Biological complexity and drug discovery: a practical systems biology approach.

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.

Rules of chemokine receptor association with T cell polarization in vivo.

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.

Bonzo/CXCR6 expression defines type 1-polarized T-cell subsets with extralymphoid tissue homing potential.

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 expression and memory T cell diversity in humans.

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.

Management of the agitated patient.

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.

Depression in Korean immigrants with hepatitis B and related liver diseases.

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).

A novel chemokine ligand for CCR10 and CCR3 expressed by epithelial cells in mucosal tissues.

Mucosae-associated epithelial chemokine (MEC) is a novel chemokine whose mRNA is most abundant in salivary gland, with strong expression in other mucosal sites, including colon, trachea, and mammary gland. MEC is constitutively expressed by epithelial cells; MEC mRNA is detected in cultured bronchial and mammary gland epithelial cell lines and in epithelia isolated from salivary gland and colon using laser capture microdissection, but not in the endothelial, hemolymphoid, or fibroblastic cell lines tested. Although MEC is poorly expressed in skin, its closest homologue is the keratinocyte-expressed cutaneous T cell-attracting chemokine (CTACK; CCL27), and MEC supports chemotaxis of transfected lymphoid cells expressing CCR10, a known CTACK receptor. In contrast to CTACK, however, MEC also supports migration through CCR3. Consistent with this, MEC attracts eosinophils in addition to memory lymphocyte subsets. These results suggest an important role for MEC in the physiology of extracutaneous epithelial tissues, including diverse mucosal organs.

Lymphocyte CC chemokine receptor 9 and epithelial thymus-expressed chemokine (TECK) expression distinguish the small intestinal immune compartment: Epithelial expression of tissue-specific chemokines as an organizing principle in regional immunity.

The immune system has evolved specialized cellular and molecular mechanisms for targeting and regulating immune responses at epithelial surfaces. Here we show that small intestinal intraepithelial lymphocytes and lamina propria lymphocytes migrate to thymus-expressed chemokine (TECK). This attraction is mediated by CC chemokine receptor (CCR)9, a chemoattractant receptor expressed at high levels by essentially all CD4(+) and CD8(+) T lymphocytes in the small intestine. Only a small subset of lymphocytes in the colon are CCR9(+), and lymphocytes from other tissues including tonsils, lung, inflamed liver, normal or inflamed skin, inflamed synovium and synovial fluid, breast milk, and seminal fluid are universally CCR9(-). TECK expression is also restricted to the small intestine: immunohistochemistry reveals that intense anti-TECK reactivity characterizes crypt epithelium in the jejunum and ileum, but not in other epithelia of the digestive tract (including stomach and colon), skin, lung, or salivary gland. These results imply a restricted role for lymphocyte CCR9 and its ligand TECK in the small intestine, and provide the first evidence for distinctive mechanisms of lymphocyte recruitment that may permit functional specialization of immune responses in different segments of the gastrointestinal tract. Selective expression of chemokines by differentiated epithelium may represent an important mechanism for targeting and specialization of immune responses.

Preparatory education for informed decision-making in prostate cancer early detection and treatment.

Patients are expected to assume increased responsibility for self-management in health care. However, little attention has been directed to the problem of preparing individuals to play a more active role in the physician-patient relationship. Preparatory education about prostate cancer early detection and treatment is needed to enable patients to recognize the importance of their role in medical decision-making, voice personal values and preferences related to health care choices, and make informed choices under conditions of uncertainty about possible outcomes. Effective decision aids are needed to facilitate shared decision-making in the context of the physician-patient relationship along the continuum of prostate cancer care. Decision aids for patients have taken the form of informational booklets, scripted telephone counseling, decision boards, educational videotapes, interactive videodiscs, computer programs, and Internet Web sites. The impact of preparatory education and the use of decision aids should be evaluated in terms of change in knowledge and understanding, shifts in decision preferences, health care utilization, and satisfaction with care. The need for this type of patient interaction will grow as technology increases patient access to health care information.

Communicating effectively with the patient and family about treatment options for prostate cancer.

To help the patient with prostate cancer, his family, and his friends, in coping with the diagnosis and its treatment, health care providers need to understand the controversies about treatment options and the impact that such controversies have on medical decision-making. To update health care providers, the authors reviewed all pertinent citations in the medicine database from 1966 to 2000, and in other relevant publications. These resources are also available to our patients through the Internet and other avenues, such as books and magazines. It is the role of the physician to counsel patients about their individual circumstances to allow them to make the best individualized treatment option. Patients who have appropriate information and are actively involved with the decision-making process are, in general, psychologically healthier. Though watchful waiting has no side effects, men must cope psychologically with issues of long-term cancer survivorship. With early detection, men can choose between different treatment options (eg, radiation versus radical prostatectomy). Urinary incontinence, sexual dysfunction, and fatigue are major emotional and physical stressors for this population. Providers of care need to be aware of the psychosocial sequelae of prostate cancer and treatment-related side effects and assist their patients in processing ever-growing data on the management of prostate cancer that technology brings.

Constant observation practices in the general hospital setting: a national survey.

The authors conducted a national survey of 355 general medical/surgical hospitals to assess constant observation (CO) practices. The authors assessed overall use, expense, staffing patterns, funding strategies, and cost-saving interventions. Virtually all responding hospitals (N = 102) reported using some form of CO. Several hospitals reported significant decreases in CO expenditures after the implementation of cost-saving interventions (the largest annual decrease reported was $340,000). Cost-saving interventions included utilizing consolidated bed spaces, relocating patients near nursing stations, placing at-risk patients in bed enclosure devices, and regularly assisting patients to the toilet. In addition, less costly personnel were hired, and volunteers and/or patient family members provided CO (or were required to assist with the cost of CO). Finally, hospital staff were educated about the costs and the appropriate use of CO. They were also taught to recognize and effectively treat delirium.

African-American men and intention to adhere to recommended follow-up for an abnormal prostate cancer early detection examination result.

OBJECTIVES: To assess the intention of African-American men to have the recommended follow-up in the event of an abnormal prostate cancer early detection examination and to identify the variables that help to explain adherence intention. METHODS: In the spring of 1995, we selected a random sample of 548 African-American men who were patients at the University of Chicago Health Service. The sample included men who were 40 to 70 years of age, did not have a personal history of prostate cancer, and had a working telephone number. A total of 413 men who completed the telephone survey received an invitation to consider undergoing a prostate cancer early detection examination. The survey provided data on personal background characteristics, knowledge, attitudes, and beliefs related to prostate cancer and early detection. Respondents were asked whether they would choose to have the recommended follow-up in the event of an abnormal early detection examination result. Univariate and multivariate analyses of intention to have follow-up were performed. RESULTS: An intention to have the recommended follow-up was reported by 77% of the survey respondents. The results of multivariate analyses revealed that the intention to have the follow-up was positively associated with education beyond high school (odds ratio [OR] 1.9); perceived self-efficacy related to prostate cancer screening (OR 2.1); the belief that prostate cancer can be cured (OR 3.3); the belief that prostate cancer screening should be done in the absence of prostate problems (OR 2.3); and physician support for prostate cancer screening (OR 2.1). CONCLUSIONS: African-American men who have a high school education or less may be at risk of nonadherence to recommended follow-up. Adherence also may be low among men who do not have favorable views of early detection or do not perceive strong physician support for early detection. Research is needed to determine whether intention and other factors predict actual adherence to follow-up in this population group.

Biopsychosocial aspects of prostate cancer.

Prostate cancer early detection choices and treatment options are fraught with controversy. To update the consultation-liaison psychiatrist who works with at-risk men, the authors reviewed all pertinent citations in the medicine database from 1966 to 1998 and in other relevant publications. Though watchful waiting for early-stage prostate cancer has no side effects, men must cope psychologically with issues of long-term cancer survivorship. Men can choose between different treatment options (e.g., radiation vs. radical prostatectomy) with early detection. Urinary incontinence, sexual dysfunction, and fatigue are major emotional and physical stressors for this population. Consultation-liaison psychiatrists and physicians need to be aware of the psychosocial sequelae of both prostate cancer and treatment-related side effects.

Leukocyte arrest during cytokine-dependent inflammation in vivo.

Leukocyte rolling along the walls of inflamed venules precedes their adhesion during inflammation. Rolling leukocytes are thought to arrest by engaging beta2 integrins following cellular activation. In vitro studies suggest that chemoattractants may instantaneously activate and arrest rolling leukocytes. However, how leukocytes stop rolling and become adherent in inflamed venules in vivo has remained rather mysterious. In this paper we use a novel method of tracking individual leukocytes through the microcirculation to show that rolling neutrophils become progressively activated while rolling down the venular tree. On average, leukocytes in wild-type mice roll for 86 s (and cover 270 microm) before becoming adherent with an efficiency around 90%. These rolling leukocytes exhibit a gradual beta2 integrin-dependent decrease in rolling velocity that correlates with an increase in intracellular free calcium concentration before arrest. Similar tracking analyses in gene-targeted mice demonstrate that the arrest of rolling leukocytes is very rare when beta2 integrins are absent or blocked by a mAb. Arrest is approximately 50% less efficient in the absence of E-selectin. These data suggest a model of leukocyte recruitment in which beta2 integrins play a critical role in stabilizing leukocyte rolling during a protracted cellular activation period before arrest and firm adhesion.

St. John's Wort.

OBJECTIVE: The objective of this article is to review the current knowledge of the pharmacology, sites of action, and therapeutic effectiveness of St. John's Wort. METHOD: The method used was a review of the available literature, using keywords to search the medline database. Bibliographies of the papers, thus obtained, were searched for further documents not referenced by medline. We reviewed papers from this collection. RESULTS: This review reveals that most of the available data on efficacy and safety of St. John's Wort involve its use in mild to moderate depression. Much, but not all of the prevailing opinion is positive. Nevertheless, the quality of therapeutic trials vary so greatly that definitive conclusions are not possible. Both the source and mode of St. John's Wort's therapeutic effect are unclear. We need further controlled studies of effectiveness, safety, and mode of action. In addition to its use in depression, there are reports suggesting possible therapeutic effects in other conditions such as certain malignancies and infections, but these are far too preliminary to permit any conclusions.

Integrating conflicting chemotactic signals. The role of memory in leukocyte navigation.

Leukocytes navigate through complex chemoattractant arrays, and in so doing, they must migrate from one chemoattractant source to another. By evaluating directional persistence and chemotaxis during neutrophil migration under agarose, we show that cells migrating away from a local chemoattractant, against a gradient, display true chemotaxis to distant agonists, often behaving as if the local gradient were without effect. We describe two interrelated properties of migrating cells that allow this to occur. First, migrating leukocytes can integrate competing chemoattractant signals, responding as if to the vector sum of the orienting signals present. Second, migrating cells display memory of their recent environment: cells' perception of the relative strength of orienting signals is influenced by their history, so that cells prioritize newly arising or newly encountered attractants. We propose that this cellular memory, by promoting sequential chemotaxis to one attractant after another, is in fact responsible for the integration of competitive orienting signals over time, and allows combinations of chemoattractants to guide leukocytes in a step-by-step fashion to their destinations within tissues.

Hematologic side effects of psychotropics.

Psychiatrists are often unaware of the potential hematologic complications of the psychotropics they prescribe. Although this review is not a hematologic text reference, relevant hematologic syndromes are described so that the consultation-liaison psychiatrist will be familiar with the usual signs, symptoms, and treatments of these syndromes. This article reviews the hematologic side effects of the commonly prescribed psychotropics, including antipsychotics, antidepressants, benzodiazepines, lithium, mood stabilizers (including some of the anticonvulsants), and the acetylcholinesterase inhibitors. Clinical signs and symptoms that should alert the physician to obtain a complete blood count are described.

Muscle test comparisons of congruent and incongruent self-referential statements.

This study investigated differences in values of manual muscle tests after exposure to congruent and incongruent semantic stimuli. Muscle testing with a computerized dynamometer was performed on the deltoid muscle group of 89 healthy college students after repetitions of congruent (true) and incongruent (false) self-referential statements. The order in which statements were repeated was controlled by a counterbalanced design. The combined data showed that approximately 17% more total force over a 59% longer period of time could be endured when subjects repeated semantically congruent statements (p < .001). Order effects were not significant. Over-all, significant differences were found in muscle-test responses between congruent and incongruent semantic stimuli.

Follow-up consultation billing and documentation.

Frequently, bills are not submitted for follow-up visits for patients who have been evaluated psychiatrically on medical-surgical services. There often is confusion regarding which procedure codes are most appropriate to use in billing. To help the consultant understand the documentation requirements for various procedure codes, information from several sources was synthesized and distilled. This paper should help minimize documentation errors and maximize reimbursement for clinical services. The authors have reviewed available billing choices, and clarified the documentation requirements for different procedure codes according to Medicare regulations.