary if EDs are to maintain an active presence in a health care system dominated by managed care plans.

Aid to Families with Dependent Children↗

Imaging in the new millennium.

The last few decades of the 20th century were marked by tremendous advances in diagnostic imaging and related therapeutic procedures. The new millennium holds great promise for more spectacular advances. Continuing evolution of computer technology coupled with existing and evolving digital imaging platforms will serve as a catalyst for significant developments in virtually all areas of imaging. This report surveys the potential of these advances in areas relevant to critical care.

Diagnostic Imaging↗