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Narcissistic couples.

When psychoanalysts work with couples, they implicitly recognize a different type of psychoanalytic space in which the dialectic between use of the other as an object and recognition of the other as another subject becomes a new focus of exploration. There is a tension between a search for oneness with a lost object and the inevitable otherness of the partner. In this paper, the author proposes that narcissistic relationships involve a shared fantasy that approaches either of two extremes: denial of difference or totalization of difference between partners. Case examples are used to illustrate this model and to present some of the technical problems of this application of psychoanalysis to couples therapy.

Adult↗

Dipeptidyl peptidase IV gene family. The DPIV family.

We have identified three novel members of the DPIV gene family using database mining approaches. Recombinant DP8 shares a post-proline dipeptidyl aminopeptidase activity with the closely related enzymes DPIV and FAP. The similarities between DP8, DP9 and DPIV in tissue expression pattern suggest a potential role for DP8 and DP9 in liver disease, T cell activation and immune function. The role of the two novel enzymes DP8 and DP9 and the other non-enzyme member DPL2 in human disease will be the focus of further studies.

Dipeptidyl Peptidase 4↗

Phylogenetic analysis using parsimony and likelihood methods.

The assumptions underlying the maximum-parsimony (MP) method of phylogenetic tree reconstruction were intuitively examined by studying the way the method works. Computer simulations were performed to corroborate the intuitive examination. Parsimony appears to involve very stringent assumptions concerning the process of sequence evolution, such as constancy of substitution rates between nucleotides, constancy of rates across nucleotide sites, and equal branch lengths in the tree. For practical data analysis, the requirement of equal branch lengths means similar substitution rates among lineages (the existence of an approximate molecular clock), relatively long interior branches, and also few species in the data. However, a small amount of evolution is neither a necessary nor a sufficient requirement of the method. The difficulties involved in the application of current statistical estimation theory to tree reconstruction were discussed, and it was suggested that the approach proposed by Felsenstein (1981, J. Mol. Evol. 17: 368-376) for topology estimation, as well as its many variations and extensions, differs fundamentally from the maximum likelihood estimation of a conventional statistical parameter. Evidence was presented showing that the Felsenstein approach does not share the asymptotic efficiency of the maximum likelihood estimator of a statistical parameter. Computer simulations were performed to study the probability that MP recovers the true tree under a hierarchy of models of nucleotide substitution; its performance relative to the likelihood method was especially noted. The results appeared to support the intuitive examination of the assumptions underlying MP. When a simple model of nucleotide substitution was assumed to generate data, the probability that MP recovers the true topology could be as high as, or even higher than, that for the likelihood method. When the assumed model became more complex and realistic, e.g., when substitution rates were allowed to differ between nucleotides or across sites, the probability that MP recovers the true topology, and especially its performance relative to that of the likelihood method, generally deteriorates. As the complexity of the process of nucleotide substitution in real sequences is well recognized, the likelihood method appears preferable to parsimony. However, the development of a statistical methodology for the efficient estimation of the tree topology remains a difficult open problem.

Animals↗

Characterizing fluorescence recovery curves for nuclear proteins undergoing binding events.

Fluorescence recovery after photobleaching (FRAP) is an experimental technique used to measure the mobility of proteins within the cell nucleus. After proteins of interest are fluorescently tagged for their visualization and monitoring, a small region of the nucleus is photobleached. The experimental FRAP data are obtained by recording the recovery of the fluorescence in this region over time. In this paper, we characterize the fluorescence recovery curves for diffusing nuclear proteins undergoing binding events with an approximate spatially homogeneous structure. We analyze two mathematical models for interpreting the experimental FRAP data, namely a reaction-diffusion model and a compartmental model. Perturbation analysis leads to a clear explanation of two important limiting dynamical types of behavior exhibited by experimental recovery curves, namely, (1) a reduced diffusive recovery, and (2) a biphasic recovery characterized by a fast phase and a slow phase. We show how the two models, describing the same type of dynamics using different approaches, relate and share common ground. The results can be used to interpret experimental FRAP data in terms of protein dynamics and to simplify the task of parameter estimation. Application of the results is demonstrated for nuclear actin and type H1 histone.

Genome↗

Shared biology of GVHD and GVT effects: potential methods of separation.

The difficult separation of clinical graft-versus-tumor (GVT) effects from graft-versus-host disease (GVHD) reflects their shared biology. Experimental approaches to mediate GVT effects while limiting GVHD include: (1) allograft T cell depletion followed by immune enhancement; (2) modulation of T cell dose or T cell subset composition; (3) donor lymphocyte infusion; (4) reduced-intensity host preparation; (5) modulation of Th1/Th2 and Tc1/Tc2 cell balance; (6) cytokine therapy or neutralization; (7) T regulatory cell therapy; (8) co-stimulatory pathway modulation; (9) chemokine pathway modulation; (10) induction of antigen-specific T cells; (11) alloreactive NK cell therapy; and (12) targeted pharmaceutical inhibition of proteosome, mammalian target of rapamycin, and histone deacetylase pathways. Clearly, a multitude of approaches exist that hold promise for separating GVT effects from GVHD. Future success in this endeavor will require a strong commitment towards translational research and continued advances in cell, vaccine, cytokine, monoclonal antibody, and targeted molecular therapy.

Cytokines↗

Opposing kinase signaling may underlie the inverse relationship between cancer and Alzheimer's disease.

Cancer and Alzheimer's disease (AD) are leading causes of mortality and exhibit an inverse relationship, where AD patients have reduced cancer risk and vice versa. However, the molecular basis of this relationship remains poorly understood. We reanalyzed published proteomic and phosphoproteomic datasets to investigate this relationship. Differentially abundant proteins were identified in lung adenocarcinoma and glioblastoma samples relative to controls and compared with proteins altered in AD brains, revealing 37 proteins with opposing abundance patterns. Protein-protein interaction and pathway analyses revealed enrichment in kinase signaling and phosphorylation pathways. Phosphoproteomic analysis identified 52 differentially phosphorylated sites with opposing patterns, while kinase-substrate enrichment analysis identified 44 kinases with opposing inferred activity profiles. Integration of kinase activity and phosphosite data identified 29 kinase-phosphosite pairs, including 4 prioritized pairs with opposing patterns relevant to both diseases. Across seven independent cancer cohorts, 17 of 20 statistically significant phosphosite-cohort comparisons (85%) were concordant with the discovery findings, supporting reproducibility of the prioritized phosphosites. Together, these findings highlight opposing kinase signaling as a prominent feature of the inverse relationship and suggest potential biomarkers and therapeutic targets. This study provides a novel systems-level framework for investigating inverse relationships, supported by an R Shiny application for data exploration (https://advscancer.shinyapps.io/advscancer/). SIGNIFICANCE: This study presents an integrated proteomic and phosphoproteomic framework for investigating the inverse relationship between cancer and Alzheimer's disease (AD). By integrating differential protein abundance, phosphosite phosphorylation, inferred kinase activity, and curated kinase-substrate relationships, we identified opposing signaling patterns and prioritized four kinase-phosphosite pairs. Independent evaluation across seven CPTAC cancer cohorts supported the reproducibility of the prioritized phosphosite patterns. These findings provide insight into molecular processes potentially associated with the inverse relationship between cancer and AD, identify candidate biomarkers and therapeutic targets, and demonstrate the value of systems-level, data-driven approaches for investigating shared and opposing disease processes.

Humans↗

Cognition in behavior therapy: agreements and differences.

The issue of cognition has often been divisive among behavior therapists. Typically the debate has centered around the causal status of cognition. Cognitive psychologists have argued for the causal efficacy of cognition, while behavior analysts have argued against it. These disputes are not entirely empirical matters. In part, they reflect irreconcilable differences at the level of theory and philosophy. Such differences may make theoretical integration impossible. However, in this paper we examine the potential for reconciliation of the cognitive and behavioral wings of behavior therapy when the issue of cognition is approached as a shared content area, rather than at the level of theory and philosophy. Behavior therapy has always been comprised of very diverse theoretical positions. Historically they found common ground around a set of shared values centered on an empirical science of clinical work. We will argue that this core of shared values still exists, and that even controversial topics can provide an arena for reconciliation when we focus on the core values that initially brought us together.

Behavior Therapy↗

Preventive care for the menopausal woman.

In summary, menopause represents a stage in a woman's life for the primary care physician to have an important impact on health [43]. Decision-making must weigh individual risk factors for health disease, osteoporosis and breast cancer. Hormone replacement therapy remains an important issue for the postmenopausal woman [44]. More evidence is needed to define the specific health benefits and risks of HRT, particularly as it relates to the prevention of CHD. A patient centered approach using a shared decision making model is most likely to result in improved patient satisfaction and desired health outcome.

Adult↗

The efficacy of a mind-body-spirit group for women with breast cancer: a randomized controlled trial.

Increasing numbers of women with breast cancer are seeking alternatives to standard group support in coping with their illness. This study examines outcomes for 181 women with breast cancer randomized to either a 12-week standard group support or a 12-week complementary and alternative medicine (CAM) support intervention. Participants in the CAM group were taught the use of meditation, affirmation, imagery and ritual. The standard group combined cognitive-behavioral approaches with group sharing and support. Both interventions were found to be associated with improved quality of life (CAM, P=0.008; Standard, P=0.006), decreased depression (CAM, P=0.004; Standard, P=0.02), decreased anxiety (CAM, P=0.0003; Standard, P=0.02) and increased "spiritual well-being" (CAM, P=002; Standard, P=0.003). Only the CAM group showed increases in measures of Spiritual Integration (P=0.001) which were also significant between groups (P=0.003). The Standard group was associated with decreased confusion (P=0.01) and decreased helplessness/hopelessness (P=0.01), while the CAM group was associated with decreased avoidance (P=0.01). None of these latter changes were significant between groups. At baseline, very high correlations were noted between measures of quality of life, mood, and spiritual integration. At the end of the intervention, the CAM group showed higher satisfaction (P=0.006) and fewer dropouts (P=0.006) compared to the standard group. Better outcomes in quality of life in the CAM group were associated with lower initial fighting spirit (r=-.39, P=0.001). No baseline factors predicted better outcomes in the Standard group. In summary, the study found equivalence on most psychosocial outcomes between the two interventions.

Adaptation, Psychological↗

Going beyond triage in Tajikistan. Health reform in the former Soviet Union.

Tajikistan is among the few countries where life expectancy diminished during the 1990's. To rebuild a health system fractured by economic collapse, political disintegration and civil war, the Essential Hospital Services Project was initiated to restore essential hospital services, encourage structural reform and build the health system's capacity to sustain itself. The article provides an overview of these reform efforts, outlines some of the challenges of health reform in Tajikistan and illustrates the benefits global partnerships can achieve when sharing creative new approaches to health reform.

Canada↗

Complex trait analysis of gene expression uncovers polygenic and pleiotropic networks that modulate nervous system function.

Patterns of gene expression in the central nervous system are highly variable and heritable. This genetic variation among normal individuals leads to considerable structural, functional and behavioral differences. We devised a general approach to dissect genetic networks systematically across biological scale, from base pairs to behavior, using a reference population of recombinant inbred strains. We profiled gene expression using Affymetrix oligonucleotide arrays in the BXD recombinant inbred strains, for which we have extensive SNP and haplotype data. We integrated a complementary database comprising 25 years of legacy phenotypic data on these strains. Covariance among gene expression and pharmacological and behavioral traits is often highly significant, corroborates known functional relations and is often generated by common quantitative trait loci. We found that a small number of major-effect quantitative trait loci jointly modulated large sets of transcripts and classical neural phenotypes in patterns specific to each tissue. We developed new analytic and graph theoretical approaches to study shared genetic modulation of networks of traits using gene sets involved in neural synapse function as an example. We built these tools into an open web resource called WebQTL that can be used to test a broad array of hypotheses.

Animals↗

Strain-specific alterations in gut microbiome and host immune responses elicited by tolerogenic Bifidobacterium pseudolongum.

The beneficial effects attributed to Bifidobacterium are largely attributed to their immunomodulatory capabilities, which are likely to be species- and even strain-specific. However, their strain-specificity in direct and indirect immune modulation remain largely uncharacterized. We have shown that B. pseudolongum UMB-MBP-01, a murine isolate strain, is capable of suppressing inflammation and reducing fibrosis in vivo. To ascertain the mechanism driving this activity and to determine if it is specific to UMB-MBP-01, we compared it to a porcine tropic strain B. pseudolongum ATCC25526 using a combination of cell culture and in vivo experimentation and comparative genomics approaches. Despite many shared features, we demonstrate that these two strains possess distinct genetic repertoires in carbohydrate assimilation, differential activation signatures and cytokine responses signatures in innate immune cells, and differential effects on lymph node morphology with unique local and systemic leukocyte distribution. Importantly, the administration of each B. pseudolongum strain resulted in major divergence in the structure, composition, and function of gut microbiota. This was accompanied by markedly different changes in intestinal transcriptional activities, suggesting strain-specific modulation of the endogenous gut microbiota as a key to immune modulatory host responses. Our study demonstrated a single probiotic strain can influence local, regional, and systemic immunity through both innate and adaptive pathways in a strain-specific manner. It highlights the importance to investigate both the endogenous gut microbiome and the intestinal responses in response to probiotic supplementation, which underpins the mechanisms through which the probiotic strains drive the strain-specific effect to impact health outcomes.

Mice↗

[Shared decision making in breast cancer patients--qualitative study on mutual decision making in breast cancer in a university hospital].

This qualitative study examines doctor-patient interactions and interviews with breast cancer patients referring to shared decision making. The interviews have been evaluated according to the method of grounded theory. Videos of doctor-patient interactions show information and discussions on therapy planning. Breast cancer is a serious, in many cases life-threatening disease. The primary therapy is characterised by confrontation with the diagnosis, fear and hope of the patients and the subsequent treatment. Central themes of the article are the context and implicit assumptions of doctors influencing the shared decision making approach.

Adaptation, Psychological↗

Tracing the LINEs of human evolution.

The amplification of DNA by LINE-1 (L1) retrotransposons has created a large fraction of the human genome. To better understand their role in human evolution we endeavored to delineate the L1 elements that have amplified since the emergence of the hominid lineage. We used an approach based on shared sequence variants to trace backwards from the currently amplifying Ta subfamily. The newly identified groups of insertions account for much of the molecular evolution of human L1s. We report the identification of a L1 subfamily that amplified both before and after the divergence of humans from our closest extant relatives. Progressively more modern groups of L1s include greater numbers of insertions. Our data are consistent with the hypothesis that the rate of L1 amplification has been increasing during recent human evolution.

Animals↗

Methods for quantifying variability and uncertainty in AP-42 emission factors: case studies for natural gas-fueled engines.

Quantitative methods for characterizing variability and uncertainty were applied to case studies of oxides of nitrogen and total organic carbon emission factors for lean-burn natural gas-fueled internal combustion engines. Parametric probability distributions were fit to represent inter-engine variability in specific emission factors. Bootstrap simulation was used to quantify uncertainty in the fitted cumulative distribution function and in the mean emission factor. Some methodological challenges were encountered in analyzing the data. For example, in one instance, five data points were available, with each data point representing a different market share. Therefore, an approach was developed in which parametric distributions were fitted to population-weighted data. The uncertainty in mean emission factors ranges from as little as approximately +/-10% to as much as -90 to +180%. The wide range of uncertainty in some emission factors emphasizes the importance of recognizing and accounting for uncertainty in emissions estimates. The skewness in some uncertainty estimates illustrates the importance of using numerical simulation approaches that do not impose restrictive symmetry assumptions on the confidence interval for the mean. In this paper, the quantitative method, the analysis results, and key findings are presented.

Air Pollutants↗

Improving the social responsiveness of medical schools: lessons from the Canadian experience.

The recent Canadian experience in promoting social accountability and social responsiveness of medical schools has been one of steady improvement in certain institutions, against a background lacking overall national policy direction. Canada has several distinct advantages in trying to devise means of enhancing social accountability of medical training and health services, including a strong national system of publicly supported and financed health care of high quality, a network of excellent academic medical centers, and well-established accreditation bodies. A review of the literature, complemented by a new survey of Canadian medical schools, confirms that some of the centers, conscious of the need to promote social responsiveness, are developing innovative programs to do so. Future progress toward the goal of social responsiveness of medical schools on a pan-Canadian basis will require a more cohesive approach involving systematic sharing of best practices among academic health centers, effective alliances with other health professionals to promote these objectives, and support by federal and provincial ministries of health. Canadian awareness of an international movement tending to similar objectives would support the efforts of Canadian health professionals engaged in practices of enhanced accountability.

Canada↗

Healthcare information systems: education lessons learned.

The educator is a key person during the implementation of a new healthcare computer system or a new software program. Computers require teamwork across departmental lines and flexibility in instructional approach. The authors share their experiences as educators at the San Francisco VA during the initiation of several new computer software packages. They examine the issues involved in this type of training and share the lessons learned.

Clinical Competence↗