Tau immunoreactivity and SDS solubility of two populations of paired helical filaments that differ in morphology

To further understand the processes that lead to the formation of neurofibrillary tangles from paired helical filaments (PHF) in Alzheimer brains, we studied two morphologically distinct fractions of PHF separated on sucrose density gradient. In a fraction with mostly short and non-aggregated PHF, the majority of filaments could be solubilized in SDS. In a fraction containing primarily PHF aggregated into clusters or bundles, sometimes resembling neurofibrillary tangles, filaments were less soluble in SDS. Immunogold labelling with a panel of tau-immunoreactive antibodies demonstrated that N-terminal epitopes of tau were preserved in the short filaments, but were reduced or absent in aggregated filaments. In contrast, C-terminal epitopes were present in both fractions. Furthermore, the accessibility of the microtubule-binding domain to immunolabelling was markedly impaired in short and non-aggregated filaments compared to aggregated filaments. These results are consistent with proteolytic degradation of the N-terminal epitopes and preservation of the C-terminal epitopes and the microtubule-binding domain of tau in the aggregated filaments. Partial proteolysis may be involved in the generation of aggregated PHF in neurofibrillary tangles.     

Anaplastic ameloblastic fibrosarcoma arising from recurrent ameloblastic fibroma: restricted molecular abnormalities of certain genes to the malignant transformation.

A rare case of anaplastic ameloblastic fibrosarcoma (AS) arising in an ameloblastic fibroma (AF) of the maxilla of a 48-year-old patient 10 years after the primary excision is presented. The recurrent tumor retained focal areas of AF but manifested heterogeneous malignant features ranging from low-grade spindle to highly pleomorphic sarcomas. Biomarker analysis showed alterations of the p53 and c-KIT genes restricted to the sarcomatous component. The biological implications of these findings in the future management of these tumors are discussed.     

A retrospective comparative study of surgery followed by chemotherapy vs. non-surgical management in limited-disease small cell lung cancer.

OBJECTIVE: The role of surgery in limited SCLC is still a matter of controversy. Even though the response rates to chemotherapy are very high, prognosis of SCLC patients has remained poor with a median survival of only 12-14 months for limited disease. High incidence of local relapses after chemotherapy in limited-stage SCLC led to reassessment of the role of local treatment in the multimodality management of this tumor. METHODS: We performed retrospective comparative analysis of survival in a series of 134 limited-stage SCLC patients treated between 1984 and 1996 with either complete resection followed by chemotherapy (67 patients), or with conventional non-surgical management (67 patients). In all patients who underwent resection, the diagnosis of SCLC was established only postoperatively. The control (non-surgical) group was selected using 'pair-matched case-control' methodology, out of 176 limited-stage patients potentially suitable for surgery (i.e. with no pleural effusion or other local advancement, no supraclavicular lymph node involvement and good performance status), but treated without resection. The major prognostic factors were well balanced between these two groups. Total series included 109 males and 25 females, 20 patients with T1 and 114 patients with T2 disease, 51 N0, 43 N1 and 40 N2 disease. RESULTS: Median survival in patients treated with and without surgery was 22 months and 11 months, respectively, (P < 0.001). The two-year and five-year survival probabilities were 43 and 27%, respectively, in the surgical group, and 17 and 4%, respectively, in the non-surgical group. Subset analysis confirmed significantly longer survival with surgery in all T and N categories, except for N2 disease. Local relapse occurred in 15 and 55% of patients treated with and without surgery, respectively, (P < 0.001). Distant relapse probabilities were similar in both groups (36 and 40%, respectively). The most common site of metastases in the entire series was brain, followed by liver, lymph nodes, bone, lung and skin. CONCLUSIONS: Our results suggest a possible role of surgery in limited-stage SCLC. Thus, a randomised study addressing this issue seems to be justified.     

Physiological Causes of Depression in the Elderly

The author outlines some common physiological causes of depression in the elderly, as well as some of the common manifestations of depressive symptoms seen in individuals within this age group.     

Genome-wide linkage analysis of families with obsessive-compulsive disorder ascertained through pediatric probands

The goal of this study was to identify chromosomal regions likely to contain susceptibility alleles for early-onset obsessive-compulsive disorder (OCD). A genome scan was done in 56 individuals from seven families ascertained through pediatric OCD probands; 27 of the 56 subjects had a lifetime diagnosis of definite OCD. Denser mapping of regions on chromosomes 2, 9, and 16 was subsequently done with those subjects and ten additional subjects from the largest family in the study. Direct interviews were completed with 65 of the 66 genotyped individuals. Relatives were interviewed blind to proband status. Of the 65 interviewed individuals, 32 had a lifetime diagnosis of definite OCD. Three of the seven probands had a history of Tourette disorder. Two of the 25 relatives with OCD had a tic history, whereas none of the 33 relatives without OCD had tics. The genome scan consisted of 349 microsatellite markers with an average between-marker distance of 11.3 centiMorgan (cM). Fine mapping was done with 24 additional markers at an average spacing of 1.6 cM. Parametric and nonparametric linkage analyses were conducted using GENEHUNTER(+). The maximum multipoint LOD score with a dominant model was 2.25 on 9p. However, with fine mapping and additional subjects, that LOD score decreased to 1.97. The maximum multipoint nonparametric LOD* score was 1.73 on 19q. The maximum multipoint LOD score with a recessive model was 1.40 on 6p. The results provide suggestive evidence for linkage on 9p and identify regions requiring further study with much larger samples.     

Serotonin transporter promoter polymorphism, peripheral indexes of serotonin function, and personality measures in families with alcoholism

A functional polymorphism in the regulatory region of the serotonin transporter gene (5-HTTLPR) is considered to be a plausible candidate gene for anxiety-related personality traits and for alcoholism. Empirical support for the association between 5-HTTLPR and psychological traits has been somewhat inconsistent; however, observations of the functional dominance of the low-activity s-allele over the l-allele have been more consistent. When studying the influence of particular genes on psychological traits, it seems useful also to assess more biological intermediate traits that may mediate the effects of those genes on the traits of interest. The present study examined relationships between 5-HTTLPR genotype, whole blood serotonin (5-HT) level, and platelet 5-HT binding in 150 Caucasian subjects from 50 biological families. Individuals with the s-allele had lower average platelet 5-HT binding availability than those with the l/l genotype (P<0.025). Whole blood 5-HT level was not associated with 5-HTTLPR genotype. In adult men, those with the s-allele had higher mean scores on the NEO-FFI personality trait of openness than did those with the l/l genotype (P=0.002). The effect was not statistically significant in women (P=0.42), although it was in the same direction. Our findings do not support an association of 5-HTTLPR genotype with alcoholism diagnosis, alcoholism subtype, or the personality trait of neuroticism. The results of this pilot study suggest that further work should examine the mediation of the genetic effects on personality traits by biochemical measures and their moderation by gender.