High resolution deletion analysis of constitutional DNA from neurofibromatosis type 2 (NF2) patients using microarray-CGH.

Neurofibromatosis type 2 (NF2) is an autosomal dominant disorder whose hallmark is bilateral vestibular schwannoma. It displays a pronounced clinical heterogeneity with mild to severe forms. The NF2 tumor suppressor (merlin/schwannomin) has been cloned and extensively analyzed for mutations in patients with different clinical variants of the disease. Correlation between the type of the NF2 gene mutation and the patient phenotype has been suggested to exist. However, several independent studies have shown that a fraction of NF2 patients with various phenotypes have constitutional deletions that partly or entirely remove one copy of the NF2 gene. The purpose of this study was to examine a 7 Mb interval in the vicinity of the NF2 gene in a large series of NF2 patients in order to determine the frequency and extent of deletions. A total of 116 NF2 patients were analyzed using high-resolution array-comparative genomic hybridization (CGH) on an array covering at least 90% of this region of 22q around the NF2 locus. Deletions, which remove one copy of the entire gene or are predicted to truncate the schwannomin protein, were detected in 8 severe, 10 moderate and 6 mild patients. This result does not support the correlation between the type of mutation affecting the NF2 gene and the disease phenotype. This work also demonstrates the general usefulness of the array-CGH methodology for rapid and comprehensive detection of small (down to 40 kb) heterozygous and/or homozygous deletions occurring in constitutional or tumor-derived DNA.

Regional cerebral blood flow during tinnitus: a PET case study with lidocaine and auditory stimulation.

Brain imaging of tinnitus has suggested central correlates of tinnitus perception. This study presents positron emission tomographic (PET) measurements of regional cerebral blood flow (rCBF) in a female tinnitus patient with bilateral left dominant tinnitus. Lidocaine infusion (75 mg during 5 min (0.2 mg/kg/min)) resulted in a 75% reduction of tinnitus and a temporary abolition of the dominant tinnitus in her left ear. Regional CBF was measured in four conditions: i) at rest while concentrating on tinnitus, ii) following maximum effect of lidocaine, iii) during sound stimulation, and iv) the following day at rest while concentrating on tinnitus. Subtraction analyses showed that tinnitus was associated with increased rCBF in the left parieto-temporal auditory cortex, including the primary and secondary auditory cortex with a focus in the parietal cortex (Brodmann areas 39, 41, 42, 21, 22). Activations were also found in right frontal paralimbic areas (Brodmann areas 47, 49 and 15). Sound stimulation resulted in bilateral activation of auditory areas. It is suggested that tinnitus is processed in primary, secondary and integrative auditory cortical areas. Tinnitus perception may involve areas related to auditory attention, while emotional processing relates to temporofrontal paralimbic areas.

Immunocompetent cells in human nasal polyps and normal mucosa.

The distribution of T- and B-lymphocytes, HLA-DR-expressing cells, and macrophages was determined using monoclonal antibodies in frozen biopsy sections of nasal polyps from 12 patients, and of nasal mucosa from five disease-free controls. The relative proportion and spatial distribution of different lymphoid cells was similar with regards to both nasal polyps and normal mucosa. Numerous scattered T lymphocytes (Leu4-positive) and HLA-DR-expressing macrophage/dendritic-like cells were shown and tended to accumulate in the subepithelial areas. Aggregates of T lymphocytes and HLA-DR-positive cells were also found close to deeper glands. In the submucosal clusters, the Leu3a-positive ("helper/inducer") cells were more common than the Leu2a-positive ("suppressor/cytotoxic") cells. Furthermore, a number of epithelial, non-lymphoid cells were found to express the HLA-DR antigen, which suggests an active role for the epithelium in the immunological response of the normal mucosa as well as that of the nasal polyp.