Enhanced expression of cytokines and chemokines by blood monocytes to in vitro lipopolysaccharide stimulation are associated with hostility and severity of depressive symptoms in healthy women

The current study investigated the relation of hostility and severity of depressive symptoms, separately and jointly, to the capacity of blood monocytes to secrete an array of cytokines when stimulated by bacterial lipopolysaccharide (LPS). Subjects were 44 healthy, non-smoking, premenopausal women (aged 23-49 years) not currently taking oral contraceptives. Data were collected during the follicular phase of the menstrual cycle. The Cook-Medley Hostility (Ho) scale and the Beck Depression Inventory (BDI) were used to assess hostility and severity of depressive symptoms, respectively. Dual-color flow cytometry was used to measure the total expression of interleukin (IL)-1alpha, IL-1beta, IL-8, tumor necrosis factor (TNF)-alpha, monocyte chemotactic protein (MCP)-1 and monocyte inflammatory protein (MIP)-1alpha in blood monocytes following 4 h in vitro LPS stimulation of whole blood. In analyses adjusting for age, body mass index (BMI), fasting cholesterol, alcohol use, race and 17beta-estradiol (E(2)), higher Ho scores were associated with greater LPS-stimulated expression of IL-1alpha (beta = 0.033, p = 0.02), IL-8 (beta = 0.046, p = 0.01) and IL-1beta (beta = 0.024, p = 0.06). Higher BDI scores were associated with greater expression of TNF-alpha (beta = 0.042, p = 0.02) and IL-8 (beta = 0.045, p = 0.04). The linear combination of Ho and BDI scores was significantly associated with IL-1beta (beta = 0.18, p = 0.057), IL-8 (beta = 0.36, p = 0.01), TNF-alpha (beta = 0.25, p = 0.03), and IL-1alpha (beta = 0.18, p < 0.07). Thus, in healthy women, these psychological risk factors, alone and in combination, induce a proinflammatory phenotype in circulating monocytes characterized by the up-regulation of proinflammatory cytokines, supporting the hypothesis that inflammation may be a key pathway whereby hostility and depressive symptoms contribute to atherosclerosis and subsequent coronary heart disease (CHD).     

The Ser460Pro mutation in recombinant protein S Heerlen does not affect its APC-cofactor and APC-independent anticoagulant activities

Protein S is a vitamin K-dependent plasma protein that functions as an APC-cofactor, but also exhibits anticoagulant activity in the absence of APC. The Heerlen polymorphism of protein S is characterized by a Ser460Pro substitution and lacks glycosylation at Asn458. It is associated with decreased protein S levels due to selective deficiency of free protein S Heerlen. To understand the lack of thrombotic complications associated with the protein S Heerlen mutation, we compared recombinant protein S Heerlen, wild type (wt) protein S and plasma-derived protein S. wt-Protein S and protein S Heerlen each bound 1:1 to C4BP with dissociation constants of 0.27 and 0.33 nM, respectively. Both wt-protein S and protein S Heerlen, either free or in complex with C4BP, were equally active as prothrombinase inhibitors in the absence of APC. All three protein S preparations stimulated APC-catalyzed inactivation of normal FVa, FVa Leiden and FVIIIa to the same extent. If extrapolated to plasma, it is not likely that the decreased free protein S levels in carriers of the protein S Heerlen mutation are compensated by an increased anticoagulant activity of protein S Heerlen-C4BP complexes. It is possible that an unrecognized plasma factor selectively enhances the anticoagulant activity of protein S Heerlen. If not, the reduction of free protein S levels in heterozygous protein S Heerlen-carriers combined with (low) normal total protein S levels apparently minimally affects the total anticoagulant activity of protein S (APC-cofactor and APC-independent activity) and hence is not associated with increased risk of venous thrombosis.     

Axotomy-dependent and -independent synapse elimination in organ cultures of Wld(s) mutant mouse skeletal muscle

Progressive "dying back" neurodegenerative diseases are debilitating due to loss of connectivity after nerve terminal and axonal withdrawal, which impairs peripheral nerve function and leads ultimately to neuronal cell death. The mutant mouse (Wallerian degeneration slow; Wld(s)) provides an accessible model system to understand orthograde and retrograde degeneration, because in these mice axotomy induces slow, progressive withdrawal of nerve terminals from motor endplates. Axon degeneration itself is about 10 times slower than in wild-type mice. We describe an organ culture paradigm that permits direct observation of the progressive changes in morphology of neuromuscular junctions in Wld(s) mutant mice. Normal nerve terminal and motor endplate morphology were maintained at most Wld(s) neuromuscular junctions for up to 72 hr in vitro. At others, synaptic boutons were removed from postsynaptic junctional folds in piecemeal fashion, as observed in adults in vivo. By contrast, nerve terminals degenerated rapidly and synchronously in wild-type muscle cultures, resembling Wallerian degeneration in vivo. These observations confirm that in Wld(s) mice, axotomy triggers a mechanism of nerve-terminal withdrawal that seems qualitatively different from that in wild-type animals. The piecemeal dismantling of presynaptic terminals resembles that occurring during neonatal synapse elimination. Organ cultures of neonatal Wld(s) muscle maintained for 1-2 days in vitro also showed no evidence of synaptic terminal degeneration, but elimination of polyneuronal innervation progressed in vitro at approximately the same rate as in vivo. Taken together, the data suggest that both natural and axotomy-induced forms of synapse withdrawal may be accessible to continuous observation and analysis, in organ-cultures of Wld(S) mouse muscles. This offers several advantages over repeated visualization of synaptic remodeling that has thus far been possible only in vivo.     

Oxidative stress‐induced death in the nervous system: Cell cycle dependent or independent?

Neuronal death, attributable to perturbed redox homeostasis, is the underlying factor in many acute and chronic neurological disorders. The mechanisms employed by oxidatively stressed neurons to commit to cell death pathways are beginning to be characterized, but this is hampered by a lack of good models that extrapolate readily to redox-dependent neuronal death paradigms. In this Mini-Review, we discuss mechanisms by which oxidative stress can result in neurodegeneration. We examine evidence on which terminally differentiated neurons might commit to death under conditions of oxidative stress. In some cases, death may be linked to an aberrant and uncoordinated reentry into the cell cycle and mitotic catastrophe. Other evidence suggests that cell cycle reentry is not mandatory for death execution. Rather, the reexpression of cell cycle proteins may induce apoptotic pathways in a cell cycle-independent manner. In contrast to these models, there is also evidence that oxidative neuronal death is independent of cell cycle proteins. We conclude that oxidative stress-induced neuronal death may be promoted via several pathways, which may be cycle protein dependent or independent. The determining factor for which or how many pathways are induced appears to be context dependent and determined by the level and duration of oxidative stress.     

A randomized controlled trial of integrated versus parallel housing services for homeless adults with severe mental illness

This study compared two contemporary approaches to linking housing and mental health services. In the integrated housing program, case management and housing services were provided by teams within a single agency and were closely coordinated. In the parallel housing condition, case management services were provided by mobile assertive community treatment teams and housing by routine community-based landlords. Adults with severe mental illness who were at high risk for homelessness (n = 121; 72.7% schizophrenia spectrum) were assigned randomly to integrated or parallel housing services and followed for 18 months. Integrated housing services led to more days of stable housing and greater life satisfaction than parallel housing services, especially for male participants. Integrated housing services were also associated with greater reductions in psychiatric symptoms. Closer integration between clinical and housing services, and greater use of supervised living settings, led to more time in stable housing for participants in the integrated housing services condition and was associated with greater gains in several outcome domains.     

A negative cranial computed tomographic scan is not adequate to support a diagnosis of pseudotumor cerebri

A 10-year-old boy with daily headache for 1 month and intermittent diplopia for 1 week was found to have a unilateral partial abducens palsy and bilateral papilledema; otherwise, his neurologic examination showed no abnormalities. A cranial computed tomographic (CT) scan was normal. Lumbar puncture disclosed a markedly elevated opening pressure of > 550 mm of cerebrospinal fluid with normal cerebrospinal fluid. Medical therapy with acetazolamide for presumed pseudotumor cerebri was begun. Magnetic resonance imaging (MRI) of the brain, done several days later because of continuing symptoms, unexpectedly showed multiple hyperintensities of cerebral white matter on T2-weighted and fluid-attenuated inversion recovery images. Despite high-dose intravenous methylprednisolone for possible demyelinating disease, he failed to improve. A left temporal brain biopsy followed and disclosed an anaplastic oligodendroglioma. In a patient with features indicating pseudotumor cerebri, a negative cranial CT scan is not adequate to rule out underlying pathology; thus, MRI of the brain should probably always be performed. A revised definition of pseudotumor cerebri could better include "normal MRI of the brain" rather than "normal neuroimaging."     

Effects of ambient stimuli on measures of behavioral state and microswitch use in adults with profound multiple impairments

The effects of different types and amounts of environmental stimuli (visual and auditory) on microswitch use and behavioral states of three individuals with profound multiple impairments were examined. The individual's switch use and behavioral states were measured under three setting conditions: natural stimuli (typical visual and auditory stimuli in a recreational situation), reduced visual stimuli, and reduced visual and auditory stimuli. Results demonstrated differential switch use in all participants with the varying environmental setting conditions. No consistent effects were observed in behavioral state related to environmental condition. Predominant behavioral state scores and switch use did not systematically covary with any participant. Results suggest the importance of considering environmental stimuli in relationship to switch use when working with individuals with profound multiple impairments.     

Lithium treatment of acute mania in adolescents: a placebo-controlled discontinuation study

OBJECTIVE: There are no published placebo-controlled studies of any agent in the treatment of acute mania in children or adolescents. This is the first placebo-controlled study of lithium's efficacy in the treatment of acute mania in adolescents. METHOD: In this discontinuation study, participants received open treatment with lithium at therapeutic serum levels (mean 0.99 mEq/L) for at least 4 weeks. Responders were randomly assigned to continue or discontinue lithium during a 2-week double-blind, placebo-controlled phase. This study had 80% power to detect a 40% difference in exacerbation rates between groups (10% on lithium versus 50% on placebo). RESULTS: Twenty-three of 40 protocol participants (57.5%) experienced a clinically significant symptom exacerbation during the 2-week double-blind phase. However, the slightly lower exacerbation rate in the group maintained on lithium (10/19 or 52.6%) versus the group switched to placebo (13/21 or 61.9%) did not reach statistical significance. CONCLUSIONS: This study does not support a large effect for lithium continuation treatment of adolescents with acute mania, mostly due to the unexpectedly high rate of exacerbations in the group that continued on lithium. Further studies are warranted to clarify whether acute mania in adolescents is lithium responsive.     

"Tectonic" hippocampal malformations in patients with temporal lobe epilepsy

Histological analysis of hippocampi removed en bloc during surgical treatment of temporal lobe epilepsy revealed a subgroup of patients with bulbous expansions of the CA1 pyramidal cell/subicular layers that were consistently accompanied by "tectonic" invaginations of the adjacent dentate gyrus. Most hippocampi containing the CA1/subicular anomaly and the tectonically deformed dentate gyrus exhibited minor cell loss compared to hippocampi with typical hippocampal sclerosis, and retrospective analysis revealed that conventional imaging methods usually failed to detect subtle hippocampal atrophy or abnormal signal characteristics in patients with this anomaly. Cells within the anomaly exhibited the spherical appearance of undifferentiated pyramidal layer neurons, and were immunopositive for the neuronal marker NeuN. Immunostaining for the synaptic marker beta-synuclein suggested abnormal dentate gyrus lamination in segments containing the pyramidal cell layer anomaly, but not in unaffected areas of the same specimens. Despite differences in the extent of neuronal loss between patients with hippocampal sclerosis and those with the CA1/subicular anomaly, the incidence of antecedent febrile seizures was similar in both groups. In a comparison group of hippocampi obtained at autopsy, structural irregularities were evident, but were consistently less disruptive to hippocampal architecture than the anomalies observed in epilepsy patients. We hypothesize that developmental malformation of the CA1 pyramidal cell/subicular layers may adversely influence the subsequent development of the adjacent dentate gyrus, and may render temporal lobe structures hyperexcitable and more vulnerable to relatively innocuous seizures and injuries. Thus, these presumably developmental hippocampal anomalies may serve as substrates for early febrile seizures and subsequent epilepsy.     

The heterogeneity of schizophrenia in disease states

PREVIOUS PRESENTATION: Some of the contents of this paper have been previously presented at the 16th Annual Meeting of the International Society for Technology Assessment in Health Care June 20, 2000 in the Hague, Netherlands and at the 21st Annual Meeting of the Society for Medical Decision Making as a poster on October 3, 1999 in Reno, NV. BACKGROUND: Studies of schizophrenia treatment often oversimplify the array of health outcomes among patients. Our objective was to derive a set of disease states for schizophrenia using the Positive and Negative Symptom Assessment Scale (PANSS) that captured the heterogeneity of symptom responses. METHODS: Using data from a 1-year clinical trial that collected PANSS scores and costs on schizophrenic patients (N=663), we conducted a k-means cluster analyses on PANSS scores for items in five factor domains. Results of the cluster analysis were compared with a conceptual framework of disease states developed by an expert panel. Final disease states were defined by combining our conceptual framework with the empirical results. We tested its utility by examining the influence of disease state on treatment costs and prognosis. RESULTS: Analyses led to an eight-state framework with varying levels of positive, negative, and cognitive impairment. The extent of hostile/aggressive symptoms and mood disorders correlated with severity of disease states. Direct treatment costs for schizophrenia vary significantly across disease states (F=27.47, df=7, p<0.0001), and disease state at baseline was among the most important predictors of treatment outcomes. CONCLUSION: The disease states we describe offer a useful paradigm for understanding the links between symptom profiles and outcomes.