c-Fos expression in the auditory pathways related to the significance of acoustic signals in rats performing a sensory-motor task

Neuronal activity was established in the auditory pathways in relation to behavioural response and cognitive information processing during a sensory-motor acoustic learning. Rats were trained in three consecutive phases. The first phase was an association between an auditory stimulus and a food reward; the second phase a simple discrimination between two sounds of different frequency components, and the third phase a more complex discrimination involving both spectral and spatial sound dimensions. Auditory stimuli were bursts of complex sounds lasting 500 ms. Neuronal activity related to the behaviourally relevant stimuli was established in 20 "learning" rats undergoing this protocol, which were progressively sacrificed at the beginning, middle and end of each phase. For comparison, activity was also established in four "control" rats exposed to the same stimuli delivered pseudo-randomly, thus carrying no behavioural meaning. Neuronal activity was assessed immunocytochemically using the functional marker Fos. To establish a baseline, two rats were unexposed to controlled acoustic stimulation ("unstimulated" rats). In the superior olivary complex (SOC), inferior colliculus (IC) and medial geniculate body (MGB), the number of Fos-like immunopositive cells was comparable in "learning" and "control" animals, but higher than in the "unstimulated" rats. In the auditory cortex (AC), most prominently in the secondary area Te2, the number of Fos-like positive cells differed between "learning" and "control" rats, suggesting that the auditory cortical areas may be involved in the encoding of the behavioural significance of the acoustic stimuli.     

Clinicopathological study of familial late infantile Hallervorden-Spatz disease: a particular form of neuroacanthocytosis

The cases of two sisters with late infantile Hallervorden-Spatz disease are reported, one of whom has died. Autopsy of the deceased patient showed typical pallidal lesions, such as axonal spheroids and iron deposits, without involvement of the substantia nigra. Ultrastructural examination revealed that pallidal axonal enlargements consisted of collecition of mitochondria, dense bodies, vesicles and amorphous material. In the living patient, brain MRI showed the classical tiger's eye appearance of the globus pallidus. Retinitis pigmentosa, acanthocytosis and slight neuromuscular involvement with an increase in serum creatine kinase were observed in both subjects. The appearance of the globus pallidus on MRI was in line with the pathological abnormalities. Ultrastructural differences between the principal disorders characterized by neuroaxonal dystrophy are compared and the clinical spectrum and similarities of the different forms of neuroacanthocytosis analysed.     

Evaluation of vesico-urethral and sweating function in disorders presenting with parkinsonism

Investigation of vesico-urethral and sweating function was performed in twelve patients with classical idiopathic Parkinson's disease and ten patients with parkinsonism associated with features suggestive of more extensive involvement of the nervous system, as in the Shy—Drager syndrome. The urodynamic studies revealed detrusor hyperreflexia with reduction of maximal cystometric capacity in only one patient with Parkinson's disease (8%), but in nine patients with parkinsonism associated with other features (90%). Urethral sphincter electromyography did not indicate denervation in any patient of either group. Delayed or incomplete relaxation of the urethral sphincter during micturition was observed in seven patients with Parkinson's disease (58%) and in two patients of the other group (20%). Decreased sweating responses were found in both groups of patients when compared with control subjects. Hypohidrosis was more pronounced in parkinsonism associated with other features than in Parkinson's disease. Differences in sweating between the two sides of the body were observed in both groups of patients. Although there are differences in vesico-urethral and sweating function, they do not precisely differentiate between patients with classical Parkinson's disease and those with parkinsonism associated with features suggestive of more extensive involvement of the nervous system.     

Intrafamilial phenotype variation in Friedreich's disease: possible exceptions to diagnostic criteria

Summary Three families are described which include members with typical Friedreich's disease (FD) and others who are ataxic but do not satisfy all the diagnostic criteria for that disease. In family A two patients have an early-onset, rapidly progressive FD, while two others have a late-onset, more benign form. In families B and C one member has typical FD, and another has a similar ataxic syndrome, except for preservation of knee jerks. Laboratory evaluation is consistent with the diagnosis of FD in all cases. FD diagnosis appears justified in secondary cases with late onset or preserved tendon reflexes, provided that the index case fulfils all diagnostic criteria. Whether the diagnosis of FD is tenable in sporadic atypical cases remains to be seen. Echocardiographic and neurophysiological examination may be valuable in classifying such cases.     

NEOPLASTIC DISEASE AND DELETION 22q11.2: A MULTICENTRIC STUDY AND REPORT OF TWO CASES

Deletion 22q11.2 is a chromosomal abnormality detected in young patients with clinical manifestations of the DiGeorge/velocardiofacial syndrome. Conotruncal heart defects are also associated with del22q11.2. An association of these cardiac malformations with neoplasias has been observed. Our series includes two cases of malignancies, a hepatoblastoma and a renal-cell carcinoma, arising in children with complex cardiac malformations. The aim of the study was to determine if the deletion at 22q11.2 was present and could be responsible for both pathological processes. Del22q11.2 was identified in both cases. Comparative genomic hybridization revealed terminal gains on chromosomes 1q and Xq and terminal loss on 1p in the hepatoblastoma, and gains in 1p, 12q, 16p, 20q, 22q, and whole chromosome 19 and loss of Xq in the renal-cell carcinoma. Our results confirm a common genetic basis for cardiac malformations, and del22q11.2 presents a risk factor for the development of pediatric tumours.     

Prognostic value of CD40 in adult soft tissue sarcomas.

PURPOSE: The purpose is to evaluate the expression of CD40, a membrane protein predominantly expressed on B cells, dendritic cells, and macrophages, in a series of adult soft tissue sarcomas and to test its possible prognostic value. EXPERIMENTAL DESIGN: CD40 expression was studied by immunohistochemistry. Correlations with other baseline characteristics of patients and tumors were analyzed with chi(2) test. The prognostic value was studied with univariable and multivariable analysis adjusted by age, sex, tumor size, grade, location, and distant metastases. RESULTS: Eighty-two patients, between January 1994 and May 2001, were analyzed. Membrane or cytoplasmic staining for CD40 protein was absent in 30% of the tumors but present in <10% of cells in 22 (27%), in 10% to 50% in 23 (28%), and in >50% of cells in 12 (15%) tumors. There was no correlation between CD40 expression and age, sex, size, grade, and location of the primary tumor and distant metastases. With 61 patients (74.4%) progressed and 31 (37.8%) dead, CD40 expression was a significant prognostic factor for disease-free and overall survival at univariable and multivariable analysis. Patients with tumors expressing CD40 in >50% of cells had a dramatically unfavorable prognosis with median disease-free and overall survival of 7 and 17 months, respectively, and hazard ratios of relapse and death as compared with patients with CD40-negative tumors of 2.89 (95% confidence interval: 1.26-6.60) and 6.92 (95% confidence interval: 2.18-22.0), respectively. CONCLUSIONS: These data suggest that expression of CD40 protein in >50% of cells might indicate an unfavorable prognosis in adult soft tissue sarcomas.     

Expression of Epstein-Barr virus latent membrane protein-1 in Hodgkin and Reed-Sternberg cells of classical Hodgkin's lymphoma: associations with presenting features, serum interleukin 10 levels, and clinical outcome.

PURPOSE: EBV-latent membrane protein-1 (LMP-1) is often expressed in Hodgkin and Reed-Sternberg (HRS) cells of classical Hodgkin's lymphoma (cHL), but its clinical significance is controversial. We correlated LMP-1 with presenting features, including serum interleukin 10 levels and clinical outcome. EXPERIMENTAL DESIGN: Patients were eligible if they had biopsy-proven cHL, were untreated, HIV-1 negative, and had available archival tissue. LMP-1 expression was determined by immunohistochemistry. RESULTS: We identified 577 patients with cHL with a median age of 30 years, 55% of whom were male. LMP-1 was expressed in HRS cells of 124 patients (21%) and was detected in 78 of 461 (17%) patients with nodular sclerosis compared with 44 of 112 (39%) with mixed cellularity (P < 0.001 by Fisher's exact test). Patients with tumors with LMP-1-positive HRS cells had higher serum interleukin 10 levels (P = 0.009 by Mann-Whitney test). For the 303 patients treated with doxorubicin, bleomycin, vinblastine, and dacarbazine or equivalent regimens, the 5-year failure-free survival (FFS) for those with LMP-1-positive tumors was 74% compared with 81% for those with LMP-1-negative tumors (P = 0.23, by log-rank test). Overall survival (OS) at 5 years for patients with LMP-1-positive tumors was 90 versus 91% for patients with LMP-1-negative tumors (P = 0.8 by log-rank test). Expression of LMP-1 was not associated with different FFS and OS in patients treated with other regimens or with radiotherapy alone. CONCLUSIONS: LMP-1 was expressed by HRS cells in 21% of cHL and correlated with mixed cellularity type and higher serum interleukin 10 levels. The presence of LMP-1 was not associated with FFS or OS in uniformly treated patients.     

p15INK4b, p14ARF, and p16INK4a inactivation in sporadic and neurofibromatosis type 1-related malignant peripheral nerve sheath tumors.

PURPOSE: Malignant peripheral nerve sheath tumor (MPNST) can arise sporadically or in association with neurofibromatosis type 1. Deletions at the 9p21 locus have been reported in these tumors. To additionally characterize the status of this chromosomal region, in this study we performed a comprehensive, mostly PCR-based molecular analysis of the three tumor suppressor genes p15(INK4b), p14(ARF) and p16(INK4a) located at the 9p21 locus in 26 cryopreserved MPNSTs. EXPERIMENTAL DESIGN: Fourteen neurofibromatosis type 1-related and 12 sporadic cases were investigated for homozygous deletion coupled with fluorescent in situ hybridization, promoter methylation, and mutational analysis, as well as m-RNA expression. RESULTS: The results showed that an inactivation of one or more genes occurred in 77% of MPNSTs and was mainly achieved through homozygous deletion (46%), which, in turn, encompassed all of the three tandemly linked genes in 83% of the deleted cases. Promoter methylation was at a less extent involved in gene silencing (18%), and no mutations were found. Loss of function at DNA level strongly correlated with loss of mRNA expression accounting for 80% of the cases. Because of the close relationship between p14(ARF) and TP53 and between p15(INK4b)/p16(INK4a) and Rb, these results support a model of a coinactivation of TP53 and Rb pathways in 75% of MPNSTs, with functional consequences on cell growth control and apoptosis. CONCLUSIONS: The inactivation of the 9p21 locus is a frequent and peculiar hallmark of MPNST genetic profile leading also to an impaired apoptosis that could be taken into account in treatment planning of these tumors.