Immune cell trafficking to the islets during type 1 diabetes.

Inhibition of immune cell trafficking to the pancreatic islets during type 1 diabetes (T1D) has therapeutic potential, since targeting of T cell and B cell trafficking has been clinically effective in other autoimmune diseases. Trafficking to the islets is characterized by redundancy in adhesion molecule and chemokine usage, which has not enabled effective targeting to date. Additionally, cognate antigen is not consistently required for T cell entry into the islets throughout the progression of disease. However, myeloid cells are required to enable T cell and B cell entry into the islets, and may serve as a convergence point in the pathways controlling this process. In this review we describe current knowledge of the factors that mediate immune cell trafficking to pancreatic islets during T1D progression.

The effects of promotion and prevention cues on creativity.

This study tested whether cues associated with promotion and prevention regulatory foci influence creativity. The authors predicted that the "risky," explorative processing style elicited by promotion cues, relative to the risk-averse, perseverant processing style elicited by prevention cues, would facilitate creative thought. These predictions were supported by two experiments in which promotion cues bolstered both creative insight (Experiment 1) and creative generation (Experiment 2) relative to prevention cues. Experiments 3 and 4 provided evidence for the process account of these findings. suggesting that promotion cues, relative to prevention cues, produce a riskier response bias (Experiment 3) and bolster memory search for novel responses (Experiment 4). A final experiment provided evidence that individual differences in regulatory focus influence creative problem solving in a manner analogous to that of incidental promotion and prevention cues.

Induction of human immunodeficiency virus (HIV)-specific CD8 T-cell responses by Listeria monocytogenes and a hyperattenuated Listeria strain engineered to express HIV antigens.

Induction of cell-mediated immunity may be essential for an effective AIDS vaccine. Listeria monocytogenes is an attractive bacterial vector to elicit T-cell immunity to human immunodeficiency virus (HIV) because it specifically infects monocytes, key antigen-presenting cells, and because natural infection originates at the mucosa. Immunization with recombinant L. monocytogenes has been shown to protect mice from lymphocytic choriomeningitis virus, influenza virus, and tumor inoculation. L. monocytogenes expressing HIV gag elicits sustained high levels of Gag-specific cytotoxic T lymphocytes (CTLs) in mice. We have examined the ability of Listeria to infect human monocytes and present HIV antigens to CD8 T lymphocytes of HIV-infected donors to induce a secondary T-cell immune response. Using this in vitro vaccination protocol, we show that L. monocytogenes expressing the HIV-1 gag gene efficiently provides a strong stimulus for Gag-specific CTLs in HIV-infected donor peripheral blood mononuclear cells. Listeria expressing Nef also elicits a secondary in vitro anti-Nef CTL response. Since L. monocytogenes is a pathogen, before it can be seriously considered as a human vaccine vector, safety concerns must be addressed. We therefore have produced a highly attenuated strain of L. monocytogenes that requires D-alanine for viability. The recombinant bacteria are attenuated at least 10(5)-fold. We show that when these hyperattenuated bacteria are engineered to express HIV-1 Gag, they are at least as efficient at stimulating Gag-specific human CTLs in vitro as wild-type recombinants. These results suggest that attenuated Listeria is an attractive candidate vaccine vector to induce T-cell immunity to HIV in humans.

The effects of approach and avoidance motor actions on the elements of creative insight.

The authors propose that the nonaffective bodily feedback produced by arm flexion and extension informs individuals about the processing requirements of the situation, leading to the adoption of differential processing styles and thereby influencing creativity. Specifically, the authors predicted that arm flexion would elicit a heuristic processing strategy and bolster insight processes, whereas arm extension would elicit a systematic processing strategy and impair insight processes. To test these predictions, the authors assessed the effects of these motor actions on 3 central elements of creative insight: contextual set-breaking, restructuring, and mental search. As predicted, in 6 experiments, arm flexion, relative to arm extension, facilitated insight-related processes. In a 7th experiment, arm extension, relative to arm flexion, facilitated analytical reasoning, supporting a cognitive tuning interpretation of the findings.

CD3zeta and CD28 down-modulation on CD8 T cells during viral infection.

Down-modulation of CD3zeta expression on CD8 T lymphocytes occurs, independently of other T-cell receptor (TCR)-CD3 components, in tumor-infiltrating lymphocytes, human immunodeficiency virus infection, and autoimmune disease. These associations suggest that it might be related to chronic antigenic stimulation. CD3zeta down-modulation was found, however, in CD8 T cells that proliferate in response to acute viral infections. In 3 otherwise healthy donors with acute gastroenteritis, infectious mononucleosis, and Epstein-Barr virus/cytomegalovirus/mononucleosis, 30% to 60% of circulating CD8 T cells had down-modulated CD3zeta to below the level of detection. The CD3zeta-T cells were also CD28- but expressed the activation markers HLA-DR and CD57. CD3zeta-CD28- T cells are effector CTL because they express perforin and produce IFN-gamma, but not IL-2, on activation and contain the viral-specific cytotoxic T lymphocyte (CTL). However, CD3zeta-CD28-T cells generally do not express CD25 after anti-CD3 and anti-CD28 stimulation and are not cytotoxic until they are cultured with IL-2 overnight. Cytotoxicity coincides with the re-expression of CD3zeta but not CD28. Down-modulation of CD3zeta and CD28 on effector CTL may control CTL triggering and proliferation to prevent immunopathogenesis.

Expansion of CD57 and CD62L-CD45RA+ CD8 T lymphocytes correlates with reduced viral plasma RNA after primary HIV infection.

OBJECTIVE: CD8 T cells, expressing cell surface molecules distinct from those on resting and naive T cells, are increased in HIV infection. The association of increased CD38 and human leukocyte antigen DR (HLA-DR) CD8 T cells with poor prognosis has suggested that activated CD8 T cells may aggravate HIV infection. We examined whether other immunological parameters might influence the viral setpoint. DESIGN: Peripheral T cells from nine untreated patients, obtained after primary HIV infection when plasma HIV had stabilized, were examined for proteins expressed in activated versus resting, memory versus naive, and cytolytic versus non-cytolytic T cells. METHODS: The proportion of CD8 T cells that stain for CD38 and HLA-DR, CD28 and CD57 was compared with plasma viraemia and CD4 cell count. These parameters were also compared with the proportion of CD4 and CD8 T cells that express CD62L and CD45RA, present on naive cells and down-modulated in memory cells. Internal staining for the cytotoxic protein granzyme A was also examined. RESULTS: An increase in CD38 and CD38 HLA-DR CD8 T cells correlated with increased plasma viral RNA (P < 0.00002, P < 0.03, respectively). An increase in CD8 T cells expressing granzyme A was associated with lower CD4 cell counts (P < 0.04). However, the expansion of CD57 and CD62L CD45RA+ CD8 T cells was associated with a lower viral setpoint (P < 0.01, P < 0.02, respectively). CONCLUSION: Phenotypically defined activated CD8 T cells may have different functions in HIV infection. Activated CD8 T cells that are CD57 or CD62L(-)CD45RA+ may be beneficial, because their expansion in untreated patients correlates with a reduced viral setpoint after primary infection.

A role for heat shock protein 27 in CTL-mediated cell death.

CTL exocytosis of granules containing perforin and granzyme proteases induces apoptotic cell death. Either granzyme A or B can act with perforin to trigger apoptosis. Granzyme B activates a ubiquitous apoptotic cascade induced by caspase cleavage, but the granzyme A pathway is largely unknown. Using affinity chromatography with recombinant mutant inactive granzyme A, we previously isolated two granzyme A-binding proteins, PHAP (putative HLA-associated protein) I and II. PHAP II, a substrate of granzyme A, is degraded within minutes of CTL attack. Two additional cytoplasmic proteins of 27 and 53 kDa bind strongly to the mutant granzyme A column, requiring 6 M urea to elute. Sequencing identified these as the monomer and dimer of hsp27, a small heat shock protein up-regulated by stress and cellular activation. Hsp27 coprecipitates with granzyme A from cytoplasmic lysates and is not a substrate of the enzyme. Hsp27 translocates to the detergent-insoluble fraction of target cells and relocalizes from diffuse cytoplasmic staining to long filamentous fibers, especially concentrated in a perinuclear region, within minutes of CTL attack. Hsp27 may participate in morphologic changes during granule-mediated lysis. Low or absent levels of hsp27 expression in T lymphocytes, even after heat shock, may play a role in CTL resistance to granule-mediated lysis.

Performance incentives and means: how regulatory focus influences goal attainment.

Study 1 demonstrated that as individuals' promotion-related ideal strength increases, performance on an anagram task is greater for a monetary task incentive framed in terms of gains and nongains (i.e., promotion framed) than one framed in terms of losses and nonlosses (i.e., prevention framed), whereas the reverse is true as individuals' prevention-related ought strength increases. Study 2 further demonstrated that with promotion-framed task incentives, individuals' ideal' strength increases motivation for promotion-related goal attainment means (gaining points), whereas with prevention-framed task incentives, individuals' ought strength increases motivation for prevention-related means (avoiding losing points). These results suggest that motivation and performance are greater when the regulatory focus of task incentives and means match (vs. mismatch) the chronic regulatory focus of the performers.

Neuropsychiatric features of acute disseminated encephalomyelitis: a review.

Acute disseminated encephalomyelitis is a disorder associated with significant morbidity and mortality. A description and literature review are presented to focus attention on the myriad neuropsychiatric manifestations of this disease. Common psychiatric symptoms include lethargy, irritability, and confusion. Ataxia, seizures, and other signs representing involvement of various areas of the brain and spinal cord are common neurologic presentations. The cerebrospinal fluid shows only nonspecific abnormalities, whereas magnetic resonance imaging may show various lesions in the white matter representing demyelination. The treatment of choice is steroids, but there can be significant residual sequelae of the disease, including intellectual and behavioral abnormalities.

A history of psychiatric consultation in America.

Consultation-liaison psychiatry emerged in a particular socio-historical context, following a major shift of medicine into a more scientific, hospital-based system. Psychiatrists realized that they needed to move outside of the asylum and reintegrate themselves with the new structures of medicine, especially the general hospital and the medical school. Psychosomatic theory and psychoanalytic influence shaped the emergence of consultation-liaison activities in the 1930s through 1950s as they shaped most psychiatric services in the United States at that time, but they were an epiphenomenon to this powerful underlying dynamic that dictated psychiatry's move into the medical hospital. The experience of other countries tends to confirm this hypothesis, though a comparative history is limited by the strong postwar US influence. Pediatric consultation-liaison had a somewhat different evolution, reflecting the later emergence of pediatrics itself as a field and its strong psychosocial and preventive medicine emphasis.

Contact lens manipulation of corneal topography after penetrating keratoplasty: a preliminary study.

We conducted a preliminary retrospective study of five eyes that had undergone penetrating keratoplasty (PK) to determine if rigid gas permeable (RGP) contact lenses could be used as splints or molds to improve postoperative corneal topography. RGP lenses were fit 3-6 months (mean: 4.1 months) after PK and 3-4 months (mean: 1.8 months) after removal of the 10-0 nylon suture. Lenses were fit to attain a contact lens resting position centered on the corneal graft. After 4 to 8 months (mean: 6.2 months) of contact lens wear, analysis of corneal topography showed a decrease in simulated keratometry cylinder from 4.7 +/- 0.6 D (mean +/- 1 standard deviation) to 1.8 +/- 0.8 D (P = 0.02) and an improvement in anterior corneal surface regularity (surface regularity index: initial = 1.40 +/- 0.2; final = 1.0 +/- 0.2; P = 0.04). Three eyes were fit with a well-centered RGP lens; two eyes were fit with lenses that rode off-center. Increased irregular astigmatism in the two eyes with decentered contact lenses suggests the importance of centering RGP lenses with respect to corneal grafts. The best corrected spectacle visual acuity either improved or remained unchanged in four of five eyes after contact lens wear. One eye demonstrated a decrease in best corrected spectacle acuity by one Snellen line after 3 months of lens wear. Further clinical studies are needed to determine the potential of postoperative use of RGP lenses to improve corneal surface regularity, to decrease astigmatism, and to optimize visual results.

Grandparent deaths and severe maternal reaction in the etiology of adolescent psychopathology.

Relationships between the extent of psychopathology and the occurrence of 21 major life events during five developmental periods (prebirth, infancy, childhood, latency, and adolescence) were examined with multiple regression and X2 analyses for 114 hospitalized male and female adolescents. Psychopathology was assessed with the Global Assessment Scale (GAS) at admission to long-term residential treatment in a private psychiatric hospital. Data on deaths, physical illnesses, psychological disturbances, and socioenvironmental events experienced by patients before admission were gleaned from interviews and institutional records. Life events and GAS were scored independently. Only deaths and socioenvironmental events were significantly associated with psychopathology. Specifically, deaths of grandparents during infancy corresponded to lower functioning at admission. Additional analyses showed that severe reactions of patients' mothers to grandparent deaths had been more common among those adolescents who were most disturbed at the time they were admitted to the hospital. These findings were largely serendipitous, however, and need replication.

The current status of psychodynamic formulation.

In this paper, we examine the current status of psychodynamic formulation in psychiatric training and clinical practice. A survey of residency training directors confirms the presence of a general belief in the central importance of formulation but the absence of a clear definition or systematic guidelines. We review the literature and propose a definition of psychodynamic formulation, distinguishing it from isolated hypothesis or focus, diagnosis, case history and interpretation. We then present a systematic but flexible format for formulation and illustrate it with two case formulations.

Profile of psychiatric emergency patients.

From this mass of data, one can assemble a statistical composite profile of the psychiatric emergency patient. This patient is young, unmarried, female, living near the emergency department, poor, diagnosed as psychotic, exhibiting some acutely disruptive or life-threatening behavior, having a history of prior contact with the psychiatric system, arriving at night by herself, and at risk for medical illness or substance abuse. Such a composite profile is misleading, however, for it is unlikely that there is a homogeneous population seeking help in psychiatric emergency services. Rather it seems likely that the composite data conceals a number of demographic and clinical subgroups: the young unmarried borderline woman, the chronically psychotic deinstitutionalized single young male, the middle-aged alcoholic, and the other depressed and organically-impaired patient are examples of such subgroups. When these groups are lumped together in overall figures, salient features and differences are obscured. Studies of these subgroups are needed. Secondly, there is substantial variation between the different studies reported above. Thus, while this summary can give some general guidance for clinical and administrative planning, it is crucial for every psychiatric emergency service to monitor its own utilization statistics. Where the profile of emergency service users does not match that of the underlying census data or that of those persons most at risk for serious psychiatric illness, administrators must raise the question of over- or under-utilization. Finally, there is a need for further studies to build on this preliminary data. Such studies must use uniform diagnostic criteria such as DSM III, prospective blind design, and better coding of the data to facilitate retrieval and processing of relevant information.

Training and research in emergency psychiatry.

In this chapter we have attempted to describe some of the issues that must be addressed in funding, designing, and running a research and training program for emergency psychiatry. Such a program serves the in-house needs of staff training, skill and morale renewal, and program evaluation. In addition it can serve as a resource for the community to train a future cadre of individuals and to seek answers that will provide a solid base of knowledge for emergency psychiatry in the future.

Resistance to alternatives to hospitalization.

Hospitalization has endured as the predominant form of psychiatric treatment for serious mental illness, despite accumulated evidence that outpatient treatment, ranging from halfway houses to day programs to traditional clinics, is equal or superior to inpatient treatment. Reasons for the apparent reluctance to use alternatives to the hospital include social prejudice against community treatment, economic disincentives, administrative chaos, training, professional sociology, and the countertransference meanings of hospitalization. The foregoing is not an argument against hospitalization, but rather an argument for being very clear about policy objectives and treatment goals. If these objectives and goals are made explicit, proposals can be evaluated for their efficacy. If community tenure, the assumption of responsibility for him or herself, and relinquishment of the patient role are goals, then hospitalization must be examined more skeptically. For society, this means the assumption of more responsibility for the establishment of a system of mental health care, for enunciating national policy goals and implementing them consistently, and for committing the necessary funds and manpower to this endeavor. For the clinician, it means examining the clinical efficacy of his or her treatment recommendations and distinguishing between responsibility for the patient's treatment and responsibility for the patient's life. The abdication of social responsibility for the patient and the assumption of omnipotent clinical responsibility for him or her lead inexorably to more institutional and more restrictive treatment, even in the absence of evidence that such measures are therapeutically effective.

Degranulation, membrane addition, and shape change during chemotactic factor-induced aggregation of human neutrophils.

Neutrophils stimulated by the chemotactic factor formyl-methionyl-leucyl-phenyl-alanine (FMLP) undergo a transient change in surface properties that permits the cells to adhere more readily to surfaces and to each other. This transient change can be monitored by light scattering as stimulated neutrophils form aggregates while stirred in a platelet aggregometer. Maximum change in light scattering occurs within 1 min and correlates with an increase in the percentage of cells that are in aggregates of four or more cells and a decrease in the percentage of single cells. With time (3-5 min), small aggregates disappear and single cells reappear. The transient change in adhesiveness is accompanied by a persistent change in cell shape; the cells become polarized and protrude ruffles from one sector of the cell surface. During aggregation the cells adhere to one another with smooth sides together and ruffles pointed outward. During disaggregation the cells dissociate laterally with the simultaneous internalization of membrane in the region opposite the ruffles. Particle bound to the surface by charge (thorotrast, cationized ferritin) are concentrated and internalized in this region. The change in cell shape from round to ruffled occurs within seconds, suggesting that membrane is added to the cell surface from an intracellular store. We therefore quantified surface membrane by electron microscopy morphometry and measured a 25% increase within 10 s of adding FMLP. The source of new membrane appeared to be the specific granule membrane since the kinetics of granule discharge (between 30% and 50% of all release occurs in the first 10 s) correlate with the appearance of new membrane. Furthermore, the amount of membrane that appears at the cell surface at 10 s correlates with that lost from intracellular granules in that time. Chemotaxin-induced aggregation thus begins with granule discharge and membrane addition followed by protrusion of ruffles. Adherence is maximal at 60 s and the gradual loss of adhesiveness that follows is associated with uropod formation and enhanced endocytic activity.