Laminar Analysis of Inhibition in the Gerbil Primary Auditory Cortex

Physiological and immunocytochemical evidence indicates a layer-dependent organization of inhibitory circuits in the neocortex. To investigate the contribution of GABAergic inhibition to frequency tuning in the different cortical layers, we recorded single and multiple units in near-radial penetrations before and during iontophoretic application of the GABA(A)-receptor antagonist bicuculline in the auditory cortex of the lightly anesthetized gerbil. Bicuculline generally increased the spontaneous rate and enhanced and prolonged onset activity. Application of bicuculline often resulted in a shift of best frequency and a decrease of threshold (5.5 dB). A broadening of the frequency tuning evident by lower Q40dB values was observed in 63% of the units. In units with multipeaked tuning curves or clearly separated response areas, bicuculline application removed the inhibitory regions and created single-peaked tuning curves. The influence of bicuculline on the receptive field size was not significantly layer-specific but tended to be most pronounced in layers V and VI. In layer VI, we frequently found "silent" neurons that responded to sound only when GABAergic inhibition was antagonized. From the analysis of postembedding GABA immunocytochemistry, the proportion of GABAergic neurons was found to be maximal in layers I and V, and the number of GABAergic perisomatic puncta (axon terminals) on cell somata peaked in layer V.     

Sporadic late onset paroxysmal cerebellar ataxia in four unrelated patients: a new disease?

We describe a peculiar form of late onset paroxysmal cerebellar ataxia including clinical features similar to episodic ataxia type 2 (EA2) but unresponsive to acetazolamide. Four unrelated patients were clinically investigated. Neuropathological examiniation was performed in one patient and molecular anlaysis in all four. All 47 exons of CACNA1A were screened by a combination of single-strand conformer polymorphism and sequencing analysis in three patients. In addition, the length of the CAG repeat was determined in all four patients. The four patients were in their 60s at the onset of the disease, which was characterized by cerebellar ataxia attacks lasting from a few minutes to 1–2 h and occurring mainly in the morning. In the interictal period a nystagmus was present together with a slowly progressive cerebellar ataxia over the years. The neuropathological examination disclosed a dramatic loss of Purkinje cells mainly in the vermis. Moreover, certain cerebellar granular neurons had a strong cytoplasmic, staining at immunopathological examination with an anti-tau protein serum. Search for truncating mutations or CAG repeat expansion in CACNA1A was negative. This lateonset paroxysmal cerebellar ataxia with neutropathological lesions restricted to Purkinje cells and with negative results both for truncating mutations and CAG expansion in the CACNA1A gene represents a new entity. Further studies are needed to delineate the underlying process. Received: 26 January 2000, Received in revised form: 19 September 2000, Accepted: 30 September 2000     

There is no disease-specific role for streptococci-responsive synovial T lymphocytes in the pathogenesis of psoriatic arthritis

The initiation or exacerbation of psoriasis vulgaris is associated with infections by group A streptococci. T lymphocytes specific for streptococcal antigens or expressing a restricted, for streptococcal superantigens typical T cell receptor Vbeta chain repertoire have been described in psoriatic skin lesions. The aim of our study was, therefore, to clarify whether streptococci-reactive T lymphocytes played a role in the pathogenesis of psoriatic arthritis (PsA), and by which antigens they might be stimulated. Synovial membrane mononuclear cells from patients with PsA and other arthropathies, separated by collagenase digestion, were expanded in interleukin-2-supplemented medium and subsequently cloned in a representative cloning procedure. The T cell lines and about 30% of the T cell clones proliferated in response to preparations of group A streptococci but not to other bacteria as tested by [3H]thymidine incorporation assays. Interestingly, they did not proliferate in response to exotoxin-negative streptococci, but did so in response to the streptococcal pyrogenic exotoxins A and C, which are known to be superantigens. Accordingly, no HLA-DR restriction was seen for the proliferative response. The remaining 70% of the established T cell clones did not react to an antigen of group A streptococci. Our results show that in patients with PsA, osteoarthritis or rheumatoid arthritis a significant number of synovial T lymphocytes were responsive to streptococcal superantigens, but not to conventional streptococcal antigens. A disease-specific role of streptococci-reactive T lymphocytes in the pathogenesis of PsA is, therefore, unlikely.     

α-Synuclein accumulation in a case of neurodegeneration with brain iron accumulation type 1 (NBIA-1, formerly Hallervorden-Spatz syndrome) with widespread cortical and brainstem-type Lewy bodies

We studied a 27-year-old woman who died after a 6-year history of progressive dementia, dystonia, ataxia, apraxia, spasticity, choreoathetosis, visual and auditory hallucinations, and optic atrophy. Magnetic resonance imaging showed decreased intensity in the globus pallidus, substantia nigra, and dentate nuclei in T2-weighted images, supporting the clinical diagnosis of neurodegeneration with brain iron accumulation type 1 (NBIA-1; formerly known as Hallervorden-Spatz syndrome). At autopsy the brain showed mild frontotemporal atrophy and discoloration of the globus pallidus and the substantia nigra pars reticularis. Histologically, features typical of NBIA-1 were found including widespread axonal spheroids and large deposits of iron pigment in the discolored regions. Additionally, excessive numbers of Lewy bodies (LBs) were found throughout all examined brain stem and cortical regions. LBs of both types, as well as Lewy neurites in this case of NBIA-1, were strongly labeled by antibodies against α-synuclein. These findings give further evidence that accumulation of α-synuclein is generally associated with LB formation, i.e., in Parkinson’s disease, dementia with Lewy bodies and NBIA-1. The case presented here is particularly notable for its high number of LBs in all areas of the cerebral cortex. Received: 26 November 1999 / Revised: 11 February 2000 / Accepted: 14 February 2000     

T-cell studies in the spondyloarthropathies

A growing body of evidence suggests that T lymphocytes play an important role in initiating and maintaining the inflammatory process characteristic of the human leukocyte antigen (HLA)-B27-associated spondyloarthropathies. T cells seem to be involved in the primary defense reaction against arthritis-triggering gram-negative bacteria at the site of extra-articular infection, in determining the systemic cytokine pattern, in the recirculation process between gut mucosa and the joint, and in mediating secondary autoimmune joint inflammation. The factors involved in disease chronicity (namely in ankylosing spondylitis and psoriatic arthritis) are still unknown. Autoreactive T cells may contribute to this process by recognition of cross-reactive self-epitopes (ie, molecular mimicry between bacterial and self-antigens). Autoreactive T cells may as well be inappropriately upregulated by bacterial superantigens, or by local inflammatory reactions leading to the uncovering of former cryptic self-epitopes. In this paper, we review recent studies on peripheral blood and synovial T cells in patients with reactive arthritis, enteropathic spondyloarthropathy, psoriatic arthritis, and ankylosing spondylitis.     

Favorable therapeutic index of a p210BCR-ABL-specific tyrosine kinase inhibitor; activity on lineage-committed and primitive chronic myelogenous leukemia progenitors

Purpose: In order to assess the effect of the tyrosine kinase inhibitor CGP57148B on lineage-committed and primitive chronic myelogenous leukemia (CML) progenitor cells, peripheral blood progenitor cells (PBPC) mobilized in chronic phase CML were exposed to this compound in vitro. Methods: Both short-term (≤1 week) and long-term exposure (≥2 weeks) to CGP57148B were investigated using suspension culture, semisolid (methylcellulose) assay or stroma-dependent long-term culture (LTC). The proportion of bcr/abl-positive progenitors was determined after direct plating [2 weeks in colony-forming cell (CFC) assay] as well as after 2 or 6 weeks LTC (LTC always followed by CFC replates). Results: Incubation of CML PBPC over 48 h in suspension culture with 100 μM CGP57148B reduced the proportion of bcr/abl-positive colonies to 4.4 ± 4.3% (n = 5) after direct plating, 6.6 ± 4.2% (n = 5) after 2 weeks LTC and 5 ± 5.6% (n = 2) after 6 weeks LTC. At this dose, survival of drug-exposed normal PBPC was 53 ± 4.2%, 51 ± 2.8% and 54.5 ± 4.9% (n = 2), respectively. Incubation with CGP57148B at a concentration of 10 μM over 1 week under LTC conditions reduced the number of bcr/abl-positive colonies to 11.8 ± 6.1% (n = 5) after direct plating, 12 ± 6.4% (n = 4) after 2 weeks LTC and 14.3 ± 11.4% (n = 3) after 6 weeks LTC; survival of normal PBPC was 84.5 ± 2.1%, 93 ± 4.2% and 86 ± 1.4% (n = 2), respectively. Following long-term exposure to CGP57148B at a concentration of 1 μM, the proportion of remaining bcr/abl-positive colonies was 35%, 9% and 25% of untreated CML samples after direct plating as well as after 2 and 6 weeks LTC, respectively. The respective values for 10 μM CGP57148B were 10%, 11% and 19%. Long-term exposure of normal progenitors to CGP57148B yielded a survival of 98%, 100% and 93% (1 μM) or 77%, 86% and 80% (10 μM), respectively. Conclusion: The results support the use of CGP57148B either for short-term exposure in vitro (e.g. purging) or for continuous treatment of CML in vivo. Received: 18 January 1999 / Accepted: 3 May 1999     

Prognostic Value of Proliferation Index and Expression of the RNA Component of Human Telomerase (hTR) in Papillary Meningiomas

Papillary meningioma is a rare subtype of meningioma that often behaves aggressively. In order to characterize factors that may influence this behavior, we chose to compare MIB-1 labeling index (LI) and telomerase RNA localization (hTR) in papillary meningiomas, meningiomas, and atypical meningiomas. LI is now often used to supplement histologic grade in the evaluation of these lesions. More recent studies indicate that increased expression of hTR is detected in many neoplastic cells, and may play an essential role in cell immortalization. The study group consisted of five papillary meningiomas (and a recurrence in one case), 11 conventional meningiomas, and eight atypical meningiomas. Conventional meningiomas showed either negative or 1+ hTR. Atypical meningiomas showed 1+ hTR. Papillary meningiomas showed the highest hTR (five of six, including recurrence, 2–3+ and one 1+). Generally, the LI was very low for conventional meningiomas (<2%). The LI of atypical meningiomas ranged from 3–19%, mean 12%, and from 5.5–17.5%, mean 11.75% for papillary meningiomas. LI differentiated between meningiomas, and papillary or atypical meningiomas. hTR further delineated papillary (moderate to high) from atypical meningiomas (low). The combined variable of LI and hTR expression could be a useful independent prognostic indicator in patients with papillary meningioma.