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1. The common HLA class I-restricted tumor-infiltrating T cell response in HPV16-induced cancer

Author

Santegoets, S.J., Welters, M.J.P., Schrikkema, D.S., Freriks, M.R., Kok, H., Weissbrich, B., Branden, A. van den, Linnemann, C., Schumacher, T.N., Adhikary, S., Bendle, G., and Burg, S.H. van der

Subjects
HPV16, Cancer Research, Oncology, Immunology, Immunology and Allergy, TIL, TCR gene transfer
Abstract

Immunotherapies targeting truly tumor-specific targets focus on the expansion and activation of T cells against neoantigens or oncogenic viruses. One target is the human papilloma virus type 16 (HPV16), responsible for several anogenital cancers and oropharyngeal carcinomas. Spontaneous and vaccine-induced HPV-specific T cells have been associated with better clinical outcome. However, the epitopes and restriction elements to which these T cells respond remained elusive. To identify CD8+ T cell epitopes in cultures of tumor infiltrating lymphocytes, we here used multimers and/or a functional screening platform exploiting single HLA class I allele-engineered antigen presenting cells. This resulted in the detection of 20 CD8+ T cell responses to 11 different endogenously processed HLA-peptide combinations within 12 HPV16-induced tumors. Specific HLA-peptide combinations dominated the response in patients expressing these HLA alleles. T cell receptors (TCRs) reactive to seven different HLA class I-restricted peptides could be isolated and analysis revealed tumor reactivity for five of the six TCRs analyzed. The tumor reactive TCRs to these dominant HLA class I peptide combinations can potentially be used to engineer tumor-specific T cells for adoptive cell transfer approaches to treat HPV16-induced cancers.

Published
2022
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11. Transient change in GABAA receptor subunit mRNA expression in Lurcher cerebellar nuclei during Purkinje cell degeneration

Author

Thier P, Schmeh I, Linnemann C, and Schwarz C

Subjects
Neurosciences. Biological psychiatry. Neuropsychiatry, RC321-571, Neurophysiology and neuropsychology, QP351-495
Abstract

Abstract Background Lurcher mice suffer from a complete Purkinje cell (PC) loss in the first four postnatal weeks. Parallel to this degeneration, GABAergic synapses in the deep cerebellar nuclei (DCN), the major recipient of the inhibitory PC projection, increase synaptic conductance. Here, we further investigated this phenomenon, using real-time RT-PCR to assess GABAA receptor subunit gene expression during PC degeneration. Results We observed a specific reduction in γ2 subunit gene expression, while α1–5, β1–2, γ1,3 and δ subunits were unaffected. We made two further specific findings. First, the difference in gene expression was shown in tissue from DCN only. Neither the hippocampus nor coronal sections through the forebrain showed such effects. Furthermore, the involvement of different levels of corticosterone, a possible humeral trigger for differences in gene expression, could be excluded. Second, like the known potentiation of GABAergic synapses, the γ2 down-regulation was present only after the onset of degeneration at p14. The difference in γ2 mRNA expression, however, appeared transient, since it was no longer detectable in adult Lurcher mice. Conclusion In conclusion, the down-regulation of γ2 subunits may be related to differences in synaptic efficacy and, as such, may reflect the initial phase of adaptive responses of DCN tissue to massive GABAergic deafferentation. Its transient course, however, does not support the idea that modulations in GABAergic transmission are at the basis of the well-known DCN-based functional benefit of Lurcher mice present throughout their life.

Published
2006
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12. Pertussis

Author

Gilchrist, M. J. R., Linnemann, C. C., Jr, Balows, A., editor, Hausler, W. J., Jr., editor, Ohashi, M., editor, Turano, A., editor, and Lennete, E. H., editor

Published
1988
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13. Using Merkel cell polyomavirus specific TCR gene therapy for treatment of Merkel cellcarcinoma

Author

Rikke Birgitte Lyngaa, Natasja Wulff Pedersen, Linnemann, C., Schrama, D., Ibrani, D., Ö, Met, Thor Straten, P., Paul Nghiem, Becker, J. C., and Sine Reker Hadrup

Subjects
SDG 3 - Good Health and Well-being
Abstract

T cell receptor gene-therapy has entered the clinic and shown potential for successful cancer treatment. However, the clinical evaluation has also highlighted the need for selection of truly cancerspecific targets. Merkel cell carcinoma (MCC) is a highly aggressive skin cancer associated with Merkel cell polyomavirus (MCPyV). Due to the clear viral correlation CD8+ T cells specific for viral epitopes could potentially form cancer-specific targets in MCC patients. We have identified MCPyV specific T cells using a high-throughput platform for T-cell enrichment and combinatorial encoding offluorescence-labeled major histocompatibility complex (MHC) class I multimers. We identified 35 T cell epitopes among 398 MCPyV derived peptides analyzed. Strikingly, T-cell responses against the two oncogenic MCPyV proteins Large T antigen and small T antigen were exclusively present in blood of MCC patients when compared to healthy donors. We demonstrate both the processing and presentation of oncoprotein-derived epitopes, as well as lytic activity of specific T cells towards MHC matched MCC cells. Demonstrating the presence of oncoprotein-specific T cells among tumorinfiltrating lymphocytes ex vivo further substantiated the relevance of the identified epitopes. The viralepitopes represents specific targets and should be ideal for TCR-gene therapy approaches. We have isolated and sequenced MCPyV oncogenic protein specific T cell receptors and are currently testing in vitro transduction systems with the purpose of introducing the TCRs into human PBMC, injecting them into immune deficient NOG mice carrying HLA matched MCPyV positive tumor to investigate the tumor rejection capacity of these gene-modified T cells.

Published
2016

14. Peripheral Neuropathy in Spinocerebellar Ataxia Type 1, 2, 3, and 6

Author

Linnemann, C., Tezenas du Montcel, S., Rakowicz, M., Schmitz-Hubsch, T., Szymanski, S., Berciano, J., Warrenburg, B.P.C. van de, Pedersen, K., Depondt, C., Rola, R., Klockgether, T., Garcia, A., Mutlu, G., Schols, L., Linnemann, C., Tezenas du Montcel, S., Rakowicz, M., Schmitz-Hubsch, T., Szymanski, S., Berciano, J., Warrenburg, B.P.C. van de, Pedersen, K., Depondt, C., Rola, R., Klockgether, T., Garcia, A., Mutlu, G., and Schols, L.

Abstract

Item does not contain fulltext, Spinocerebellar ataxias (SCAs) are characterized by autosomal dominantly inherited progressive ataxia but are clinically heterogeneous due to variable involvement of non-cerebellar parts of the nervous system. Non-cerebellar symptoms contribute significantly to the burden of SCAs, may guide the clinician to the underlying genetic subtype, and might be useful markers to monitor disease. Peripheral neuropathy is frequently observed in SCA, but subtype-specific features and subclinical manifestations have rarely been evaluated. We performed a multicenter nerve conduction study with 162 patients with genetically confirmed SCA1, SCA2, SCA3, and SCA6. The study proved peripheral nerves to be involved in the neurodegenerative process in 82 % of SCA1, 63 % of SCA2, 55 % of SCA3, and 22 % of SCA6 patients. Most patients of all subtypes revealed affection of both sensory and motor fibers. Neuropathy was most frequently of mixed type with axonal and demyelinating characteristics in all SCA subtypes. However, nerve conduction velocities of SCA1 patients were slower compared to other genotypes. SCA6 patients revealed less axonal damage than patients with other subtypes. No influence of CAG repeat length or biometric determinants on peripheral neuropathy could be identified in SCA1, SCA3, and SCA6. In SCA2, earlier onset and more severe ataxia were associated with peripheral neuropathy. We proved peripheral neuropathy to be a frequent site of the neurodegenerative process in all common SCA subtypes. Since damage to peripheral nerves is readily assessable by electrophysiological means, nerve conduction studies should be performed in a longitudinal approach to assess these parameters as potential progression markers.

Published
2016

15. Using Merkel cell polyomavirus specific TCR gene therapy for treatment of Merkel cellcarcinoma

Author

Lyngaa, Rikke Birgitte, Pedersen, Natasja Wulff, Linnemann, C., Schrama, D., Ibrani, D., Met, Ö., Straten, P. Thor, Nghiem, Paul, Becker, J. C., Hadrup, Sine Reker, Lyngaa, Rikke Birgitte, Pedersen, Natasja Wulff, Linnemann, C., Schrama, D., Ibrani, D., Met, Ö., Straten, P. Thor, Nghiem, Paul, Becker, J. C., and Hadrup, Sine Reker

Abstract

T cell receptor gene-therapy has entered the clinic and shown potential for successful cancer treatment. However, the clinical evaluation has also highlighted the need for selection of truly cancerspecific targets. Merkel cell carcinoma (MCC) is a highly aggressive skin cancer associated with Merkel cell polyomavirus (MCPyV). Due to the clear viral correlation CD8+ T cells specific for viral epitopes could potentially form cancer-specific targets in MCC patients. We have identified MCPyV specific T cells using a high-throughput platform for T-cell enrichment and combinatorial encoding offluorescence-labeled major histocompatibility complex (MHC) class I multimers. We identified 35 T cell epitopes among 398 MCPyV derived peptides analyzed. Strikingly, T-cell responses against the two oncogenic MCPyV proteins Large T antigen and small T antigen were exclusively present in blood of MCC patients when compared to healthy donors. We demonstrate both the processing and presentation of oncoprotein-derived epitopes, as well as lytic activity of specific T cells towards MHC matched MCC cells. Demonstrating the presence of oncoprotein-specific T cells among tumorinfiltrating lymphocytes ex vivo further substantiated the relevance of the identified epitopes. The viralepitopes represents specific targets and should be ideal for TCR-gene therapy approaches. We have isolated and sequenced MCPyV oncogenic protein specific T cell receptors and are currently testing in vitro transduction systems with the purpose of introducing the TCRs into human PBMC, injecting them into immune deficient NOG mice carrying HLA matched MCPyV positive tumor to investigate the tumor rejection capacity of these gene-modified T cells.

Published
2016

16. Engineering T cell immunity by TCR gene transfer

Author

Linnemann, C., Schumacher, T.N.M., and Leiden University

Subjects
Gene capture, Genetic engineering, chemical and pharmacologic phenomena, Immunotherapy, T cell receptor, Graft-versus-host disease, MHC-multime
Abstract

T cell responses against tumor-antigens are frequently observed for some human malignancies, in particular melanoma. However, the spontaneous development of T cell responses of a sufficient strength to eradicate human malignancies is rare. The transfer of T cell receptor (TCR) __ genes into autologous T cells, a process called TCR gene transfer, allows one to engineer antigen-specific T cell responses of interest. Over the last decade, TCR gene transfer has progressed to the stage of clinical evaluation as a strategy to engineer T cell responses against tumor-antigens, in order to treat metastatic melanoma and other malignancies. The scope of the work in this thesis is to advance the development of TCR gene transfer as an engineering strategy for T cell immunity against cancer. This involves the assessment of the safety of TCR gene transfer, the evaluation of strategies to enhance the function of TCR-modified T cells in vivo, and the development of technologies to identify tumor-reactive TCR__ genes

Published
2013

17. The natural history of spinocerebellar ataxia type 1, 2, 3 and 6 : A 2-year follow-up study

Author

Jacobi, H., Bauer, Peter, Giunti, P., Labrum, R., Sweeney, M. G., Charles, P., Durr, A., Marelli, C., Globas, C., Linnemann, C., Schols, L., Rakowicz, M., Rola, R., Zdzienicka, E., Schmitz-Hubsch, T., Facellu, R., Mariotti, C., Tomasello, C., Baliko, L., Melegh, B., Filla, A., Rinaldi, C., van de Warrenburg, B. P., Verstappen, CCP, Szymanski, S., Berciano, J., Infante, J., Timmann-Braun, Dagmar, Boesch, S., Hering, S., Depondt, C., Pandolfo, M., Kang, J. S., Ratzka, S., Schulz, J., du Montcel, S. T., and Klockgether, T.

Subjects
Medizin, ComputingMethodologies_GENERAL
Abstract

Poster-Abstract

Published
2011

18. Innovative diagnostic tools for early detection of Alzheimer's disease

Author

Laske, C., Sohrabi, H.R., Frost, S.M., López-de-Ipiña, K., Garrard, P., Buscema, M., Dauwels, J., Soekadar, S.R., Mueller, S., Linnemann, C., Bridenbaugh, S.A., Kanagasingam, Y., Martins, R.N., O'Bryant, S.E., Laske, C., Sohrabi, H.R., Frost, S.M., López-de-Ipiña, K., Garrard, P., Buscema, M., Dauwels, J., Soekadar, S.R., Mueller, S., Linnemann, C., Bridenbaugh, S.A., Kanagasingam, Y., Martins, R.N., and O'Bryant, S.E.

Abstract

Current state‐of‐the‐art diagnostic measures of Alzheimer's disease (AD) are invasive (cerebrospinal fluid analysis), expensive (neuroimaging) and time‐consuming (neuropsychological assessment) and thus have limited accessibility as frontline screening and diagnostic tools for AD. Thus, there is an increasing need for additional noninvasive and/or cost‐effective tools, allowing identification of subjects in the preclinical or early clinical stages of AD who could be suitable for further cognitive evaluation and dementia diagnostics. Implementation of such tests may facilitate early and potentially more effective therapeutic and preventative strategies for AD. Before applying them in clinical practice, these tools should be examined in ongoing large clinical trials. This review will summarize and highlight the most promising screening tools including neuropsychometric, clinical, blood, and neurophysiological tests

Published
2014

19. Genotype-specific patterns of atrophy progression are more sensitive than clinical decline in SCA1, SCA3 and SCA6

Author

Reetz, K., Costa, A.S., Mirzazade, S., Lehmann, A., Juzek, A., Rakowicz, M., Boguslawska, R., Schols, L., Linnemann, C., Mariotti, C., Grisoli, M., Durr, A., Warrenburg, B.P.C. van de, Timmann, D., Pandolfo, M., Bauer, P., Jacobi, H., Hauser, T.K., Klockgether, T., Schulz, J.B., et al., Reetz, K., Costa, A.S., Mirzazade, S., Lehmann, A., Juzek, A., Rakowicz, M., Boguslawska, R., Schols, L., Linnemann, C., Mariotti, C., Grisoli, M., Durr, A., Warrenburg, B.P.C. van de, Timmann, D., Pandolfo, M., Bauer, P., Jacobi, H., Hauser, T.K., Klockgether, T., Schulz, J.B., and et al.

Abstract

Item does not contain fulltext, Spinocerebellar ataxias are dominantly inherited disorders that are associated with progressive brain degeneration, mainly affecting the cerebellum and brainstem. As part of the multicentre European integrated project on spinocerebellar ataxias study, 37 patients with spinocerebellar ataxia-1, 19 with spinocerebellar ataxia-3 and seven with spinocerebellar ataxia-6 were clinically examined and underwent magnetic resonance imaging at baseline and after a 2-year follow-up. All patients were compared with age-matched and gender-matched healthy control subjects. Magnetic resonance imaging analysis included three-dimensional volumetry and observer-independent longitudinal voxel-based morphometry. Volumetry revealed loss of brainstem, cerebellar and basal ganglia volume in all genotypes. Most sensitive to change was the pontine volume in spinocerebellar ataxia-1, striatal volume in spinocerebellar ataxia-3 and caudate volume in spinocerebellar ataxia-6. Sensitivity to change, as measured by standard response mean, of the respective MRI measures was greater than that of the most sensitive clinical measure, the Scale for the Assessment and Rating of Ataxia. Longitudinal voxel-based morphometry revealed greatest grey matter loss in the cerebellum and brainstem in spinocerebellar ataxia-1, in the putamen and pallidum in spinocerebellar ataxia-3 and in the cerebellum, thalamus, putamen and pallidum in spinocerebellar ataxia-6. There was a mild correlation between CAG repeat length and volume loss of the bilateral cerebellum and the pons in spinocerebellar ataxia-1. Quantitative volumetry and voxel-based morphometry imaging demonstrated genotype-specific patterns of atrophy progression in spinocerebellar ataxias-1, 3 and 6, and they showed a high sensitivity to detect change that was superior to clinical scales. These structural magnetic resonance imaging findings have the potential to serve as surrogate markers, which might help to delineate quantifiable endpoints and non-inva

Published
2013

21. Depression comorbidity in spinocerebellar ataxia

Author

Schmitz-Hubsch, T., Coudert, M., Tezenas du Montcel, S., Giunti, P., Labrum, R., Durr, A., Ribai, P., Charles, P., Linnemann, C., Schols, L., Rakowicz, M., Rola, R., Zdzienicka, E., Fancellu, R., Mariotti, C., Baliko, L., Melegh, B., Filla, A., Salvatore, E., Warrenburg, B.P.C. van de, Szymanski, S., Infante, J., Timmann, D., Boesch, S., Depondt, C., Kang, J.S., Schulz, J.B., Klopstock, T., Lossnitzer, N., Lowe, B., Frick, C., Rottlander, D., Schlaepfer, T.E., Klockgether, T., Schmitz-Hubsch, T., Coudert, M., Tezenas du Montcel, S., Giunti, P., Labrum, R., Durr, A., Ribai, P., Charles, P., Linnemann, C., Schols, L., Rakowicz, M., Rola, R., Zdzienicka, E., Fancellu, R., Mariotti, C., Baliko, L., Melegh, B., Filla, A., Salvatore, E., Warrenburg, B.P.C. van de, Szymanski, S., Infante, J., Timmann, D., Boesch, S., Depondt, C., Kang, J.S., Schulz, J.B., Klopstock, T., Lossnitzer, N., Lowe, B., Frick, C., Rottlander, D., Schlaepfer, T.E., and Klockgether, T.

Abstract

Item does not contain fulltext, This is a description of the prevalence and profile of depressive symptoms in dominant spinocerebellar ataxia (SCA). Depressive symptoms were assessed in a convenience sample of 526 genetically confirmed and clinically affected patients (117 SCA1, 163 SCA2, 139 SCA3, and 107 SCA6) using the Patient Health Questionnaire (PHQ). In addition, depressive status according to the examiner and the use of antidepressants was recorded. Depression self-assessment was compared with an interview-based psychiatric assessment in a subset of 26 patients. Depression prevalence estimates were 17.1% according to the PHQ algorithm and 15.4% when assessed clinically. The sensitivity of clinical impression compared with PHQ classification was low (0.35), whereas diagnostic accuracy of PHQ compared with psychiatric interview in the subset was high. Antidepressants were used by 17.7% of patients and in >10% of patients without current clinically relevant depressive symptoms. Depression profile in SCA did not differ from a sample of patients with major depressive disorder except for the movement-related item. Neither depression prevalence nor use of antidepressants differed between genetic subtypes, with only sleep disturbance more common in SCA3. In a multivariate analysis, ataxia severity and female sex independently predicted depressive status in SCA. The PHQ algorithmic classification is appropriate for use in SCA but should stimulate further psychiatric evaluation if depression is indicated. Despite a higher risk for depression with more severe disease, the relation of depressive symptoms to SCA neurodegeneration remains to be shown.

Published
2011

22. Depression comorbidity in spinocerebellar ataxia.

Author

Schmitz-Hübsch, T, Coudert, Mathieu, Tezenas du Montcel, Sophie, Giunti, P, Labrum, R, Dürr, Alexandra, Ribaï, Pascale, Charles, P, Linnemann, C, Schöls, Lüdger, Rakowicz, M, Rola, R, Zdzienicka, E, Fancellu, Roberto, Mariotti, Christian, Balikó, Lazlo, Melegh, Bela, Filla, A, Salvatore, E., van de Warrenburg, B P, Szymanski, S, Infante, J, Timmann, D, Boesch, S, Depondt, Chantal, Kang, J-S, Schulz, Jörg Bernhard, Klopstock, Thomas, Lossnitzer, Nicole, Löwe, Bernd, Frick, Caroline, Rottländer, Daniela, Schlaepfer, Thomas E, Klockgether, T, Schmitz-Hübsch, T, Coudert, Mathieu, Tezenas du Montcel, Sophie, Giunti, P, Labrum, R, Dürr, Alexandra, Ribaï, Pascale, Charles, P, Linnemann, C, Schöls, Lüdger, Rakowicz, M, Rola, R, Zdzienicka, E, Fancellu, Roberto, Mariotti, Christian, Balikó, Lazlo, Melegh, Bela, Filla, A, Salvatore, E., van de Warrenburg, B P, Szymanski, S, Infante, J, Timmann, D, Boesch, S, Depondt, Chantal, Kang, J-S, Schulz, Jörg Bernhard, Klopstock, Thomas, Lossnitzer, Nicole, Löwe, Bernd, Frick, Caroline, Rottländer, Daniela, Schlaepfer, Thomas E, and Klockgether, T

Abstract

This is a description of the prevalence and profile of depressive symptoms in dominant spinocerebellar ataxia (SCA). Depressive symptoms were assessed in a convenience sample of 526 genetically confirmed and clinically affected patients (117 SCA1, 163 SCA2, 139 SCA3, and 107 SCA6) using the Patient Health Questionnaire (PHQ). In addition, depressive status according to the examiner and the use of antidepressants was recorded. Depression self-assessment was compared with an interview-based psychiatric assessment in a subset of 26 patients. Depression prevalence estimates were 17.1% according to the PHQ algorithm and 15.4% when assessed clinically. The sensitivity of clinical impression compared with PHQ classification was low (0.35), whereas diagnostic accuracy of PHQ compared with psychiatric interview in the subset was high. Antidepressants were used by 17.7% of patients and in >10% of patients without current clinically relevant depressive symptoms. Depression profile in SCA did not differ from a sample of patients with major depressive disorder except for the movement-related item. Neither depression prevalence nor use of antidepressants differed between genetic subtypes, with only sleep disturbance more common in SCA3. In a multivariate analysis, ataxia severity and female sex independently predicted depressive status in SCA. The PHQ algorithmic classification is appropriate for use in SCA but should stimulate further psychiatric evaluation if depression is indicated. Despite a higher risk for depression with more severe disease, the relation of depressive symptoms to SCA neurodegeneration remains to be shown., Journal Article, Research Support, Non-U.S. Gov't, FLWIN, SCOPUS: ar.j, info:eu-repo/semantics/published

Published
2011

23. The natural history of spinocerebellar ataxia type 1, 2, 3, and 6: a 2-year follow-up study.

Author

Jacobi, Heike, Bauer, Peter, Giunti, P, Labrum, R, Sweeney, M G, Charles, P, Dürr, A, Marelli, C, Globas, C, Linnemann, C, Schöls, Lüdger, Rakowicz, M, Rola, R, Zdzienicka, E, Schmitz-Hübsch, T, Fancellu, Roberto, Mariotti, Christian, Tomasello, C, Baliko, L, Melegh, Bela, Filla, A, Rinaldi, Carlo, van de Warrenburg, B P, Verstappen, Carla C, Szymanski, S, Berciano, J, Infante, J, Timmann, D, Boesch, S, Hering, S, Depondt, Chantal, Pandolfo, Massimo, Kang, J-S, Ratzka, Susanne, Schulz, Jörg Bernhard, Tezenas du Montcel, Sophie, Klockgether, T, Jacobi, Heike, Bauer, Peter, Giunti, P, Labrum, R, Sweeney, M G, Charles, P, Dürr, A, Marelli, C, Globas, C, Linnemann, C, Schöls, Lüdger, Rakowicz, M, Rola, R, Zdzienicka, E, Schmitz-Hübsch, T, Fancellu, Roberto, Mariotti, Christian, Tomasello, C, Baliko, L, Melegh, Bela, Filla, A, Rinaldi, Carlo, van de Warrenburg, B P, Verstappen, Carla C, Szymanski, S, Berciano, J, Infante, J, Timmann, D, Boesch, S, Hering, S, Depondt, Chantal, Pandolfo, Massimo, Kang, J-S, Ratzka, Susanne, Schulz, Jörg Bernhard, Tezenas du Montcel, Sophie, and Klockgether, T

Abstract

To obtain quantitative data on the progression of the most common spinocerebellar ataxias (SCAs) and identify factors that influence their progression, we initiated the EUROSCA natural history study, a multicentric longitudinal cohort study of 526 patients with SCA1, SCA2, SCA3, or SCA6. We report the results of the 1- and 2-year follow-up visits., Comparative Study, Journal Article, Multicenter Study, Research Support, Non-U.S. Gov't, info:eu-repo/semantics/published

Published
2011

24. Responsiveness of different rating instruments in spinocerebellar ataxia patients.

Author

Schmitz-Hubsch, T., Fimmers, R., Rakowicz, M., Rola, R., Zdzienicka, E., Fancellu, R., Mariotti, C., Linnemann, C., Schols, L., Timmann, D., Filla, A., Salvatore, E., Infante, J., Giunti, P., Labrum, R., Kremer, B., Warrenburg, B.P.C. van de, Baliko, L., Melegh, B., Depondt, C., Schulz, J., Montcel, S.T. du, Klockgether, T., Schmitz-Hubsch, T., Fimmers, R., Rakowicz, M., Rola, R., Zdzienicka, E., Fancellu, R., Mariotti, C., Linnemann, C., Schols, L., Timmann, D., Filla, A., Salvatore, E., Infante, J., Giunti, P., Labrum, R., Kremer, B., Warrenburg, B.P.C. van de, Baliko, L., Melegh, B., Depondt, C., Schulz, J., Montcel, S.T. du, and Klockgether, T.

Abstract

Contains fulltext : 89370.pdf (publisher's version ) (Closed access), OBJECTIVE: To determine the longitudinal metric properties of recently developed clinical assessment tools in spinocerebellar ataxia (SCA). METHODS: A subset of 171 patients from the EUROSCA natural history study cohort (43 SCA1, 61 SCA2, 37 SCA3, and 30 SCA6) were examined after 1 year of follow-up. Score changes and effect size indices were calculated for clinical scales (Scale for the Assessment and Rating of Ataxia [SARA], Inventory of Non-Ataxia Symptoms [INAS]), functional tests (SCA Functional Index [SCAFI] and components), and a patient-based scale for subjective health status (EQ-5D visual analogue scale [EQVAS]). Responsiveness was determined in relation to the patient's global impression (PGI) of change and reproducibility described as retest reliability for the stable groups and smallest detectable change. RESULTS: Within the 1-year follow-up period, SARA, INAS, and SCAFI but not EQVAS indicated worsening in the whole group and in the groups with subjective (PGI) worsening. SCAFI and its 9-hole pegboard (9HPT) component also deteriorated in the stable groups. Standardized response means were highest for 9HPT (-0.67), SARA (0.50), and SCAFI (-0.48) with accordingly lower sample size estimates of 143, 250, or 275 per group for a 2-arm interventional trial that aims to reduce disease progression by 50%. SARA and EQVAS performed best to distinguish groups classified as worse by PGI. All scales except EQVAS reached the criterion for retest reliability. CONCLUSION: While both the Scale for the Assessment and Rating of Ataxia and the SCA Functional Index (SCAFI) (and its 9-hole pegboard component) had favorable measurement precision, the clinical relevance of SCAFI and 9-hole pegboard score changes warrants further exploration. The EQ-5D visual analogue scale proved insufficient for longitudinal assessment, but validly reflected patients' impression of change.

Published
2010

25. Responsiveness of different rating instruments in spinocerebellar ataxia patients.

Author

Schmitz-Hübsch, T, Fimmers, R, Rakowicz, M, Rola, R, Zdzienicka, E, Fancellu, Roberto, Mariotti, Christian, Linnemann, C, Schöls, Lüdger, Timmann, D, Filla, A, Salvatore, E., Infante, J, Giunti, P, Labrum, R, Kremer, B, van de Warrenburg, B P, Balikó, Lazlo, Melegh, Bela, Depondt, Chantal, Schulz, Jörg Bernhard, du Montcel, S Tezenas, Klockgether, T, Schmitz-Hübsch, T, Fimmers, R, Rakowicz, M, Rola, R, Zdzienicka, E, Fancellu, Roberto, Mariotti, Christian, Linnemann, C, Schöls, Lüdger, Timmann, D, Filla, A, Salvatore, E., Infante, J, Giunti, P, Labrum, R, Kremer, B, van de Warrenburg, B P, Balikó, Lazlo, Melegh, Bela, Depondt, Chantal, Schulz, Jörg Bernhard, du Montcel, S Tezenas, and Klockgether, T

Abstract

To determine the longitudinal metric properties of recently developed clinical assessment tools in spinocerebellar ataxia (SCA)., Journal Article, Research Support, Non-U.S. Gov't, info:eu-repo/semantics/published

Published
2010

28. Inventory of Non-Ataxia Signs (INAS): Validation of a New Clinical Assessment Instrument

Author

Jacobi, H., primary, Rakowicz, M., additional, Rola, R., additional, Fancellu, R., additional, Mariotti, C., additional, Charles, P., additional, Dürr, A., additional, Küper, M., additional, Timmann, D., additional, Linnemann, C., additional, Schöls, L., additional, Kaut, O., additional, Schaub, C., additional, Filla, A., additional, Baliko, L., additional, Melegh, B., additional, Kang, J.-S., additional, Giunti, P., additional, van de Warrenburg, B. P. C., additional, Fimmers, R., additional, and Klockgether, T., additional

Published
2012
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30. The natural history of spinocerebellar ataxia type 1, 2, 3, and 6: A 2-year follow-up study

Author

Jacobi, H., primary, Bauer, P., additional, Giunti, P., additional, Labrum, R., additional, Sweeney, M. G., additional, Charles, P., additional, Durr, A., additional, Marelli, C., additional, Globas, C., additional, Linnemann, C., additional, Schols, L., additional, Rakowicz, M., additional, Rola, R., additional, Zdzienicka, E., additional, Schmitz-Hubsch, T., additional, Fancellu, R., additional, Mariotti, C., additional, Tomasello, C., additional, Baliko, L., additional, Melegh, B., additional, Filla, A., additional, Rinaldi, C., additional, van de Warrenburg, B. P., additional, Verstappen, C. C. P., additional, Szymanski, S., additional, Berciano, J., additional, Infante, J., additional, Timmann, D., additional, Boesch, S., additional, Hering, S., additional, Depondt, C., additional, Pandolfo, M., additional, Kang, J.- S., additional, Ratzka, S., additional, Schulz, J., additional, Tezenas du Montcel, S., additional, and Klockgether, T., additional

Published
2011
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33. Responsiveness of different rating instruments in spinocerebellar ataxia patients

Author

Schmitz-Hubsch, T., primary, Fimmers, R., additional, Rakowicz, M., additional, Rola, R., additional, Zdzienicka, E., additional, Fancellu, R., additional, Mariotti, C., additional, Linnemann, C., additional, Schols, L., additional, Timmann, D., additional, Filla, A., additional, Salvatore, E., additional, Infante, J., additional, Giunti, P., additional, Labrum, R., additional, Kremer, B., additional, van de Warrenburg, B.P.C., additional, Baliko, L., additional, Melegh, B., additional, Depondt, C., additional, Schulz, J., additional, du Montcel, S. T., additional, and Klockgether, T., additional

Published
2010
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39. Rubella antibody levels in juvenile rheumatoid arthritis.

Author

Linnemann, C C, Levinson, J E, Buncher, C R, Schiff, G M, and Linnemann, C C Jr

Subjects
AUTOANTIBODY analysis, IMMUNOGLOBULIN analysis, HEMAGGLUTINATION tests, PARAMYXOVIRUSES, JUVENILE idiopathic arthritis, RNA viruses, RUBELLA vaccines, VIRAL antibodies
Abstract

Increased rubella antibody titres have been reported in patients with juvenile rheumatoid arthritis (JRA) and it has been suggested that rubella virus may be of importance in the aetiology or pathogenesis of the disease. In the present study, rubella and rubeola antibody titres in 85 patients with JRA were compared to age- and sex-matched controls. 41% of the patients did not have rubella antibody, but the geometric mean titre of those with JRA who had antibody was slightly higher than that of the controls with antibody (58-9 against 42-7; P less than 0-05). The level of rubella antibody titre correlated with serum IgG levels. There was no difference in rubeola antibody titres between patients and controls, and rubeola antibody did not correlate with serum IgG. Fifteen JRA patients developed rubella antibody after rubella vaccine or natural disease. This did not result in unusually high antibody titres and was associated with a mild exacerbation of symptoms in only two patients. This study suggests that the slight increase in rubella antibody in JRA is a nonspecific manifestation of increased immunoglobulins. [ABSTRACT FROM PUBLISHER]

Published
1975
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45. Transient change in GABAA receptor subunit mRNA expression in Lurcher cerebellar nuclei during Purkinje cell degeneration.

Author

Linnemann, C., Schmeh, I., Thier, P., and Schwarz, C.

Subjects
*MICE, *RODENTS, *PURKINJE cells, *CELL death, *NERVE endings
Abstract

Background: Lurcher mice suffer from a complete Purkinje cell (PC) loss in the first four postnatal weeks. Parallel to this degeneration, GABAergic synapses in the deep cerebellar nuclei (DCN), the major recipient of the inhibitory PC projection, increase synaptic conductance. Here, we further investigated this phenomenon, using real-time RT-PCR to assess GABAA receptor subunit gene expression during PC degeneration. Results: We observed a specific reduction in γ2 subunit gene expression, while α1-5, β1-2, γ1,3 and δ subunits were unaffected. We made two further specific findings. First, the difference in gene expression was shown in tissue from DCN only. Neither the hippocampus nor coronal sections through the forebrain showed such effects. Furthermore, the involvement of different levels of corticosterone, a possible humeral trigger for differences in gene expression, could be excluded. Second, like the known potentiation of GABAergic synapses, the γ2 down-regulation was present only after the onset of degeneration at p14. The difference in γ2 mRNA expression, however, appeared transient, since it was no longer detectable in adult Lurcher mice. Conclusion: In conclusion, the down-regulation of γ2 subunits may be related to differences in synaptic efficacy and, as such, may reflect the initial phase of adaptive responses of DCN tissue to massive GABAergic deafferentation. Its transient course, however, does not support the idea that modulations in GABAergic transmission are at the basis of the well-known DCN-based functional benefit of Lurcher mice present throughout their life. [ABSTRACT FROM AUTHOR]

Published
2006
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46. A thermodynamic analysis of a novel high efficiency reciprocating internal combustion engine—the isoengine

Author

Coney, M.W., Linnemann, C., and Abdallah, H.S.

Subjects
*COMBUSTION, *SMOKE, *ELECTRIC power production, *NATURAL gas
Abstract

A novel concept for a high efficiency reciprocating internal combustion engine (the isoengine) is described and its cycle is analysed. The highly turbocharged engine configuration, which is intended primarily for on-site and distributed power generation, has a predicted electrical output of 7.3 MW. It has the option for co-generation of up to 3.2 MW of hot water at 95 °C supply temperature. The maximum net electrical plant efficiency is predicted to be about 60% on diesel fuel and 58% on natural gas. The key to the high electrical efficiency is the quasi-isothermal compression of the combustion air in cylinders, which are separate from the power cylinders. This achieves a significant saving in compression work and allows the recovery of waste heat back into the cycle, mainly from the exhaust gas by means of a recuperator. The construction of a first 3 MWe prototype isoengine has been completed and its testing has begun. Relevant test results are expected in the near future. [Copyright &y& Elsevier]

Published
2004
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47. Lurcher mice exhibit potentiation of GABA(A)-receptor-mediated conductance in cerebellar nuclei neurons in close temporal relationship to Purkinje cell death.

Author

Linnemann C, Sultan F, Pedroarena C M, Schwarz C, and Thier P

Subjects
*CEREBELLAR nuclei, *NEURONS, *CELL death, *PURKINJE cells
Abstract

In heterozygous Lurcher mice (Lc/+), the Purkinje cells (PCs) degenerate almost totally during postnatal development. On the other hand, their projection target, the deep cerebellar nuclei (DCN), shows few signs of degeneration and seems to play an important role in maintaining a residual cerebellar function in Lc/+. We asked whether the DCN in Lc/+ develop cellular adaptations allowing them to cope with the loss of GABAergic PC input. Using whole-cell patch-clamp recordings, we measured inhibitory postsynaptic currents from DCN of Lc/+ and wild-type mice (WT). In experiments on phenotypically striking Lc/+ studied well after the onset of the PC degeneration, we found enlarged average synaptic conductances (g(syn)) compared with WT. We next investigated postnatal mice before and after the onset of PC death. In younger animals

Published
2004
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50. Effect of viral and bacterial pneumonias on cell-mediated immunity in humans

Author

Kauffman, C A, Linnemann, C C, Schiff, G M, and Phair, J P

Abstract

Cell-mediated immunity (CMI) was assessed during infection and after convalescence in 12 patients with influenza pneumonia and 10 patients with bacterial pneumonia. The patients with influenza pneumonia had a marked impairment of skin test reactivity, and their lymphocytes showed a diminished response to phytohemagglutinin and streptokinase-streptodornase stimulation in vitro. Suppression of CMI was related to the severity of the pneumonia. Patients with bacterial pneumonia showed as great a suppression of the response to phytohemagglutinin and streptokinase-streptodornase as the patients with viral pneumonia. All parameters of CMI returned to normal in both groups after convalescence. The depression of CMI could not be related to a decrease in the number of thymus-derived lymphocytes or to serum-suppressive factors in these patients.

Published
1976
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