Histiocytic lymphoma cell lines: immunologic and cytogenetic studies

Cell lines were established from 15 patients with diffuse histiocytic lymphoma (DHL) of the intermediate grade, diffuse large cell (class G), and high-grade, large cell immunoblastic (class H) types. Immunologic studies indicated that 11 of the 15 DHL cell lines were B cell in origin, 2 were histiocytic, and 2 were null cell. Cytogenetic studies revealed 1 hypodiploid, 11 hyperdiploid, and 3 near-tetraploid cell lines. Chromosome #7 was trisomic in 3 lines, chromosomes #12 in 4 lines, and chromosome #13 in 3 lines. Chromosome #2 was monosomic in 3 lines, chromosome #8 was monosomic in 5 lines, chromosome #14 in 4 lines, and chromosome #22 in 6 cell lines. This is of special interest, as chromosomes #2, #8, #14, and #22 are clearly concerned with rearrangements in Burkitt's lymphoma and immunoglobulin expression. The most common rearrangement in the DHL cell lines involved chromosome #14 at band 14q32. However, in contrast to Burkitt's lymphoma, the pattern of translocation in DHL is between chromosome #14 and usually chromosome #11 or chromosome #18. The 14;18 translocation is not restricted to patients with low-grade follicular, small cleaved cell lymphomas, as has been reported. The 14q+ chromosome is characteristic of lymphoid malignancies in general. It is due, invariably, to a translocation with the breakpoint in band 14q32, which is the locus of the immunoglobulin heavy chain genes. We propose that in each translocation, for example, chromosomes #11 or #18, an oncogene may be transposed onto chromosome #14, and that each 14q+ translocation in DHL represents an event that transposes an oncogene from another chromosome to chromosome #14.     

Prostate Stem Cell Compartments : Expression of the Cell Cycle Inhibitor p27Kip1 in Normal, Hyperplastic, and Neoplastic Cells

The stem cells of rapidly renewing tissues give rise to transiently proliferating cells, which in turn give rise to postmitotic terminally differentiated cells. Although the existence of a transiently proliferating compartment has been proposed for the prostate, little molecular anatomical evidence for its presence has been obtained to date. We used down-regulation of the cyclin-dependent kinase inhibitor p27^Kip1 to identify cells capable of entering the proliferative phase of the cell cycle and, therefore, competent to fulfill the role of the transiently proliferating compartment. We examined the expression of p27^Kip1 in relation to its role in the development of prostatic carcinoma. Formalin-fixed paraffin-embedded specimens from matched samples of normal-appearing prostate tissue, benign prostatic hyperplasia, high-grade prostatic intraepithelial neoplasia, primary adenocarcinomas, and pelvic lymph node metastases were evaluated by comparative immunohistochemistry against p27^Kip1. In normal-appearing prostate epithelium, moderate to strong nuclear staining of p27^Kip1 was present in greater than 85% of the terminally differentiated secretory cells. The normal basal cell compartment, believed to contain prostatic stem cells, showed distinctive p27^Kip1 expression; acini in epithelial benign prostatic hyperplasia tissue contained more p27^Kip1-negative basal cells than acini from non-benign prostatic hyperplasia tissue. A third layer of cells was identified that was sandwiched between the basal cells and the luminal cells, and this layer was consistently p27^Kip1 negative. This intermediate layer was accentuated in the periurethral region, as well as in prostate tissue that had been subjected to prior combined androgen blockade. We hypothesize that, on appropriate additional mitogenic stimulation, cells in this layer, and other p27^Kip1-negative basal cells, are competent for rapid entry into the cell cycle. Consistent with the fact that cancer cells are capable of cell division, all cases of high-grade prostatic intraepithelial neoplasia and invasive carcinoma also showed down-regulation of p27^Kip1 as compared with the surrounding normal-appearing secretory cells. In pelvic lymph node metastases, p27^Kip1 expression was also reduced. In summary, our results suggest that lack of nuclear p27^Kip1 protein may delineate a potential transiently proliferating subcompartment within the basal cell compartment of the human prostate. In addition, these studies support the hypothesis that reduced expression of p27^Kip1 removes a block to the cell cycle in human prostate epithelial cells and that dysregulation of p27^Kip1 protein levels may be a critical early event in the development of prostatic neoplasia.     

Comparison between testosterone oenanthate-induced azoospermia and oligozoospermia in a male contraceptive study. IV. Suppression of endogenous testicular and adrenal androgens

Administration of supraphysiological doses of testosterone to normal men causes inhibition of spermatogenesis, but while most become azoospermic, 30-55% maintain a low rate of spermatogenesis. We have investigated whether there are differences in endogenous androgen production, of testicular and adrenal origin, which may be related to the degree of suppression of spermatogenesis. Thirty-three healthy Caucasian men were given weekly i.m. injections of 200 mg testosterone oenanthate (TE), 18 became azoospermic, while 15 remained oligozoospermic. Urinary excretion of epitestosterone, a specific testicular product, was reduced to <10% of pretreatment values, with no differences between the groups. Similar results were obtained for other markers of testicular steroidogenesis. Urinary and plasma adrenal androgens were also reduced during TE treatment: a statistically significant decrease in both (P < 0.001 and P < 0.05 respectively) was seen in the azoospermic but not oligozoospermic responders. These results suggest that testicular steroidogenesis is decreased to <10% by the administration of supraphysiological doses of exogenous testosterone. Differences in the degree of ongoing steroidogenesis in the testis do not appear to account for incomplete suppression of spermatogenesis, thus differences in androgen metabolism may underlie this heterogeneous response. A small but significant reduction in secretion of adrenal androgens was also detectable, the relevance of which is unclear.      

Differential effects of upper gastrointestinal fill on milk ingestion and nipple attachment in the suckling rat

Milk intake and nipple attachment behaviors were studied in the natural suckling situation after gastrointestinal preloading. Rat pups, deprived of their dam for 9 hr at 1, 10, or 20 days of age, were preloaded by gavage with volumes ranging from 2 to 16% of their body weight and returned to suckle. Preloads of artificial bitch's milk decreased the intake of mother's milk in a volume-related manner at all ages. At 1 and 10 days 4% preloads decreased milk intake without affecting attachment behaviors; larger prelods of 8 and 16% decreased intake and reduced the incidence of attachment. At 20 days of age small and large preloads decreased both incidence of attachment and milk intake. Preloads up to 8% of body weight had no effect on latency to attach at any age. Complete subdiaphragmatic bilateral vagotomy increased milk intake of 7–9–day-old pups fed automatically through an anterior mouth cannula in a nonsuckling situation. Vagotomy combined with spinal cordotomy (T2-T3) resulted in a synergistic hyperphagia and massive distension of the upper GI tract. The results indicate that suckling rats can control their intake of mother's milk while remaining attached to a nipple as early as 1 day of age. The suppression of ingestion in response to GI filling appears to be mediated by visceral afferent activity. Conversely, attachment behaviors are less affected by GI fill. This suggests that ingestive behaviors and attachment behaviors have different controls during the 1st 10 days of postnatal development.     

Apolipoprotein epsilon4 allele frequency in young Africans of Ugandan descent versus African Americans

Through its role in lipid metabolism, Apolipoprotein epsilon4 (ApoE4) may affect "brain repair" in stroke, brain hemorrhage, Alzheimer's disease, and other brain injury syndromes for which African Americans may have greater morbidity and mortality. Cross-cultural evaluations of these and other genetic factors may provide insight on possible ethnic differences in risk of morbidity to acute central nervous system (CNS) injury and chronic neurodegenerative processes. As an initial step toward expanding knowledge of ApoE allele frequencies for persons of African descent, we compared ApoE genotype of a group of 70 young Ugandans to 59 (subset of a larger group of 342 African Americans of all ages) age-matched African Americans and to published frequencies for Caucasians and Asians. We found that the ApoE4 and epsilon2 alleles are more frequent in Ugandans (U) than Caucasians (C) or Asians (A) with corresponding alleles showing significant elevations of epsilon2 (U 15.71%, C 8.40%, A 4.20%) and 14 (U 25%, C 13.70%, A 8.90%) (p < .001). Comparing the differences between Ugandans and age-appropriate African Americans (AA) was not statically significant, but this outcome may be due to small sample size. These results provide the only published ApoE frequencies for Ugandans and the complete set of data provides the largest published community group of ApoE frequencies for African Americans.     

Self-perceptions of competence in children with ADHD and comparison children

The self-perceptions of children with attention-deficit/hyperactivity disorder (ADHD; n = 487) were compared with those of children in a local normative comparison group (n = 287), relative to teacher- and parent-rated perceptions of their competence. Children were participants in the ongoing follow-up portion of the Multimodal Treatment Study of Children with ADHD. Children with ADHD were much more likely than comparison children to overestimate their competence relative to adult report, regardless of who was used as the criterion rater (teacher, mother, or father). Examination by comorbidity subgroups revealed that children with ADHD inflated their self-perceptions the most in domains of greatest deficit. Gender effects also are reported.     

STXBP1: the second synaptic vesicle release gene involved in epilepsy

De novo mutations in the gene encoding STXBP1 (MUNC18‐1) cause early infantile epileptic encephalopathy
Saitsu et al. (2008)
Nature Genetics 40: 782–788     

Predominance of null mutations in ataxia-telangiectasia

Ataxia-telangiectasia (A-T) is an autosomal recessive disorder involving cerebellar degeneration, immunodeficiency, chromosomal instability, radiosensitivity and cancer predisposition. The responsible gene, ATM, was recently identified by positional cloning and found to encode a putative 350 kDa protein with a Pl 3-kinase-like domain, presumably involved in mediating cell cycle arrest in response to radiation-induced DNA damage. The nature and location of A-T mutations should provide insight into the function of the ATM protein and the molecular basis of this pleiotropic disease. Of 44 A-T mutations identified by us to date, 39 (89%) are expected to inactivate the ATM protein by truncating it, by abolishing correct initiation or termination of translation, or by deleting large segments. Additional mutations are four smaller in-frame deletions and insertions, and one substitution of a highly conserved amino acid at the Pl 3-kinase domain. The emerging profile of mutations causing A-T is thus dominated by those expected to completely inactivate the ATM protein. ATM mutations with milder effects may result in phenotypes related, but not identical, to A-T.