Adenovirus death protein (ADP) is required for lytic infection of human lymphocytes.

The adenovirus death protein (ADP) is expressed at late times during a lytic infection of species C adenoviruses. ADP promotes the release of progeny virus by accelerating the lysis and death of the host cell. Since some human lymphocytes survive while maintaining a persistent infection with species C adenovirus, we compared ADP expression in these cells with ADP expression in lymphocytes that proceed with a lytic infection. Levels of ADP were low in KE37 and BJAB cells, which support a persistent infection. In contrast, levels of ADP mRNA and protein were higher in Jurkat cells, which proceed with a lytic infection. Epithelial cells infected with an ADP-overexpressing virus died more quickly than epithelial cells infected with an ADP-deleted virus. However, KE37, and BJAB cells remained viable after infection with the ADP-overexpressing virus. Although the levels of ADP mRNA increased in KE37 and BJAB cells infected with the ADP-overexpressing virus, the fraction of cells with detectable ADP was unchanged, suggesting that the control of ADP expression differs between epithelial and lymphocytic cells. When infected with an ADP-deleted adenovirus, Jurkat cells survived and maintained viral DNA for greater than 1 month. These findings are consistent with the notion that the level of ADP expression determines whether lymphocytic cells proceed with a lytic or a persistent adenovirus infection.

TLR2 down-regulates FcεRI and its transcription factor PU.1 in human Langerhans cells.

BACKGROUND: Epidermal Langerhans cells (LC) expressing the high-affinity receptor for IgE (FcεRI) play a key role in atopic dermatitis (AD). AD skin is highly colonized with Staphylococcus aureus (S.a.), which are sensed by Toll-like receptor 2 (TLR2). We hypothesized that TLR2 may impact on the expression of FcεRI on LC. OBJECTIVES: To study a putative impact of TLR2 signaling on FcεRI, we analyzed FcεRI and known transcription factors of the receptor after ligand binding to TLR2. METHODS: We generated LC from CD34(+) progenitors in vitro (CD34LC) expressing FcεRI and TLR2 as well as its partners TLR1 and TLR6. The expression of FcεRI and known transcription factors of the receptor was analyzed on the protein and RNA level by flow cytometry, Western blotting, and real-time PCR. RESULTS: For CD34LC from 123 donors, we observed a high heterogeneity in FcεRI surface expression correlating with mRNA level of its α-chain. Stimulation of TLR1/2 or TLR2/6 dramatically down-regulated FcεRI on protein and mRNA level of both α- and γ-chain. Further analysis of putative transcription factors for FCER1A revealed the lack of GATA1 in CD34LC, weak expression of ELF1 and YY1, and high expression of PU.1. While ELF1 and YY1 appeared to be little affected by TLR2 engagement, PU.1 was significantly down-regulated. CONCLUSIONS: Taken together, our findings show that in human, LC ligation of TLR2 by S.a.-derived products down-regulates FcεRI and its transcription factor PU.1, thus suggesting that FcεRI is controlled by PU.1 in these cells.

Effects of deep brain stimulation of the cerebellothalamic pathways on the sense of smell.

The cerebellum and the motor thalamus, connected by cerebellothalamic pathways, are traditionally considered part of the motor-control system. Yet, functional imaging studies and clinical studies including patients with cerebellar disease suggest an involvement of the cerebellum in olfaction. Additionally, there are anecdotal clinical reports of olfactory disturbances elicited by electrical stimulation of the motor thalamus and its neighbouring subthalamic region. Deep brain stimulation (DBS) targeting the cerebellothalamic pathways is an effective treatment for essential tremor (ET), which also offers the possibility to explore the involvement of cerebellothalamic pathways in the sense of smell. This may be important for patient care given the increased use of DBS for the treatment of tremor disorders. Therefore, 21 none-medicated patients with ET treated with DBS (13 bilateral, 8 unilateral) were examined with "Sniffin' Sticks," an established and reliable method for olfactory testing. Patients were studied either with DBS switched on and then off or in reversed order. DBS impaired odor threshold and, to a lesser extent, odor discrimination. These effects were sub-clinical as none of the patients reported changes in olfactory function. The findings, however, demonstrate that olfaction can be modulated in a circumscribed area of the posterior (sub-) thalamic region. We propose that the impairment of the odor threshold with DBS is related to effects on an olfacto-motor loop, while disturbed odor discrimination may be related to effects of DBS on short-term memory.

Suppression of MAP kinases inhibits microglial activation and attenuates neuronal cell death induced by alpha-synuclein protofibrils.

Alpha-Synuclein (alpha-Syn) accounts, as a major component of Lewy bodies (LB), for the filamentous deposits in many cases of neurodegenerative diseases. Yet, little is known about the molecular mechanisms of neuronal loss in these diseases. The correlation between alpha-Syn oligomerization/aggregation and pathologies raises the key question of which molecular form of alpha-Syn (i.e. monomeric alpha-Syn, protofibrils or mature fibrils) represents the damage-inducing culprit in the scenario of synucleinopathies. We show that human alpha-Syn protofibrils (PFs) are potent activators of parallel proinflammatory signalling pathways (p38 and ERK1/2 MAP kinases and NF-kappaB) in microglial cells in vitro. Furthermore, stereotactic injection of alpha-Syn PFs into the substantia nigra of adult rats leads to a profound activation of microglia and adjacent neuronal cell loss, which can be attenuated by the MAP kinase inhibitor semapimod. We propose that the neurodegenerative process of alpha-synucleinopathies involves microglial activation through alpha-Syn released or extruded from cells with pathogenic alpha-Syn metabolism. Compounds that inhibit the MAPK/NF-kappaB pathways might be a promising pharmacological strategy for the treatment of the inflammatory component of synucleinopathies including PD.

[Tremor. Differential diagnosis and treatment]. / Tremor. Differenzialdiagnose und Therapie.

Tremor is one of the most frequent neurological signs; the diagnosis is mainly clinical. The most frequent tremor is essential tremor, which manifests itself as a postural and kinetic tremor. Tremor may occur not only in the hands, but also in the head and voice. Parkinsonian tremor is a tremor at rest; the legs and face are frequently involved. Orthostatic tremor mainly manifests itself in the legs and gives rise to postural instability. Dystonic tremor is an action tremor of the affected region of the body. Drug therapy mostly depends on the clinical manifestation. Postural and action tremors respond to beta blockers, primidone, some antiepileptics and benzodiazepines. Classical rest tremors are improved by dopaminergic substances or anticholinergics. Dystonic tremor may be successfully treated by injecting botulinum toxin. Orthostatic tremor responds to gabapentin or benzodiazepines in some patients. In patients with severely disability, implantation of thalamic stimulation electrodes may be considered.

Inflammation in Parkinson's diseases and other neurodegenerative diseases: cause and therapeutic implications.

Agents suppressing microglial activation are attracting attention as candidate drugs for neuroprotection in Parkinson s disease (PD): While different mechanisms including environmental toxins and genetic factors initiate neuronal damage in the substantia nigra and striatum in PD, there is unequivocal evidence that activation of neuroinflammatory cells aggravates this neurodegenerative process. It was shown that following an acute exposure to the neurotoxin 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) and other toxins the degenerative process continues for years in absence of the toxin. Reactive microglia has been observed in the substantia nigra of patients with PD, indicating that this inflammatory process might aggravate neurodegeneration. By releasing various kinds of noxious factors such as cytokines or proinflammatory molecules microglia may damage CNS cells. The stimuli triggering microgliosis in Parkinsonian syndromes are unknown so far: However, analysis of neuronal loss in PD patients shows that it is not uniform but that neurons containing neuromelanin (NM) are predominantly involved. We hypothesized that extraneuronal melanin might trigger microgliosis, microglial chemotaxis and microglial activation in PD with subsequent release of neurotoxic mediators. The addition of human NM to microglial cell cultures induced positive chemotactic effects, activated the pro-inflammatory transcription factor nuclear factor kappa B (NF-kappaB) via phosphorylation and degradation of the inhibitor protein kappaB (IkappaB), and led to an upregulation of TNF-alpha, IL-6 and NO. These findings demonstrate a crucial role of NM in the pathogenesis of Parkinson's disease by augmentation of microglial activation, leading to a vicious cycle of neuronal death, exposure of additional neuromelanin and chronification of inflammation. Antiinflammatory drugs may be one of the new approaches in the treatment of PD.

[Validating the efficacy of a group intervention program on the quality of life of depressed patient's spouses]. / Uberprüfung der Wirksamkeit eines neu entwickelten Gruppeninterventionsprogramms auf die Lebensqualität von Angehörigen depressiv Erkrankter.

A new group intervention program has been assessed, rating its ability to increase the quality of life in partners of patients suffering under depression. Over a period of six months 66 subjects participated in an intervention group for a total of twelve sessions. The control group consisted of 50 persons, and quality of life was assessed with the WHOQOL-BREF. The five WHOLQOL domains were used as independent variables in random-effects regression models measuring the time effect. Although the quality of life of the subjects was below that of the general population at the beginning of the intervention, the study resulted in no significant improvement in quality of life. In contrast, satisfaction of participants with the intervention was high.

[A group intervention for spouses of patients with depression - is it effective?]. / Gruppenintervention zur unterstützung von partnerndepressiv erkrankter - eine lohnende massnahme?

OBJECTIVE: Spouses of patients with depression have an elevated risk to develop an affective disorder themselves. We evaluate whether a group intervention program for spouses of patients with depression does improve participants' depressive and anxiety symptoms. METHODS: 66 spouses participated in a six months intervention with 12 group sessions. 50 nonparticipants were included as a control group. We measured depressive and anxiety symptoms with the Beck Depression Inventory (BDI) and the Beck Anxiety Inventory (BAI) at the beginning and the end as well as 3 and 9 months after the intervention. RESULTS: The intervention did not cause any improvement with regard to BDI and BAI scores. Scores in the BDI and BAI were normal in most participants before the intervention. Regardless, satisfaction with the program among participants was very high. CONCLUSION: The influence of the intervention concept on the wanting participation of more severely affected spouses is discussed and adaptations of the program are proposed.

[Efficacy of an intervention programme on burnout symptoms of partners of depressed patients]. / Wirksamkeit eines Interventionsprogramms auf die Burnout-Belastung von Lebenspartnern depressiv Erkrankter.

AIM OF THE STUDY: A newly developed group intervention programme was evaluated with regard to its effectiveness to decrease the burnout symptoms of the partners of depressed patients. METHODS: Within a period of six months, a group of 66 persons has taken part in the intervention for a total of twelve group sessions. A control group consisted of 50 persons without any intervention. Burnout was assessed using the German version of the Maslach Burnout Inventory (MBI). To evaluate the time effect, the burnout dimensions were used as independent variables in random effects models. RESULTS: Over the analyzed period of time no significant positive effect was measured on any of the assessed burnout dimensions. CONCLUSIONS: An increased inclusion of depressed patients in the intervention as well as an increased intensity and a lowering of the admission threshold for the heavily burdened relatives could increase the effectiveness of the program.

[A programme to assist close relatives and lifelong partners in caring for persons suffering from depressions or schizophrenic disorders]. / Ein Unterstützungsprogramm für Lebenspartner von Menschen mit depressiven oder schizophrenen Störungen.

OBJECTIVE: Lifelong partners or close relatives of persons suffering from mental disorders will naturally step in to help by assuming a great variety of tasks. By witnessing their relative's illness on a daily basis, they are exposed to many burdens with a negative impact on their own well-being. Hence, supporting the relatives of persons with mental disorders appears imperative. While there are various approaches to working with relatives, there are hardly any specific programmes for working with certain groups of relatives such as spouses, children or siblings. METHODS: Basing on a discussion of the various approaches to looking after relatives, development of a programme is described aimed at specifically supporting spouses of persons suffering from depression or schizophrenia. RESULTS: The concept of our programme is presented and results of its evaluation by participants are reported. CONCLUSION: The initial experiences with the support programme are quite promising. An evaluation of its effects, based on a case-control-design, is currently under way.

[Illness related costs for spouses of patients suffering from a mental illness: results of a study with repeated measurements]. / Erkrankungsbedingte Kosten für Partner psychisch Kranker: Ergebnisse einer Mehrfacherhebung.

OBJECTIVE: Aim of this study is the documentation of illness-associated costs for spouses, whose relative is suffering from a mental illness. METHOD: Over a period of 12 month, 117 spouses of patients who are suffering from schizophrenia, depression or anxiety disorders repeatedly filled in a standardized questionnaire about illness related expenses and financial losses. RESULTS: 90 % of the spouses reported direct cash expenditures on behalf of the patients' illness. On average, these costs amounted to yearly expenditures of euro 1146 (range: euro 0 - 11 910). Costs did not differ significantly across types of illness and income was not found to be a significant covariate. CONCLUSIONS: Spouses reported substantial direct cash expenditures on behalf of the patients' illness. Since these expenditures varied to a large extent over the three points of measurement, repeated measurement designs seem to be a prerequisite for a reliable assessment of illness-associated costs. Since living together with a mentally ill partner is associated with an increased risk of developing a burden-related psychiatric illness for spouses themselves which may lead to double costs and double decreases in income, these aspects should be taken into consideration when planning changes in health policy.

Involvement of benzodiazepine receptors in neuroinflammatory and neurodegenerative diseases: evidence from activated microglial cells in vitro.

Increased binding of a ligand for the peripheral benzodiazepine binding receptor is currently used in PET studies as an in vivo measurement of inflammation in diseases like multiple sclerosis and Alzheimer's disease. Although peripheral-type benzodiazepin receptors (PBRs) are abundant in many cell types and expressed in the CNS physiologically only at low levels, previous reports suggest that after experimental lesions in animal models and in human neurodegenerative/-inflammatory diseases upregulated PBR expression with increased binding of its ligand PK11195 is confined mainly to activated microglia in vivo/in situ. Because the functional role of the PBR is unknown, we confirm by immunohistochemistry and PCR (I) that this receptor is expressed on microglia in vitro and (II) that benzodiazepines modulate proliferation of microglial cells and the release of the inflammatory molecules nitric oxide (NO) and tumor necrosis factor-alpha (TNF-alpha) in cell culture supernatants of primary rat microglia. Compared to lipopolysaccharide-activated controls the release of NO was markedly decreased in cultures treated with benzodiazepines (clonazepam, midazolam, diazepam) and the PBR ligand PK11195. Moreover, release of TNF-alpha and proliferation was significantly inhibited in the benzodiazepine-treated groups. These findings link the in vivo data of elevated PBR levels in neurodegenerative/-inflammatory diseases to a functional role and opens up possible therapeutic intervention targeting the PBR in microglia.

Intrathecal synthesis of monocyte chemoattractant protein-1 (MCP-1) in amyotrophic lateral sclerosis: further evidence for microglial activation in neurodegeneration.

Autopsy studies and animal experiments suggest that microglial inflammation contributes to the pathogenesis of amyotrophic lateral sclerosis (ALS). Monocyte-chemoattractant protein (MCP-1) might play an important role in microglial recruitment. We studied MCP-1 levels in sera and cerebrospinal fluid of 29 ALS patients and compared the results with 11 control patients with tension headache. The MCP-1 level was determined using enzyme-linked immunosorbent assays (ELISA). A significant increase in cerebrospinal fluid MCP-1 level but not serum level was seen in the patients with ALS compared to the control subjects. These results suggest that cerebrospinal fluid MCP-1 activity may be a sensitive marker for neuroinflammation in ALS useful for monitoring treatment trials in ALS.

Cerebral occlusive artery disease in Noonan syndrome.

Noonan syndrome is an autosomal-dominant inherited syndrome with variable expression of multiple malformations including cardiovascular and craniofacial anomalies. While cerebrovascular insults due to cardiogenic emboli, coagulation abnormalities or cerebrovascular malformations have been documented before, intracerebral occlusive artery disease is not well recognized as a cause of stroke in this syndrome. A 6-year-old girl with Noonan syndrome presented with repetitive transient ischemic attacks consisting of dysphasia and right-sided central facial and arm weakness. Neuroimaging showed acute ischemic lesions in the left putamen and caudate nucleus. Multiple intracranial stenoses were found during transcranial Doppler examination and MR angiography. Although hypertrophic cardiomyopathy was documented by transesophageal echocardiography, a cardioembolic origin of the ischemic attacks was unlikely in this case. The symptoms resolved and did not recur after antiplatelet and anticoagulant therapy was initiated. Stenoses of intracranial cerebral arteries should be considered among the causes of stroke in young patients with Noonan syndrome.

Depressive disorders in spouses of mentally ill patients.

BACKGROUND: According to the literature on stress and coping, the burden of caregiving to a mentally ill partner might have an impact on the mental health of the spouse. METHOD: As part of a study on the burden of caregiving to mentally ill family members, a structured psychiatric interview (DIA-X-M-CIDI) was conducted with spouses of patients suffering from depression, anxiety disorders, or schizophrenia (n = 151). RESULTS: Covarying with the partner's gender and the severity of the patient's illness a significantly increased prevalence of depressive disorders could be found. CONCLUSION: Psychiatric patients' partners are at a high risk of developing a depressive disorder. It appears necessary to develop special interventions for spouses reducing stress and the risk of getting depressed.

Cerebrospinal fluid from patients with neurodegenerative and neuroinflammatory diseases: no evidence for rat glial activation in vitro.

To determine the possible contribution of glial cells via oxidative stress/cytokine secretion in the pathogenesis of Parkinson's disease (PD), Alzheimer disease (AD), amyotrophic lateral sclerosis (ALS) or multiple sclerosis (MS) the concentration of nitric oxide (NO) (by the Griess method) and Interleukin-6 (IL-6) (by enzyme-linked immunosorbent assay) were measured in resting rat microglial and astrocytic cell culture supernatants stimulated by cerebrospinal fluid (CSF) (dilution 1:4, 1:10) from patients with the aforementioned diseases. Neither the concentration of NO (optical density at 450 nm: control, 0.036+/-0.006; MS, 0.034+/-0.008; AD, 0.031+/-0.006; PD, 0.02+/-0.01; lipopolysaccharide (LPS), 0.26+/-0.018) nor the amount of IL-6 (ng/ml: control, 0.112+/-0.026; PD, 0.12+/-0.027; MS, 0.123+/-0.008; ALS, 0.137+/-0.01; LPS, 1.81+/-0.11) differed in any disease group from those of unaffected controls. These findings suggest that the stimuli for inflammatory activation of glia are quite localized and not present in sufficient concentrations in the CSF of affected patients.

[Need for help and nursing care in the elderly of the new German territories: results of a Leipzig long-term study of the elderly population (LEILA75+)]. / Hilfe- und Pflegebedürftigkeit im Alter in den neuen Bundesländern: Ergebnisse aus der Leipziger Langzeitstudie in der Altenbevölkerung (LEILA75+).

In a representative sample of the Leipzig population age 75 and older 61.8% of the participants showed relevant deficits in their capacity of independent living as assessed by a combined ADL/IADL scale. According to a staging model of care as promoted by Schneekloth and coworkers, 17% of the sample was in need of care. Especially, mobility-related instrumental activities of daily living (IADL) such as shopping, cleaning and visiting are affected, but also basic activities (ADL) such as climbing stairs, walking or taking a shower/bath. Each of these activities created problems for more than 45% of the participants. Between 18 and 33% of the sample even regarded it as impossible to carry out these activities. Expectedly, the percentages of assistance needed with ADLs/IADLs appeared to be strongly age-related with exponential increases beyond the age of 85. Beyond effects of sampling and life expectancy, significantly more women suffered from decreases in their capacity of independent living. Community-dwelling elderly on average had a 10% higher rate of problems with ADLs/IADLs as compared to German reference data from the studies on "Chances and Limits of Independent Living in Old Age"; the rate of institutionalized participants, who regarded it impossible to carry out these activities, was even higher by about 30%. As discussed by Schneekloth et al., data from the LEILA study support the hypothesized pattern that ecological disadvantages under both community-dwelling as well as insitutionalized living conditions lead to higher percentages of elderly in the former East German states who are in need of care. As a consequence and although more disabled, elderly seem to stay longer under community-dwelling living conditions and move even more disabled into an institutionalized form of living.

From theory to therapy: implications from an in vitro model of ramified microglia.

Microglia are the principal immune cells in the central nervous system (CNS), characterized by a highly specific morphology and unusual antigenic phenotype. An increasing number of studies have focused on the role of microglia in the pathogenesis of neurodegenerative diseases. To elucidate the function of microglial cells under several neuropathological conditions, we have studied and established a cell culture model that allows us to cultivate microglial cells in their inactive, resting (ramified) phenotype. In the first part of this work, we describe the interaction of microglia cells with their epithelial (astrocytic) microenvironment. The second part reviews experiments with microglia cell cultures to elucidate underlying signalling pathways and summarizes recent advances of our knowledge in microglial molecular pathways that may ultimately lead to neurodegeneration.

The Alzheimer's disease activities of daily living international scale (ADL-IS).

BACKGROUND: Activities of daily living (ADL) deficits are integral components of dementia disorders, and ADL measures are among the most robust markers of the course of Alzheimer's disease (AD). Despite this acknowledged importance, no clearly useful ADL instrument for cross-cultural application in pharmacologic trials in the early stages of AD had been available. METHOD: An international effort was launched to develop an ADL scale for pharmacologic trials in early AD. Steps taken from 1990 to the present included: (1) international scientific working group meetings and reviews, (2) reviews of existing measures, (3) collating of existent, nonredundant items, (4) querying experts for new items, (5) interviews with informants and subjects in the USA, France, and Germany, toward the identification of potential new items, (6) identification of an item pool based upon these procedures, (7) creation of a trial instrument, (8) piloting of this instrument, and (9) refinement of the scale based upon statistical analysis of the pilot data. Final item selection was based upon: (1) relevance for > or = 80% of subjects in severity-stratified USA and German samples; (2) absence of gender and national biases; (3) significant (p <.05) discrimination between (a) normal versus mildly impaired and (b) mildly impaired versus moderately to moderately severely impaired subjects; and (4) Global Deterioration Scale (GDS) scores accounting for > or = 12% of variance in the item after controlling for age and gender. RESULTS: An ADL scale consisting of 40 items that correlate with the global and cognitive progress of AD is developed for international usage in pharmacologic trials in incipient, mild, moderate, and moderately severe AD. The scale contains 40 items falling within 13 ADL categories. The 40-item scale is shown to have .81 correlation with GDS staging, .81 with mental status assessment (Mini-Mental State Examination), and .81 with a psychometric test (the SKT) (p values < .001). CONCLUSION: This scale can be used to measure therapeutic response in AD.

ATP and adenosine induce ramification of microglia in vitro.

Microglial cells in the healthy adult brain possess a characteristic ramified morphology with multiple branched processes, small somata and down-regulated inflammatory properties. In contrast, microglial cells isolated from new-born rat brain inevitably show a non-ramified amoeboid phenotype, which is observed in vivo after pathologic activation or during development. To identify factors that control microglial morphology we investigated the effects of purines alone or in combination with astrocyte-conditioned medium (ACM). Under optimized culture conditions postnatal rat microglial cells developed an amoeboid to ovoid phenotype. Addition of 0.6-1 mM ATP or adenosine induced the outgrowth of numerous processes after 2-3 days that could be observed also in the presence of ACM as previously reported. Culture in ACM plus ATP or adenosine yielded an optimized ramified phenotype. ATP or adenosine, but not ACM alone, also prevented the formation of a flat, amoeboid morphology induced by lipopolysaccharide (LPS); however, at 0.6-1 mM they did not reduce the initial LPS-induced activation of the transcription factor NF-kappaB. By using specific agonists or antagonists the morphological transformations could not be confined to a distinct purinoreceptor subtype, but appeared to be mediated by long-term presence of adenosine in the medium to which phosphorylated purines were rapidly hydrolyzed by microglial cells. Since ACM did not contain sufficient concentrations of ATP or adenosine, purines are not the only ramification-inducing factors present in ACM; however, they are a valuable tool to induce microglial ramification in vitro.