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PubMed2006

Evolving combinatorial problem instances that are difficult to solve.

This paper demonstrates how evolutionary computation can be used to acquire difficult to solve combinatorial problem instances. As a result of this technique, the corresponding algorithms used to solve these instances are stress-tested. The technique is applied in three important domains of combinatorial optimisation, binary constraint satisfaction, Boolean satisfiability, and the travelling salesman problem. The problem instances acquired through this technique are more difficult than the ones found in popular benchmarks. In this paper, these evolved instances are analysed with the aim to explain their difficulty in terms of structural properties, thereby exposing the weaknesses of corresponding algorithms.

Algorithms↗
PubMed1973

Early estimation of myocardial damage in conscious dogs and patients with evolving acute myocardial infarction.

To estimate the ultimate extent of myocardial damage during evolving myocardial infarction in conscious dogs and patients, we analyzed early serum creatine phosphokinase (CPK) changes with nonlinear curve-fitting techniques. In experiments with dogs, serial serum CPK changes were fit to a log-normal function by the least squares method; the extent of the completed infarct was calculated by analysis of observed serum CPK changes and verified by measurement of myocardial CPK depletion 24 h after coronary occlusion. Early prediction of myocardial damage was based on projected serum CPK values from best fit curves based on data obtained during the first 5 h after initial elevation of enzyme activity. The correlation between predicted and observed values was close (r > 0.96, n = 11). In 11 additional conscious animals subjected to coronary occlusion, isoproterenol was administered continuously as soon as damage had been estimated from projected serum CPK values. The extent of the completed infarct was assessed by analysis of all serial serum CPK values and verified by analysis of myocardial CPK depletion 24 h after coronary occlusion. In each experiment the calculated completed infarct size exceeded infarct size projected before administration of isoproterenol (average increase = 44+/-10 [SE]%). When similar calculations were applied in experiments with eight dogs treated with propranolol, myocardial salvage was detected in 50% of the animals. In 30 patients with uncomplicated acute myocardial infarction the extent of the completed infarct, measured by analysis of CPK activity in serum samples obtained every 2 h, was compared with damage estimated from CPK values projected by the best fit log-normal curve derived from data obtained during the first 7 h after the initial serum CPK elevation. The estimate of damage based on early data correlated closely with the extent of infarction calculated from all available serial serum CPK values (r = 0.93, n = 30). Thus, the extent of the completed infarct could be estimated accurately during the early evolution of infarction. In patients with spontaneous extension of infarction manifested by chest pain and electrocardiographic changes, the calculated extent of the completed infarct exceeded that predicted. Conversely, salvage of myocardium, after reduction of myocardial oxygen requirements by administration of trimethaphan, was reflected by reduction of the extent of the calculated completed infarct with respect to that predicted from early serum CPK changes.

Acute Disease↗
PubMed2003

A homozygous mutation in HESX1 is associated with evolving hypopituitarism due to impaired repressor-corepressor interaction.

The paired-like homeobox gene expressed in embryonic stem cells Hesx1/HESX1 encodes a developmental repressor and is expressed in early development in a region fated to form the forebrain, with subsequent localization to Rathke's pouch, the primordium of the anterior pituitary gland. Mutations within the gene have been associated with septo-optic dysplasia, a constellation of phenotypes including eye, forebrain, and pituitary abnormalities, or milder degrees of hypopituitarism. We identified a novel homozygous nonconservative missense mutation (I26T) in the critical Engrailed homology repressor domain (eh1) of HESX1, the first, to our knowledge, to be described in humans, in a girl with evolving combined pituitary hormone deficiency born to consanguineous parents. Neuroimaging revealed a thin pituitary stalk with anterior pituitary hypoplasia and an ectopic posterior pituitary, but no midline or optic nerve abnormalities. This I26T mutation did not affect the DNA-binding ability of HESX1 but led to an impaired ability to recruit the mammalian Groucho homolog/Transducin-like enhancer of split-1 (Gro/TLE1), a crucial corepressor for HESX1, thereby leading to partial loss of repression. Thus, the novel pituitary phenotype highlighted here appears to be a specific consequence of the inability of HESX1 to recruit Groucho-related corepressors, suggesting that other molecular mechanisms govern HESX1 function in the forebrain.

Adolescent↗
PubMed1987

The evolving subspecialization of psychiatry: implications for the profession.

Psychiatry is likely to evolve into a number of subspecialty areas, paralleling developments in other medical specialties. These changes are impelled both from within psychiatry, where the rapid increase in knowledge and skills makes mastery of the entire field by any one practitioner less possible, and from without, related to new expectations for psychiatric services from referral sources and patients, increasing competition by other physicians and nonphysician mental health care providers, and shifting reimbursement patterns. The authors discuss the advantages and disadvantages of subspecialization as well as implications for psychiatric practitioners and training programs.

Humans↗
PubMed2001

Four men in treatment: an evolving perspective on homosexuality and bisexuality, 1965 to 2000.

The author surveys his work with gay and bisexual men and his evolving clinical understanding, spanning a thirty-five-year period from 1965 to 2000. Four cases are discussed briefly, one from each decade, to illustrate the changing clinical approach, and the following conclusions drawn: (1) sexual orientation and mental health should be approached as independent dimensions; (2) heterosexual orientation is not a required outcome for successful analysis; (3) an analytic process focused on uncovering a presumed "pathological etiology" inevitably distorts the process and obscures more relevant analytic needs; (4) unrecognized heterosexist assumptions and unfamiliarity with norms of gay men's lives pose special barriers to analytic work with gay men. Ongoing self-analysis and self-education are necessary to reduce interferences that keep analysts from listening to their gay patients with open and unbiased attention.

Adult↗
PubMed1988

Evaluating very small and rapidly evolving programs. Consultation in the case of a health careers information program.

The case of a health careers program evaluation illustrates some aspects of evaluating very small and rapidly evolving programs. Such programs can change quickly, since there is no massive bureaucracy to restrain them. Rigid evaluation research methods would frustrate both researchers and program staff. The authors suggest that flexible design, use of specialized interviewing and analytical experiments--in this case, telephone surveys testing program response--and a recognition that a consultative relationship exists will result in outcomes useful to the program and rich in evaluation data.

Career Choice↗
PubMed1992

Evolving misidentification syndromes and facial recognition deficits.

In this paper, the authors report the case of a 33 year old man with several misidentification delusions involving the self. Evidence suggests that one type of misidentification delusion may evolve into another type. Neuropsychological testing further suggests that misidentification delusions may be associated with subtle abnormalities in facial recognition abilities and with non dominant cerebral compromise.

Adult↗
PubMedDate not supplied

The evolving art of caring for pregnant women with HIV infection.

Care for the pregnant woman who has human immunodeficiency virus (HIV) is highly complex and constantly evolving. The purpose of this article is to describe the pertinent issues regarding women and HIV during pregnancy, including epidemiology of mother-to-child transmission, the effect of the disease on pregnancy, care issues in the perinatal period, and the issues in women's lives that place them at risk for HIV infection. Antiretroviral therapy offers significant reduction in the rate of mother-to-child transmission, and this is presently the cornerstone of therapy for the pregnant woman with HIV. Careful intrapartum management may also reduce the risk of transmission. Clinical studies of treatment modalities continue to offer new hope to prevent transmission of the virus to the fetus.

Anti-HIV Agents↗
PubMed2003

Nurse-parent dialogue: illuminating the evolving pattern of families with children who are medically fragile.

Guided by Newman's theory of health as expanding consciousness, this study explored the pattern of nurse-parent interaction in families with children who were medically fragile by applying the hermeneutic, dialectic method of interviewing and analysis. Living with children who are medically fragile was manifested by continual uncertainity. Families changed from trying to gain control of their uncertainty to learning to live in the uncertainty, as they evolved through an initial p[eriod of disruption and disorganization to organization at another level. This required new ways of relating to friends, family, healthcare providers, and the community, expanding the consciousness of the family.

Adaptation, Psychological↗
PubMed1993

Psychological determinism and the evolving nursing paradigm.

The purpose of this article is to explore three behaviorist theories and their roles within the evolving paradigm of nursing. The authors suggest that the behaviorist theories of locus of control, self-efficacy, and the health belief model are derived from deterministic philosophical premises. These premises are in direct conflict with the premise of free will. As interpreted by the authors and many others, the emerging paradigm of nursing relies on the free will of the individual, the ability of the individual to choose for himself/herself what course of action to take, to avoid, or to pursue. The authors address the psychological deterministic philosophical premises within the three theories and utilize nursing theories to compare and contrast the views of free will and determinism. Finally, they suggest that the use of borrowed and applied theories should decline when nurse scientists are true to the philosophical assumptions of theories within nursing science.

Attitude to Health↗
PubMed2002

Evolving routines: preventing fatigue associated with lung and colorectal cancer.

Some individuals with cancer develop fatigue whereas others do not. To begin the development of a biobehavioral model that could explain this phenomenon, the authors interviewed 29 individuals with lung and colorectal cancer before, during, and after treatment and obtained evaluable data for 18. Blood samples and body weight were obtained at the time of each interview. A three-stage process, evolving routines, and an adaptive behavioral mode labeled gliding characterized those who reported little or no fatigue, even when hemoglobin levels were low. Three other nonadaptive behavioral modes (inertia, disorganization, and overexertion) characterized those who reported fatigue. Individuals with similar disease and treatment profiles seldom demonstrated the same behavioral or biological response patterns.

Adult↗
PubMedDate not supplied

Laboratory testing for HER2/neu in breast carcinoma: an evolving strategy to predict response to targeted therapy.

BACKGROUND: Laboratory testing of HER2/neu in breast carcinoma has become vital to patient care following the approval of trastuzumab as the first therapy to target the HER2/neu oncoprotein. Initial clinical trials used immunohistochemistry (IHC) to test for HER2/neu overexpression in order to select patients for therapy. Fluorescence in situ hybridization (FISH), which tests for gene amplification, is more specific and sensitive than IHC when either assay is compared with HER2/neu overexpression as determined by Northern or Western blot analysis. Many weak overexpressors on IHC testing are not gene amplified on FISH analysis. Such weak overexpressors may be considered false-positives and raise the question of how best to test for HER2/neu. METHODS: The literature was surveyed regarding testing for HER2/neu overexpression in breast carcinomas and alternative testing strategies. RESULTS: False-positive results are a significant problem when IHC is exclusively used to test for HER2/neu overexpression. The false-positives are overwhelmingly confined to the group of 2+ positives and do not respond to targeted therapy. In contrast, concordance between IHC and FISH is high when immunostaining is interpreted as either negative or strongly positive (3+). Whereas some recent studies have suggested that FISH may better predict response to anti-HER2/neu therapy than IHC, others have indicated that IHC is as effective a predictor as FISH. IHC is less technically demanding and costly than FISH. CONCLUSIONS: IHC analysis of HER2/neu in breast carcinoma is a useful predictor of response to therapy with trastuzumab when strongly positive. Negative immunostaining is highly concordant with a lack of gene amplification by FISH. Most weakly positive overexpressors are false-positives on testing with FISH. Thus, screening of breast carcinomas with IHC and confirmation of weakly positive IHC results by FISH is an effective evolving strategy for testing HER2/neu as a predictor of response to targeted therapy.

Antibodies, Monoclonal↗
PubMed2006

PET-CT: evolving role in 3-D radiation therapy.

Traditional imaging techniques, such as computed tomography (CT), have high spatial resolution for changes in the anatomy or structure of organs, but are not very useful for detecting early biochemical changes. Conversely, positron emission tomography (PET) relies on changes in molecular biology to identify the earliest stages of disease but, if used alone, has sub-optimal spatial delineation. However, computer-assisted fused-image and/or single-machine integrated PET-CT can show early biochemical changes with improved anatomic resolution, often before there is any structural change. This approach enables the clinician to view and assess the patient's body from a biochemical perspective. In an era of rapidly evolving 3D conformal radiation treatment, accurate target delineation is a crucial factor in optimization of clinical results. This paper reviews some of the basic-science underpinnings of PET-CT, and highlights some important findings in the early clinical work thus far performed.

Fluorodeoxyglucose F18↗
PubMed2004

Hodgkin's lymphoma: evolving concepts with implications for practice.

Hodgkin's lymphoma is a unique neoplasm of B lymphocytes. Recent data provide new understandings of the pathogenesis and options for staging and therapy of the disease. Three specific topics are addressed in this chapter. In Section I, Dr. Richard Ambinder reviews implications of the relationship of Epstein-Barr virus (EBV) and Hodgkin's lymphoma. This relation includes varying geographic epidemiologic associations, including varying associations with the clinical syndrome of infectious mononucleosis. There are plausible mechanisms, including processes initiated by viral proteins, by which EBV might lead to tumorigenesis. These mechanisms include promotion of genetic instability and alteration of normal processes of apoptosis. In addition to an epidemiologic association and potential role in pathogenesis, viral antigens may pose theoretical targets for anti-cancer therapies, including vaccination. In Section II, Dr. Sigrid Stroobants describes the potential role of positron emission tomographic (PET) scanning. By assessing differences in the metabolic activities of cancer cells, PET scanning may be superior to computerized tomographic scanning, which is limited to showing structural anatomical abnormalities. In patients with Hodgkin's and non-Hodgkin's lymphoma, PET scanning has been tested as an initial staging tool, to assess the rate of therapeutic response from a prognostic perspective, and to differentiate residual tumor from fibrotic masses in patients who have completed therapy. Particularly in assessing the nature of a residual mass seen with other post-therapeutic imaging modalities, PET scanning may provide unique information; very high negative predictive values have been reported. However, before this technology can be recommended for incorporation into standard management, properly conducted prospective trials are required to better evaluate the clinical utility of PET with respect to eventual patient outcomes. In Section III, Dr. Ralph Meyer reviews current data regarding the management of patients with limited-stage Hodgkin's lymphoma. Over the past decade, standard treatment has evolved to consist of combined-modality therapy that includes an abbreviated course of chemotherapy and involved-field radiation. As this therapy continues to include radiation therapy, patients will remain at risk of long-term toxicities that include the development of second cancers and cardiovascular events. These "late-effects" now account for more deaths than those attributed to progressive Hodgkin's lymphoma. Comparative data testing the role of chemotherapy alone are now available and demonstrate that omission of radiation therapy results in small but statistically significant reduction in disease control, but no detectable differences in overall survival. Further follow-up will clarify whether chemotherapy alone is the preferred treatment option; at present patients should be informed of the trade-offs involved in choosing between this option and combined modality therapy.

Combined Modality Therapy↗
PubMed2002

Late relapses evolve from slow-responding subclones in t(12;21)-positive acute lymphoblastic leukemia: evidence for the persistence of a preleukemic clone.

TEL/AML1-positive childhood acute lymphoblastic leukemias (ALLs) generally have low-risk features, but still about 20% of patients relapse. Our initial molecular genetic analyses in 2 off-treatment relapses suggested that the initial and relapse clones represent different subclones that evolved from a common TEL/AML1-positive, treatment-resistant precursor. In order to further elaborate on this hypothesis, we studied 2 patients with late systemic relapses of their TEL/AML1-positive ALL (41 months and 49 months after initial diagnosis, respectively) who had distinct clonal antigen receptor gene rearrangements at diagnosis and relapse. These clone-specific markers enabled us to determine the responsiveness of the individual clones to treatment. The matching genomic TEL/AML1 breakpoints of the initial and the relapse clones in these patients confirmed their origin from a common progenitor cell. This proof was especially important in one of these 2 leukemias without a common antigen receptor gene rearrangement. Our retrospective analysis revealed that in both cases the relapse clone was already present at diagnosis. Despite their small sizes (5 x 10(-3) and 1 x 10(-4), respectively), we were able to detect their much slower responses to therapy compared with the dominant leukemic clone. Moreover, in all instances, these initially slow-responding clones, after they had developed into the relapse leukemia, were rapidly eradicated by the relapse treatment, underlining their different biology at the 2 time points of leukemia manifestation. We thus hypothesize that the minor clone was not fully malignant at initial diagnosis but acquired further mutations that may be necessary for the manifestation of relapse.

Antineoplastic Combined Chemotherapy Protocols↗
PubMed2002

Acute promyelocytic leukemia: evolving therapeutic strategies.

Acute promyelocytic leukemia (APL) is now the most curable subtype of acute myeloid leukemia in adults. All-trans retinoic acid (ATRA), which induces differentiation of the leukemic cells into mature granulocytes, represents the important advance. The incorporation of ATRA in induction results in a high complete remission rate, leads to rapid resolution of the characteristic life-threatening coagulopathy, and, most importantly, decreases the relapse rate compared with treatment with chemotherapy alone. However, ATRA is associated with unique toxicities not observed with conventional cytotoxic chemotherapy. A number of clinical trials have been performed to define the optimal role of ATRA in the treatment of patients. The therapeutic strategies have rapidly evolved as a result of both single institution and large cooperative group trials. Arsenic trioxide and stem cell transplantation are effective treatments for patients with APL who relapse after or are refractory to ATRA-based therapy. As experience with ATRA and arsenic trioxide in patients with APL accumulates, a number of important questions arise that need to be addressed.

Animals↗
PubMed2004

Duplicated genes evolve slower than singletons despite the initial rate increase.

BACKGROUND: Gene duplication is an important mechanism that can lead to the emergence of new functions during evolution. The impact of duplication on the mode of gene evolution has been the subject of several theoretical and empirical comparative-genomic studies. It has been shown that, shortly after the duplication, genes seem to experience a considerable relaxation of purifying selection. RESULTS: Here we demonstrate two opposite effects of gene duplication on evolutionary rates. Sequence comparisons between paralogs show that, in accord with previous observations, a substantial acceleration in the evolution of paralogs occurs after duplication, presumably due to relaxation of purifying selection. The effect of gene duplication on evolutionary rate was also assessed by sequence comparison between orthologs that have paralogs (duplicates) and those that do not (singletons). It is shown that, in eukaryotes, duplicates, on average, evolve significantly slower than singletons. Eukaryotic ortholog evolutionary rates for duplicates are also negatively correlated with the number of paralogs per gene and the strength of selection between paralogs. A tally of annotated gene functions shows that duplicates tend to be enriched for proteins with known functions, particularly those involved in signaling and related cellular processes; by contrast, singletons include an over-abundance of poorly characterized proteins. CONCLUSIONS: These results suggest that whether or not a gene duplicate is retained by selection depends critically on the pre-existing functional utility of the protein encoded by the ancestral singleton. Duplicates of genes of a higher biological import, which are subject to strong functional constraints on the sequence, are retained relatively more often. Thus, the evolutionary trajectory of duplicated genes appears to be determined by two opposing trends, namely, the post-duplication rate acceleration and the generally slow evolutionary rate owing to the high level of functional constraints.

Animals↗
PubMed2005

The evolving role of the dynamic thermal analysis in the early detection of breast cancer.

It is now recognised that the breast exhibits a circadian rhythm which reflects its physiology. There is increasing evidence that rhythms associated with malignant cells proliferation are largely non-circadian and that a circadian to ultradian shift may be a general correlation to neoplasia.Cancer development appears to generate its own thermal signatures and the complexity of these signatures may be a reflection of its degree of development.The limitations of mammography as a screening modality especially in young women with dense breasts necessitated the development of novel and more effective screening strategies with a high sensitivity and specificity. Dynamic thermal analysis of the breast is a safe, non invasive approach that seems to be sensitive for the early detection of breast cancer.This article focuses on dynamic thermal analysis as an evolving method in breast cancer detection in pre-menopausal women with dense breast tissue. Prospective multi-centre trials are required to validate this promising modality in screening.The issue of false positives require further investigation using molecular genetic markers of malignancy and novel techniques such as mammary ductoscopy.

Editorial↗