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Linkage studies of bipolar disorder: methodologic and analytic issues. Report of MacArthur Foundation Workshop on Linkage and Clinical Features in Affective Disorders.

To review the findings of the linkage studies of affective disorders, a workshop, "Linkage and Clinical Features in Affective Disorders," was organized by the MacArthur Foundation Mental Health Research Network I on the Psychobiology of Depression meeting in Alexandria, Va, April 13 to 15, 1989. The major goals of the workshop for affective disorders were to explore the relationship between genetic and clinical heterogeneity, to identify major impediments to linkage studies, and to develop recommendations for the application of standardized methods of conducting linkage studies. The participants in the conference presented detailed demographic and clinical data from most of the published linkage studies of affective disorders. No systematic correspondence between genetic and clinical subtypes of bipolar disorder pedigrees was evident. The major problems hampering the linkage analyses of psychiatric disorders that were identified follow: (1) the major psychiatric disorders--the affective disorders in particular--constituting complex human disorders; (2) the lack of valid definitions of affective disorders; (3) comorbidity between the affective disorders with other disorders; (4) nonrandom mating; (5) a cohort effect, with younger birth cohorts exhibiting higher rates of affective disorders; and (6) the lack of replication of current linkage studies. The recommendations that were made for linkage study designs that incorporate some of the complexities of the affective disorders are reported.

Bipolar Disorder↗

The evaluation of different approaches to randomized clinical trials. Report on the 1987 MacArthur Foundation Network I Methodology Workshop.

The second annual MacArthur Foundation Network I Methodology Workshop focused on the different approaches to implementing randomized controlled clinical trials (RCTs) and the situations in which each approach seems to be most appropriate. We reviewed the advantages and disadvantages of various approaches (single-site RCTs, multisite collaborative RCTs, multiple single-site RCTs, and meta-analysis of existing RCTs), and we make recommendations based on these considerations proposed.

Cost-Benefit Analysis↗

Conference report: CIBA Foundation meeting on enteroviruses and early childhood diabetes.

A symposium held at the CIBA Foundation in April 1996 discussed recent research on the relationship between enteroviruses and the onset of insulin-dependent (Type 1) diabetes mellitus. New data were presented and discussed concerning the frequency of viral infection in the probands and mothers of children with diabetes and the immune responses associated with candidate viruses. Further evidence was presented but yet more is needed to look at the role of viruses in the pathogenesis of IDDM and the mechanisms by which it might occur.

Child, Preschool↗

Morphological foundations of precartilage development in mesenchyme.

Hyaline cartilage is archetypic for the appendicular skeleton and the vertebral column. It arises from pluirpotential mesenchymal ancestor cells that remain morphologically undifferentiated prior to a localized cell aggregation in specific regions destined to undergo chondrogenesis. The critical ultrastructural studies of limb bud mesenchymal differentiation prior to, during, and after aggregation were largely completed during the 1970s. These studies accurately and reproducibly described the changes in the cells and matrix with reference to the developmental stages of the embryonic chick and mouse. Collectively, the morphological literature concerning mouse and chick chondrogenesis is in fundamental agreement on the timing and sequence of cell and matrix changes. The morphological observations are foundational and are now extensively correlated with the molecular events of cartilage differentiation.

Animals↗

Conservative management of operable breast cancer: ten years experience at the Foundation Curie.

514 patients were treated for a surgically operable (T1, T2, T3, N0, N1a, N1b) infiltrating breast carcinoma at the Foundation Curie, Paris, France, from 1960 to 1970 inclusive. Patients with tumors 3 cm or less and without axillary adenopathy had lumpectomy followed by radiotherapy. Patients with larger tumors and all patients with clinically significant lymph nodes (N1b) had exclusive radiotherapy (without lumpectomy). 120 had lumpectomy and 394 had exclusive radiotherapy. The five and ten years absolute survivals, free of disease (N.E.D.), for the lumpectomy are 85% and 75%, respectively. 12% had secondary surgery for local recurrence. The cosmetic results were satisfactory in 98%, with no severe radiation sequelae. The five and ten years, N.E.D., of the exclusive radiotherapy group are 68% and 43%. 55% had secondary surgery for persistent or recurrent disease. The cosmetic results were satisfactory in 85%. There were only three patients with severe radiation sequelae. The overall survival for 514 patients at five and ten years are 72% and 51%. Two-thirds of patients, alive at five years, had a preserved breast. Our conservative treatment resulted in survival at five and ten years comparable to those of radical surgery.

Adult↗

National Neurofibromatosis Foundation International Database.

The National Neurofibromatosis Foundation International Database is a system for collecting comprehensive information on the clinical manifestations and natural history of neurofibromatosis. Data are entered into personal computers at participating centres and are pooled at the Central Database and coordinating centre in Vancouver, Canada. The system includes special mechanisms to assure consistency among centres and to maintain patient confidentiality. The database is designed to foster collaborative clinical and molecular genetic research in many aspects of neurofibromatosis.

Canada↗

Conceptual frameworks and the philosophical foundations of general living systems theory.

The continued expansion and fragmentation of biological disciplines impede education, communication, and efficient advance of biological research. Reversing these trends may require a unification of theories and concepts from all levels of biological organization. One form of this unification is the statement of generalizations that apply to all living systems. We explore the philosophical foundations of general theories of living systems by analyzing conceptual frameworks as they apply to biology. This analysis examines the relation of empirical observation, theories, and conceptual frameworks within the context of an individual scientist's conceptual continuum. Also presented are a small set of translevel generalizations that articulate our conceptual framework of living systems in terms of organismic system organization, the environmental system-organismic system dyad, system capacity, and system incorporation. A set of procedural rules are stated which suggest minimum criteria for the evaluation of the explanatory adequacy of biological theories. The relation of this work to other similar analyses and syntheses of biological knowledge is discussed.

Animals↗

The normative and conceptual foundations of a clinical duty to protect.

The continuing controversy surrounding the Tarasoff inspired duty to protect as developed by the courts and legislatures has not adequately weighed the jurisprudential foundations of such an obligation. The authors argue that the duty's misguided thrust of social control grounded in character and status seriously violates broad principles of political morality underlying the law of social control. They conceptualize an alternative--a clinical duty to protect--that coheres with these underlying values and the limits of professional abilities. They contend that any extra-clinical intervention on the part of the psychotherapist entails a role transformation requiring independent justification.

Confidentiality↗

Foundations of chemical microscopy. 3. Derivatives of some chiral phenylalkylamines and phenylalkylamino acids with 5-nitrobarbituric acid.

At one time, 5-nitrobarbituric acid (also known as dilituric acid) was extensively used as a chemical reagent for the qualitative identification of a variety of basic substances by light microscopy. This methodology was based on evaluation of observed crystal morphologies, because skilled observers could associate a unique crystal habit with the products formed with analytes when those were crystallized using standardized methods. As part of a study to understand the scientific foundations that permitted chemical microscopy to function as a useful analytical technique during its heyday, the products formed by dilituric acid with resolved and racemic phenylalkylamines and phenylalkylamino acids were characterized using a variety of physical analytical techniques. It was found that the different crystal morphologies associated with each of the crystalline adducts were derived from the ability of the systems to form differing structural types and/or hydrate crystal forms upon crystallization.

Alkylation↗

Dual injection capillary electrophoresis: foundations and applications.

The state of the art of capillary electrophoresis (CE) approaches based on dual injection is here reported. Dual injection strategies have been proposed with three main objectives: (i) to provide information about reaction kinetics and/or related parameters, (ii) to perform in-capillary derivatization for improving separation and/or determination, (iii) to develop electrophoretic methods for the simultaneous analysis of anionic and cationic compounds. For the first two purposes, dual injection, which involves sample and reagent, can be realized either from the same end of the capillary (electrophoretically mediated microanalysis, EMMA) or from the two ends of the capillary (electroinjection analysis, EIA). The third objective, with dual injection of sample from the two ends of the capillary, takes advantage of moving cationic and anionic compounds with opposite directions. The foundations of each alternative, conditions necessary for working with them, restrictions, applications as well as perspectives are reviewed in order to establish the advantages, shortcomings, and convenience or no of their use in comparison to conventional CE.

Electrophoresis, Capillary↗

Mammalian hepatocytes as a foundation for treatment in human liver failure.

Technological advances in the separation and culture of mammalian hepatocytes have facilitated the use of these cells as the foundation for either hepatocyte transplantation or hepatocyte-seeded hollow fiber liver assist devices (LAD). To fully appreciate the practical applications of these tissue engineering solutions, it is necessary to understand the types of human liver failure as well as the corresponding animal models. The most immediate application of this type of technology is the treatment of hepatic encephalopathy (HE), an acute and highly fatal complication of fulminant hepatic failure. Although the pathogenesis of HE is unknown, failure of the detoxification function of the liver is accepted as playing an important role in this disorder. Consequently, the assaying and preservation of P450 activity in the grafted cells or in the LAD must be among the main targets of this research. This review explores the problems in hepatocyte transplantation and culture that deserve special consideration and emphasizes the conditions contributing to the in vitro maintenance of phenotypic expression of these cells.

Animals↗

HIV global surveillance: foundation for retroviral discovery and assay development.

The high level of HIV genetic diversity has important implications for screening, diagnostic testing and patient monitoring. Continued diversification and global redistribution of HIV groups, subtypes and recombinants make it imperative that serological and molecular assays be designed and evaluated to ensure reliable performance on all HIV infections. Recognizing the importance of this issue, we initiated a comprehensive program to monitor global diversification of HIV, search for newly emerging variants, assemble large-volume panels of genetically and geographically diverse strains, and develop strategies to determine the impact of HIV diversity on assays used for detecting and monitoring HIV infection. Efforts to identify and characterize rare and emerging HIV strains have lead to the identification of HIV-1 group O, group N, and dual infections of groups M and O. A panel of plasma specimens was established that includes specimens collected from 12 countries in Africa, Asia, Europe, and South America; the panel comprises infections due to HIV-1 group M subtypes A, B, C, D, F, and G, as well as CRF01, CRF02, and unique recombinant forms, group N, and group O. Serological and molecular characterization of this unique panel has provided vital sequence data to support assay development and an invaluable source of well-defined specimens to evaluate and compare assay performance. The ability to address the challenge posed by ongoing evolution of HIV and the emergence of new variants requires continued surveillance of global HIV strain diversity, a sound scientific foundation for assay development, and suitable panels to evaluate and validate assay performance.

Africa↗

Class-directed structure determination: foundation for a protein structure initiative.

The recent sequencing of many complete genomes, combined with the development of methods that allow rapid structure determination for many proteins, has changed the way in which protein structure determinations can be approached. One-by-one determinations of individual protein structures will soon be augmented by class-directed structure analyses in which a group of proteins is targeted and structures of representative members are determined and used to represent the entire group. Such a shift in approach would be the foundation for a broad protein structure initiative targeting classes of proteins important for biotechnology and for a fundamental understanding of protein function.

Animals↗

Mode of colony foundation influences the primary sex ratio in ants.

In ants, young queens can found new colonies independently (without the help of workers) or dependently (with the help of workers). It has been suggested that differences in the mode of colony founding strongly influence queen survival and colony development. This is because independent queens are constrained to produce a worker force rapidly, before they deplete their body reserves and to resist the intense intercolony competition during the founding stage. By contrast, queens that found colonies dependently remain with the workers, which probably results in a lower mortality rate and earlier production of reproductive offspring. Consequently, in species that found independently, queens of incipient colonies are expected to produce mostly worker brood by laying a lower fraction of haploid (male) eggs than queens in mature colonies; such a difference would not occur in species founding dependently. We compared the primary sex ratio (proportion of male-determined eggs) laid by queens in incipient and mature colonies of two ant species Lasius nigerLinepithema humile, showing independent and dependent modes of colony founding, respectively. As predicted L. niger queens of incipient colonies laid a lower proportion of haploid eggs than queens from mature colonies. By contrast, queens of L. humile laid a similar proportion of haploid eggs in both incipient and mature colonies. These results provide the first evidence that (1) the primary sex ratio varies according to the mode of colony foundation, and (2) queens can adjust the primary sex ratio according to the life history stage of the colony in ants. Copyright 1999 The Association for the Study of Animal Behaviour.

Journal Article↗

Multifactorial processes in recovery from aphasia: developing the foundations for a multileveled framework.

This paper develops the foundations for a framework of recovery from aphasia which attempts to integrate knowledge from several domains to form a basis for an approach to treatment as managed recovery. We still have a mainly operational appreciation of recovery derived from atheoretical group investigations using psychometric batteries and generic definitions of aphasia and a lack of clarity in the use of the terms restoration, compensation, and reorganization. There is a failure to appreciate the interrelation of different levels (e.g., neural, cognitive, behavioral) and the importance of different perceptions (e.g., patient, relative, clinician) in individual recovery. The multileveled framework may improve understanding of what underlies individual recovery and form a framework for mapping interactions between levels as a basis for intervention.

Aphasia↗

Direct Determination of the Dependence of the Surface Shear and Dilatational Viscosities on the Thermodynamic State of the Interface: Theoretical Foundations.

Recent developments in nonlinear optical techniques for noninvasive probing of a surfactant influenced gas/liquid interface allow for the measurement of the surfactant surface concentration, c, and thus provide new opportunities for the direct determination of its intrinsic viscosities. Here, we present the theoretical foundations, based on the Boussinesq-Scriven surface model without the usual simplification of constant viscosities, for an experimental technique to directly measure the surface shear (µs) and dilatational (kappas) viscosities of a Newtonian interface as functions of the surfactant surface concentration. This ability to directly measure the surfactant concentration permits the use of a simple surface flow for the measurement of the surface viscosities. The requirements are that the interface must be nearly flat, and the flow steady, axisymmetric, and swirling; these flow conditions can be achieved in the deep-channel viscometer driven at relatively fast rates. The tangential stress balance on such an interface leads to two equations; the balance in the azimuthal direction involves only µs and its gradients, and the balance in the radial direction involves both µs and kappas and their gradients. By further exploiting recent developments in laser-based flow measuring techniques, the surface velocities and their gradients which appear in the two equations can be measured directly. The surface tension gradient, which appears in the radial balance equation, is incorporated from the equation of state for the surfactant system and direct measurements of the surfactant surface concentration distribution. The stress balance equations are then ordinary differential equations in the surface viscosities as functions of radial position, which can be readily integrated. Since c is measured as a function of radial position, we then have a direct measurement of µs and kappas as functions of c. Numerical computations of the Navier-Stokes equations are performed to determine the appropriate conditions to achieve the requisite secondary flow. Copyright 1998 Academic Press.

Journal Article↗

The scientific foundations of clinical enzymology.

Clinical enzymology is the study of the activity and properties of enzymes in specimens (usually of blood) taken from patients, as an aid to the diagnosis and understanding of disease. Research in many areas of enzymology is undertaken to strengthen the foundations on which the clinical interpretation of such enzyme measurements rests. Some aspects of this research are briefly described.

Alkaline Phosphatase↗

A study of the foundations of ethical decision making of clinical medical ethicists.

A study of clinical medical ethicists was conducted to determine the various philosophical positions they hold with respect to ethical decision making in medicine and their various positions' relationship to the subjective-objective controversy in value theory. The study consisted of analyzing and interpreting data gathered from questionnaires from 52 clinical medical ethicists at 28 major health care centers in the United States. The study revealed that most clinical medical ethicists tend to be objectivists in value theory, i.e., believe that value judgments are knowledge claims capable of being true or false and therefore expressions of moral requirements and normative imperatives emanating from an external value structure or moral order in the world. In addition, the study revealed that most clinical medical ethicists are consistent in the philosophical foundations of their ethical decision making, i.e., in decision making regarding values they tend not to hold beliefs which are incompatible with other beliefs they hold about values.

Adult↗