Validation of the motivational phase of the integrated motivational-volitional model of suicidal behavior in a German high-risk sample.

BACKGROUND: The Integrated Motivational-Volitional (IMV) model of suicidal behavior proposes in its motivational phase that perceptions of defeat and entrapment (total, internal and external entrapment) lead to the development of suicidal ideation and that thwarted belongingness and perceived burdensomeness moderate this process. The aim of this study was to test the motivational phase of the IMV model cross-sectionally in a German sample of psychiatric inpatients. METHODS: A total of 308 psychiatric inpatients (53% female) aged 18 to 81 years (M = 36.92, SD = 14.30) were included in the study and investigated within 14 days after psychiatric admission due to suicide attempt (53%) or acute suicidal crisis (47%). Statistical analyses included a mediation analysis and moderation analyses. RESULTS: Results demonstrate a simple mediation of defeat via entrapment (total, internal and external entrapment) on suicidal ideation. The interaction between thwarted belongingness and perceived burdensomeness was confirmed as a motivational moderator. LIMITATIONS: Limiting factors of the present study are the cross-sectional design and the retrospective assessment of suicidal ideation. CONCLUSION: The main assumptions of the motivational phase of the IMV model could empirically be confirmed. Perceptions of defeat, internal and external entrapment, thwarted belongingness, and perceived burdensomeness should be taken into account with regard to prevention, risk assessment and interventions of suicidal ideation and attempts. However, future investigations based on prospective data are warranted.

Chromosome instability predicts the progression of premalignant oral lesions.

OBJECTIVES: One of the main problems in reducing the incidence of oral squamous cell carcinoma (OSCC) is the inability to appropriately deal with leukoplakia. Accurately identifying lesions which will progress to malignancy is currently not possible. The present study aims to establish the value of chromosome instability (CI) detection by DNA image cytometry and FISH analysis for prognosis and monitoring of oral leukoplakia. MATERIALS AND METHODS: For this purpose, we included from our archives 102 oral leukoplakia cases, which had been diagnosed between 1991 and 2008. Patient follow-up data were collected and the histopathological diagnosis was revised. CI assessment was carried out on paraffin-embedded tissue sections using both DNA image cytometry (ICM) and dual target FISH for chromosomes 1 and 7. RESULTS: 16 of 102 Patients developed carcinoma in situ or OSCC. Both detection methods were found to yield prognostic information independent of the histopathological diagnosis. CI was a strong individual marker of progression, with hazard ratios (HRs) of 7.2 and 6.8 for ICM and FISH respectively. Moreover, this approach seems suitable for monitoring lesions over time (especially ICM). Combining histopathology and CI enables subdivision of patients into three risk groups, with different probabilities of malignant progression. CONCLUSION: CI detection seems a reliable method for risk assessment of oral premalignancies and its application may contribute to a better risk-counselling and appropriate treatment regimen or watchfull-waiting approach of patients.

Startle stimuli exert opposite effects on human cortical and spinal motor system excitability in leg muscles.

Increased excitability of the spinal motor system has been observed after loud and unexpected acoustic stimuli (AS) preceding H-reflexes. The paradigm has been proposed as an electrophysiological marker of reticulospinal tract activity in humans. The brainstem reticular formation also maintains dense anatomical interconnections with the cortical motor system. When a startling AS is delivered, prior to transcranial magnetic stimulation (TMS), the AS produces a suppression of motor evoked potential (MEP) amplitude in hand and arm muscles of healthy subjects. Here we analyzed the conditioning effect of a startling AS on MEP amplitude evoked by TMS to the primary motor leg area. Ten healthy volunteers participated in two experiments that used a conditioning-test paradigm. In the first experiment, a startling AS preceded a suprathreshold transcranial test stimulus. The interstimulus interval (ISI) varied between 20 to 160 ms. When given alone, the test stimulus evoked a MEP amplitude of approximately 0.5 mV in the slightly preinervated soleus muscle (SOL). In the second experiment, the startling AS was used to condition the size of the H-reflex in SOL muscle. Mean MEP amplitude was calculated for each ISI. The conditioning AS suppressed MEP amplitude at ISIs of 30-80 ms. By contrast, H-reflex amplitude was augmented at ISIs of 100-200 ms. In conclusions, acoustic stimulation exerts opposite and ISI-specific effects on the amplitude of MEPs and H-reflex in the SOL muscle, indicating different mechanism of auditory-to-motor interactions at cortical and spinal level of motor system.

Targeted therapy for Ewing's sarcoma: significance of heterogeneity.

BACKGROUND: Survival in Ewing's sarcoma (ES) is limited. Experience with insulin-like growth factor targeting drugs, which require specific molecular tumour alterations, herald a major breakthrough. We screened for tumour heterogeneity within patients by DNA quantification. MATERIALS AND METHODS: DNA image cytometry (IC) was performed on 41 samples from 21 patients, evaluating if ploidy state remained constant over time and between different lesions within patients and the prognostic value of ploidy was assessed. RESULTS: DNA content varied over time and different ploidy states were found to coexist at a single timepoint. Non-diploid DNA content was associated with shorter overall survival (median, 19 vs. 84 months, p=0.047). CONCLUSION: We encountered a change and heterogeneity of ploidy state. This implies that screening for targets on a single tumour sample is insufficient and may lead to under- or overtreatment. The fact that non-diploid DNA content was associated with an adverse outcome confirms that this technique discriminates biologically different tumour clones.

Apple and peach consumption habits across European countries.

The aim of this study was to gain information concerning apple and peach consumption frequency within different European countries in relation to age and gender. The survey was a part of a complex experiment with the aim of evaluating consumers' preferences towards new varieties, and the data is based on the self-reported declarations of respondents, male and female, between 15 and 70 years old. 4271 consumers from 7 European countries were invited to supply information about their apple consumption habits, whereas 499 respondents from 5 countries answered questions relating to frequency of peach and nectarine consumption. In both, the apple and the peach surveys, data analysis of declared intake showed significant differences between nationalities. The highest apple consumption was in Poland, where over 55% declared a consumption of more than 5 apples per week. In comparison, Italian consumers most often indicated eating 3-5 apples per week (39.3%). The lowest apple consumption was in the Netherlands and Spain. In the case of peaches, the highest consumption was indicated in France where 48% of respondents declared a peach consumption of 3-5 per week with 40% eating more than 5 fruits per week. The lowest peach intake was declared in Germany. Irrespective of country women were shown to eat more apples that men. Furthermore, the group of older people (61-70 years) consume apples more often than the adult group (36-60), while within the youngest group of consumers (16-35) eating apples was not at all popular. As with apples females declared a higher peach consumption, and again significantly lower fruit consumption by the youngest group (16-35) was indicated. Although the availability of fruit at the market remains a prime factor in determining apple and peach consumption, our survey confirmed the trends of declining this popular fruit intake by the younger generation, as well as the persistent tendency of lower frequency of fruit consumption among men than women.

Slow pre-movement cortical potentials do not reflect individual response to therapy in writer's cramp.

OBJECTIVE: To investigate whether movement-related cortical potentials (MRCP) provide a physiological correlate that indicates the response to treatment in patients with writer's cramp. METHODS: In 21 patients with writer's cramp, who underwent 4 weeks of limb immobilization followed by re-training for 8 weeks, we recorded MRCPs preceding a self-initiated brisk finger abduction movement. MRCP measurements of pre-movement activity were performed at baseline, after the end of immobilization and four and 8 weeks of re-training. We examined 12 controls, who received no intervention, twice 4 weeks apart. RESULTS: Patients benefited from the therapeutical intervention (Zeuner et al., 2008). They showed no abnormalities of the MRCPs at baseline. In controls, MRCPs did not significantly change after 4 weeks. In patients, immobilization and re-training had no effect on MRCPs. There was no correlation between the severity of dystonic symptoms or the individual treatment response and MRCPs. CONCLUSION: MRCPs are stable measures for interventional studies. However, they do not reflect clinical severity of dystonic symptoms or improvement after therapeutic interventions. SIGNIFICANCE: This is the first study to investigate MRCPs in a large cohort of patients with writer's cramp compared to a control group at different time points. These potentials do not reflect the motor control disorder in patients with writer's cramp.

The prediction of mandibular invasion by squamous cell carcinomas with the expression of osteoclast-related cytokines in biopsy specimens.

Destruction of bone by tumour is caused by osteoclasts rather than by tumour cells directly. Tumour cells of invasive oral squamous cell carcinomas (SCC) release osteoclast-related cytokines and cytokines activate osteoclasts. The purpose of this study was to investigate the possibility of predicting mandibular invasion by SCC by analysis of the expression of osteoclast-related cytokines in biopsy specimens of SCC, adjacent or fixed to the mandible. Thirty-five biopsy specimens from the pathology archives were examined from patients who had been treated for SCC, adjacent or fixed to the mandible. The patients were divided into those with and without medullary invasion. The expression of tumour necrosis factor (TNF)-alpha, interleukin (IL)-6 and IL-11 was studied by immunohistochemical analysis. No significant differences were found in expression of TNF-alpha, IL-6 and IL-11 between biopsy specimens with or without medullary invasion. Quantification of the density of tumour-infiltrating lymphocytes was not reproducible. In conclusion, the expression of TNF-alpha, IL-6 and IL-11 in biopsy specimens of SCC, adjacent or fixed to the mandible, is not an appropriate method for predicting the presence of medullary invasion of the mandible.

Specific association of small heat shock proteins with the pathological hallmarks of Alzheimer's disease brains.

The small heat shock protein family (sHsp) comprises molecular chaperones able to interact with incorrectly folded proteins. Alzheimer's disease (AD) is characterized by pathological lesions such as senile plaques (SPs), cerebral amyloid angiopathy (CAA) and neurofibrillary tangles (NFTs), predominantly consisting of the incorrectly folded proteins amyloid-beta (Abeta) and tau respectively. The aim of this study was to investigate the association of the chaperones Hsp20, HspB2, alphaB-crystallin and Hsp27 with the pathological lesions of AD brains. For this purpose, a panel of well-characterized antibodies directed against these sHsps was used in immunohistochemistry and immunoblotting. We observed extracellular expression of Hsp20, Hsp27 and HspB2 in classic SPs, and Hsp20 expression in diffuse SPs. In addition, extracellular expression of HspB2 was observed in CAA. Both Hsp27 and alphaB-crystallin were also observed in astrocytes associated with both SPs and CAA. Furthermore, none of the sHsps were observed in NFTs in AD brains. We conclude that specific sHsp species may be involved in the pathogenesis of either SPs or CAA in AD.

Reduced sensorimotor inhibition in the ipsilesional motor cortex in a patient with chronic stroke of the paramedian thalamus.

OBJECTIVE: Unilateral or bilateral paramedian infarction in the region of the thalamus and upper midbrain may lead to hypersomnia. To determine whether unilateral infarction of the paramedian thalamus leads to changes in excitability of ipsilesional primary motor hand area (M1). METHODS: We describe a patient with chronic stroke of the right dorsomedian and intralaminar thalamic nuclei, who suffered from mild persistent hypersomnia. We studied the excitability of the right and left M1 with transcranial magnetic stimulation (TMS) in the patient, and in 10 healthy controls. RESULTS: In contrast to healthy controls, contralateral electrical stimulation of the median nerve failed to induce short-latency afferent inhibition (SAI) in the ipsilesional M1. Other measures of corticomotor excitability and somatosensory evoked potentials were normal. CONCLUSIONS: The selective loss of ipsilateral SAI in a patient with paramedian thalamic stroke suggests that during wakefulness, the intact paramedian thalamus facilitates the excitability of intracortical inhibitory circuits, which process thalamocortical sensory inputs in the ipsilateral M1. This preliminary finding suggests that measurements of SAI may provide a means of probing the integrity of some neural pathways, which are involved in the control of wakefulness and arousal. SIGNIFICANCE: In addition to the established role of the paramedian thalamus in arousal and memory, our observation suggests that thalamocortical projections from the paramedian thalamus contribute to the integration of sensory input at the cortical level during wakefulness.

Differential gene expression in human brain pericytes induced by amyloid-beta protein.

Cerebral amyloid angiopathy is one of the characteristics of Alzheimer's disease (AD) and this accumulation of fibrillar amyloid-beta (Alphabeta) in the vascular wall is accompanied by marked vascular damage. In vitro, Abeta1-40 carrying the 'Dutch' mutation (DAbeta1-40) induces degeneration of cultured human brain pericytes (HBP). To identify possible intracellular mediators of Abeta-induced cell death, a comparative cDNA expression array was performed to detect differential gene expression of Abeta-treated vs. untreated HBP. Messenger RNA expression of cyclin D1, integrin beta4, defender against cell death-1, neuroleukin, thymosin beta10, and integrin alpha5 were increased in DAbeta1-40-treated HBP, whereas insulin-like growth factor binding protein-2 mRNA expression was decreased. Corresponding protein expression was investigated in AD and control brains to explore a potential role for these proteins in pathological lesions of the AD brain. Cyclin D1 expression was increased in cerebral amyloid angiopathy and cells in a perivascular position, suggesting that the cell cycle may be disturbed during Abeta-mediated degeneration of cerebrovascular cells. Moreover, cyclin D1 expression, but also that of integrin beta4, defender against cell death-1, neuroleukin and thymosin beta10 was found in a subset of senile plaques, suggesting a role for these proteins in the pathogenesis of senile plaques.

Heparan sulfate proteoglycan expression in cerebrovascular amyloid beta deposits in Alzheimer's disease and hereditary cerebral hemorrhage with amyloidosis (Dutch) brains.

Cerebrovascular deposition of amyloid beta protein (A beta) is a characteristic lesion of Alzheimer's disease (AD) and hereditary cerebral hemorrhage with amyloidosis of the Dutch type (HCHWA-D). Besides A beta, several other proteins and proteoglycans accumulate in cerebral amyloid angiopathy (CAA). We have now analyzed the expression of the heparan sulfate proteoglycan (HSPG) subtypes agrin, perlecan, glypican-1, syndecans 1-3 and HS glycosaminoglycan (GAG) side chains in CAA in brains of patients with AD and HCHWA-D. Hereto, specific well-characterized antibodies directed against the core protein of these HSPGs and against the GAG side chains were used for immunostaining. Glypican-1 was abundantly expressed in CAA both in AD and HCHWA-D brains, whereas perlecan and syndecans-1 and -3 were absent in both. Colocalization of agrin with vascular A beta was clearly observed in CAA in HCHWA-D brains, but only in a minority of the AD cases. Conversely, syndecan-2 was frequently associated with vascular A beta in AD, but did not colocalize with vascular A beta deposits in HCHWA-D. The three different syndecans, agrin, glypican-1 and HS GAG, but not perlecan, were associated with the majority of senile plaques (SPs) in all brains. Our results suggest a role for agrin in the formation of SPs and of CAA in HCHWA-D, but not in the pathogenesis of CAA in AD. Both syndecan-2 and glypican, but not perlecan, may be involved in the formation of CAA. We conclude that specific HSPG species may be involved in the pathogenesis of CAA in both AD and HCHWA-D, and that the pathogenesis of CAA and SPs may differ with regard to the involvement of HSPG species.

Amyloid-beta-induced degeneration of human brain pericytes is dependent on the apolipoprotein E genotype.

Amyloid-beta (A beta) deposition in cerebral vessels (cerebral amyloid angiopathy, CAA) is accompanied by degeneration of vascular cells, including pericytes and smooth muscle cells. Previous studies indicated that specific A beta protein isoforms are toxic for cultured human brain pericytes and smooth muscle cells. In particular, A beta 1-40 carrying the E22Q mutation, as in hereditary cerebral hemorrhage with amyloidosis of the Dutch type (HCHWA-D), is toxic. We investigated the effects of the A beta-binding protein apolipoprotein E (ApoE) on the toxicity of A beta for cultured human brain pericytes. We compared the toxicity of HCHWA-D A beta 1-40 for pericyte cultures with different ApoE genotypes, studied the accumulation of A beta and ApoE in these different cell cultures, and investigated the effects of exogenous ApoE. Pericyte cultures with an ApoE epsilon 2/epsilon 3 genotype were more resistant to HCHWA-D A beta 1-40 treatment than cultures with a epsilon 3/epsilon 3 or epsilon 3/epsilon 4 genotype. Cell death was highest in cultures homozygous for ApoE epsilon 4. The extent to which both A beta ApoE accumulated at the cell surface was parallel to the degree of toxicity. The addition of purified ApoE resulted in a decrease in cell death. These data suggest that ApoE4 may direct A beta more efficiently than other ApoE isoforms into a pathological interaction with the HBP cell surface. The results of this study are in line with the observations that inheritance of the ApoE epsilon 4 allele increases the risk of developing Alzheimer's disease, and that the ApoE epsilon 2 allele has a relatively protective effect.

Agrin is a major heparan sulfate proteoglycan accumulating in Alzheimer's disease brain.

Heparan sulfate proteoglycans (HSPGs) have been suggested to play an important role in the formation and persistence of senile plaques and neurofibrillary tangles in dementia of the Alzheimer's type (DAT). We performed a comparative immunohistochemical analysis of the expression of the HSPGs agrin, perlecan, glypican-1, and syndecans 1-3 in the lesions of DAT brain neocortex and hippocampus. Using a panel of specific antibodies directed against the protein backbone of the various HSPG species and against the glycosaminoglycan (GAG) side-chains, we demonstrated the following. The basement membrane-associated HSPG, agrin, is widely expressed in senile plaques, neurofibrillary tangles and cerebral blood vessels, whereas the expression of the other basement membrane-associated HSPG, perlecan, is lacking in senile plaques and neurofibrillary tangles and is restricted to the cerebral vasculature. Glypican and three different syndecans, all cell membrane-associated HSPG species, are also expressed in senile plaques and neurofibrillary tangles, albeit at a lower frequency than agrin. Heparan sulfate GAG side chains are also associated with both senile plaques and neurofibrillary tangles. Our results suggest that glycosaminoglycan side chains of the HSPGs agrin, syndecan, and glypican, but not perlecan, may play an important role in the formation of both senile plaques and neurofibrillary tangles. In addition, we speculate that agrin, because it contains nine protease-inhibiting domains, may protect the protein aggregates in senile plaques and neurofibrillary tangles against extracellular proteolytic degradation, leading to the persistence of these deposits.

Human brain pericytes as a model system to study the pathogenesis of cerebrovascular amyloidosis in Alzheimer's disease.

Cerebrovascular amyloidosis belongs to the pathological hallmarks of Alzheimer's disease brains. Although definite proof is still lacking, it is very well possible that the amyloid and its associated proteins are produced locally in the brain. In this paper we describe the development of a model system of cultured human brain pericytes to study the mechanisms of microvascular amyloid formation in vitro. These cultured cells may serve to study several aspects of cerebrovascular amyloidosis, which include the production of the amyloid precursor protein and of amyloid beta-protein-associated proteins as well as cytotoxic effects of amyloid beta-protein on perivascular cells. We demonstrated that pericytes produce and metabolize the amyloid precursor protein, and that they produce amyloid beta-protein-associated proteins, such as heparan sulfate proteoglycans, apolipoprotein E, and complement factor C1q. They are also prone to cellular degeneration after treatment with amyloid beta-protein, which is accompanied by increased expression of a number of amyloid beta-protein-associated proteins. This may be an important mechanism to explain the cell death observed in vivo. Our data indicate that this cell culture model of human brain pericytes provides a useful and pathophysiologically relevant tool to study cerebrovascular amyloidosis.

Distribution of A beta-associated proteins in cerebrovascular amyloid of Alzheimer's disease.

Senile plaques and cerebrovascular amyloidosis (CA) are two of the major neuropathological lesions in brains of patients with dementia of the Alzheimer type. We studied the expression of a number of amyloid beta (A beta)-associated proteins in CA, which have previously been identified in senile plaques and which were suggested to play an important role in the pathogenesis of these lesions. Our findings show that involvement of inflammatory components in CA is restricted to activation of the complement system, resulting in deposition of the complement factors C1q, C3c, C4d and the membrane attack complex C5b-9 as well as of the complement inhibitor clusterin. Furthermore, we observed expression of apolipoprotein E, amyloid P component and heparan sulfate proteoglycans in CA, whereas expression of lactoferrin was almost absent. Other inflammatory proteins, known to be present in senile plaques, such as alpha1-antichymotrypsin, alpha2-macroglobulin and intercellular adhesion molecule-1, were absent or detectable only in small amounts. These data suggest that an incomplete inflammatory response occurs in CA as compared to senile plaques. This was confirmed by the finding that the number of cells of the monocyte/macrophage lineage around CA was not increased compared to unaffected vessels. Based on their expression patterns, complement factors, apolipoprotein E and heparan sulfate proteoglycans may be produced early in the process of CA formation and may play an important role in the formation of A beta fibrils in CA. The absence of a number of A beta-associated proteins in CA in comparison to senile plaques is in support of a different pathogenesis for these two lesions.

[Inflammatory mechanisms in the pathogenesis of Alzheimer's disease]. / Ontstekingsmechanismen in de pathogenese van de ziekte van Alzheimer.

Senile plaques belong to the pathological hallmarks of the brains of patients with Alzheimer's disease. There is an increasing amount of evidence that the formation of senile plaques is accompanied by an acute phase reaction, involving the production of several inflammation-associated proteins and the activation of microglial cells. The products of these inflammatory reactions may contribute to the fibrillogenesis of the amyloid beta protein, the major constituent of senile plaques. Both fibrils of the amyloid beta protein and products of activated microglial cells may be neurotoxic, leading to neuronal degeneration and to clinical symptoms of dementia. Recent epidemiological findings have drawn attention to the possibility of therapy with anti-inflammatory agents. Although the results of these studies suggest a beneficial effect of such therapy, further study is warranted to gain more insight into the fundamental aspects of such treatment as well as to develop specific drugs that have little side-effects.

Differential expression of intercellular adhesion molecule-1 (ICAM-1) in the A beta-containing lesions in brains of patients with dementia of the Alzheimer type.

Inflammatory processes have been implicated in the formation of senile plaques in the cerebral cortex of patients with dementia of the Alzheimer type (DAT), since several inflammation-induced proteins are present within these plaques. The relation between inflammatory components and other amyloid beta protein (A beta)-containing lesions of the DAT brain [cerebrovascular amyloidosis (CA) and cerebellar senile plaques] is unclear. We studied the distribution of the inflammation-inducible protein intercellular adhesion molecule-1 (ICAM-1) in CA and in senile plaques of the cerebellum, using an immunohistochemical approach. We observed striking differences in ICAM-1 reactivity between the different types of A beta-containing lesions. ICAM-1 was only expressed in classic senile plaques in the granular and Purkinje cell layer of the cerebellum, and not in diffuse senile plaques of the molecular layer. Also, ICAM-1 was not associated with CA; only when the vascular amyloid extended into the neuropil (dyshoric angiopathy) was perivascular ICAM-1 reactivity observed. This is in contrast to the putative primary involvement of inflammation in the formation of cerebrocortical classic and diffuse senile plaques. Our findings indicate that ICAM-1 expression, which may be an indicator of an inflammatory reaction, is induced in the neuropil depending on the specific site of A beta production.

A lysosomal marker for activated microglial cells involved in Alzheimer classic senile plaques.

One of the major histopathological lesions in brains of patients with dementia of the Alzheimer type (DAT) is the senile plaque. Although previous studies have shown that senile plaques are often accompanied by microglial cells, the role of these cells in DAT pathology is still unclear. In an immunohistochemical and immunoelectron microscopical analysis of DAT and control brain tissues we addressed this issue using two monoclonal antibodies (mAbs KP1 and 25F9) directed against lysosomal antigens in monocytes and macrophages. Whereas KP1 stained lysosomes in both resting and activated microglial cells, 25F9-staining was predominantly found in lysosomes of activated microglial cells in classic senile plaques. The number and size of 25F9-positive lysosomes in activated microglial cells was increased compared to 25F9-staining in unaffected areas in DAT and control sections. We conclude that mAb 25F9 is a unique and useful lysosomal marker, with a higher specificity than other known markers, for activated microglial cells associated with classic, but not with diffuse, senile plaques.