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Sharing decisions with patients doesn't mean you won't offer solid advice or attempt friendly persuasion. It does imply a full discussion and exchange of information so as to arrive at the best course of treatment for each of your patients. [ABSTRACT FROM AUTHOR]

According to William Anthony's "Recovery from mental illness: the guiding vision of the mental health service system in the 1990s," mental health recovery means "changing one's attitudes, values, feelings, goals, and skills in order to live a satisfying life within the limitations caused by illness." This seminal work served as an overarching goal, a call to action, and a roadmap for the enhancement of psychiatric recovery. Unfortunately, from many viewpoints, the goals encouraged by Anthony have not been achieved. Through semi-structured interviews with psychiatry clinicians and senior faculty members, this article aims to elucidate the current status of psychiatric recovery, how the movement progressed to this point, and where we could go from here. The development of the recovery movement will be discussed, along with its assumptions and explicit goals. The interviews focus on the extent to which these goals have been achieved, barriers to progress, whether goals should be revised, and how to achieve these goals., (© 2024. The Author(s), under exclusive licence to Springer Science+Business Media, LLC, part of Springer Nature.)

Despite considerable regulatory and clinical hurdles, the development and use of cell-based therapies are gaining momentum. As more of these therapies move toward commercial approval and larger-scale distribution, associated manufacturing and processing technologies are being advanced. Modern technologies directed at downstream processing seek to distribute such therapies from the manufacturing site to the patient more efficiently and reliably. Novel small-scale downstream solutions boost the transformation of cell therapies from abstraction to reality., (Copyright © 2015 International Society for Cellular Therapy. Published by Elsevier Inc. All rights reserved.)

Objectives: Acquiring communication and interpersonal skills is an important part of providing patient-centered care and improving patient satisfaction. This study explores whether residents' own values about patient communication can be influenced by training., Methods: As part of service excellence, a three-hour communication skills training in AIDET™ (Acknowledge, Introduce, Duration, Explanation, Thank You) was delivered to first and second Post-Graduate Year (PGY) residents (n = 123). A survey was designed to measure the value of patient communication and administered pre/post communication skills training., Results: Residents' scores about communication values improved significantly for all areas pre- to post-training for patient communication skills (p<0.04). After training, there was little difference by medical specialty, other than surgical specialties, which showed the greatest increase in valuing requesting permission (p=0.034). Gender was also not associated with differences in values, except men showed a greater increase in valuing sitting down (p=0.021) and introductions (p=0.005) than women who already valued these specific behaviors prior to training., Conclusions: Residents value communication, and AIDET™ training is a useful tool to increase the values of good communication and interpersonal skills to enhance service excellence.

Objective: It is well documented that stress is associated with negative health outcomes in cancer patients. The purpose of this study was to assess the effects of a novel mindfulness intervention called mindfulness-based art therapy (MBAT) versus standard educational support, on indices of stress and quality of life in breast cancer patients with high stress levels., Methods: A total of 191 women were enrolled, stratified by age and stress level, and randomized to receive either an 8-week MBAT intervention or a breast cancer educational support program of equal time and duration. Psychosocial stress was measured using the Symptoms Checklist-90-Revised, and quality of life was measured using the Medical Outcomes Study Short-Form Health Survey at baseline, immediately post-intervention, and at 6 months., Results: Results showed overall significant improvements in psychosocial stress and quality of life in both the MBAT and educational support groups immediately post-intervention; however, participants with high stress levels at baseline had significantly improved overall outcomes only in the MBAT group, both immediately post-intervention and at 6 months. In addition, at 6 months follow-up, participants attending five or more sessions trended toward retaining treatment effects better in the MBAT than in the control group. Finally, black women and white women were similar in terms of how they benefited from the MBAT intervention, even though white participants tended to have higher educational level and marital status., Conclusions: In conclusion, MBAT is associated with significant, sustained benefits across a diverse range of breast cancer patients, particularly those with high stress levels., (Copyright © 2013 John Wiley & Sons, Ltd.)

This study employed functional magnetic resonance imaging to evaluate changes in cerebral blood flow (CBF) associated with the Mindfulness-based Art Therapy (MBAT) programme and correlate such changes to stress and anxiety in women with breast cancer. Eighteen breast cancer patients were randomized to the MBAT or education control group. The patients received the diagnosis of breast cancer between 6 months and 3 years prior to enrollment and were not in active treatment. The age of participants ranged from 52 to 77 years. A voxel-based analysis was performed to assess differences at rest, during meditation and during a stress task. The anxiety sub-scale of the Symptoms Checklist-90-Revised was compared with changes in resting CBF before and after the programmes. Subjects in the MBAT arm demonstrated significant increases in CBF at rest and during meditation in multiple limbic regions, including the left insula, right amygdala, right hippocampus and bilateral caudate. Patients in the MBAT programme also had a significant correlation between increased CBF in the left caudate and decreased anxiety scores. In the MBAT group, responses to a stressful cue resulted in reduced activation of the posterior cingulate. The results demonstrate that the MBAT programme was associated with significant changes in CBF, which correlated with decreased anxiety over an 8-week period., (Copyright © 2012 John Wiley & Sons, Ltd.)

Purpose: To measure the extent of informed decision making (IDM) about prostate cancer screening in physician-patient encounters, describe the coding process, and assess the reliability of the IDM measure., Methods: Audiorecoded encounters of 146 older adult men and their primary care physicians were obtained in a randomized controlled trial of mediated decision support related to prostate cancer screening. Each encounter was dual coded for the presence or absence of 9 elements that reflect several important dimensions of IDM, such as information sharing, patient empowerment, and engaging patients in preference clarification. An IDM-9 score (range = 0-9) was determined for each encounter by summing the number of elements that were coded as present. Estimates of coding reliability and internal consistency were calculated., Results: Male patients tended to be white (59%), married (70%), and between the ages of 50 and 59 (70%). Physicians tended to be white (90%), male (74%), and have more than 10 years of practice experience (74%). IDM-9 scores ranged from 0 to 7.5 (mean [SD], 2.7 [2.1]). Reliability (0.90) and internal consistency (0.81) of the IDM-9 were both high. The IDM dimension observed most frequently was information sharing (74%), whereas the dimension least frequently observed was engagement in preference clarification (3.4%)., Conclusions: In physician-patient encounters, the level of IDM concerning prostate cancer screening was low. The use of a dual-coding approach with audiorecorded encounters produced a measure of IDM that was reliable and internally consistent.

Cotransins are cyclic heptadepsipeptides that bind the Sec61 translocon to inhibit cotranslational translocation of a subset of secreted and type I transmembrane proteins. The few known cotransin-sensitive substrates are all targeted to the translocon by a cleavable signal sequence, previously shown to be a critical determinant of cotransin sensitivity. By profiling two cotransin variants against a panel of secreted and transmembrane proteins, we demonstrate that cotransin side-chain differences profoundly affect substrate selectivity. Among the most sensitive substrates we identified is the proinflammatory cytokine tumor necrosis factor alpha (TNF-α). Like all type II transmembrane proteins, TNF-α is targeted to the translocon by its membrane-spanning domain, indicating that a cleavable signal sequence is not strictly required for cotransin sensitivity. Our results thus reveal an unanticipated breadth of translocon substrates whose expression is inhibited by Sec61 modulators., (Copyright © 2011 Elsevier Ltd. All rights reserved.)

Objective: This randomized trial was conducted to assess the impact of a mediated decision support intervention on primary care patient prostate cancer screening knowledge, decisional conflict, informed decision making (IDM), and screening., Methods: Before a routine office visit, 313 male patients eligible for prostate cancer screening completed a baseline telephone survey and received a mailed brochure on prostate cancer screening. At the visit, participants were randomized to either an enhanced intervention (EI) or a standard intervention (SI) group. Before meeting with their physician, EI Group men had a nurse-led "decision counseling" session, while SI Group men completed a practice satisfaction survey. An endpoint survey was administered. Survey data, encounter audio-recordings, and chart audit data were used to assess study outcomes., Results: Knowledge increased in the EI Group (mean difference of +0.8 on a 10-point scale, p=0.001), but decisional conflict did not change (mean difference of -0.02 on a 4-point scale, p=0.620). The EI Group had higher IDM (rate ratio=1.30, p=0.029) and lower screening (odds ratio=0.67, p=0.102)., Conclusion: Nurse-mediated decision counseling increased participant prostate cancer screening knowledge, and influenced informed decision making and screening., Practice Implications: Nurses trained in decision counseling can facilitate shared decision making about screening., (Copyright © 2010 Elsevier Ireland Ltd. All rights reserved.)

Background: The treatment of psychiatric illnesses, prevalent in the general hospital, requires broadly trained providers with expertise at the interface of psychiatry and medicine. Since each hospital operates under different economic constraints, it is difficult to establish an appropriate ratio of such providers to patients., Objective: The authors sought to determine the current staffing patterns and ratios of Psychosomatic Medicine practitioners in general hospitals, to better align manpower with clinical service and educational requirements on consultation-liaison psychiatry services., Method: Program directors of seven academic Psychosomatic Medicine (PM) programs in the Northeast were surveyed to establish current staffing patterns and patient volumes. Survey data were reviewed and analyzed along with data from the literature and The Academy of Psychosomatic Medicine (APM) fellowship directory., Results: Staffing patterns varied widely, both in terms of the number and disciplines of staff providing care for medical and surgical inpatients. The ratio of initial consultations performed per hospital bed varied from 1.6 to 4.6., Conclusion: Although staffing patterns vary, below a minimum staffing level, there is likely to be significant human and financial cost. Efficient sizing of a PM staff must be accomplished in the context of a given institution's patient population, the experience of providers, the presence/absence and needs of trainees, and the financial constraints of the department and institution. National survey data are needed to provide benchmarks for both academic and nonacademic PM services.

Breast cancer is a relatively common diagnosis for American women and depressive symptoms occur in many women with breast cancer. Identification of women with breast cancer and concomitant depressive symptoms and mood disorders requires particular attention by heath care providers, and may be aided by the administration of a variety of diagnostic and/or screening tools. Insomnia is also a significant problem for women with breast cancer at various stages of diagnosis and treatment, including after remission. Although many studies on the treatment of depression in women with breast cancer have been done, and the data do point to the efficacy of several antidepressants in this population, there are no data to support the widely held hypothesis that treatment of depression in patients with breast cancer may positively affect morbidity and mortality. Breast cancer treatments may give rise to depressive symptoms and this should be considered in the approach to pharmacotherapy. Several psychotherapeutic modalities offer relief of the symptoms and syndromes of depression in breast cancer. Future research can answer the question of which approach is most appropriate for which patients, and whether therapy can improve a variety of health outcomes and survival for women with breast cancer., (Copyright 2010 Elsevier Inc. All rights reserved.)

PI3Kdelta and PI3Kgamma regulate immune cell signaling, while the related PI3Kalpha and PI3Kbeta regulate cell survival and metabolism. Selective inhibitors of PI3Kdelta/gamma represent a potential class of anti-inflammatory agents lacking the antiproliferative effects associated with PI3Kalpha/beta inhibition. Here we report the discovery of PI3Kdelta/gamma inhibitors that display up to 1000-fold selectivity over PI3Kalpha/beta and evaluate these compounds in a high-content inflammation assay using mixtures of primary human cells. We find selective inhibition of only PI3Kdelta is weakly anti-inflammatory, but PI3Kdelta/gamma inhibitors show superior inflammatory marker suppression through suppression of lipopolysaccharide-induced TNFalpha production and T cell activation. Moreover, PI3Kdelta/gamma inhibition yields an anti-inflammatory signature distinct from pan-PI3K inhibition and known anti-inflammatory drugs, yet bears striking similarities to glucocorticoid receptor agonists. These results highlight the potential of selectively designing drugs that target kinases with shared biological function., (Copyright 2010 Elsevier Ltd. All rights reserved.)

Introduction: The ability to predict the health effects resulting from drug or chemical exposure has been challenging due to the complexity of human biology. Approaches that detect and discriminate a broad range of mechanisms in testing formats that are predictive and yet cost-effective are needed., Methods: Here, we evaluated the performance of BioMAP systems, primary human cell-based disease models, as a platform for characterization of chemical toxicity mechanisms. For this we tested a set of compounds with known or well-studied mechanisms in a panel of 8 BioMAP assays relevant to human respiratory, skin, immune and vascular exposure sites., Results: We evaluated the ability to detect and distinguish compounds based on mechanisms of action, comparing the BioMAP activity profiles generated in a reduced sample number format to reference database profiles derived from multiple experiments. We also studied the role of BioMAP assay panel size and concentration effects, both of which were found to contribute to the ability to discriminate chemicals and mechanisms., Discussion: Compounds with diverse mechanisms, including modulators of the NFkappaB pathway, microtubule function and mitochondrial activity, could be discriminated and classified into target and pathway mechanisms in both assay formats. Certain inhibitors of mitochondrial function, such as rotenone and sodium azide, but not others, were classified with inducers of endoplasmic reticulum stress, providing insight into the toxicity mechanisms of these agents. This method may have utility in classifying novel agents with unknown modes of action according to their effects on toxicity pathways., (Copyright 2009 Elsevier Inc. All rights reserved.)

Prostate cancer is now a chronic condition. Screening, diagnosis, and treatment pose specific psychosocial challenges for men diagnosed and surviving with prostate cancer. Depression, anxiety, and cognitive impairment lead to emotional distress and difficulty coping. Treatments for psychosocial distress are targeted at couples and individuals. Lifestyle modification may improve coping and quality-of-life indicators.

Background: In their current configuration, traditional reactive consultation-liaison services see a small percentage of the general-hospital patients who could benefit from their care. These services are poorly reimbursed and bring limited value in terms of clinical improvement and reduction in health-service use., Method: The authors examine models of cross-disciplinary, integrated health services that have been shown to promote health and lower cost in medically-complex patients, those with complicated admixtures of physical, mental, social, and health-system difficulties., Conclusion: Psychiatrists who specialize in the treatment of medically-complex patients must now consider a transition from traditional consultation to proactive, value-added programs and bill for services from medical, rather than behavioral, insurance dollars, since the majority of health-enhancement and cost-savings from these programs occur in the medical sector. The authors provide the clinical and financial arguments for such program-creation and the steps that can be taken as psychiatrists for medically-complex patients move to the next generation of interdisciplinary service.

Vitamin B12 deficiency is associated with problems in cognition, mood, psychosis, and less commonly, anxiety. Folate deficiency primarily is associated with problems in mood. Patients who have sickle cell disease, a disease of chronic pain, experience difficulties with depression, anxiety, stigma, and are at risk for substance abuse and dependence. Patients with hemophilia have benefited from advances in treatment; however, their morbidity and mortality were compounded in those who received blood products contaminated with HIV, or hepatitis B and C. Psychiatrists who practice psychosomatic medicine should expect to encounter patients with the above problems, as they are frequently seen in medical settings. Finally, most of the commonly used psychotropic medications have uncommon but potentially important hematologic side effects or may interact with the anticoagulants used in medically ill patients.

The signaling network underlying eukaryotic chemosensing is a complex combination of receptor-mediated transmembrane signals, lipid modifications, protein translocations, and differential activation/deactivation of membrane-bound and cytosolic components. As such, it provides particularly interesting challenges for a combined computational and experimental analysis. We developed a novel detailed molecular signaling model that, when used to simulate the response to the attractant cyclic adenosine monophosphate (cAMP), made nontrivial predictions about Dictyostelium chemosensing. These predictions, including the unexpected existence of spatially asymmetrical, multiphasic, cyclic adenosine monophosphate-induced PTEN translocation and phosphatidylinositol-(3,4,5)P3 generation, were experimentally verified by quantitative single-cell microscopy leading us to propose significant modifications to the current standard model for chemoattractant-induced biochemical polarization in this organism. Key to this successful modeling effort was the use of "Simmune," a new software package that supports the facile development and testing of detailed computational representations of cellular behavior. An intuitive interface allows user definition of complex signaling networks based on the definition of specific molecular binding site interactions and the subcellular localization of molecules. It automatically translates such inputs into spatially resolved simulations and dynamic graphical representations of the resulting signaling network that can be explored in a manner that closely parallels wet lab experimental procedures. These features of Simmune were critical to the model development and analysis presented here and are likely to be useful in the computational investigation of many aspects of cell biology.

The field of psycho-oncology is moving forward rapidly, especially for a relatively new field. Cancer patients and survivors are willing to discuss their needs and interests relating to diagnosis and treatment. There are guidelines and algorithms for determining levels of distress in cancer patients in both inpatient and outpatient settings. The pharmacologic treatment of distress, particularly depression, has vastly improved. Randomized controlled trials are becoming available for patients in order to determine the efficacy of psychotropic drugs. Numerous interventions are available to help cancer patients move forward with their lives. Some of these interventions began in the 1980s and have progressed to the use of complementary and alternative medicine techniques as coping strategies for cancer. With the rapid expansion of the Internet, cancer survivors' thirst for information also has grown. Many resources are available to help guide cancer patients through the maze of the diagnosis and treatment of cancer.

The purpose of this study was to gather data on the efficacy of a newly developed psychosocial group intervention for cancer patients, called mindfulness-based art therapy (MBAT). One hundred and eleven women with a variety of cancer diagnoses were paired by age and randomized to either an eight-week MBAT intervention group or a wait-list control group. Ninety-three participants (84%) completed both the pre- and post-study measurements. As compared to the control group, the MBAT group demonstrated a significant decrease in symptoms of distress (as measured by the Symptoms Checklist-90-Revised) and significant improvements in key aspects of health-related quality of life (as measured by the Medical Outcomes Study Short-Form Health Survey). This investigation of MBAT provides initial encouraging data that support a possible future role for the intervention as a psychosocial treatment option for cancer patients., (Copyright 2005 John Wiley & Sons, Ltd.)

Evaluations of patients' capacity to make medical decisions are among the most common and most complex consultations that psychiatrists are asked to perform. We describe tips that we have found to be helpful while performing capacity evaluations. We also share tips that should help the clinician make up his or her mind regarding the patient following capacity evaluations.

Introduction: Unexpected drug activities account for many of the failures of new chemical entities in clinical trials. These activities can be target-dependent, resulting from feedback mechanisms downstream of the primary target, or they can occur as a result of unanticipated secondary target(s). Methods that would provide rapid and efficient characterization of compounds with respect to a broad range of biological pathways and mechanisms relevant to human disease have the potential to improve preclinical and clinical success rates., Methods: BioMAP assays containing primary human cells (endothelial cells and co-cultures with peripheral blood leukocytes) were stimulated in complex formats (specific combinations of inflammatory mediators) for 24 h in the presence or absence of test agents (drugs, experimental compounds, etc.). The levels of selected protein readouts (adhesion receptors, cytokines, enzymes, etc.) were measured and activity profiles (normalized data sets comprising BioMAP profiles) were generated for each test agent. The resulting profiles were compared by statistical methods to identify similarities and mechanistic insights., Results: Compounds with known mechanisms including inhibitors of histamine H1 receptor, angiotensin converting enzyme, IkappaB kinase-2, beta2 adrenergic receptor and others were shown to generate reproducible and distinguishable BioMAP activity profiles. Similarities were observed between compounds targeting components within the same signal transduction pathway (e.g. NFkappaB), and also between compounds that share secondary targets (e.g. ibuprofen and FMOC-L-leucine, a PPARgamma agonist)., Discussion: Complex primary cell-based assays can be applied for detecting and distinguishing unexpected activities that may be of relevance to drug action in vivo. The ability to rapidly test compounds prior to animal or clinical studies may reduce the number of compounds that unexpectedly fail in preclinical or clinical studies.

Drugs fail in clinical studies most often from lack of efficacy or unexpected toxicities. These failures result from an inadequate understanding of drug action and follow, in part, from our dependence on drug discovery technologies that do not take into account the complexity of human disease biology. Biological systems exhibit many features of complex engineering systems, including modularity, redundancy, robustness, and emergent properties. Addressing these features has contributed to the successful design of an improved biological assay technology for inflammation drug discovery. This approach, termed Biologically Multiplexed Activity Profiling (BioMAP), involves the statistical analysis of protein datasets generated from novel complex primary human cell-based assay systems. Compound profiling in these systems has revealed that a surprisingly large number of biological mechanisms can be detected and distinguished. Features of these assays relevant to the behaviour of complex systems are described.

Background: This study was a randomized trial to test the impact of an informed decision-making intervention on prostate cancer screening use., Methods: The study population included 242 African-American men from three primary care practices who were 40-69 years of age and had no history of prostate cancer. Participants completed a baseline survey questionnaire and were randomly assigned either to a Standard Intervention (SI) group (N=121) or an Enhanced Intervention (EI) group (N=121). An informational booklet was mailed to both groups. EI group men were also offered a screening decision education session. Two outcomes were considered: (1) complete screening (i.e., having a digital rectal exam (DRE) and prostate specific antigen (PSA) testing), and (2) complete or partial screening (i.e., having a PSA test with or without DRE). An endpoint chart audit was performed six months after initial intervention contact. The data were analyzed via exact logistic regression., Results: Overall, screening use was low among study participants. EI group men had a screening frequency two times greater than that of SI group men, but the difference was not statistically significant: 8% vs. 4 % (OR = 1.94) fo rcomplete screening, and 19% vs. 10% (OR = 2.08) for complete or partial screening. Multivariable analyses showed that being in the EI group and primary care practice were significant predictors of complete or partial screening (OR = 3.9 and OR = 5.64, respectively)., Conclusion: Prostate cancer screening use may be influenced by exposure to decision education and the influence of screening-related primary care practice factors.

The segregation of secretory and membrane proteins to the mammalian endoplasmic reticulum is mediated by remarkably diverse signal sequences that have little or no homology with each other. Despite such sequence diversity, these signals are all recognized and interpreted by a highly conserved protein-conducting channel composed of the Sec61 complex. Signal recognition by Sec61 is essential for productive insertion of the nascent polypeptide into the translocation site, channel gating and initiation of transport. Although subtle differences in these steps can be detected between different substrates, it is not known whether they can be exploited to modulate protein translocation selectively. Here we describe cotransin, a small molecule that inhibits protein translocation into the endoplasmic reticulum. Cotransin acts in a signal-sequence-discriminatory manner to prevent the stable insertion of select nascent chains into the Sec61 translocation channel. Thus, the range of substrates accommodated by the channel can be specifically and reversibly modulated by a cell-permeable small molecule that alters the interaction between signal sequences and the Sec61 complex.

Increasing attention is being paid to the emotional and psychosocial needs of cancer patients. As a result of huge advances in early detection and in treatment modalities, there now are millions of cancer survivors in the United States. There has been a realization that cancer survivors have distinct psychosocial needs. As cancer survivors live longer, reduction of psychological distress has been recognized as being an important part of having an improved quality of life. There have been numerous changes in the field of psychosocial oncology since it first began 25 years ago. Guidelines now exist for the definition of distress and decision trees are available for making the appropriate referrals. Advances in pharmacologic treatment for depression and anxiety have made it possible to decrease distress and increase coping in cancer patients undergoing treatment as well as in cancer survivors. Numerous individual and group therapies have demonstrated effectiveness in improving mood and quality of life in cancer patients and those at high risk for developing cancer. Due to the forthright efforts of cancer patients, there are now many organizations and list serves (e-mailing lists) that cancer survivors can turn to for help before, during, and after cancer treatment. Finally, with the rapid expansion of the internet not only are there websites available as resources, but also the creation of interactive online support is becoming a reality. One of the most important issues in providing supportive care to cancer patients in the future is to meet the individual needs of patients and provide the type of psychological therapy that will work best for them.

The ability to predict the safety and efficacy of novel drugs prior to clinical testing is a key goal in pharmaceutical drug discovery. Gaining a mechanistic understanding of the complex cell signaling networks (CSNs) underlying disease processes promises to help reduce the number of clinical failures by identifying points of intervention as well as redundancies and feedback mechanisms that contribute to toxicities, lack of efficacy and unexpected biological activities. Experimental and computational approaches to analyzing and modeling CSNs are currently being validated using simple organisms and cell lines. In vitro cell systems of sufficient complexity to resemble human disease physiology, but which are also amenable to chemical and genetic perturbations on a large scale, are now required for deciphering the signaling networks operating in human disease. In this review, experimental and computational methods for modeling complex CSNs and the applications of these approaches to pharmaceutical drug discovery are discussed.

The hope of the rapid translation of 'genes to drugs' has foundered on the reality that disease biology is complex, and that drug development must be driven by insights into biological responses. Systems biology aims to describe and to understand the operation of complex biological systems and ultimately to develop predictive models of human disease. Although meaningful molecular level models of human cell and tissue function are a distant goal, systems biology efforts are already influencing drug discovery. Large-scale gene, protein and metabolite measurements ('omics') dramatically accelerate hypothesis generation and testing in disease models. Computer simulations integrating knowledge of organ and system-level responses help prioritize targets and design clinical trials. Automation of complex primary human cell-based assay systems designed to capture emergent properties can now integrate a broad range of disease-relevant human biology into the drug discovery process, informing target and compound validation, lead optimization, and clinical indication selection. These systems biology approaches promise to improve decision making in pharmaceutical development.

We have previously studied B cells, from people and mice, that express rotavirus-specific surface immunoglobulin (RV-sIg) by flow cytometry with recombinant virus-like particles that contain green fluorescent protein. In the present study we characterized circulating B cells with RV-sIg in children with acute and convalescent infection. During acute infection, circulating RV-sIgD(-) B cells are predominantly large, CD38(high), CD27(high), CD138(+/-), CCR6(-), alpha4beta7(+), CCR9(+), CCR10(+), cutaneous lymphocyte antigen-negative (CLA(-)), L-selectin(int/-), and sIgM(+), sIgG(-), sIgA(+/-) lymphocytes. This phenotype likely corresponds to gut-targeted plasma cells and plasmablasts. During convalescence the phenotype switches to small and large lymphocytes, CD38(int/-), CD27(int/-), CCR6(+), alpha4beta7(+/-), CCR9(+/-) and CCR10(-), most likely representing RV-specific memory B cells with both gut and systemic trafficking profiles. Of note, during acute RV infection both total and RV-specific murine IgM and IgA antibody-secreting cells migrate efficiently to CCL28 (the CCR10 ligand) and to a lesser extent to CCL25 (the CCR9 ligand). Our results show that CCR10 and CCR9 can be expressed on IgM as well as IgA antibody-secreting cells in response to acute intestinal infection, likely helping target these cells to the gut. However, these intestinal infection-induced plasmablasts lack the CLA homing receptor for skin, consistent with mechanisms of differential CCR10 participation in skin T versus intestinal plasma cell homing. Interestingly, RV memory cells generally lack CCR9 and CCR10 and instead express CCR6, which may enable recruitment to diverse epithelial sites of inflammation.

Rapid, quantitative methods for characterizing the biological activities of kinase inhibitors in complex human cell systems could allow the biological consequences of differential target selectivity to be monitored early in development, improving the selection of drug candidates. We have previously shown that Biologically Multiplexed Activity Profiling (BioMAP) permits rapid characterization of drug function based on statistical analysis of protein expression data sets from complex primary human cellbased models of disease biology. Here, using four such model systems containing primary human endothelial cells and peripheral blood mononuclear cells in which multiple signaling pathways relevant to inflammation and immune responses are simultaneously activated, we demonstrate that BioMAP analysis can detect and distinguish a wide range of inhibitors directed against different kinase targets. Using a panel of p38 mitogen-activated protein kinase antagonists as a test set, we show further that related compounds can be distinguished by unique features of the biological responses they induce in complex systems, and can be classified according to their induction of shared (on-target) and secondary activities. Statistical comparisons of quantitative BioMAP profiles and analysis of profile features allow correlation of induced biological effects with chemical structure and mapping of biological responses to chemical series or substituents on a common scaffold. Integration of automated BioMAP analysis for prioritization of hits and for structure-activity relationship studies may improve and accelerate the design and selection of optimal therapeutic candidates.

Unexpected drug activities discovered during clinical testing establish the need for better characterization of compounds in human disease-relevant conditions early in the discovery process. Here, we describe an approach to characterize drug function based on statistical analysis of protein expression datasets from multiple primary human cell-based models of inflammatory disease. This approach, termed Biologically Multiplexed Activity Profiling (BioMAP), provides rapid characterization of drug function, including mechanism of action, secondary or off-target activities, and insights into clinical phenomena. Using three model systems containing primary human endothelial cells and peripheral blood mononuclear cells in different environments relevant to vascular inflammation and immune activation, we show that BioMAP profiles detect and discriminate multiple functional drug classes, including glucocorticoids; TNF-alpha antagonists; and inhibitors of HMG-CoA reductase, calcineurin, IMPDH, PDE4, PI-3 kinase, hsp90, and p38 MAPK, among others. The ability of cholesterol lowering HMG-CoA reductase inhibitors (statins) to improve outcomes in rheumatic disease patients correlates with the activities of these compounds in our BioMAP assays. In addition, the activity profiles identified for the immunosuppressants mycophenolic acid, cyclosporin A, and FK-506 provide a potential explanation for a reduced incidence of posttransplant cardiovascular disease in patients receiving mycophenolic acid. BioMAP profiling can allow integration of meaningful human biology into drug development programs.

This paper reports on behaviors men use to protect themselves against prostate cancer. Data were collected via a telephone or mailed survey from 353 men enrolled in two studies of prostate cancer screening. Respondents reported behaviors they used to protect themselves against prostate cancer, and responses were coded as conventional care, self-care, or nothing. Men who reported using both conventional care and self-care were categorized as conventional care users. Polytomous logistic regression was conducted to evaluate the association between sociodemographic background, prior prostate screening, and cognitive, affective, and social support and influence factors with protective behavior type. The distribution of protective behaviors was as follows: conventional care, 63%; self-care only, 19%; and nothing, 18%. In multivariable analyses, higher education level was found to be positively associated with conventional care use. Perceived salience and coherence of prostate cancer screening was positively associated with conventional care use among men in one of the two studies. Low concern about screening was positively associated with self-care use, as was mailed survey completion. This study presents self-report data regarding prostate cancer protection behaviors. Most men in the study reported using some type of prostate cancer protective behavior. Decision-making about whether or not to take protective action and what type of behavior to use may be influenced by socioeconomic background, cognitive perceptions related to behavioral options, and concern about risk.

Recent studies indicate that chemoattractant cytokines (chemokines), together with tissue-specific adhesion molecules, coordinate the migration of antibody-secreting cells (ASCs) from their sites of antigen-driven differentiation in lymphoid tissues to target effector tissues. Developing ASCs downregulate the expression of receptors for lymphoid tissue chemokines and selectively upregulate the expression of chemokine receptors that might target the migration of IgA ASCs to mucosal surfaces, IgG ASCs to sites of tissue inflammation and both types of ASC to the bone marrow - an important site for serum antibody production. By directing plasma-cell homing, chemokines might help to determine the character and efficiency of mucosal, inflammatory and systemic antibody responses.

Women with breast cancer face not only cancer-related taboos but also issues related to changes in sexuality, femininity, and fertility. Although increased emphasis on the woman's participation in the medical decision-making process has afforded her more treatment options, it also gives her more responsibility in determining her course of treatment through the continuum of cancer care. Patients must deal with a variety of issues related to social reintegration, long-term effects of cancer treatment, employment, disability, sexuality, family, and social networks. Screening for distress related to psychological, spiritual/religious, or social concerns can provide guidance for service delivery to those in need.

Lymphocyte migration through gut-associated lymphoid tissues (GALT) and into intestinal effector sites is critical to intestinal immune system function and homeostasis. Chemokines contribute to lymphocyte trafficking by triggering integrin activation and firm arrest in the vasculature and mediating chemotactic localization within tissues. Several chemokines have been identified that are expressed in the GALT and/or the intestines themselves (TECK/CCL25, MEC/CCL28, and MIP-3alpha/CCL20) and play a role in intestinal lymphocyte localization, including unification of intestinal and other mucosa-associated effector sites; segmental specialization of the intestines; and subset selective localization to the intestines. This review examines the role of these chemokines (and their receptors CCR9, CCR10, and CCR6, respectively) in lymphocyte homing to the GALT, in the induction and differentiation of intestinal effector and memory lymphocytes, and in the homeostatic and inflammatory localization of lymphocytes to the intestines.

IgA immunoblasts can seed both intestinal and nonintestinal mucosal sites following localized mucosal immunization, an observation that has led to the concept of a common mucosal immune system. In this study, we demonstrate that the mucosae-associated epithelial chemokine, MEC (CCL28), which is expressed by epithelia in diverse mucosal tissues, is selectively chemotactic for IgA Ab-secreting cells (ASC): MEC attracts IgA- but not IgG- or IgM-producing ASC from both intestinal and nonintestinal lymphoid and effector tissues, including the intestines, lungs, and lymph nodes draining the bronchopulmonary tree and oral cavity. In contrast, the small intestinal chemokine, TECK (CCL25), attracts an overlapping subpopulation of IgA ASC concentrated in the small intestines and its draining lymphoid tissues. Surprisingly, T cells from mucosal sites fail to respond to MEC. These findings suggest a broad and unifying role for MEC in the physiology of the mucosal IgA immune system.

The dissemination of IgA-dependent immunity between mucosal sites has important implications for mucosal immunoprotection and vaccine development. Epithelial cells in diverse gastrointestinal and nonintestinal mucosal tissues express the chemokine MEC/CCL28. Here we demonstrate that CCR10, a receptor for MEC, is selectively expressed by IgA Ab-secreting cells (large s/cIgA(+)CD38(hi)CD19(int/-)CD20(-)), including circulating IgA(+) plasmablasts and almost all IgA(+) plasma cells in the salivary gland, small intestine, large intestine, appendix, and tonsils. Few T cells in any mucosal tissue examined express CCR10. Moreover, tonsil IgA plasmablasts migrate to MEC, consistent with the selectivity of CCR10 expression. In contrast, CCR9, whose ligand TECK/CCL25 is predominantly restricted to the small intestine and thymus, is expressed by a fraction of IgA Ab-secreting cells and almost all T cells in the small intestine, but by only a small percentage of plasma cells and plasmablasts in other sites. These results point to a unifying role for CCR10 and its mucosal epithelial ligand MEC in the migration of circulating IgA plasmablasts and, together with other tissue-specific homing mechanisms, provides a mechanistic basis for the specific dissemination of IgA Ab-secreting cells after local immunization.

Background: Hepatitis C virus (HCV) is a leading cause of chronic liver disease, yet little is known about the intrahepatic immune response in end-stage patients. Chemokines and their receptors are important regulators of immunity, particularly in the migration and localization of circulating leukocytes within peripheral tissues., Aims: This report provides a comprehensive comparison of the chemokine receptor and activation phenotype of the major leukocyte subsets present in end-stage HCV-infected and non-HCV infected livers., Methods: Lymphocytes were purified from homogenized explant liver tissue and analyzed by flow cytometry., Results: NK cells are the predominant cell type, followed by T cells, B cells and NK-T cells, independent of HCV status. T cells displayed a memory phenotype and low levels of activation markers. CCR5, CXCR3 and CXCR6 were expressed on a large fraction of activated cells, while moderate to low expression of CCR2, CCR6 and CX(3)CR1 was observed. Several other tissue-specific and inflammatory chemokine receptors were absent from infiltrating lymphocytes., Conclusions: These results identify the chemokine receptors present on infiltrating lymphocytes during end-stage liver disease and suggest that such infiltration is predominantly controlled by non-tissue-specific inflammatory chemokines, a situation that may be distinct from liver homing pathways under normal conditions.

Immunoglobulin A (IgA) provides protection against pathogens at mucosal surfaces. Chemotactic responses have been hypothesized to target IgA plasma cells involved in mucosal immune responses. We show here that thymus-expressed chemokine (TECK, CCL25) is a potent and selective chemoattractant for IgA antibody-secreting cells (ASC), efficiently recruiting IgA-producing cells from spleen, Peyer's patches, and mesenteric lymph node. Cells secreting IgA antibody in response to rotavirus, an intestinal pathogen, also respond well. In contrast, IgG- and IgM-ASC respond poorly. Epithelial cells in the small intestines, a principal site of IgA-ASC localization and IgA production in the body, highly and selectively express TECK. The migration of IgA-ASC to the intestinal epithelial cell chemokine TECK may help target IgA-producing cells to the gut wall, thus helping define and segregate the intestinal immune response.

Tissue-selective trafficking of memory and effector T and B lymphocytes is mediated by unique combinations of adhesion molecules and chemokines. The discovery of several related epithelial-expressed chemokines (TECK/CCL25 in small intestine, CTACK/CCL27 in skin, and MEC/CCL28 in diverse mucosal sites) now highlights an important role for epithelial cells in controlling homeostatic lymphocyte trafficking, including the localization of cutaneous and intestinal memory T cells, and of IgA plasma cells. Constitutively expressed epithelial chemokines may help determine the character of local immune responses and contribute to the systemic organization of the immune system.

Differential expression of adhesion molecules and chemokine receptors has been useful for identification of peripheral blood memory lymphocyte subsets with distinct tissue and microenvironmental tropisms. Expression of CCR4 by circulating memory CD4(+) lymphocytes is associated with cutaneous and other systemic populations while expression of CCR9 is associated with a small intestine-homing subset. CCR5 and CXCR3 are also expressed by discrete memory CD4(+) populations in blood, as well as by tissue-infiltrating lymphocytes from a number of sites. To characterize the similarities and differences among tissue-infiltrating lymphocytes, and to shed light on the specialization of lymphocyte subsets that mediate inflammation and immune surveillance in particular tissues, we have examined the expression of CCR4, CXCR3, and CCR5 on CD4(+) lymphocytes directly isolated from a wide variety of normal and inflamed tissues. Extra-lymphoid tissues contained only memory lymphocytes, many of which were activated (CD69(+)). As predicted by classical studies, skin lymphocytes were enriched in CLA expression whereas intestinal lymphocytes were enriched in alpha(4)beta(7) expression. CCR4 was expressed at high levels by skin-infiltrating lymphocytes, at lower levels by lung and synovial fluid lymphocytes, but never by intestinal lymphocytes. Only the high CCR4 levels characteristic of skin lymphocytes were associated with robust chemotactic and adhesive responses to TARC, consistent with a selective role for CCR4 in skin lymphocyte homing. In contrast, CXCR3 and CCR5 were present on the majority of lymphocytes from each non-lymphoid tissue examined, suggesting that these receptors are unlikely to determine tissue specificity, but rather, may play a wider role in tissue inflammation.

Current concepts of chemokine receptor (CKR) association with Th1 and Th2 cell polarization and effector function have largely ignored the diverse nature of effector and memory T cells in vivo. Here, we systematically investigated the association of 11 CKRs, singly or in combination, with CD4 T cell polarization. We show that Th1, Th2, Th0, and nonpolarized T cells in blood and tissue can express any of the CKRs studied but that each CKR defines a characteristic pool of polarized and nonpolarized CD4 T cells. Certain combinations of CKRs define populations that are markedly enriched in major subsets of Th1 versus Th2 cells. For example, although Th0, Th1, and Th2 cells are each found among blood CD4 T cells coordinately expressing CXCR3 and CCR4, Th1 but not Th2 cells can be CXCR3(+)CCR4(-), and Th2 but only rare Th1 cells are CCR4(+)CXCR3(-). Contrary to recent reports, although CCR7(-) cells contain a higher frequency of polarized CD4 T cells, most Th1 and Th2 effector cells are CCR7(+) and thus may be capable of lymphoid organ homing. Interestingly, Th1-associated CKRs show little or no preference for Th1 cells except when they are coexpressed with CXCR3. We conclude that the combinatorial expression of CKRs, which allow tissue- and subset-dependent targeting of effector cells during chemotactic navigation, defines physiologically significant subsets of polarized and nonpolarized T cells.

Chemokine receptor expression is finely controlled during T-cell development. We show that newly identified chemokine receptor Bonzo/CXCR6 is expressed by subsets of Th1 or T-cytotoxic 1 (Tc1) cells, but not by Th2 or Tc2 cells, establishing Bonzo as a differential marker of polarized type 1 T cells in vitro and in vivo. Priming of naive T cells by dendritic cells induces expression of Bonzo on T cells. IL-12 enhances this dendritic cell-dependent upregulation, while IL-4 inhibits it. In blood, 35-56% of Bonzo+ CD4 T cells are Th1 cells, and 60-65% of Bonzo+ CD8 T cells are Tc1 cells, while few Bonzo+ cells are type 2 T cells. Almost all Bonzo+ Tc1 cells contain preformed granzyme A and display cytotoxic effector phenotype. Most Bonzo+ T cells lack L-selectin and/or CCR7, homing receptors for lymphoid tissues. Instead, Bonzo+ T cells are dramatically enriched among T cells in tissue sites of inflammation, such as rheumatoid joints and inflamed livers. Bonzo may be important in trafficking of effector T cells that mediate type 1 inflammation, making it a potential target for therapeutic modulation of inflammatory diseases.

CCR7, along with L-selectin and LFA-1, mediates homing of T cells to secondary lymphoid organs via high endothelial venules (HEV). CCR7 has also been implicated in microenvironmental positioning of lymphocytes within secondary lymphoid organs and in return of lymphocytes and dendritic cells to the lymph after passage through nonlymphoid tissues. We have generated mAbs to human CCR7, whose specificities correlate with functional migration of lymphocyte subsets to known CCR7 ligands. We find that CCR7 is expressed on the vast majority of peripheral blood T cells, including most cells that express adhesion molecules (cutaneous lymphocyte Ag alpha(4)beta(7) integrin) required for homing to nonlymphoid tissues. A subset of CD27(neg) memory CD4 T cells from human peripheral blood is greatly enriched in the CCR7(neg) population, as well as L-selectin(neg) cells, suggesting that these cells are incapable of homing to secondary lymphoid organs. Accordingly, CD27(neg) T cells are rare within tonsil, a representative secondary lymphoid organ. All resting T cells within secondary lymphoid organs express high levels of CCR7, but many activated cells lack CCR7. CCR7 loss in activated CD4 cells accompanies CXC chemokine receptor (CXCR)5 gain, suggesting that the reciprocal expression of these two receptors may contribute to differential positioning of resting vs activated cells within the organ. Lymphocytes isolated from nonlymphoid tissues (such as skin, lung, or intestine) contain many CD27(neg) cells lacking CCR7. The ratio of CD27(neg)/CCR7(neg) cells to CD27(pos)/CCR7(pos) cells varies from tissue to tissue, and may correlate with the number of cells actively engaged in Ag recognition within a given tissue.

Unfortunately, although delirium is common in the general hospital, the diagnosis is frequently missed. As delirium often indicates a serious, sometimes life-threatening, medical or surgical condition, successful management and subsequent prevention of morbidity and mortality require prompt recognition and early intervention. Failure to recognize, diagnose, and treat delirium and the underlying pathology can result in death. This article presents current thinking on the management of delirium and related agitation in the general medical hospital.

The authors evaluated 50 Korean immigrants who had chronic viral hepatitis or who were healthy carriers for the hepatitis B virus in terms of the relationships between their depression scores, psychosocial stressors, social support, and biological markers of dysfunction. All participants completed a questionnaire, describing their worries and concerns, and the shortform of the Beck Depression Inventory (BDI-sf). Hepatic transaminases, albumin levels, and prothrombin times were measured during routine clinic follow-up visits and were abstracted from the medical record. Values recorded within 3 months before and within 3 months after the psychiatric interview were correlated with BDI scores. BDI-sf total scores were significantly associated with transaminase elevations (P<0.001) both before and after BDI-sf administration. BDI scores were not associated with other measures of liver dysfunction or other medical causes of depression. Patients with higher BDI-sf total scores had more psychosocial stressors (P = 0.008) and lower Global Assessment of Functioning (GAF) scores (P = 0.000).