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Proof of principle and first cases using preimplantation genetic haplotyping--a paradigm shift for embryo diagnosis.

Preimplantation genetic haplotyping (PGH) proof-of-principle was demonstrated by multiple displacement amplification (MDA) of single buccal cells from a female donor and genotyping using 12 polymorphic markers within the dystrophin gene; the known paternal genotype enabled identification of the paternal haplotype in the MDA products despite 27% allele dropout. MDA amplified DNA from 49 single human blastomeres with 100% success. The MDA products were genotyped using a total of 57 polymorphic markers for chromosomes 1, 7, 13, 18, 21, X and Y; 72% of alleles amplified providing results at 90% of the loci tested. A PGH cycle was carried out for Duchenne muscular dystrophy. One embryo was biopsied: PGH showed a non-carrier female, which was transferred with no resulting pregnancy. A PGH cycle was carried out for cystic fibrosis. Seven embryos were biopsied and PGH allowed the exclusion of 2 affected embryos; a carrier and a non-carrier embryo were transferred resulting in an on-going twin pregnancy. PGH represents a paradigm shift in embryo diagnosis, as one panel of markers can be used for all carriers of the same monogenic disease, bypassing the need for development of mutation-specific tests, and widening the scope and availability of preimplantation genetic testing.

Adult↗

Patient-centred measurement in ophthalmology--a paradigm shift.

Ophthalmologists and researchers in ophthalmology understand what a rapidly evolving field ophthalmology is, and that to conduct good research it is essential to use the latest and best methods. In outcomes research, one modern initiative has been to conduct holistic measurement of outcomes inclusive of the patient's point of view; patient-centred outcome. This, of course, means including a questionnaire. However, the irony of trying to improve outcomes research by being inclusive of many measures is that the researcher may not be expert in all measures used. Certainly, few people conducting outcomes research in ophthalmology would claim to be questionnaire experts. Most tend to be experts in their ophthalmic subspecialty and probably simply choose a popular questionnaire that appears to fit their needs and think little more about it. Perhaps, unlike our own field, we assume that the field of questionnaire research is relatively stable. This is far from the case. The measurement of patient-centred outcomes with questionnaires is a rapidly evolving field. Indeed, over the last few years a paradigm shift has occurred in patient-centred measurement.

Humans↗

Recent advances in sentinel node navigation for gastric cancer: a paradigm shift of surgical management.

The sentinel node (SN) is defined as the first draining node from the primary lesion and it has proven to be a good indicator of the metastatic status of regional lymph nodes in solid tumors. In the past 5 years, the validity of SN concept for gastric cancer has been demonstrated by a number of single institutional studies. Using a dual tracer method as the optimal procedure, the radio-guided method allows us to confirm the complete harvest of SNs by gamma probing, while the dye procedure enables us to perform real time observation of the lymphatic vessels. From previous reports, clinically staged T1N0 gastric cancer seems to be a good entity on which to try to change the therapeutic approach based on SN biopsy. At present, two large scale prospective multicenter trials are on-going in Japan. To overcome some remaining issues, such as limited sensitivity of intra-operative diagnosis of metastasis, and technical difficulty in laparoscopic SN detection, further technical and instrumental developments will be required. During this transitional phase, focused lymph node dissection targeted to sentinel lymphatic basins and modified resection of the stomach is an acceptable approach. Although there are several remaining issues, SN navigation should provide a paradigm shift for the surgical management of early gastric cancer in near future.

Clinical Trials as Topic↗

Promoting well-being: time for a paradigm shift in health and human services1.

The promotion of personal, relational, and collective well-being has evolved markedly in the last three decades. However positive and needed, recent developments in health promotion require further conceptual clarification and synergistic applications. To assist with conceptual clarification, this article proposes to distinguish among sites, signs, sources, and strategies of well-being. With respect to applications, progress is discussed along four domains: temporal, ecological, participation, and capabilities. The temporal domain refers to the timing of interventions and entails a continuum from reactive to proactive strategies. The ecological domain pertains to the site of interventions, ranging from person-centered to community-centered. The participation domain refers to voice and choice of citizens and consumers in delivery of services and access to resources. At one end of this continuum there is empowerment, while at the opposite end we see disempowerment and detachment. Finally, the capabilities domain refers to the concentration on either strengths or deficits. This article argues that a singular focus on strength, prevention, empowerment, or community conditions is insufficient. It presents a framework for the conceptual integration of these four approaches, while illustrating the benefits of their synergy and the risks of their fragmentation. It is high time for a paradigm shift in health and human services, and this article argues that only a new approach that focuses on strengths, prevention, empowerment, and community conditions can make considerable progress towards the achievement of well-being for all.

Community Networks↗

Paradigm shifts in Alzheimer's disease and other neurodegenerative disorders: the emerging role of oligomeric assemblies.

Alzheimer's disease (AD) is a progressive, neurodegenerative disorder characterized by amyloid deposition in the cerebral neuropil and vasculature. These amyloid deposits comprise predominantly fragments and full-length (40 or 42 residue) forms of the amyloid beta-protein (Abeta) organized into fibrillar assemblies. Compelling evidence indicates that factors that increase overall Abeta production or the ratio of longer to shorter forms, or which facilitate deposition or inhibit elimination of amyloid deposits, cause AD or are risk factors for the disease. In vitro studies have demonstrated that fibrillar Abeta has potent neurotoxic effects on cultured neurons. In vivo experiments in non-human primates have demonstrated that Abeta fibrils directly cause pathologic changes, including tau hyperphosphorylation. In concert with histologic studies revealing a lack of tissue injury in areas of the neuropil in which non-fibrillar deposits were found, these data suggested that fibril assembly was a prerequisite for Abeta-mediated neurotoxicity in vivo. Recently, however, both in vitro and in vivo studies have revealed that soluble, oligomeric forms of Abeta also have potent neurotoxic activities, and in fact, may be the proximate effectors of the neuronal injury and death occurring in AD. A paradigm shift is thus emerging that necessitates the reevaluation of the relative importance of polymeric (fibrillar) vs. oligomeric assemblies in the pathobiology of AD. In addition to AD, an increasing number of neurodegenerative disorders, including Parkinson's disease, familial British dementia, familial amyloid polyneuropathy, amyotrophic lateral sclerosis, and prion diseases, are associated with abnormal protein assembly processes. The archetypal features of the assembly-dependent neuropathogenetic effects of Abeta may thus be of relevance not only to AD but to these other disorders as well.

Alzheimer Disease↗

Achieving a paradigm shift in environmental and living resources management in the Gulf of Guinea: the large marine ecosystem approach.

The Gulf of Guinea is situated in the narrow protrusion of eastern Equatorial Atlantic between latitudes 2 degrees S and 5 degrees N and longitudes 8 degrees W to 12 degrees E, spanning a coastline length of approximately 130 nautical miles. The dominant feature of this shallow ocean off the coast of countries in Western Africa is the Guinea Current. The distinctive bathymetry, hydrography, productivity and trophodynamics of this shallow ocean qualify it as a large marine ecosystem (LME) and is indeed recognized as the number 28 of the 64 delineated LMEs globally. This area is one of the world's productive marine areas that is rich in fishery resources, oil and gas reserves, precious minerals and an important global reservoir of marine biological diversity. Unfortunately, pollution from residential and industrial sources has affected the waters of the Gulf of Guinea resulting in habitat degradation, loss of biological diversity and productivity, and degenerating human health. In reversing this trend of marine environmental degradation, the countries of the region adopted an integrated and holistic approach using the LME concept to sustainably manage the environmental and living resources of the region. The concept is predicated on the fact that marine environmental pollution and living resources respect no political or geographical boundaries and so require a holistic and regional approach for its management. The Gulf of Guinea countries through the Global Environment facility funded regional/communal project on water pollution control and biodiversity conservation achieved a paradigm shift in living resources and environmental management in the region using the LME concept.

Atlantic Ocean↗

Stroke and severe preeclampsia and eclampsia: a paradigm shift focusing on systolic blood pressure.

OBJECTIVE: To identify important clinical correlates of stroke in patients with preeclampsia and eclampsia. METHODS: The case histories of 28 patients who sustained a stroke in association with severe preeclampsia and eclampsia were scrutinized with particular attention to blood pressures. RESULTS: Stroke occurred antepartum in 12 patients, postpartum in 16. Stroke was classified as hemorrhagic-arterial in 25 of 27 patients (92.6%) and thrombotic-arterial in 2 others. Multiple sites were involved in 37% without distinct pattern. In the 24 patients being treated immediately before stroke, systolic pressure was 160 mm Hg or greater in 23 (95.8%) and more than 155 mm Hg in 100%. In contrast, only 3 of 24 patients (12.5%) exhibited prestroke diastolic pressures of 110 mm Hg or greater, only 5 of 28 reached 105 mm Hg, and only 6 (25%) exceeded a mean arterial pressure of 130 mm Hg before stroke. Only 3 patients received prestroke antihypertensives. Twelve patients sustained a stroke while receiving magnesium sulfate infusion; 8 had eclampsia. Although all blood pressure means after stroke were significantly higher than prestroke, only 5 patients exhibited more than 110 mm Hg diastolic pressures. In 18 of 28 patients, hemolysis, elevated liver enzymes, low platelets syndrome did not significantly alter blood pressures compared with non-hemolysis, elevated liver enzymes, low platelets. Mean systolic and diastolic changes from pregnancy baseline to prestroke values were 64.4 and 30.6 mm Hg, respectively. Maternal mortality was 53.6%; only 3 patients escaped permanent significant morbidity. CONCLUSION: In contrast to severe systolic hypertension, severe diastolic hypertension does not develop before stroke in most patients with severe preeclampsia and eclampsia. A paradigm shift is needed toward considering antihypertensive therapy for severely preeclamptic and eclamptic patients when systolic blood pressure reaches or exceeds 155-160 mm Hg. LEVEL OF EVIDENCE: III.

Adolescent↗

Blunt hepatic injury: a paradigm shift from operative to nonoperative management in the 1990s.

OBJECTIVE: To analyze the outcome of hemodynamically stable patients with blunt hepatic injury managed nonoperatively, and to examine the impact of this approach on the outcome of all patients with blunt hepatic injury. SUMMARY BACKGROUND DATA: Until recently, operative management has been the standard for liver injury. A prospective trial from the authors' institution had shown that nonoperative management could safely be applied to hemodynamically stable patients with blunt hepatic injury. The present study reviewed the authors' institutional experience with blunt hepatic trauma since that trial and compared the results with prior institutional experience. METHODS: Six hundred sixty-one patients with blunt hepatic trauma during the 5-year period ending December 1998 were reviewed (NONOP2). The outcomes were compared with two previous studies from this institution: operative 1985 to 1990 (OP) and nonoperative 1993 to 1994 (NONOP1). RESULTS: All 168 OP patients were managed operatively. Twenty-four (18%) of 136 NONOP1 patients and 101 (15%) of the 661 NONOP2 patients required immediate exploration for hemodynamic instability. Forty-two (7%) patients failed nonoperative management; 20 were liver-related. Liver-related failures of nonoperative management were associated with higher-grade injuries and with larger amounts of hemoperitoneum on computed tomography scanning. Twenty-four-hour transfusions, abdominal infections, and hospital length of stay were all significantly lower in the NONOP1 and NONOP2 groups versus the OP cohort. The liver-related death rate was constant at 4% in the three cohorts over the three time periods. CONCLUSIONS: Although urgent surgery continues to be the standard for hemodynamically compromised patients with blunt hepatic trauma, there has been a paradigm shift in the management of hemodynamically stable patients. Approximately 85% of all patients with blunt hepatic trauma are stable. In this group, nonoperative management significantly improves outcomes over operative management in terms of decreased abdominal infections, decreased transfusions, and decreased lengths of hospital stay.

Abdominal Abscess↗

Inhaled Glucocorticosteroid and Long-Acting beta(2)-Adrenoceptor Agonist Single-Inhaler Combination for Both Maintenance and Rescue Therapy : A Paradigm Shift in Asthma Management.

Despite aggressive fixed-dose (FD) combination therapy with inhaled glucocorticosteroids (ICS) and long acting beta(2)-adrenoceptor agonists (LABA), many patients with asthma remain suboptimally controlled, based on the need for rescue therapy and rates of severe exacerbations. The strategy of adjustable maintenance dosing (AMD) involves adjustment of the maintenance dose, (using a single combination [budesonide/formoterol] inhaler, Symbicort((R))) in response to variability of asthma control over time. The AMD strategy, like the FD approach, involves the use of a short-acting beta(2)-adrenoceptor agonist (SABA) for rapid relief of bronchospasm. The dose-response characteristics of budesonide/formoterol make the AMD strategy a feasible option that cannot be exploited with the combination of salmeterol/fluticasone propionate (Advair((R))). Several studies suggest that the AMD strategy is superior to a FD approach in terms of overall asthma control.Budesonide/formoterol in a single inhaler is as effective as albuterol (salbutamol) for relief of acute asthma episodes, a feature that makes it possible to use this combination for both maintenance and reliever therapy without the need for the use of a SABA. The single-inhaler strategy has been shown to be safe and more efficacious than FD therapy. In particular, the COSMOS study has demonstrated that exacerbation burden is reduced more effectively when the combination (budesonide/formoterol) single inhaler is used for both maintenance and relief compared with FD therapy with salmeterol/fluticasone and albuterol for rescue in patients with moderate-to-severe asthma. These findings suggest that we will have to reconsider our definition of reliever therapy for patients that require long-term therapy with combination ICS and LABA.The concept of single-inhaler therapy represents a paradigm shift in asthma management that has been validated in several large studies involving thousands of patients. The single-inhaler strategy represents one of the most significant advances in asthma management in many years, and one that appears ideal for adoption in primary care.

Albuterol↗

Control and prevention of rabies in animals: paradigm shifts.

Animal management is the keystone of any modern programme for the prevention and control of rabies. Historically, "animal control" for local elimination of disease was largely equated with population reduction. However, with relatively few exceptions, culling alone has not led to effective control of rabies. In most documented examples of effective control of rabies in the 20th century, an integrated management approach was used that included public education, responsible stewardship of animal populations, manipulation of the population carrying capacity of the local habitat, and vaccination strategies. Globally, the greatest burden on human health that is attributable to this zoonosis is caused by uncontrolled rabies in dogs. Where political willingness, biomedical infrastructure, and economic stability permit the sustained use of control measures (e.g. stray animal removal and mandatory parenteral vaccination), canine rabies has been significantly suppressed and even eliminated over large geographical areas. Examples include many island nations, most of North America, Europe, and increasingly in South America. Despite the effectiveness of such proven control techniques, however, their implementation in parts of Asia, Africa, and elsewhere has been limited, primarily because of a lack of dedicated resources and intersectoral cooperation, and also because of the burden of high-density populations of dogs. Implementation is often complicated by cultural and social factors, e.g. reluctance to cull apparently ownerless, nuisance animals that are suspected to have been exposed to rabies, partly on the basis of religious beliefs). Attempts to modify animal fertility (such as the encouragement of voluntary spay-neuter programmes or individual chemical contraception, and the extension of such actions to animals in the community) may provide ancillary support in line with other traditional methods of control of canine rabies. With the identification of complex situations in which wildlife rabies persists despite the elimination of canine rabies, e.g. in North America and Europe, cats can pose a significant public health risk requiring consideration of alternative approaches. In any model system, the threat of translocation of infected animals, unintentional or otherwise, provides a strong rationale for the creation of barriers to prevent reintroduction or exacerbation of the disease, and the maintenance of a minimum body of expertise related to surveillance, diagnosis, and the enactment of mitigating measures. While control activities have traditionally focused upon certain Carnivora species, bats represent another worldwide rabies reservoir. Indiscriminate killing of bats and destruction of roosts was once the norm, but such activities are not sanctioned by reputable organizations today. Even vampire bats, responsible for substantial effects on health and agricultural losses in the New World (Mexico to Argentina), should be targeted only by specific control applications, rather than by more widespread, unconventional, non-specific methodology. Bats should be excluded from human living quarters. Implementing measures to prevent bats from gaining access to homes should occur at an appropriate time when the bats are absent, especially to avoid sealing the non-flying young within a building. Although great progress has been made during the past four decades in the induction of herd immunity among free-ranging carnivores via oral vaccination against rabies, similar novel solutions have not been readily applied to bat populations. Given these challenges, new paradigm shifts are eagerly anticipated as additional biotechnological applications (including contraceptives and anticoagulants) are developed to deal with domestic animals and wildlife.

Animals↗

Laser de-epithelialization for enhanced guided tissue regeneration. A paradigm shift?

The rationale for laser de-epithelialization stems from the attempts to block the down-growth of epithelium into the healing periodontal wound after surgery and prevent formation of a long junctional epithelial attachment. This concept has seen numerous techniques for accomplishing the blockage of epithelium. The advent of GTR was an offshoot of this concept and led Gottlow et al [table: see text] to examine the effects of selectively blocking certain cell types from contacting the root surface during periodontal wound healing. The use of a CO2 laser to de-epithelialize the gingival flaps is an attempt to exclude this cell type from the healing wound and has been used with and without the benefit of GTR membranes. In a study on beagle dogs, the histologic results of using membranes and the laser procedure enhanced the wound healing and regeneration of new bone, cementum, and connective tissue attachment when compared with paired defects using the membranes alone. The results from the human studies and case reports combined with the animal studies indicate a positive benefit in wound healing because of the laser de-epithelialization technique. The use of an osseous graft in treatment of periodontal defects has been shown to stimulate new bone growth effectively and to regenerate new attachment. It has been speculated that the additional benefit of an osseous graft in GTR procedures is the organization of the blood clot at initial healing, which may tend to maintain the space needed for regeneration and to provide a matrix for the fibrin clot to retard epithelial down-growth. Studies comparing the results of osseous grafting with flap debridement always have shown that the amount of new bone formation and clinical new attachment favor the grafted sites versus paired nongrafted sites. The effects of removal of the pocket epithelium at the time of periodontal surgery have been studied by several authors, and these studies generally shown an incomplete removal of the sulcular epithelium by the inverse bevel incision. Epithelial excision was studied by Centty et al, who compared the removal of sulcular epithelium by the CO2 laser technique with conventional methods. Their results confirm that (1) a more complete removal of sulcular epithelium was obtained by laser than by knives, and (2) the technique effectively removes the oral and sulcular epithelium from a gingival flap without damaging the viability of the flap during wound healing. The technique as described in this article was used by Israel et al to verify further the ability to maintain a viable gingival flap during multiple laser deepithelialization procedures in humans during the first 30 days of healing. [table: see text] The concept of laser de-epithelialization as an adjunct to regenerative periodontal procedures currently is being studied in a multicenter university setting using a parallel study in controlled clinical trials. The first of these reports was mentioned previously (Araujo et al, unpublished data) and shows the enhanced wound healing of periodontal defects through use of the laser de-epithelialization technique. The authors believe that this technique has shown significantly better results than those obtained through conventional osseous grafting alone and appears to be comparable to the results reported for GTR procedures with barrier membranes. This concept provides a paradigm shift from the conventional use of GTR therapy by acknowledging the difficulty in controlling epithelium during the early wound healing. It also allows a more comprehensive therapy for treating periodontal disease that addresses the generalized nature of the disease, with multiple lesions being treated concurrently in an economical manner. The patient presenting with generalized advanced periodontal disease could have several defects definitively treated in one quadrant using the laser deepithelialization technique without the need for multiple membrane therapy. (ABSTRACT TRUNCATE

Alveolar Bone Loss↗

Genomic instability and bystander effects: a paradigm shift in radiation biology?

A basic paradigm in radiobiology is that, following exposure to ionizing radiation, the deposition of energy in the cell nucleus and the resulting damage to DNA, the principal target, are responsible for the radiation's deleterious biological effects. Findings in two rapidly expanding fields of research--radiation-induced genomic instability and bystander effects--have caused us to reevaluate these central tenets. In this article, the potential influence of induced genomic instability and bystander effects on cellular injury after exposure to low-level radiation will be reviewed.

Animals↗

The evolving role of the health care supervisor: shifting paradigms, changing perceptions, and other traps.

As health care comes under mounting pressure to reduce costs, organizations are restructuring. Delivery systems are changing. As layoffs occur and changes are made in numbers and responsibilities of managers, supervisors find themselves in dramatically changing roles. Job security has become as illusory in health care as elsewhere. Morale among health workers is sagging, and motivational concerns are increasing. The supervisor has been put in the position of having to do more with less and to do it in the face of demoralized forces. The paradigms that were once operational are shifting, and the evolving role of the health care supervisor suggests that a completely new set of paradigms is taking over that suggests the supervisor's future security lies in the ability to learn new things and to shift and change with the environment.

Employment↗

Effect of age and strain on working memory in mice as measured by win-shift paradigm.

Working memory is disrupted in Alzheimer's disease and stroke; therefore, any therapeutic drug should restore deficits in working memory. The win-shift foraging paradigm has been demonstrated to be a model of working memory in rats. In the present study, this paradigm was adapted to mice because of the greater ease and economy of testing potential drugs in mice and the wider availability of strains of aged mice with naturally occurring working memory deficits. This study has demonstrated strain differences in the working memory trace and that age induces a deficit that can be detected at 11 months of age in mice. Tacrine and physostigmine enhance the memory trace in normal mice and physostigmine can reverse age-induced working memory deficits in subjects with mild and moderate deficits but not in subjects with severe deficits.

Aging↗

Highlights of alternative splicing regulation session: yes, no, maybe--a history of paradigm shifts.

Highlights from the Sixth Annual Meeting of the RNA Society, Banff, Alberta, Canada, 29 May to 3 June 2001. Cooper summarizes the discussions and presentations from the session entitled "Control of Splice Site Selection" held at the Sixth Annual Meeting of the RNA Society. Paradigms are shifting as experiments show that some of the proteins involved in regulating splicing can act as splicing enhancers or repressors, depending on the cellular context. The complex interactions among the ribonucleoproteins (RNPs) and proteins, and the role of cis elements, in controlling cell-specific splicing are highlighted. The importance of properly regulated splicing is emphasized by examples of disease pathologies in which alternative splicing is aberrant.

Alternative Splicing↗

The CNS and staff empowerment: a case of shifting paradigms.

The essence of nursing practice occurs at the bedside. In the midst of shifting health care dynamics, the need for excellence and stability at the bedside remains paramount. Past bureaucratic paradigms, focused on power hoarding and competitiveness, create dysfunctional work conditions in nursing units. Successful nursing administrations are turning to newer paradigms of staff empowerment where values focus on initiative, creativity and perpetual learning in the work place. The CNS has a unique opportunity to contribute to staff empowerment by enhancing staff impact in clinical practice, building staff competence in dynamic situations, revitalizing the meaningfulness of patient care and facilitating intelligent choice alternatives in complex situations.

Clinical Competence↗

From optimization to adaptation: shifting paradigms in environmental management and their application to remedial decisions.

Current uncertainties in our understanding of ecosystems require shifting from optimization-based management to an adaptive management paradigm. Risk managers routinely make suboptimal decisions because they are forced to predict environmental response to different management policies in the face of complex environmental challenges, changing environmental conditions, and even changing social priorities. Rather than force risk managers to make single suboptimal management choices, adaptive management explicitly acknowledges the uncertainties at the time of the decision, providing mechanisms to design and institute a set of more flexible alternatives that can be monitored to gain information and reduce the uncertainties associated with future management decisions. Although adaptive management concepts were introduced more than 20 y ago, their implementation has often been limited or piecemeal, especially in remedial decision making. We believe that viable tools exist for using adaptive management more fully. In this commentary, we propose that an adaptive management approach combined with multicriteria decision analysis techniques would result in a more efficient management decision-making process as well as more effective environmental management strategies. A preliminary framework combining the 2 concepts is proposed for future testing and discussion.

Conservation of Natural Resources↗

Shifting paradigms in gene-mapping methodology for complex traits.

The analysis of genetic linkage has been highly successful in the mapping of the genes responsible for Mendelian diseases. In the past decade, attempts have been made to extend this approach to multifactorial disorders and other health-related traits. It has proved difficult, however, to obtain strong and replicable linkage findings for the common forms of heritable diseases. This, together with the rapid pace of development of molecular technology and expansion of genome sequence information, has resulted in significant shifts in research paradigm. There is an increasing recognition of the need to understand the population genetics and biometrical properties of clinically relevant traits so that phenotypes can be defined in such a way that maximises the chances of successful gene mapping. There is a trend towards systematic association analysis with increasing sophistication in the analysis of pooled DNA samples and multi-locus haplotypes, and in the use of unlinked background markers to protect against spurious associations. We can expect increasing integration between genetics, epidemiology and clinical trials leading to genetically informative designs that will not only identify susceptibility genes but also clarify how the environment influences their effects and how they may modify the response to therapeutic interventions.

Animals↗